CADTH Reimbursement Review

Atogepant (Qulipta)

Sponsor: AbbVie

Therapeutic area: Migraine, prevention

This multi-part report includes:

Clinical Review

Pharmacoeconomic Review

Stakeholder Input

Clinical Review

Executive Summary

An overview of the submission details for the drug under review is provided in Table 1.

Table 1: Submitted for Review

NOC = Notice of Compliance.

Introduction

Migraine is a complex neurologic disease, the precise cause of which is not completely understood. Migraine is characterized by recurrent episodes of pulsating headache pain of at least moderate severity.¹ Migraine episodes may last from 4 hours to 74 hours and can be accompanied by symptoms such as photophobia, phonophobia, nausea, and vomiting.² The type of migraine can be refined by the frequency of monthly migraine days (MMDs) and monthly headache days (MHDs).¹ Individuals who experience headaches on 14 or fewer days per month over the previous 3 months, which on some days is migraine, are defined as having episodic migraine (EM).³ In Canada (2010 to 2011), 9.6% of the population older than 18 years experienced migraine attacks; it is more common in females (13.8%) than males (5.3%).⁴ In a longitudinal web-based study of migraine in the US (N = 16,789), 91.2% of patients had EM.⁵ An estimated 2.5% of patients with EM transition to having chronic migraine (CM).⁶ Migraine attacks are associated with missed activities at work, school, and/or home.⁷ Additionally, prevalence is highest during peak productive years (i.e., aged around 30 years to 64 years), which maximizes the impact on the patient, family, and society.^7-10

There are 2 approaches to treating migraine: management of acute attacks, and prophylaxis. These approaches can be used simultaneously. Comprehensive therapy also includes the management of lifestyle factors and triggers.^2,11 Treatment goals aim to relieve pain, restore function, improve health-related quality of life (HRQoL), reduce headache frequency, and prevent the progression of EM to CM.¹² Preventive medications for EM include calcitonin gene–related peptide (CGRP) receptor inhibitors (e.g., galcanezumab, fremanezumab, erenumab, eptinezumab), blood pressure medications (e.g., beta-blockers such as propranolol or metoprolol; calcium channel blockers such as flunarizine or verapamil), antidepressants (e.g., amitriptyline, nortriptyline), serotonin-norepinephrine reuptake inhibitors (e.g., venlafaxine), anticonvulsants (e.g., topiramate, gabapentin, divalproex), and serotonin antagonists (e.g., pizotifen). Only topiramate and the CGRP inhibitors have been approved by Health Canada for the prevention of EM.

Atogepant (Qulipta) is a small-molecule, selective CGRP receptor antagonist that blocks the binding of the CGRP to its receptor, a neuropeptide associated with migraine pathophysiology. The Health Canada indication for atogepant is for the prevention of EM (< 15 MMDs) in adults. The sponsor requested reimbursement of atogepant for the prevention of migraine in adults with EM (< 15 migraine days per month) who have experienced an inadequate response, an intolerance, or a contraindication to at least 2 oral prophylactic migraine medications, which differs from the Health Canada indication.

The objective of the current review is to perform a systematic review of the beneficial and harmful effects of atogepant 10 mg, 30 mg, or 60 mg once daily for the prevention of migraine in adults with EM (< 15 migraine days per month).

Stakeholder Perspectives

The information in this section is a summary of input provided by the patient groups that responded to CADTH’s call for patient input and from clinical expert(s) consulted by CADTH for the purpose of this review.

Patient Input

CADTH received a joint submission from Migraine Canada and Migraine Quebec for the review of atogepant. Both organizations are not-for-profit organizations that have a mission to support and inform individuals living with migraines and raise awareness about the impact of the disease.

The information used to inform the submission was based on 2 online surveys, as well as direct input from 8 patients with experience with atogepant. A total of 1,165 patients and caregivers responded to the first survey conducted by Migraine Canada; the majority of patients were aged between 30 years and 59 years (68%). Among the respondents to the survey, 19% experience 1 migraine day per month to 6 migraine days per month, 28% experience 8 migraine days per month to 14 migraine days per month, and 52% experience 15 migraine days or more per month (i.e., CM). In a second survey conducted by Migraine Canada, a total of 300 patients living in Canada responded. Of these respondents, 15% experience 1 migraine day per month to 6 migraine days per month, 26% experience 8 migraine days per month to 14 migraine days per month, and 59% have CM. The majority (74%) of respondents were aged between 30 years and 59 years.

Respondents to the surveys by Migraine Canada narrated how living with migraine has impacted their HRQoL, sleep, mental health, social relationships, and day-to-day functioning at work and school. The majority (73%) of respondents indicated that they live in fear of the next migraine attack and have difficulty with planning ahead. Most (67%) respondents reported regularly needing to change or cancel plans and avoid interacting with people altogether. More than 20% of respondents indicated that they are on short-term or long-term disability or have retired early due to migraines and 38% reported having their sleep always or regularly disrupted by migraines. Migraines led to the development of moderate to severe depression and/or anxiety that required counselling and/or medications in 39% of patients, and 31% and 35% of respondents felt that they were a burden to others for 16 days per month to 30 days per month and 6 days per month to 15 days per month, respectively.

Most (78%) of the survey respondents indicated that they have taken a prescription medication for the prevention of migraines — most commonly, topiramate, amitriptyline, and botulinum toxin. In the second survey, 21% and 62% of respondents indicated that they have tried 3 to 4 preventive treatments and 5 or more preventive treatments, respectively. According to 66% of respondents, treatment discontinuation was a result of side effects associated with their preventive medication, while 25% of respondents reported that they had experienced side effects but tolerated them. Most respondents to both surveys (85% for the first survey and 73% for the second survey) indicated there is a need for a new oral daily preventive medication. From the second survey, 30% of respondents indicated they have found a preventive treatment that provides greater than 50% improvement in frequency and/or intensity of migraines with no significant side effects. Further, 25% of respondents indicated that the care they have received thus far has led to no improvement in HRQoL, while 49% of respondents reported mild improvement and 24% of respondents experienced marked improvement. Finally, 57% of respondents had not filled their prescription in the past 6 months due to cost and lack of coverage. Eight patients (2 in Canada and 6 in the US) provided direct input on their experience with atogepant. Of these, 75% of patients reported improvement in the frequency and/or intensity of their migraines and 66% of patients reported experiencing some side effects, but these were either slight and/or improved or stopped over time.

According to all survey respondents, the most valuable outcomes for preventive medications are improvement in HRQoL, and decreases in headache intensity, frequency, and symptoms other than pain such as sensitivity to light and sound, nausea, and brain fog. Overall, patients living with migraines indicated that there is a need to have access to new treatment options that will address the gaps in the currently available treatment options, many of which are not effective and are associated with intolerable side effects.

Clinician Input

Input From Clinical Expert Consulted by CADTH

The clinical expert consulted by CADTH emphasized that currently available treatments for patients with migraine have several issues: notably, not all patients respond to current treatments and, in the case of monoclonal antibodies (mAbs) for migraine prevention, patients become refractory to treatment, requiring a change of treatment. Migraine attacks are treated with abortive drugs as well as preventive strategies. mAbs (fremanezumab or galcanezumab) are used following the failure of prior prophylactic migraine prevention therapy such as antidepressants, antihypertensives, or anticonvulsants. The clinical expert noted that atogepant is not a cure — rather, it reduces symptomatic events of EM.

The expert noted that patients with higher migraine headache frequency and major functional disability are more likely to receive atogepant, though it likely wouldn’t be considered the first choice for most patients and would likely be considered in patients who have not responded to or are intolerant of anti-CGRP mAbs. The clinical expert noted that identifying patients who would have better response to atogepant was unlikely, though patients least likely to benefit from atogepant are those with a history of poor compliance. Aside from intolerability due to side effects or poor compliance, the clinical expert stated that failure to reach a 50% reduction in MMDs without any improvements in HRQoL are the main reasons to discontinue treatment with atogepant.

The clinical expert noted that clinicians concentrate on what can be quickly quantified and understood from similar metrics used in studies, with a 50% reduction in MMDs, coupled with change in consumption of abortive medications. The expert did note that change in MMDs is not a perfect metric as some patients have no change in daily frequency but may have significant reductions in severity or duration of migraine.

The clinical expert highlighted that no specialized settings are required, and that neurologists or other experts with headache expertise (e.g., pain clinic specialists, family medicine practitioners with expertise) should prescribe atogepant.

Clinician Group Input

One clinician group, the Canadian Headache Society (CHS), consisting of 5 headache specialists, provided input to CADTH for the review of atogepant. CHS is a scientific society of health care professionals dedicated to research, the education of residents and physicians, and the promotion of better care for patients experiencing headache disorders.

The clinician group emphasized that migraine is often underdiagnosed and undertreated, with limited access to specialized care for migraine in Canada. Along with unmet needs similar to those identified by the clinical expert consulted by CADTH — notably, that current treatments are not effective for all patients (response rate of 40% to 50% for oral medications) and may lose effectiveness over time — the clinician group also highlighted difficulties in access due to limited coverage, and regional variation in funding by province and territory, particularly for triptans, onabotulinumtoxin A, and CGRP mAbs.

The clinician group indicated that atogepant could be used as a first-line treatment option for the prevention of migraines but noted that its place in therapy will be determined in part by its cost; thus, could be considered before other CGRP antibodies. Moreover, the clinician group emphasized that atogepant could be provided in primary care, increasing access to patients in need. In contrast, the clinical expert consulted by CADTH indicated atogepant would be considered as a last-line treatment or used in specific circumstances such as nonresponse, intolerance, or a contraindication to, and where risks outweigh the benefits in patients of child-bearing potential with other first-line treatment options (i.e., monoclonals). The clinician group and clinical expert consulted by CADTH considered the potential for concurrent use of atogepant with mAbs or onabotulinumtoxin A.

Drug Program Input

The drug programs identified the following jurisdictional implementation issues: relevant comparators, considerations for the initiation of therapy, considerations for the continuation or renewal of therapy, considerations for the discontinuation of therapy, considerations for the prescribing of therapy, generalizability, and care provision. Refer to Table 4 for more details.

Clinical Evidence

Pivotal Studies and Protocol-Selected Studies

Description of Studies

A total of 3 studies were included in this review: Study 301 (ADVANCE), the CGP-MD-01 study, and Study 304 (ELEVATE). The ADVANCE and CGP-MD-01 studies were provided to CADTH when the submission was initially provided by the sponsor, while the ELEVATE study was provided to CADTH during the later stages of the review.

ADVANCE was a phase III, double-blind, randomized controlled trial (RCT) evaluating the safety and tolerability of atogepant for the preventive treatment of migraine in patients with EM. Patients in the ADVANCE trial were required to have a 1-year history of migraine consisting of 4 migraine days per month to 14 migraine days per month, with or without aura, and migraine onset before aged 50 years. A total of 910 patients were randomized 1:1:1:1 to atogepant 10 mg once daily (n = 222), atogepant 30 mg once daily (n = 230), atogepant 60 mg once daily (n = 235), or placebo (n = 223). The primary outcome of the ADVANCE trial was change from baseline in mean MMDs, with key secondary end points of change from baseline in MHDs, change from baseline in acute medication use days (MUDs), a 50% or greater reduction in a 3-month average of MMDs, change from baseline in the Migraine-Specific Quality-of-Life Questionnaire (MSQ) version 2.1 role function-restrictive domain score, and change from baseline in the performance of daily activities domain score and mean monthly physical impairment domain score of the Activity Impairment in Migraine–Diary (AIM-D). The ADVANCE trial was conducted at 136 sites in the US. There were no Canadian investigative sites included. No interim analyses were conducted.

The CGP-MD-01 study was a phase II/III, double-blind RCT evaluating the safety and tolerability of 10 mg once daily, 30 mg once daily, 30 mg twice daily, 60 mg once daily, and 60 mg twice daily dosage regimens of atogepant for the prevention of EM. Included patients for the CGP-MD-01 trial were similar to those in the ADVANCE trial, though diagnosis of migraine was based on International Classification of Headache Disorders (ICHD) 2013. In total, 834 patients were randomized to 1 of 6 different groups in a 2:1:2:1:2:1 randomization sequence of placebo (n = 186), atogepant 10 mg once daily (n = 94), atogepant 30 mg once daily (n = 185), atogepant 30 mg twice daily (n = 89), atogepant 60 mg once daily (n = 187), or atogepant 60 mg twice daily (n = 93). Only Health Canada–approved dosages are summarized in this report; thus, results for the atogepant 30 mg twice daily and atogepant 60 mg twice daily dosages are not discussed. The primary outcome of the CGP-MD-01 study was the same as the ADVANCE study: the change from baseline in mean MMDs, with 3 secondary end points of change from baseline in mean MHDs; the proportion of patients with at least a 50% reduction in mean MMDs; and the change from baseline in mean monthly acute MUDs. The CGP-MD-01 study was conducted at 78 sites in the US. There were no Canadian investigative sites included. No interim analyses were conducted.

ELEVATE was a phase III, randomized, double-blind, placebo-controlled study. The objective of the ELEVATE study was to evaluate the efficacy and safety of atogepant 60 mg once daily for the prevention of migraine in adult patients with EM who have previously failed 2 classes to 4 classes of oral medications for the prophylaxis of migraine. A total of 315 patients were randomized 1:1 to atogepant 60 mg once daily (n = 157) or placebo (n = 158). The primary and key secondary outcomes of the ELEVATE study were identical to those of the ADVANCE study. A total of 73 sites in North America and Europe screened patients for eligibility, and 6 patients were included from Canada. No interim analyses were conducted.

Demographic and baseline characteristics in all studies were well balanced. Most patients were female (ADVANCE study = 86.1% to 90.5%, CGP-MD-01 study = 82.8% to 90.7%, ELEVATE study = ||||| || |||||), white (ADVANCE study = 81.1% to 89.2%; CGP-MD-01 study = 71.5% to 79.2%, ELEVATE study = ||||| || |||||), and the median age ranged from 38.5 years to 42.0 years in the ADVANCE study, 38.0 years to 40.5 years in the CGP-MD-01 study, and |||| || |||| years in the ELEVATE study. The included studies differed in the proportion of patients who had received prior migraine prevention medicine, with ||||| || ||||| of patients in the ADVANCE trial receiving prior migraine therapy, and only 25.1% to 31.2% of patients receiving prior migraine therapy in the CGP-MD-01 trial, while all patients in the ELEVATE trial received prior migraine therapy.

Efficacy Results

The primary efficacy end point of the included studies was change from baseline in MMDs to week 12. In all trials, atogepant resulted in statistically significant differences compared with placebo in the reduction of mean MMDs across the 12-week treatment period. In the ADVANCE trial, the least squares mean (LSM) difference in mean change from baseline in MMDs at 12 weeks compared to placebo was –1.21 days (95% confidence interval [CI], –1.78 to –0.64 days; P < 0.0001) for the atogepant 10 mg group, –1.38 days (95% CI, –1.94 to –0.82 days; P < 0.0001) for the atogepant 30 mg group, and –1.72 days (95% CI, –2.28 to –1.15 days; P < 0.0001) for the atogepant 60 mg group. In the CGP-MD-01 trial, the LSM difference for mean change from baseline in MMDs at 12 weeks compared to placebo was –1.15 days (95% CI, –1.93 to –0.37 days; P = 0.0039) for the atogepant 10 mg group, –0.91 days (95% CI, –1.55 to –0.27 days; P = 0.0056) for the atogepant 30 mg group, and –0.70 days (95% CI, –1.35 to –0.06 days; P = 0.0325) for the atogepant 60 mg group. In the ELEVATE trial, the LSM difference in mean change from baseline in MMDs between atogepant 60 mg once daily and placebo at 12 weeks was ||||| |||| |||| || ||||| || |||||| | | |||||||. Results for the subgroup analyses of the ADVANCE study in patients with or without prior exposure to migraine prevention therapy were consistent with the primary analysis. A post hoc subgroup analysis of the ADVANCE trial by number of prior preventive treatment failures exhibited results similar to the primary analysis, though the mean difference from placebo was higher in the subgroup of patients with 2 or more prior treatment failures, and results were consistent with those of the ELEVATE study.

Results for key secondary outcomes were in line with the primary end point, with atogepant demonstrating statistically significantly greater efficacy compared to placebo. In the ADVANCE study, a greater proportion of patients achieved a greater than or equal to 50% reduction in mean MMDs with atogepant (55.6%, 58.7%, and 60.8% for the atogepant 10 mg group, 30 mg group, and 60 mg group, respectively) compared to placebo (29.0%). In the CGP-MD-01 study, a greater proportion of patients achieved a reduction of 50% or more in mean MMDs with atogepant (57.6%, 53.3% and 52.0% in the atogepant 10 mg group, 30 mg group, and 60 mg group, respectively) compared to placebo (40.4%). In the ELEVATE study, a greater proportion of patients achieved a reduction of 50% or more in mean MMDs with atogepant 60 mg once daily (|||||) compared to placebo (|||||). Post hoc subgroup analysis from the ADVANCE study for patients with 2 or more prior treatment failures were |||||||||| |||| || ||||||| |||||||| || |||| || ||||||| |||||| ||||||||||||| ||||||| ||||||| for the proportion of patients achieving at least a 50% reduction in mean MMDs with atogepant (ranging from ||||| || ||||| across atogepant treatment groups) compared to a lower placebo group rate (|||||).

Results for secondary outcomes of MHDs and acute MUDs were consistent with the primary analysis for all studies, demonstrating statistically significant efficacy compared to placebo. In the ADVANCE study, the LSM difference in change from baseline in MHDs and acute MUDs compared to placebo was –1.42 days (95% CI, –2.03 to –0.81 days; P < 0.0001) and –1.31 days (95% CI, –1.81 to –0.82 days; P < 0.0001) for the atogepant 10 mg group, –1.53 days (95% CI, –2.13 to –0.92 days; P < 0.0001) and –1.33 days (95% CI, –1.82 to –0.83 days; P < 0.0001) for the atogepant 30 mg group, and –1.71 days (95% CI, –2.32 to –1.10 days; P < 0.0001) and –1.50 days (95% CI, –2.00 to –1.01 days; P < 0.0001) for the atogepant 60 mg group, respectively. In the CGP-MD-01 study, the LSM difference in change from baseline in MHDs and acute MUDs compared to placebo was –1.38 days (95% CI, –2.23 to –0.54 days; P = 0.0014) and –1.30 days (95% CI, –1.99 to –0.60 days; P = 0.0002) for the atogepant 10 mg group, –1.24 days (95% CI, –1.94 to –0.55 days; P = 0.0005) and –1.44 days (95% CI, –2.01 to –0.87 days; P < 0.0001) for the atogepant 30 mg group, and –0.94 days (95% CI, –1.64 to –0.24 days; P = 0.0087) and –1.11 days (95% CI, –1.68 to –0.54 days; P = 0.0001) for the atogepant 60 mg group, respectively. In the ELEVATE study, the LSM difference in change from baseline in MHDs and acute MUDs compared to placebo was ||||| |||| |||| || ||||| || |||||| | | ||||||| |||||||| |||| |||| || ||||| || |||||| | | |||||||, respectively.

Change from baseline at week 12 in the MSQ version 2.1 role function-restrictive domain score was a key secondary end point of the ADVANCE and ELEVATE studies. In the ADVANCE study, the LSM difference in change from baseline versus placebo was statistically significant in favour of atogepant with a mean difference of 9.90 points (95% CI, 5.45 points to 14.36 points; P < 0.0001) for the atogepant 10 mg group, 10.08 points (95% CI, 5.71 points to 14.46 points; P < 0.0001) for the atogepant 30 mg group, and 10.80 points (95% CI, 6.42 points to 15.18 points; P < 0.0001) for the atogepant 60 mg group. In the ELEVATE study, the LSM difference in change from baseline versus placebo was ||||| |||||| |||| | ||||| || |||||| | | ||||||| || |||||| || ||||||||| || || |||.

Change from baseline in the 6-item Headache Impact Test (HIT-6) total score was an additional efficacy outcome end point of the ADVANCE, CGP-MD-01, and ELEVATE studies. In the ADVANCE study, the LSM difference change from baseline in the HIT-6 total score compared to placebo at week 12 was ||||| |||||| |||| || ||||| || |||||| for the atogepant 10 mg group, ||||| |||||| |||| || ||||| || |||||| for the atogepant 30 mg group, and ||||| |||||| |||| || ||||| || |||||| for the atogepant 60 mg group. Higher proportions of HIT-6 responders (defined as patients who had at least a 5-point improvement [decrease] from baseline in the HIT-6 total score) were observed for the atogepant 10 mg group (|||||), 30 mg group (|||||), and 60 mg group (|||||) compared to placebo (|||||). In study CGP-MD-01, the LSM difference change from baseline in HIT-6 scores was greater for all atogepant doses compared to placebo at all time points. Over 12 weeks, the LSM difference versus placebo was |||| |||||| |||| || |||| || |||| for the atogepant 10 mg group, |||| |||||| |||| || |||| || ||||| for the atogepant 30 mg group, and |||| |||||| |||| || |||| || |||| for the atogepant 60 mg group. In the ELEVATE study, the LSM difference change from baseline in HIT-6 scores was ||||| |||||| |||| || ||||| || |||||| in favour of the atogepant 60 mg once daily group over 12 weeks compared to placebo.

Harms Results

The incidence of treatment-emergent adverse events (TEAEs) was generally consistent between atogepant and placebo-treated patients, as well as across trials, with at least 1 TEAE experienced by 52.9%, 52.2%, 53.7%, and 56.8% of patients with the atogepant 10 mg group, the atogepant 30 mg group, the atogepant 60 mg group, and the placebo group, respectively, in the ADVANCE study; 65.6%, 62.8%, 57.5%, and 49.5% of patients with the atogepant 10 mg group, the atogepant 30 mg group, the atogepant 60 mg group, and the placebo group, respectively, in the CGP-MD-01 study; and ||||| || ||||| of patients in the atogepant 60 mg and placebo groups, respectively, in the ELEVATE study. The most frequently reported TEAEs in the ADVANCE study were constipation (7.7%, 7.0%, 6.9%, and 0.5%), nausea (5.0%, 4.4%, 6.1%, and 1.8%), and upper respiratory tract infections (4.1%, 5.7%, 3.9%, and 4.5%) in the atogepant 10 mg group, the atogepant 30 mg group, the atogepant 60 mg group, and the placebo group, respectively. The most frequently reported TEAEs in the CGP-MD-01 study were |||||| |||||| ||||| |||||| and 4.8%), upper respiratory tract infection (6.5%, 7.7%, 5.4%, and 8.1%), nasopharyngitis (3.2%, 6.0%, 7.5%, and 2.2%), and constipation (2.2%, 5.5%, 4.8%, and 2.2%) for the atogepant 10 mg group, the atogepant 30 mg group, the atogepant 60 mg group, and the placebo group, respectively. The most frequently reported TEAEs in the ELEVATE study were |||||||||||| |||||| || |||||| |||||| ||||| || |||||| |||||||| ||||| || |||||| || ||||||||||||||| ||||| || |||||| In all studies, most TEAEs were mild to moderate in severity.

Serious adverse events (SAEs) in the ADVANCE, CGP-MD-01, and ELEVATE trials were infrequent, occurring in only 2 (0.9%) patients in the atogepant 10 mg and placebo groups in the ADVANCE study, and | SAEs occurring in 7 patients in the CGP-MD-01 study (1 [1.1%] patient with the atogepant 10 mg group, 2 [1.1%] patients with the atogepant 30 mg group, 2 [1.1%] patients with the atogepant 60 mg once daily group, and 2 [1.1%] patients with the placebo group), and in 4 |||||| || ||||||| patients in the atogepant and placebo groups of the ELEVATE study, respectively.

In the ADVANCE study, the incidence of withdrawals due to adverse events (WDAEs) was similar across treatment groups, occurring in 4 (1.8%) atogepant-treated patients to 9 (4.1%) atogepant-treated patients and 6 (2.7%) patients in the placebo group. In the CGP-MD-01 study, WDAEs were more common in the atogepant groups (4.3%, 6.0%, and 3.2% for the atogepant 10 mg group, the atogepant 30 mg group, and the atogepant 60 mg group, respectively) than in the placebo group (2.7%). In the ELEVATE study, | |||||| || ||||||| patients in the atogepant and placebo groups had WDAEs. There were no deaths reported during any of the included studies.

In the ADVANCE study, 1 patient in the placebo group reported suicidal behaviour during the double-blind treatment period. No patients reported suicidal ideation with intent to act via their Columbia-Suicide Severity Rating Scale (C-SSRS) assessments. In the CGP-MD-01 trial, no patients reported suicidal behaviour during the study; however, 1 patient in the placebo group reported suicidal ideation limited to a “wish to be dead” during the double-blind treatment period. In the ELEVATE study, | |||||| || ||||||| patients in the atogepant and placebo groups reported suicidal behaviours during the study, respectively.

Table 2: Summary of Key Results From Pivotal and Protocol-Selected Studies

AE = adverse event; ALT = alanine aminotransferase; AST = aspartate aminotransferase; CFB = change from baseline; CI = confidence interval; HIT-6 = 6-item Headache Impact Test; LSM = least squares mean; MHD = monthly headache day; MMD = monthly migraine day; MUD = medication use day; NR = not reported; OR = odds ratio; PBO = placebo; q.d. = once daily; SAE = serious adverse event; SE = standard error; ULN = upper limit of normal; vs. = versus; WDAE = withdrawal due to adverse event.

^aThe OR (95% CI) and P value are based on logistic regression with treatment group, baseline value, and prior exposure (yes or no) to a migraine prevention medication with proven efficacy as explanatory variables.

^bAnalyses were based on a generalized linear mixed model of repeated measures. The model included treatment group and visit as fixed effects, the baseline value as a covariate, and treatment-group-by-visit and baseline-by-visit as interaction terms, with an unstructured covariance matrix. P values were from the test between the atogepant dose group and the PBO group.

^cNot adjusted for multiplicity.

^dValues were n of N1, where N1 = the number of patients with at least 1 nonmissing postbaseline value.

^eOne of these 3 patients had elevated liver function values that were not treatment-emergent values related to pre-existing rhabdomyolysis; as a result, this case was not subject to adjudication.

Sources: ADVANCE Clinical Study Report,¹³ CGP-MD-01 Clinical Study Report,¹⁴ and ELEVATE Clinical Study Report.¹⁵

Critical Appraisal

The ADVANCE, CGP-MD-01, and ELEVATE studies were all double-blind RCTs. Appropriate methods for randomization (via interactive web response system [IWRS]), treatment allocation, and maintenance of blinding to treatment assignment were used in all studies, reducing the possibility for selection, performance, and detection biases. There was a high proportion of screening failures in the ADVANCE, CGP-MD-01, and ELEVATE studies (60%, 53%, and |||, respectively), mostly due to patients not meeting eligibility criteria. In study CGP-MD-01, more patients discontinued based on withdrawal of consent or withdrawal by patient in the placebo group; however, it is unclear how such discontinuations would have affected blinding or the study results. The rate of constipation was more frequent in the atogepant groups across trials, which may have led to unblinding. Given that the overall rates were generally low, it is unclear what effect this would have had on the results. Sensitivity analyses to account for missing data were conducted on the primary end point in all studies, and were in line with the primary results, suggesting that missing data had little impact. Acceptable methods to account for multiplicity were used in all trials. In the ADVANCE and ELEVATE studies, the primary end point and the 6 key secondary end points were controlled for multiplicity using the overall familywise error rate at the 0.05 level. One prespecified subgroup analysis of the ADVANCE study was conducted; it included patients with or without prior exposure to migraine prevention medication with proven efficacy. An additional post hoc subgroup analysis of the ADVANCE study was submitted to CADTH by request for patients in the ADVANCE study with 1 or more prior migraine prevention treatment failures, and with 2 or more prior migraine prevention treatment failures, which represents the population for the reimbursement request. Given that this subgroup was conducted post hoc and was not part of the randomization scheme or statistically powered to detect within-group or between-group differences, the results from the subgroup analysis may confound the observed results and should only be interpreted as supportive evidence for the overall effect of atogepant. Moreover, missing data were unaccounted for, and the analyses did not adjust for multiplicity. The population for this post hoc subgroup analysis was the target population for the ELEVATE study, which also comprised 3 prespecified subgroups, including 2 prespecified subgroups of interest to this review (prior oral prophylactic treatment failure and migraine days at baseline).

The inclusion and exclusion criteria for the ADVANCE, CGP-MD-01, and ELEVATE studies were appropriate, and generalizable to the Canadian population according to the clinical expert consulted by CADTH. As part of the inclusion and exclusion criteria for the ADVANCE and CGP-MD-01 studies, patients were required to have an inadequate response to no more than 3 medications prescribed for the prevention of migraine, and patients were excluded if they had had previous exposure to CGRP mAbs. Conversely, the ELEVATE study enrolled patients who had failed 2 to 4 oral prophylactic migraine medications, and was the only trial that was reflective of the population included in the reimbursement request. One of the major differences between the ADVANCE, CGP-MD-01, and ELEVATE studies was the proportion of patients who had received prior migraine prevention medications, where ||||| || ||||| of patients received prior migraine therapy in the ADVANCE trial compared to 25.1% to 31.2% of patients in the CGP-MD-01 study, and |||| of patients in the ELEVATE trial. As noted in the post hoc subgroup analysis for the ADVANCE trial, only 119 patients had failed 2 or more prior preventive migraine treatments, though given that baseline characteristics for this subgroup were not presented, it was unclear if any of these patients had received prior anti-CGRP mAbs. Thus, the full population of the ADVANCE study does not entirely represent the population for the reimbursement request and may not be generalizable to this population in Canada. All included trials were placebo-controlled and did not include an active comparator, which allows for adequate evaluation of the treatment effect of atogepant. As a result, the trials may overestimate the treatment effects. In all studies, there was a high placebo response, impacting the ability to interpret the efficacy of atogepant.

Baseline demographic and clinical characteristics, including the average number of MMDs and MHDs at baseline, were observed to be a true reflection of what would be seen in Canadian clinical practice as noted by the clinical expert. However, it is worth noting that patients enrolled in the studies had to have a history of 4 migraine days per month to 14 migraine days per month on average in the 3 months before the first visit. Hence, all studies excluded patients with 1 migraine day per month to 3 migraine days per month, and it is uncertain if results from the ADVANCE, CGP-MD-01, and ELEVATE trials are generalizable to patients with fewer than 4 migraine days per month. Outcomes of the ADVANCE and CGP-MD-01 trials were similar to those reported in other clinical trials for migraine and are reflective and important in guiding treatment decisions in Canadian clinical practice.

Indirect Comparisons

Description of Studies

For the purposes of the Canadian submission, the sponsor-submitted network meta-analysis (NMA) included 2 analysis scenarios from the original NMA that had been updated to reflect the following relevant comparators and reimbursement request:

• Scenario 2 — CGRP inhibitors and key oral preventives approved in the US as a treatment for EM

• Scenario 4 — Global patients who have experienced 2 or more prior preventive treatment failures, versus CGRP preventives

The objective of the sponsor-submitted report was to evaluate the relative efficacy, safety, and tolerability of atogepant compared with injectable CGRP inhibitors and key oral preventives approved for the treatment of EM. The sponsor-submitted NMA was informed by a systematic literature review (SLR) (updated to August 9, 2021) to identify all existing RCTs assessing the efficacy, safety, and tolerability of preventive treatments for adults with EM compared to other preventive treatments, placebo, or standard care. The analyses were conducted using a Bayesian NMA. Fixed and random effects were selected. In analysis scenario 2, random-effects models for the analyses excluding Japanese studies were selected as the base-case analysis, given the larger evidence base, and the variability in the Japanese studies. In analysis scenario 4, fixed-effects models were selected as the base case due to the fewer number of trials and the lower deviance information criterion (DIC). In the updated NMAs, where available, efficacy analyses included a 50% response in MMDs, between-treatment change from baseline in MMDs, and between-treatment change from baseline in monthly migraine MUDs. Safety outcomes included all-cause discontinuation and TEAEs.

Efficacy Results

In analysis scenario 2, ||| || |||||||| |||||||||| ||||| || |||||||| ||||| |||| || |||||||||| |||| |||||||| |||| |||||||| |||||||| ||||| || || |||||||||| ||||||| ||||||||| || || ||||| |||||| ||||||||||| ||||||| || ||||||||||| |||||||| ||||||||| |||||||| |||||||| |||| |||||||||| |||| || |||| |||| |||||||||.

In analysis scenario 4, ||| |||| |||||||||| |||| |||||||| |||| ||||||| || || |||||||| |||||||||| |||| |||||||||||| || || || || || || |||||||||||| ||||||| || ||||||||||||| || |||||||| ||||||| |||| |||||||| |||||||| || |||||||| || || |||||||||| ||||| || || |||||||||| ||||||| |||||| |||||||||||.

Harms Results

In analysis scenario 2, ||||| || || |||||||||| ||||||| || ||||||||| |||||||||| || ||||||||| |||||||||||||||| || ||||| || ||||||||| || |||||||||| ||||||| |||||||||| || |||||| |||||| ||||||||||||| |||||| || || |||||||||| || || |||| |||||||| |||| || ||||| || ||||||||||.

||||| |||| || ||||||||| || || |||||||| || |||||||| |||| |||||||| |||||||| |||| || ||||||| |||| |||||||||||| || |||||||| |||| ||||||| |||| || ||||| || |||||||||| |||||||||.

Critical Appraisal

There were several limitations associated with the sponsor-submitted NMA, particularly the clinical and methodological heterogeneity, which resulted in limited interpretability and generalizability of the results. The SLR and feasibility assessment were generally well conducted; however, the list of treatments for the NMA was narrower than that of the SLR. The NMA did not include valproic acid or candesartan which, according to the clinical expert consulted by CADTH, could be considered relevant comparators for the treatment of EM. Important outcomes such as HRQoL were not considered based on a low availability of data. Following the submission of the ELEVATE study to CADTH, the SLR and NMA were not updated to include this relevant study in this patient population.

Analysis scenario 2 evaluated CGRP inhibitors and key oral preventives, while analysis scenario 4 evaluated patients who have experienced 2 or more prior preventive treatment failures in only CGRP inhibitors. In analysis scenario 2, it is unclear how the number of prior treatment failures as a factor of heterogeneity may have impacted the results, and the direction of bias remains uncertain. In analysis scenario 4, trial populations often included small sample sizes ranging from 19 patients to 137 patients per treatment group, with the ADVANCE trial including only 122 patients in total in the subgroup of 2 or more treatment failures; this limits the precision and generalizability of the treatment effect. The follow-up duration of the included trials generally varied and was also a significant source of heterogeneity across trials, with treatment periods ranging from 12 weeks to 56 weeks. For the primary efficacy end point, the time of assessment of 1 week to 12 weeks was chosen, as this was the time frame of the primary efficacy end point in the ADVANCE study. However, other included studies varied on when change from baseline was assessed.

Clinical heterogeneity was assessed visually for baseline characteristics including age, sex, race or ethnicity, body mass index (BMI), baseline MMDs, and baseline MHDs, as well as for time points and end point availability. The sponsors reported that in general, the studies were similar, including mostly patients of the same age group, sex, and gender. The sponsor considered the main difference between studies to be with regard to race or ethnicity, whereby Japanese studies were excluded from the base case of the primary analysis in the original NMA, with 2 other Japanese studies excluded in the NMA update due to a lower or negligible placebo response compared to other studies, potentially due to unaccounted-for baseline or study centre characteristics that varied. Consideration was given to many baseline characteristics as treatment effect modifiers or prognostic factors; however, it was unclear how this was managed in any statistical analyses. Though not reported, there may have been several differences in study and baseline characteristics across the trials that remain unaccounted for, including study design. This comprised RCTs, open-label studies, and crossover studies, as well as varying definitions of MMD and MHD, with some trials not reporting any MMD or MHD inclusion criteria. As noted by the sponsor, none of the trials published before 2001 reported MMD or MHD inclusion criteria.

All studies included in the NMA were believed to be statistically heterogeneous based on the considerable range of I² values, though it is unclear what the source of heterogeneity was, as it was not explored. Though the authors relied on visual inspection of clinical heterogeneity, the observed heterogeneity is likely due to the observed and unobserved differences in patient populations across the included studies, data imputation analysis methods, and the specific prior or background treatments allowed or received.

In the analyses comparing atogepant to all other treatments, ||||| || ||||||||| || |||||||||| ||||||| ||||||||| || || || || ||||| |||||||||| || |||||||| |||||||| || || || ||||| |||| |||||||||| in analysis scenario 4. Moreover, there were wide credible intervals (CrIs) that crossed the null threshold, further challenging the precision of the results. The general results in analysis scenario 2 displayed a ||||||||||||||||||||| |||||||||||| for atogepant, whereby the atogepant 10 mg dose demonstrated the |||||||| ||||||||, while the atogepant 60 mg dose |||||||||||| |||| || |||||||||| ||||| || || |||||||| of what was seen in the ADVANCE trial. No rationale for this observation was provided, and the reason for this remains uncertain; however, it may have been due to the pooling of estimates from the ADVANCE and CGP-MD-01 trials. This effect was not observed in analysis scenario 4.

Other Relevant Evidence

Description of Studies

Two studies, Study 309 and Study 302, were included as other relevant evidence for the review of atogepant. Study 309 was a phase III, open-label extension study that examined the long-term safety and tolerability of oral atogepant 60 mg once daily in adult patients with EM for up to 40 weeks of treatment. Patients were eligible to enrol in Study 309 if they completed the lead-in ADVANCE study. A total of 685 patients received at least 1 dosage of atogepant 60 mg once daily and 511 (74.6%) patients completed the study. The mean age of patients in the study was 41.8 (standard deviation [SD] = 12.3) years. Most (43.9%) patients were diagnosed with migraine without aura and the mean duration of the migraine disorder was 21.6 (SD = 12.8) years. The mean number of MMDs and MHDs in the last 3 months were ||| |||| |||| || || |||| ||||, respectively.

Study 302 was a phase III, randomized, open-label study that examined the long-term safety and tolerability of oral atogepant 60 mg once daily in adult patients with EM for up to 52 weeks of treatment. Patients were eligible to enrol in Study 302 if they had completed the lead-in study CGP-MD-01, and new patients who met the eligibility criteria were also eligible to enrol. Patients were randomized at visit 2 to receive atogepant 60 mg once daily or standard of care (SOC) (oral migraine-preventive medication) in a 5:2 ratio. The SOC treatment group only served to provide context for interpreting the safety results of atogepant. A total of 543 patients and 196 patients received at least 1 dosage of atogepant 60 mg once daily and SOC, respectively. The mean age of patients was 42.5 (SD = 12.0) years in the atogepant group and 41.1 (SD = 12.1) years in the SOC group. Most (||||| || ||||| in the atogepant and SOC groups, respectively) patients were diagnosed with migraine without aura. The mean duration of the migraine disorder was |||| (SD = ||||) years and |||| (SD = 12.4) years in the atogepant and SOC groups, respectively. The mean number of MMDs and MHDs in the last 3 months were 7.3 (SD = 2.6) days and ||| |||| ||||, respectively, in the atogepant group. The mean number of MMDs and MHDs in the last 3 months were ||| |||| |||| || || |||| ||||, respectively, in the SOC group. A total of 373 (68.3%) patients and 136 (68.7%) patients completed the open-label treatment period in the atogepant and SOC groups, respectively.

Efficacy Results

Study 309 did not evaluate the efficacy of atogepant 60 mg once daily.

Efficacy outcomes in Study 302 were collected daily at home via an electronic diary and at clinic visits via an electronic tablet from patients in the atogepant group only. The mean number of MMDs decreased at week 49 to week 52 from baseline; mean MMDs at baseline was 7.28 (SD = 2.70) days and LSM change was –5.19 (standard error [SE] = 0.16; 95% CI, –5.50 to –4.87). The proportion of patients who achieved a reduction in 50% or more, 75% or more, or 100% in MMDs at week 49 to week 52 was |||||| |||||| || |||||| respectively. The mean number of MHDs decreased at week 49 to week 52 from baseline; mean MHDs at baseline was 8.33 (SD = 2.97) days and LSM change was ||||| |||| ||||| || || ||||| || ||||||. At week 49 to week 52, the LSM change from baseline in the number of monthly moderate to severe headache days and severe headache days was ||||| || |||||, respectively. The LSM change from baseline in the number of monthly cumulative headache hours was |||||| hours at week 49 to week 52. The mean number of MUDs decreased at week 49 to week 52 from baseline; mean MUDs at baseline was |||| |||| ||||| and LSM change was ||||| |||| ||||| || || ||||| || ||||||. The LSM change from baseline in the number of monthly triptan use days was ||||| days at week 49 to week 52. The LSM change from baseline in the MSQ version 2.1 role function-restrictive domain score was ||||| |||| |||||| || || ||||| || |||||| at week 52. The LSM change from baseline in the AIM-D performance of daily activities domain score was |||||| |||| ||||| || || |||||| || |||||| at week 49 to week 52. The LSM change from baseline in the AIM-D physical impairment domain score was ||||| |||| ||||| || || ||||| || |||||| at week 49 to week 52.

Harms Results

In Study 309, TEAEs were reported in 428 (62.5%) patients during open-label treatment, including upper respiratory tract infection (5.5%) and urinary tract infection (5.3%). SAEs were reported in 23 (3.4%) patients and no deaths were reported during the open-label treatment. Premature discontinuation due to at least 1 TEAE was reported in 22 (3.2%) patients during the open-label treatment. For notable harms, 23 (3.4%) patients reported constipation and 4 (0.6%) patients reported ALT or AST values greater than or equal to 3 times the upper limit of normal (ULN) value. No Hy’s law cases or suicidal ideation were reported.

In Study 302, TEAEs were reported in 364 (67.0%) patients during the open-label treatment, including upper respiratory tract infection (10.3%), constipation (7.2%), nausea (6.3%), and urinary tract infection (5.2%). For context, TEAEs were reported in 154 (78.6%) patients in the SOC group. SAEs were reported in 24 (4.4%) patients and 7 (3.6%) patients during the open-label treatment with atogepant and SOC, respectively. Two deaths were reported in the safety population in the atogepant group (no deaths were reported in the SOC group). Premature discontinuation due to at least 1 TEAE was reported in 31 (5.7%) patients and 5 (2.6%) patients during the open-label treatment with atogepant and SOC, respectively. Notable harms identified in the atogepant group included constipation in 39 (7.2%) patients, suicidal ideation in 3 (0.6%) patients, and elevations in ALT or AST values that were greater than or equal to 3 times the ULN value in 13 (2.4%) patients. No Hy’s law cases were reported.

Critical Appraisal

The open-label study design of the long-term extension study, Study 309, could have biased the reporting of end points, particularly any subjective measures included in the safety parameters (and efficacy parameters in Study 302) due to the unblinding of the study drug during the treatment period. Since patients were required to have completed the lead-in study without any significant deviations from the protocol (i.e., noncompliance with procedures) and to have not experienced any adverse events (AEs) that could indicate an unacceptable safety risk per investigator judgment, the resultant population could have been more tolerant of atogepant, leading to an underreporting of AEs, and were also more likely to have benefits of atogepant, overestimating the efficacy of treatment as those patients without benefit were unlikely to continue. In the absence of an active comparator or placebo group, the interpretation of the results was limited. This was compounded using descriptive statistics only.

The limitations could also be applied to Study 302. The enrolment of new patients without prior experience with atogepant and patients who had completed a lead-in study further limited the interpretation of the results. It should be noted that the SOC treatment group only served to provide context for interpreting the safety results of atogepant. The oral migraine preventives were prescribed in a manner that reflected routine clinical practice. A flexible treatment paradigm was used that permitted the discontinuation of, or switching from, 1 drug to an alternative for migraine prevention as needed and per investigator judgment. Regardless of the type of change made, patients in the SOC group were permitted to continue with the study. Thus, AE reporting in the SOC group could have been influenced by investigator choice as the AEs could have differed based on the oral migraine preventive selected.

Conclusions

Three randomized, double-blind studies were included in this review: the ADVANCE, CGP-MD-01, and ELEVATE studies. However, only the population from the ELEVATE study reflected the reimbursement request for patients who have experienced an inadequate response, an intolerance, or a contraindication to at least 2 oral prophylactic migraine medications. In the ADVANCE, CGP-MD-01, and ELEVATE studies, atogepant demonstrated a statistically significant change from baseline compared to placebo in mean MMDs, MHDs, and acute MUDs. Atogepant was also associated with clinically meaningful 50% reductions in average 3-month MMDs. Results for other key secondary end points, including change from baseline in MSQ version 2.1 and AIM-D, were generally in line with the primary outcome. Together, the migraine frequency, HRQoL, and patient-reported efficacy outcomes were appropriate and reflective of clinical practice in Canada; however, there was generally a high placebo response in these outcomes, limiting the interpretability and generalizability of the efficacy of atogepant. Overall, treatment with atogepant was well tolerated over the study period and did not appear to be associated with more TEAEs or SAEs compared to placebo. Known AEs for CGRP inhibitors, including constipation, were more frequent in the atogepant groups; however, there were no concerns.

The sponsor submitted a series of NMAs evaluating atogepant and appropriate comparators in the treatment of EM. However, the results of the indirect evidence on the comparative efficacy and safety of atogepant and relevant treatments was inconclusive, given that there was no difference between atogepant and other active comparators for important outcomes of interest, including the reduction of migraine frequency, and the results from the ELEVATE study were not included in the analysis.

Overall, the available evidence suggests that treatment with atogepant provides an additional treatment option for patients with EM, reducing the frequency and intensity of migraine headaches compared to placebo, and provides a meaningful clinical response in patients with EM. However, it is worth noting that patients enrolled in the studies had to have a history of 4 migraine days per month to 14 migraine days per month on average in the 3 months before the first visit; hence, all studies excluded patients with 1 migraine day per month to 3 migraine days per month, and it is uncertain if results from the ADVANCE, CGP-MD-01, and ELEVATE studies are generalizable to patients with fewer than 4 migraine days per month.

Introduction

Disease Background

Migraine is a complex neurologic disease, the precise cause of which is not completely understood. Migraine is characterized by recurrent episodes of pulsating headache pain of at least moderate severity.¹ Migraine episodes may last from 4 hours to 74 hours and can be accompanied by symptoms such as photophobia, phonophobia, nausea, and vomiting.² The type of migraine can be refined by the frequency of monthly MMDs and MHDs.¹ A diagnosis of migraine is made using a history, a physical examination, and a neurologic examination.²

Individuals who experience headaches on 14 or fewer days per month over the previous 3 months, which on some days is migraine, are defined as having EM.³

In Canada (2010 to 2011), 9.6% of the population older than 18 years experienced migraine attacks, with more females (13.8%) than males (5.3%) having had migraine.⁴ In a longitudinal web-based panel study of migraine in the US (N = 16,789), 91.2% of patients had EM.⁵ An estimated 2.5% of patients with EM transition to having CM.⁶

Among those patients who experienced migraine in Canada (aged ≥ 15 years, 2011), 38.2% reported that migraine at least moderately affected their life and 25.5% reported that the pain prevented them from activities.⁷ In a cross-sectional, web-based observational survey of patients with migraine (N = 8,726), it was found that nearly half of all respondents reported moderate or severe disability, with more headache days per month being associated with more severe disability.¹⁶ Among the respondents, 5.7% had CM and 94.3% had EM.¹⁶ Patients with CM reported longer, more painful headaches and more comorbidities than those with EM.¹⁶ Additionally, patients with CM reported worse headache-related disability compared with those with EM, as measured by the Migraine Disability Assessment (MIDAS), which is a validated tool that measures disability in patients with migraine.¹⁶ Migraine attacks are often disabling. Headache disorders are among the 3 highest causes of years lived with a disability worldwide (1990 to 2017), with migraine accounting for 47,245.4 years lived with a disability in 2017.¹⁷

Migraine attacks are associated with missed activities at work, school, and/or home.⁷ Additionally, prevalence is highest during peak productive years (i.e., aged around 30 years to 64 years); this maximizes the impact on the patient, family, and society.^7-10 Migraine reduces productivity, leading to missed work days and substantial economic costs. Loss of productivity accounts for up to 70% of total migraine-related annual costs.¹⁸ In Canada (2011), 34% of individuals with migraine reported limitations in job opportunities due to their disease, 36% of those currently employed reported missing at least 1 day of work in the past 3 months due to migraine, and 18% who had previously been employed reported that they had changed their work activities (hours or type of work, or had stopped work) for 3 months or longer due to migraine.⁷

Standards of Therapy

There are 2 approaches to treating migraine: the management of acute attacks, and prophylaxis. These approaches can be used simultaneously. Comprehensive migraine therapy also includes the management of lifestyle factors and triggers.^2,11 The goals of migraine treatments are to relieve pain, restore function, improve HRQoL, reduce headache frequency, and prevent the progression of EM to CM.¹² CHS has guidelines for the acute treatment of migraine and for preventing attacks.²

Migraine prophylaxis is an important part of the overall approach for a proportion of individuals with migraine. Preventive medications for EM include CGRP receptor inhibitors (galcanezumab, fremanezumab, erenumab, and eptinezumab), blood pressure medications (e.g., beta-blockers such as propranolol or metoprolol; calcium channel blockers such as flunarizine or verapamil), antidepressants (e.g., amitriptyline, nortriptyline), serotonin-norepinephrine reuptake inhibitors (e.g., venlafaxine), anticonvulsants (e.g., topiramate, gabapentin, divalproex), and serotonin antagonist (e.g., pizotifen). Only topiramate and the CGRP inhibitors have been approved by Health Canada for the prevention of EM. Of patients with migraine who have received preventive medications, 87% have had an inadequate response to 2 or more preventive therapies.¹⁹

Drug

Atogepant (Qulipta) is a small-molecule, selective CGRP receptor antagonist that blocks the binding of the CGRP to its receptor, a neuropeptide associated with migraine pathophysiology. Atogepant is available as an oral tablet. The recommended dosage of atogepant is 10 mg, 30 mg, or 60 mg orally once daily to a maximum of 60 mg per day.²⁰

The Health Canada indication for atogepant is for the prevention of EM (< 15 migraine days per month) in adults. The Health Canada Notice of Compliance was granted on December 22, 2022. The US FDA had approved atogepant for the preventive treatment of EM in adults on September 28, 2021.

The sponsor requested reimbursement of atogepant for the prevention of migraine in adults with EM (< 15 migraine days per month) who have experienced an inadequate response, an intolerance, or a contraindication to at least 2 oral prophylactic migraine medications; this differs from the Health Canada indication. Atogepant has not previously been reviewed by CADTH.

Table 3: Key Characteristics of Atogepant, Galcanezumab, Fremanezumab, Beta-Blockers, Anticonvulsants, TCAs and SNRIs, CCBs, ACE Inhibitors and ARBs, and Pizotifen

ACE = angiotensin-converting enzyme; ARB = angiotensin receptor blocker; CCB = calcium channel blocker; CGRP = calcitonin gene–related peptide; CM = chronic migraine; EM = episodic migraine; NA = not applicable; QoL = quality of life; SC = subcutaneous; SNRI = serotonin-norepinephrine reuptake inhibitor; TCA = tricyclic antidepressant.

^aHealth Canada–approved indication.

Sources: Atogepant product monograph²⁰ and CADTH clinical review of galcanezumab.²¹

Stakeholder Perspectives

Patient Group Input

This section was prepared by CADTH staff based on the input provided by patient groups.

CADTH received a joint submission from Migraine Canada and Migraine Quebec for the review of atogepant. Both are not-for-profit organizations that have a mission to support and inform individuals living with migraines and raise awareness about the impact of the disease, and both advocate for optimal care for patients experiencing migraines and support research to find cures to improve HRQoL. This joint submission was supported by the Women’s Health Coalition of Alberta Society, a network that is committed to empowering individuals to learn, engage, and speak openly to address barriers, gaps, practices, and unconscious bias that impact women’s menstrual, reproductive, and sexual health.

The information used to inform the submission was based on 2 online surveys conducted in the late fall of 2021 and mid-January 2022, as well as direct input from 8 patients (2 Canadians and 6 Americans) with experience with atogepant. A total of 1,165 patients and caregivers responded to the first survey conducted by Migraine Canada, the majority of whom were aged between 30 years and 59 years (68%). Among the respondents to the survey, 19% live with 1 migraine day per month to 6 migraine days per month, 28% live with 8 migraine days per month to 14 migraine days per month, and 52% live with 15 or more migraine days per month (i.e., CM). In a second survey conducted by Migraine Canada, a total of 300 patients living with migraine in Canada responded. Of these respondents, 15% live with 1 migraine day per month to 6 migraine days per month, 26% live with 8 migraine days per month to 14 migraine days per month, and 59% live with CM. The majority (74%) of respondents were aged between 30 years and 59 years.

Respondents to the surveys by Migraine Canada narrated how living with migraine has impacted their HRQoL and sleep, mental health, social relationships, and day-to-day functioning at work and school. The majority (73%) of respondents indicated they live in fear of the next migraine attack and have difficulty with planning ahead. Most (67%) respondents reported regularly needing to change or cancel plans and avoid interacting with people altogether. More than 20% of respondents indicated they are on short- or long-term disability or have retired early due to migraines and 38% reported having their sleep always or regularly disrupted by migraines. Migraines led to the development of moderate to severe depression and/or anxiety that required counselling and/or medications in 39% of patients, and 31% and 35% of respondents felt they were a burden to others for 16 days per month to 30 days per month and 6 days per month to 15 days per month, respectively.

Most (78%) of the survey respondents indicated they have taken a prescription medication for the prevention of migraines — most commonly, topiramate, amitriptyline, and botulinum toxin. In the second survey, 21% and 62% of respondents indicated they have tried 3 to 4 preventive treatments and 5 or more preventive treatments, respectively. According to 66% of respondents, treatment discontinuation was a result of side effects associated with their preventive medication, while 25% of respondents reported they had experienced side effects but tolerated them. Most respondents to both surveys (85% for the first survey and 73% for the second survey) indicated there is a need for a new oral daily preventive medication. From the second survey, 30% of respondents indicated they have found a preventive treatment that provides greater than 50% improvement in frequency and/or intensity of migraines with no significant side effects. Further, 25% of respondents indicated that the care they have received thus far has led to no improvement in HRQoL, while 49% of respondents reported mild improvement and 24% of respondents experienced marked improvement. Finally, 57% of respondents had not filled their prescription in the past 6 months due to cost and lack of coverage. Eight patients (2 Canadians and 6 Americans) provided direct input on their experience with atogepant. Of these, 75% of patients reported improvement in the frequency and/or intensity of their migraines and 66% of patients reported experiencing some side effects but these were either slight and/or improved or stopped over time.

According to all survey respondents, the most valuable outcomes for preventive medications are improvement in HRQoL, and decreases in headache intensity, headache frequency, and symptoms other than pain such as sensitivity to light and sound, nausea, and brain fog. Overall, Canadians living with migraines indicated that there is a need to have access to new treatment options that will address the gaps in the currently available treatment options, many of which are not effective and associated with intolerable side effects.

A copy of the patient input is presented at the end of this report.

Clinician Input

Input From Clinical Experts Consulted by CADTH

All CADTH review teams include at least 1 clinical specialist with expertise regarding the diagnosis and management of the condition for which the drug is indicated. Clinical experts are a critical part of the review team and are involved in all phases of the review process (e.g., providing guidance on the development of the review protocol, assisting in the critical appraisal of clinical evidence, interpreting the clinical relevance of the results, providing guidance on the potential place in therapy). The following input was provided by 1 clinical specialist with expertise in the diagnosis and management of EM.

Unmet Needs

The clinical expert consulted by CADTH emphasized that currently available treatments for patients with migraine have several issues: notably, not all patients respond to current treatments and, in the case of mAbs for migraine prevention, patients become refractory to treatment, requiring a change of treatment. Additionally, the expert highlighted that some current migraine prevention therapies have a prolonged half-life, making them difficult to use with people of child-bearing potential who may wish to conceive.

Place in Therapy

The clinical expert consulted by CADTH noted that current migraine therapies provide significant relief and functional improvements compared to historical treatment methods, despite the fact that some patients do not benefit from available treatment options. Currently, the initiation of migraine treatment begins with the identification of triggers and subsequent lifestyle modifications. Early on, migraine attacks are treated with abortive drugs as well as preventive strategies, including the use of riboflavin, antidepressants, antihypertensives, and anticonvulsants. The goal of these preventive medications is to prevent the patient from developing CM. mAbs (fremanezumab or galcanezumab) are used following the failure of prior prophylactic migraine prevention therapy. The clinical expert noted that atogepant would be used following the mAbs, as the mechanism of action of atogepant does not lead to a cure — rather, it reduces symptomatic events of EM.

Patient Population

The expert noted that at diagnosis, it is important for patients to understand their migraine (headache and interictal symptoms) and comorbid conditions (anxiety, depression, muscular pain syndromes); their physician should also reinforce the importance of a headache journal in assessment and follow-up. The expert also stated the importance of understanding medication overuse, though this may not be as much of an issue in patients with EM compared to patients with CM.

The clinical expert noted that identifying patients who would have better response to atogepant was unlikely. The expert noted that patients with higher migraine headache frequency and major functional disability are more likely to receive atogepant, though it likely would not be considered the first choice for most patients. It was highlighted that atogepant would likely be considered in patients who have not responded to or are intolerant of anti-CGRP mAbs or who are considering conceiving. The expert also noted that atogepant could be considered in patients who meet ICHD-3 criteria for CM but who have fewer than 15 MMDs. Conversely, the expert noted that patients with a history of poor compliance would not be suitable candidates for atogepant, mainly due to the daily dosing regimen.

Assessing Response to Treatment

In general, outcomes used in clinical practice reflect those typically used in clinical trials. The clinical expert noted that clinicians concentrate on what can be quickly quantified and understood from similar metrics used in studies, with a 50% reduction in MMDs, coupled with a change in consumption of abortive medications, used to demonstrate to third-party payers that a medication is working. The expert noted that HRQoL is important; however, it is not routinely quantified in clinical practice. The expert also noted that change in MMDs is not a perfect metric as some patients have no change in daily frequency but may have significant reductions in severity or duration of migraine.

Discontinuing Treatment

The clinical expert stated that failure to reach a 50% reduction in MMDs, without any other improvements in HRQoL is the main reason to discontinue treatment with atogepant. Additionally, intolerable side effects or poor compliance with the medication are also considerable factors.

Prescribing Conditions

The expert highlighted that no specialized settings are required, and that neurologists or other experts with headache expertise (e.g., pain clinic specialists, family medicine practitioners with expertise) should prescribe atogepant.

Additional Considerations

The clinical expert noted that the reimbursement request is not recognized by current international guidelines (ICHD-3), as only CM has a defined threshold, while EM represents patients who do not meet the requirements for CM. The expert highlighted that the issues with this nomenclature may result in differing classifications of patients based on their migraine type.

Clinician Group Input

This section was prepared by CADTH staff based on the input provided by clinician groups.

One clinician group, CHS, consisting of 5 headache specialists, provided input to CADTH for the review of atogepant. CHS is a scientific society of health care professionals dedicated to research, the education of residents and physicians, and the promotion of better care for patients experiencing headache disorders.

The clinician group emphasized that migraine is often underdiagnosed and undertreated, with limited access to specialized care for migraine in Canada. Along with unmet needs similar to those identified by the clinical expert consulted by CADTH — notably, that current treatments are not effective for all patients (a response rate of 40% to 50% for oral medications) and may lose effectiveness over time — the clinician group also highlighted difficulties in access due to limited coverage, and regional variation in funding by province and territory, particularly for triptans, onabotulinumtoxin A, and CGRP mAbs.

The clinician group indicated that atogepant could be used as a first-line treatment option for the prevention of migraines but noted its place in therapy will be determined in part by its cost; thus, could be considered before other CGRP antibodies. Moreover, the clinician group emphasized that atogepant could be provided in primary care, increasing access to patients in need. In contrast, the clinical expert consulted by CADTH indicated atogepant would be considered as a last-line treatment or for use in specific circumstances such as nonresponse, intolerance, or a contraindication to, and where risks outweigh the benefits in people of child-bearing potential with other first-line treatment options (i.e., mAbs). The clinician group and clinical expert consulted by CADTH considered the potential for concurrent use of atogepant with mAbs or onabotulinumtoxin A.

Drug Program Input

The drug programs provide input on each drug being reviewed through CADTH’s reimbursement review processes by identifying issues that may impact their ability to implement a recommendation. The implementation questions and corresponding responses from the clinical experts consulted by CADTH are summarized in Table 4.

Table 4: Summary of Drug Plan Input and Clinical Expert Response

CDEC = CADTH Canadian Drug Expert Committee; CGRP = calcitonin gene–related peptide; ICHD = International Classification of Headache Disorders; mAb = monoclonal antibody.

Clinical Evidence

The clinical evidence included in the review of atogepant is presented in 3 sections. The first section, the systematic review, includes pivotal studies provided in the sponsor’s submission to CADTH and Health Canada, as well as those studies that were selected according to an a priori protocol. The second section includes indirect evidence from the sponsor and indirect evidence selected from the literature that met the selection criteria specified in the review. The third section includes sponsor-submitted long-term extension studies and additional relevant studies that were considered to address important gaps in the evidence included in the systematic review.

Systematic Review (Pivotal and Protocol-Selected Studies)

Objectives

To perform a systematic review of the beneficial and harmful effects of atogepant 10 mg, atogepant 30 mg, or atogepant 60 mg once daily for the prevention of migraine in adults with EM (< 15 migraine days per month).

Methods

Studies selected for inclusion in the systematic review included pivotal studies provided in the sponsor’s submission to CADTH and Health Canada, as well as those meeting the selection criteria presented in Table 5. Outcomes included in the CADTH review protocol reflect outcomes considered to be important to patients, clinicians, and drug plans.

Table 5: Inclusion Criteria for the Systematic Review

ACE = angiotensin-converting enzyme; AE = adverse event; CGRP = calcitonin gene–related peptide; HIT-6 = 6-item Headache Impact Test; HRQoL = health-related quality of life; MIDAS = Migraine Disability Assessment; MPFID = Migraine Physical Function Impact Diary; MSQ = Migraine-Specific Quality-of-Life Questionnaire; RCT = randomized controlled trial; SAE = serious adverse event; WDAE = withdrawal due to adverse event.

The literature search for clinical studies was performed by an information specialist using a peer-reviewed search strategy according to the PRESS Peer Review of Electronic Search Strategies checklist.²²

Published literature was identified by searching the following bibliographic databases: MEDLINE via Ovid and Embase via Ovid. All Ovid searches were run simultaneously as a multifile search. Duplicates were removed using Ovid deduplication for multifile searches, followed by manual deduplication in Endnote. The search strategy comprised both controlled vocabulary, such as the US National Library of Medicine’s MeSH (Medical Subject Headings), and keywords. The main search concept was atogepant. Clinical trials registries were searched: the US National Institutes of Health’s ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform search portal, Health Canada’s Clinical Trials Database, and the European Union Clinical Trials Register.

No filters were applied to limit the retrieval by study type. Retrieval was not limited by publication date or by language. Conference abstracts were excluded from the search results. Refer to Appendix 1 for the detailed search strategies.

The initial search was completed on March 22, 2022. Regular alerts updated the search until the meeting of the CADTH Canadian Drug Expert Committee on April 26, 2023.

Grey literature (literature that is not commercially published) was identified by searching relevant websites from the Grey Matters: A Practical Tool For Searching Health-Related Grey Literature checklist. Included in this search were the websites of regulatory agencies (US FDA and European Medicines Agency). Google was used to search for additional internet-based materials. Refer to Appendix 1 for more information on the grey literature search strategy.

Two CADTH clinical reviewers independently selected studies for inclusion in the review based on titles and abstracts, according to the predetermined protocol. Full-text articles of all citations considered potentially relevant by at least 1 reviewer were acquired. Reviewers independently made the final selection of studies to be included in the review, and differences were resolved through discussion.

Findings From the Literature

A total of 39 studies were identified from the literature for inclusion in the systematic review (Figure 1). The included studies are summarized in Table 6.

Figure 1: Flow Diagram for Inclusion and Exclusion of Studies

Table 6: Details of Included Studies

ACM-I = Assessment of Chronic Migraine–Impact; AIM-D = Activity Impairment in Migraine–Diary; ALT = alanine aminotransferase; AST = aspartate aminotransferase; b.i.d. = twice a day; C-SSRS = Columbia-Suicide Severity Rating Scale; CFB = change from baseline; CGRP = calcitonin gene–related peptide; CGRP-RA = calcitonin gene–related peptide receptor antagonist; CM = chronic migraine; DB = double-blind; DBP = diastolic blood pressure; ECG = electrocardiogram; EQ VAS = EQ-5D Visual analogue scale; GFR = glomerular filtration rate; GI = gastrointestinal; HIT-6 = 6-item Headache Impact Test; ICHD-3 = International Classification of Headache Disorders; IgM = immunoglobulin M; mAb = monoclonal antibody; MHD = monthly headache day; MIDAS = Migraine Disability Assessment; MMD = monthly migraine day; MSQ = Migraine-Specific Quality-of-Life Questionnaire; MUD = medication use day; NSAID = nonsteroidal anti-inflammatory drug; NYHA = New York Heart Association; PGI-S = Patient Global Impression–Severity; PGIC = Patient Global Impression of Change; PHQ-9 = Patient Health Questionnaire-9; PROMIS = Patient-Reported Outcome Measurement Information System; PSSM = Patient Satisfaction with Study Medication; q.d. = once daily; QTcF = QT interval corrected for heart rate using the Fridericia formula; RCT = randomized controlled trial; SBP = systolic blood pressure; ULN = upper limit of normal; WPAI:Migraine = Work Productivity and Activity Impairment Questionnaire: Migraine.

Sources: ADVANCE Clinical Study Report,¹³ CGP-MD-01 Clinical Study Report,¹⁴ and ELEVATE Clinical Study Report.¹⁵

Description of Studies

Initially, 2 studies were included in this review: Study 301 (the ADVANCE study) and the CGP-MD-01 study, which were a phase III RCT and a phase II/III RCT, respectively, comparing atogepant to placebo in adult patients with EM. Both studies were funded by the sponsor.

The Clinical Study Report for the ELEVATE study was provided to CADTH during the later stages of the review when the clinical review report was nearly complete. The ELEVATE study was conducted similarly to the ADVANCE study — as a phase III RCT comparing atogepant to placebo in adult patients with EM who have previously failed 2 classes to 4 classes of oral prophylactic treatments — and has been included within the body of the report. The ELEVATE study was also funded by the sponsor.

Figure 2: Study Flow Diagram — ADVANCE Study

V = visit; wk = week.

Source: ADVANCE Clinical Study Report.¹³

Study 301 (ADVANCE Study)

The ADVANCE study was conducted based on the results of the CGP-MD-01 study, and was a multicentre, randomized, double-blind, placebo-controlled, parallel-group study that enrolled patients with EM from 136 sites in the US. The objective of the ADVANCE study was to evaluate the safety and tolerability of atogepant for the preventive treatment of migraine in patients with EM, as well as to prospectively determine the superiority of atogepant versus placebo for the preventive treatment of migraine in patients with EM. A total of 910 patients were randomized in a 1:1:1:1 sequence to atogepant 10 mg once daily (n = 222), atogepant 30 mg once daily (n = 230), atogepant 60 mg once daily (n = 235), or placebo (n = 223). Randomization was stratified based on prior exposure (yes versus no) to a migraine prevention medication with proven efficacy. No Canadian study sites or patients were included in the ADVANCE trial. The total study duration was 20 weeks, consisting of a 4-week screening and baseline period, a 12-week double-blind treatment period, and a 4-week safety follow-up period.¹³ A schematic overview of the study design for the ADVANCE study is displayed in Figure 2. The last observation was June 19, 2020, and the study database was locked as of July 6, 2020.¹³

Study CGP-MD-01

Study CGP-MD-01 was a phase II/III multicentre, randomized, double-blind, placebo-controlled, parallel-group study that enrolled adult patients with a history of EM (4 migraine days per month to 14 migraine days per month) from 78 sites in the US. The objective of the CGP-MD-01 study was to evaluate the safety and tolerability of 10 mg once daily, 30 mg once daily, 30 mg twice daily, 60 mg once daily, and 60 mg twice daily dosage regimens of atogepant for the prevention of EM. A total of 834 patients were randomized to 1 of 6 different groups in a 2:1:2:1:2:1 randomization sequence of placebo (n = 186), atogepant 10 mg once daily (n = 94), atogepant 30 mg once daily (n = 185), atogepant 30 mg twice daily (n = 89), atogepant 60 mg once daily (n = 187), or atogepant 60 mg twice daily (n = 93), respectively. No stratification was performed. No Canadian study sites or patients were included in the CGP-MD-01 study. The total study duration was 20 weeks, consisting of a 4-week screening and baseline period, a 12-week double-blind treatment period, and a 4-week safety follow-up period, for a total of 8 scheduled clinic visits.¹⁴ A schematic overview of the study design for the CGP-MD-01 study is displayed in Figure 3. The last observation was April 23, 2018, and the study database was locked as of May 23, 2018.¹⁴

Only Health Canada–approved dosages are summarized in this report; thus, results for the atogepant 30 mg twice daily and atogepant 60 mg twice daily dosages are not discussed.

Study 304 (ELEVATE Study)

ELEVATE was a phase III, randomized, double-blind, placebo-controlled study. The objective of the ELEVATE study was to evaluate the efficacy and safety of atogepant 60 mg once daily for the prevention of migraine in adult patients with EM who have previously failed 2 classes to 4 classes of oral medications for the prophylaxis of migraine. A total of 315 patients were randomized 1:1 to atogepant 60 mg once daily (| ||||) or placebo (| ||||). Randomization was stratified via IWRS based on region (North America and Europe), number of migraine days during the screening or baseline period (4 to < 8 and ≥ 8), and number of classes of failed prior prophylactic treatments (2 and > 2). A total of 73 sites in North America (Canada and the US) and Europe (Czech Republic, Denmark, France, Germany, Hungary, Italy, the Netherlands, Poland, Russia, Spain, and the UK) screened patients for eligibility. The total study duration was 20 weeks, consisting of a 4-week screening and baseline period, a 12-week double-blind treatment period, and a 4-week safety follow-up period.¹⁵ A schematic overview of the study design for the ELEVATE study is displayed in Figure 4.

Figure 3: Study Flow Diagram— CGP-MD-01 Study

BID = twice daily; QD = once daily; V = visit.

Source: CGP-MD-01 Clinical Study Report.¹⁴

Figure 4: Study Flow Diagram — ELEVATE Study

ET = end of treatment; QD = once daily; V = visit.

Source: ELEVATE Clinical Study Report.¹⁵

Populations

Inclusion and Exclusion Criteria

The inclusion and exclusion criteria for the ADVANCE study, the CGP-MD-01 study, and the ELEVATE study are summarized in Table 6. Overall, the 3 included trials had similar inclusion criteria. In general, adult patients (18 years to 80 years) with a 1-year history of migraine consisting of 4 migraine days per month to 14 migraine days per month, with or without aura, and migraine onset before aged 50 years were included.^13,14 In study CGP-MD-01, diagnosis was confirmed according to ICHD-3 beta, 2013,¹⁴ while ICHD-3, 2018, was used in the ADVANCE and ELEVATE studies.^13,15 One additional inclusion criterion for the ELEVATE trial was the failure of 2 to 4 oral migraine prophylaxis medications,¹⁵ which was in line with the reimbursement request for patients who have experienced an inadequate response, an intolerance, or a contraindication to at least 2 oral prophylactic migraine medications. In the ADVANCE study, patients were excluded if they had had inadequate response to more than 4 medications (2 of which had different mechanisms of action) prescribed for the prevention of migraine,¹³ and patients in the CGP-MD-01 trial were excluded who had inadequate response to 3 or more medications (2 of which had different mechanisms of action) prescribed for the prevention of migraine.¹⁴

All trials also had similar exclusion criteria. Patients were ineligible if they had a history of migraine accompanied by diplopia or decreased level of consciousness, or retinal migraine, or a diagnosis of CM according to ICHD-3, 2018 (the ADVANCE and ELEVATE studies) or ICHD-3 beta, 2013 (study CGP-MD-01). Patients with 15 or more MHDs in the 3 months before visit 1 or in the baseline period were also excluded. In all trials, patients were also ineligible based on the prior use of acute migraine medications, including opioids or barbiturates, more than 2 days per month, triptans or ergots 10 or more days per month, or simple analgesics (e.g., Aspirin, nonsteroidal anti-inflammatory drugs [NSAIDs], acetaminophen) 15 or more days per month in the 3 months before visit 1, or during the baseline period. Patients in the ADVANCE study and study CGP-MD-01 were also excluded based on prior exposure to the investigational product and other CGRP inhibitors.^13-15

Baseline Characteristics

Baseline characteristics for the ADVANCE, CGP-MD-01, and ELEVATE studies are summarized in Table 7. Baseline characteristics were well balanced across groups in each trial. In all studies, most patients were female (ADVANCE study = 86.1% to 90.5%, CGP-MD-01 study = 82.8% to 90.7%, ELEVATE study = ||||| || |||||) and white (ADVANCE study = 81.1% to 89.2%, CGP-MD-01 study = 71.5% to 79.2%, ELEVATE study = ||||| || |||||), and the median age ranged from 38.5 years to 42.0 years in the ADVANCE study, from 38.0 years to 40.5 years in study CGP-MD-01, and |||| || |||| years in the ELEVATE study.^13-15

In the ADVANCE study, the mean duration of migraine disorder was |||| |||| |||||| || |||| |||| ||||| ||||||, and ||||| || ||||| of patients had received prior migraine prevention medicine, with the most frequently used acute migraine treatments consisting of NSAIDs (||||| || |||||), triptans (||||| || |||||), and others (||||| || |||||). The mean number of migraine days per month 3 months before the study ranged from 7.2 (SD = 2.47) days to 7.7 (SD = 2.57) days, with the mean number of MHDs ranging from 9.1 (SD = 2.71) days to 9.5 (SD = 2.76) days.¹³

In study CGP-MD-01, the mean duration of migraine was 18.65 (SD = 10.9) years to 20.58 (SD = 11.7) years, and contrary to the ADVANCE trial, the majority of patients did not have prior migraine prevention therapy (range = ||||| || |||||). The most frequently used acute migraine treatments were NSAIDs (||||| || |||||), triptans (||||| || |||||), and others (||||| || |||||). Similar to the ADVANCE trial, the mean number of migraine days per month ranged from ||| |||| |||| |||| || || |||| |||| ||||, with the mean number of MHDs ranging from || |||| |||| |||| || || |||| |||| ||||.¹⁴

In the ELEVATE study, all patients had prior prophylactic migraine therapy. The mean duration of migraine disorder was similar across the atogepant and placebo groups (|||| ||||| ||||||| ||||||| ||||| |||| ||||||), with the most frequently used acute migraine treatments consisting of triptans (||||| || |||||), NSAIDs (||||| || |||||), and others (||||| || |||||). The mean number of migraine days per month 3 months before the study was higher in the ELEVATE study than in the ADVANCE study and was ||| |||| |||| ||||| || || |||| |||| ||||).¹⁵

Interventions

Treatments Administered

The ADVANCE study, the CGP-MD-01 study, and the ELEVATE study were double-blind, placebo-controlled RCTs comparing atogepant to placebo.

In the ADVANCE study, eligible patients were randomized (at visit 2) in a 1:1:1:1 ratio via IWRS to 1 of 4 treatment groups, as follows:¹³

• placebo once daily (placebo 10 mg, placebo 30 mg, and placebo 60 mg)

• atogepant 10 mg once daily (atogepant 10 mg, placebo 30 mg, and placebo 60 mg)

• atogepant 30 mg once daily (atogepant 30 mg, placebo 10 mg, and placebo 60 mg)

• atogepant 60 mg once daily (atogepant 60 mg, placebo 10 mg, and placebo 30 mg).

Patients were instructed to take the study intervention (3 tablets) once a day at approximately the same time each day. Patients took their first dose of study intervention at the clinic at visit 2 (i.e., at randomization). Randomization was stratified based on prior exposure (yes versus no) to a migraine prevention medication with proven efficacy. Each site was dynamically allocated entire blocks based on strata, and treatment was assigned sequentially within a block. A double-dummy design was used to maintain blinding.¹³

In study CGP-MD-01, eligible patients were randomly assigned by blocks in a 2:1:2:1:2:1 ratio via IWRS into the following groups:¹⁴

• placebo (placebo in the morning and placebo in the evening)

• atogepant 10 mg once daily (atogepant 10 mg in the morning and placebo in the evening)

• atogepant 30 mg once daily (atogepant 30 mg in the morning and placebo in the evening)

• atogepant 60 mg once daily (atogepant 60 mg in the morning and placebo in the evening).

The last 2 groups of the CGP-MD-01 trial were for atogepant 30 mg and 60 mg twice daily; however, given that these dosages are not approved by Health Canada, they were omitted from this report.

Table 7: Summary of Baseline Characteristics of Included Studies

AIM-D = Activity Impairment in Migraine–Diary; ATO = atogepant; BMI = body mass index; ITT = intention to treat; mITT = modified intention to treat; MSQ = Migraine-Specific Quality-of-Life Questionnaire; NA = not applicable; NSAID = nonsteroidal anti-inflammatory drug; PBO = placebo; q.d. = once daily; SD = standard deviation.

^aIn the ADVANCE study, patients who reported multiple races or ethnicities are only included in the “multiple” category.

^bIn the CGP-MD-01 study, patients who reported 2 or more races or ethnicities, including patients who reported white and 1 or more other races or ethnicities were included in the “multiple” category.

Sources: ADVANCE Clinical Study Report,¹³ CGP-MD-01 Clinical Study Report,¹⁴ and ELEVATE Clinical Study Report.¹⁵

All investigational products were provided in identical blister cards to maintain blinding. Over-encapsulation was implemented to maintain study masking. Given the twice daily dosing regimen in 2 groups, all patients took their first dose of study intervention at the clinic at visit 2 (i.e., at randomization) and were to take the second dose of study intervention (or placebo) approximately 12 hours later. No stratification was performed.¹⁴

In the ELEVATE trial, eligible patients were randomized 1:1 via IWRS to atogepant 60 mg once daily or placebo. Randomization was stratified based on region (North America and Europe), number of migraine days during the screening or baseline period (4 to < 8 and ≥ 8), and number of classes of failed prior prophylactic treatments (2 and > 2). Patients were instructed to take the study intervention once a day at approximately the same time each day. A randomization cap of 20% was instituted to ensure that the planned randomized patients included no more than 20% of patients with 4 migraine days to fewer than 8 migraine days at baseline. Approximately 50% of randomized patients were also to have failed more than 2 classes of prior prophylactic treatments.¹⁵

In all studies, atogepant and placebo were provided as oral tablets containing placebo, atogepant 10 mg (or matching placebo), atogepant 30 mg (or matching placebo), or atogepant 60 mg (or matching placebo) on an outpatient basis. Patients were required to take the assigned intervention for 12 weeks and were followed for 4 weeks after discontinuation of the study intervention. Study sites dispensed the study intervention to patients at visit 3, visit 4, visit 5, and visit 6. Compliance was closely monitored by counting the number of tablets dispensed and returned.^13-15

Withdrawal criteria for all studies included patients who became pregnant, patients who had postbaseline clinical laboratory values that met any of the laboratory criteria related to abnormal liver function (alanine aminotransferase [ALT] or aspartate aminotransferase [AST] ≥ 3 × ULN and the patient was symptomatic with the appearance of fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, or eosinophilia [> 5%], ALT or AST ≥ 3 × ULN and total bilirubin > 2 × ULN, ALT or AST ≥ 3 × ULN and international normalized ratio > 1.5, ALT or AST ≥ 5 × ULN for more than 2 weeks, or ALT or AST ≥ 8 × ULN), and who were advised not to be rechallenged, and patients who replied with “yes” to question 4 or question 5 in the suicidal ideation section or “yes” to any question in the suicidal behaviour section of the C-SSRS at visit 3 through visit 6. A patient with a condition and/or a situation that, in the investigator's opinion, may have put them at significant risk, may have confounded the study results, or may have interfered significantly with their participation in the study were withdrawn from treatment. All randomized patients who prematurely discontinued from the study, regardless of cause, were to return to the clinic for final study assessments.^13-15

Prior and Concomitant Therapy

The following medications for acute migraine treatment were allowed during all studies: any triptan, any ergot derivative, any opioid (although opioids were not permitted in the ELEVATE study),¹⁵ any other form of analgesic (including acetaminophen), any NSAID, and any antiemetic drug.^13,14 In all studies, Aspirin up to 325 mg per day was allowed for cardiac prophylaxis and selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors were permitted if treatment had been stable for at least 60 days before screening and continued without change in dose throughout the studies.^13-15 Study CGP-MD-01 noted that the daily use of pregabalin was permitted.¹⁴

The following medications were prohibited 30 days before visit 1 and throughout the study period for the ADVANCE, CGP-MD-01, and ELEVATE studies: strong and moderate cytochrome P450 3A4 inhibitors (e.g., itraconazole, ketoconazole, fluconazole) and inducers (e.g., phenobarbital and primidone), strong organic anion-transporting polypeptide 1B1 inhibitors (e.g., gemfibrozil), drugs with narrow therapeutic margins with theoretical potential for cytochrome P450 drug interactions (e.g., warfarin), medications with demonstrated efficacy for the prevention of migraine (e.g., amitriptyline, topiramate, propranolol), botulinum toxin injections into areas of the head, face, or neck within 6 months before visit 1, and acupuncture, transcutaneous electrical nerve stimulation, cranial traction, nociceptive trigeminal inhibition or occipital nerve block treatments, or dental splints for headache, within 4 weeks before entry into the baseline phase.^13-15 Additional prohibited medications in the ADVANCE and ELEVATE studies included cannabidiol oil, and injectable mAbs blocking the CGRP pathway (e.g., Aimovig, Emgality, Ajovy) within 6 months before visit 1 and through the study period.^13,15

In addition, patients in all studies were asked to refrain from making significant changes to their diet or caffeine intake during the study and were to refrain from consuming grapefruit or grapefruit juice. Alcohol intake was to be limited to no more than 1 drink per day in the ADVANCE and ELEVATE studies,^13,15 and 3 drinks per day in study CGP-MD-01.¹⁴

Table 8: Summary of Outcomes of Interest Identified in the CADTH Review Protocol

AIM-D = Activity Impairment in Migraine–Diary; HIT-6 = 6-item Headache Impact Test; MIDAS = Migraine Disability Assessment; MSQ = Migraine-Specific Quality-of-Life Questionnaire; MUD = medication use day; PGI-S = Patient Global Impression–Severity; PGIC = Patient Global Impression of Change; WPAI:Migraine = Work Productivity and Activity Impairment Questionnaire: Migraine.

Outcomes

A list of efficacy end points identified in the CADTH review protocol that were assessed in the clinical trials included in this review is summarized in Table 8. A detailed discussion and critical appraisal of the outcome measures is provided in Appendix 4.

Efficacy Outcomes

In all studies, efficacy measurements including headache duration, headache characteristics, symptoms, and acute medication use were based on information recorded by the patient in an eDiary.^13-15

A complete list of the primary and secondary end points in the included trials is summarized in Table 6. The primary efficacy end point of the ADVANCE, CGP-MD-01, and ELEVATE studies was the change from baseline in mean MMDs across the 12-week treatment period.^13,14 Baseline was defined as the number of migraine days during the last 28 days of the baseline phase. A migraine day (a migraine headache day in study CGP-MD-01) was defined as any calendar day on which a headache occurred that met criteria 1, 2, and 3, or met criteria 4 and 5 (a probable migraine headache day in study CGP-MD-01), per the eDiary:^13-15

1. Headache with at least 2 of the following characteristics — unilateral location, pulsating quality, or moderate or severe pain intensity, or had been aggravated by or causing avoidance of routine physical activity (e.g., walking, climbing stairs)

2. Headache with at least 1 of the following — nausea and/or vomiting, photophobia and phonophobia, or typical aura (i.e., visual, sensory, or speech and/or language) accompanying or within 60 minutes before headache begins

3. Headache whose duration lasts 2 hours or longer on a calendar day unless an acute, migraine-specific medication (i.e., triptan or ergot derivative) was used after the start of the headache, in which case no minimum duration was specified

4. Any headache that fulfilled 1 criterion from (1) and at least 1 criterion from (2) or fulfilled at least 2 criteria from (1) and no criteria from (2)

5. Headache whose duration lasts 2 hours or longer on a calendar day unless an acute, migraine-specific medication (i.e., triptan or ergot derivative) was used after the start of the headache, in which case no minimum duration was specified.

Additional headache-related outcomes and definitions in the included trials were:^13-15

• headache days, which were defined as any calendar day on which headache pain lasting 2 hours or longer occurred unless an acute headache medication (e.g., ibuprofen, triptan) was used after the start of the headache, in which case no minimum duration was specified

• monthly acute MUDs, which were defined as any day on which a patient reported, per their eDiary, the intake of allowed medication(s) for the acute treatment of migraine

• monthly triptan use days, which were defined as any day on which a patient reported the intake of a triptan to treat a migraine per patient eDiary.

Health outcome measures included in the ADVANCE study and the CGP-MD-01 study included MSQ version 2.1, HIT-6, AIM-D, MIDAS, Patient Global Impression of Change (PGIC), Patient Global Impression–Severity (PGI-S), and the Work Productivity and Activity Impairment questionnaire.^13,14 A detailed discussion of these outcomes is provided in Appendix 4.

The MSQ version 2.1 is a 14-item questionnaire designed to measure HRQoL impairments attributed to migraine in the past 4 weeks. It is divided into 3 domains: role function-restrictive, which assesses how migraines limit one’s daily social and work-related activities; role function-preventive, which assesses how migraines prevent these activities; and the emotional function (EF) domain, which assesses the emotions associated with migraines. Patients respond to items using a 6-point scale ranging from “none of the time” to “all of the time.” Raw dimension scores are computed as a sum of item responses and rescaled to a 0 to 100 scale, where higher scores indicate better quality of life.^13,26 The minimal important difference (MID) at the group level has been estimated at a change of 3.2 points for the role function-restrictive domain, 4.6 points for the role function-preventive domain, and 7.5 points for the EF domain.²⁷

AIM-D is an 11-item daily diary measure that assesses the impact of migraine; it comprises 2 domains that evaluate performance of daily activities (7 items) and physical impairment (4 items). Patients are asked to rate the level of difficulty experienced in the past 24 hours with performance of daily activities (i.e., difficulty with household chores, errands, leisure activities at home, leisure or social activities outside the home, strenuous physical activities, concentrating, and thinking clearly) and physical impairment (i.e., difficulty walking, moving body, bending forward, and moving head) using a 6-point rating scale ranging from “not difficult at all,” “a little difficult,” “somewhat difficult,” “very difficult,” “extremely difficult,” and “I could not do it at all.” In addition to the 2 domain scores, a total score using all 11 items can also be calculated. Each raw daily domain score, as well as the raw daily total score, is transformed to a 0 to 100 scale, with higher scores indicating greater impact of migraine.^13,15,26 Two items based on a 24-hour recall were administered daily using headache and non-headache versions as additional health outcome measures and for the evaluation of AIM-D. The first item was used to assess activity level within the past 24 hours with a 5-level response scale ranging from “no activity – spent all day lying down” to “exercised – brisk walk, running, jogging, biking or other activity for 30 or more minutes.” The second item was used to evaluate activity limitation with a 5-level response scale ranging from “not at all limited – I could do everything” to “extremely limited.”^13,15,26 No MID was identified for patients with EM.

HIT-6 is a 6-question assessment used to measure the impact headaches have on a participant’s ability to function on the job, at school, at home, and in social situations. It assesses the effect that headaches have on normal daily life and the participants’ ability to function. Responses are based on frequency using a 5-point scale ranging from “never” to “always.” The HIT-6 total score, which ranges from 36 to 78, is the sum of the responses — each of which is assigned a score ranging from 6 points (never) to 13 points (always).^13-15,26 The estimated within-group MID for the HIT-6 was 2.5 points, while the estimated between-group MID was 1.5 points in patients with EM.²⁸

MIDAS is a 7-item questionnaire designed to quantify headache-related disability over a 3-month period. The MIDAS score is the sum of missed work or school days, days at work or school plus days of household work where productivity was reduced by half or more, missed household workdays, and missed nonwork activity days due to headaches in the last 3 months.^13,15,26 The estimated MID for MIDAS was a change of 3.7 points to 4.5 points for patients with EM and CM.^29,30

PGIC is a single item used to measure the participant’s impression of overall change in migraine since the first dose of study intervention. The measure uses a 7-point rating scale with responses ranging from “very much better” to “very much worse.”^13,14,26 No MID was identified for patients with EM.

The Work Productivity and Activity Impairment Questionnaire: Migraine (WPAI:Migraine) is used to assess work productivity specific to migraine. The measure uses a 1-week recall and contains 6 questions related to work productivity. The WPAI:Migraine measures both presenteeism and absenteeism. The measure yields 4 scores expressed as impairment percentages ranging from 0 to 100%: the percentage of work time missed, the percentage of impairment while working, the percentage of overall work impairment, and the percentage of activity impairment due to migraine.^13,14,26 No MID was identified for patients with EM.

PGI-S is a single item used to measure the participant’s impression of severity in relation to migraine symptoms overall at the time of administration of the measure. The measure uses a 5-point rating scale with responses ranging from “none” to “very severe.”^13,26 No MID was identified for patients with EM.

In the ADVANCE and ELEVATE studies, the AIM-D data were collected daily via the eDiary. Additional health outcome measures such as HIT-6, MIDAS, PGIC, WPAI:Migraine, and MSQ version 2.1 were administered in an eTablet at specified clinic visits.¹³

In study CGP-MD-01, health outcome measures (HIT-6, PGIC, WPAI:Migraine) were completed via the eDiary — at predose (baseline) and at week 4, week 8, and week 12 (for HIT-6), at week 12 (for PGIC), and at predose (baseline) and at week 6 and week 12 (for WPAI:Migraine).¹⁴

Harms Outcomes

The safety and tolerability of atogepant in the ADVANCE, CGP-MD-01, and ELEVATE studies was measured by AEs, SAEs, clinical laboratory evaluations, vital sign measurements, electrocardiogram (ECG) parameters, and the C-SSRS. Subjective AEs were collected throughout the study and at each 4-week follow-up visit. For all AEs, the investigator provided an assessment of the severity, causal relationship to the investigational product, start and stop dates, and seriousness of the event. The following criteria defined AEs of special interest for this study: treatment-emergent suicidal ideations with intent, with or without a plan (i.e., type 4 or type 5 on C-SSRS) or any suicidal behaviours; treatment-emergent elevated ALT or AST laboratory value 3 or more times the ULN; and potential Hy’s law cases (defined as concurrent ALT or AST elevation ≥ 3 × ULN and total bilirubin elevation ≥ 2 × ULN and alkaline phosphatase value < 2 × ULN).^13-15,26

AEs were defined as any untoward medical occurrence in a patient or clinical study patient associated with the use of study intervention, whether or not considered related to the study intervention. SAEs were defined as those AEs that resulted in death, were considered to be life-threatening, resulted in the hospitalization or prolongation of existing hospitalization, resulted in persistent disability or incapacity, or were congenital anomalies or birth defects.^13-15,26

Statistical Analysis

Sample Size and Power Calculation

Study 301 (ADVANCE Study)

The sample size of the ADVANCE study was selected to provide sufficient power for the primary efficacy end point (change from baseline in mean MMDs over 12 weeks) and the first 3 secondary end points (change from baseline in mean MHDs, mean monthly acute MUDs, and the proportion of participants with at least a 50% reduction in mean MMDs over 12 weeks).^13,26

A total sample size of 218 participants per treatment group provided at least 98% power to detect the treatment difference between each of the 3 atogepant doses (assumed equally effective) and placebo for the primary efficacy end point. A treatment difference of –1.5 days and a SD of 3.5 days from placebo in change from baseline in mean MMDs across the 12-week treatment period was assumed for the primary end point, based on the phase II/III CGP-MD-01 study, and studies of telcagepant and the CGRP mAbs, as well as an internal study that randomized approximately 800 participants. The statistical testing plan controlled the overall type I error at 5%.^13,26

The power calculations of the primary and secondary end points have taken the multiple comparisons into consideration by testing each dose versus placebo at a 2-sided 0.0167 significance level. Once the primary end point for each dose was significant at 0.0167 (2-sided), the secondary end points were tested sequentially. The treatment differences from placebo for the secondary end points were –1.5 (SD = 3.8) for change from baseline in mean MHDs over 12 weeks, –1.2 (SD = 3.2) for mean monthly acute MUDs over 12 weeks, and 33% placebo rate (SD = 50% atogepant rate) for the proportion of participants with at least a 50% reduction in mean MMDs over 12 weeks, resulting in statistical power of 95%, 93%, and 89%, respectively.^13,26

Study CGP-MD-01

Statistical comparisons for study CGP-MD-01 were conducted for 30 mg atogepant or 60 mg atogepant once daily versus placebo, and 30 mg atogepant or 60 mg atogepant twice daily versus placebo. The statistical power calculations focused on dosages of 30 mg atogepant once daily, 60 mg atogepant once daily, 30 mg atogepant twice daily, and 60 mg atogepant twice daily, because the 10 mg atogepant once daily was considered to be a suboptimal dose and was only tested if at least 1 of the 4 dose comparisons was significant.

The assumed effect size and estimated power for the primary end point of study CGP-MD-01 are summarized in Table 9. For critical alpha level 0.0125, the powers are displayed based on an SD estimate of 4.0 in the study’s Statistical Analysis Plan. In the protocol and Clinical Study Report, however, the powers were based on an SD estimate of 3.0. Power was calculated via 10,000 simulations based on multiplicity adjustment for the 5 doses and primary and secondary end points. With the allocated one-quarter weight, each of the hypotheses will be tested at an alpha level of 0.0125 using the Bonferroni approach.^14,26

Differences between treatment groups in the change from baseline in the mean number of migraine or probable migraine headache days at the primary time point (week 9 to week 12) was assumed to be 1.5 for the comparison of 30 mg atogepant or 60 mg atogepant once daily (assumed equally effective) versus placebo and 1.75 for the comparison of 30 mg atogepant or 60 mg atogepant twice daily (assumed equally effective) versus placebo. Treatment differences were assumed based on results from other EM prevention studies. The placebo-adjusted reduction in MMDs observed from other EM prevention studies ranged from 1.1 days to 2 days (topiramate, telcagepant, and CGRP mAbs).^14,26

Table 9: Assumed Effect Size and Estimated Power for Primary Efficacy End Point

q.d. = once daily; SD = standard deviation; vs. = versus.

^aThe common SD was estimated based on blinded interim data assessments.

Source: Sponsor’s submission.²⁶

Study 304 (ELEVATE Study)

The sample size for the ELEVATE study was selected to provide sufficient power for the primary efficacy end point (change from baseline in mean MMDs) and the secondary end points in both the US and European Union (EU) applications (a 50% reduction in MMDs, change from baseline in mean MHDs, acute MUDs, MSQ version 2.1 role function-restrictive domain score, mean monthly AIM-D performance of daily activities domain score, and physical impairment domain score).¹⁵ Statistical power for the primary and secondary end points of the ELEVATE study are summarized in Table 10.

Assuming a 15% dropout rate, the sample size of 150 patients per treatment group was selected to provide a 97% power to detect the treatment difference of –1.7 MMDs (SD = 3.5 days) between atogepant and placebo for the primary efficacy end point. Treatment differences were assumed based on the results of the comparison between atogepant 60 mg once daily and placebo from the ADVANCE study. Assumptions for SD were based on the variance in the LIBERTY study³¹ and monthly variance observed in the ADVANCE study for the primary end point.¹⁵

A dropout rate of 21% was assumed for the AIM-D end points based on the higher missingness of AIM-D end points observed in the ADVANCE study.¹⁵

Table 10: Statistical Power for Primary and Secondary End Points for the US Filing — mITT Population, ELEVATE Study

AIM-D = Activity Impairment in Migraine–Diary; ATO = atogepant; CFB = change from baseline; MHD = monthly headache day; mITT = modified intention to treat; MMD = monthly migraine day; MSQ = Migraine-Specific Quality-of-Life Questionnaire; MUD = medication use day; NA = not applicable; PBO = placebo; SD = standard deviation; vs. = versus.

Source: ELEVATE Clinical Study Report.¹⁵

Statistical and Analytical Plans

Efficacy Analysis

ADVANCE and ELEVATE Studies

Primary and secondary end point analyses: In the ADVANCE and ELEVATE studies, all efficacy analyses were performed using the modified intention-to-treat (mITT) population. The primary comparison between treatment groups in the ADVANCE and ELEVATE trials was analyzed using a mixed model of repeated measures (MMRM) of the change from baseline. In the ADVANCE study, the statistical model included treatment group, visit, prior exposure to a migraine prevention medication with proven efficacy (yes or no), and treatment-group-by-visit interaction as categorical fixed effects. It also included the baseline score and baseline-by-visit interaction as covariates. An unstructured covariance matrix was used to model the covariance of within-participant repeated measurements. The Kenward-Roger approximation was used to estimate the denominator degrees of freedom. The analysis was performed based on all postbaseline values using only the observed cases without imputation of missing values. Pairwise contrasts in the MMRM model were used to make the pairwise comparisons of each atogepant dose to placebo. A reduction of at least 50% in the 3-month average of MMDs was analyzed using a logistic regression model. The other secondary efficacy end points were analyzed in the same manner as that used to analyze the primary end point.¹³

In the ELEVATE study, the statistical model included treatment group, visit (derived as week 1 to week 4, week 5 to week 8, and week 9 to week 12), region, number of classes of failed prior prophylactic treatments (2 and > 2), and treatment-group-by-visit interaction as categorical fixed effects, as well as baseline MMDs and baseline-by-visit interaction as covariates. A restricted maximum likelihood method was used, including an unstructured covariance matrix to model the covariance of within-participant repeated measurements. If there was no convergence in the model, then the Toeplitz covariance structure was used, and if the Toeplitz model did not converge, the compound symmetry covariance structure was used. The Kenward-Roger approximation was used to estimate the denominator degrees of freedom. Treatment effect and treatment comparison were estimated by the LSMs and their difference in LSMs, along with their SE and 95% CI, and the P value corresponding to the between–treatment group difference. The secondary end points for MHDs, acute MUDs, the performance of daily activities domain score of the AIM-D, and the physical impairment domain score of the AIM-D were analyzed in the same manner as that used to analyze the primary end point. For the MSQ version 2.1 role function-restrictive domain score and the HIT-6 total score, the analyses were performed similarly to the primary MMRM, with a focus on the pairwise contrasts of the atogepant dose group to placebo at week 12. A logistic regression model was used to analyze the 50% responders across the 12-week treatment period. The model assumed a binary distribution for the response and used a logit link. The analysis model included treatment group, region, the stratification of number of classes of failed prior prophylactic treatments (2 and > 2), and baseline MMDs. The treatment difference in terms of the odds ratio (OR) between each atogepant dose group and placebo was estimated and tested from this model.¹⁵

In the ADVANCE study, the overall familywise error rate was controlled at an alpha of 0.05 for the set of primary and secondary end point comparisons between each dose level of atogepant versus placebo. Specifically, the overall type I error rate for multiple comparisons across 3 atogepant doses and the primary and secondary efficacy end points was controlled at the 0.05 level using a graphical approach with a weighted Bonferroni test procedure. The graphical approach to multiplicity adjustment is summarized in Figure 5. The 3 doses were treated equally. The initial allocation of the overall significance level to the 3 primary hypotheses was one-third of the overall significance level for each dose, and no initial alpha level was allocated to the hypotheses for secondary end points. Within each individual dose, testing started from the primary end point (change from baseline in mean MMDs), and the secondary end points were then tested in a prespecified order (change from baseline in MHDs, change from baseline in acute MUDs, a 50% or greater reduction in a 3-month average of MMDs, change from baseline in the MSQ version 2.1 role function-restrictive domain score, change from baseline in the performance of daily activities domain score of AIM-D, and change from baseline in the mean monthly physical impairment domain score of AIM-D). If the null hypotheses for both the primary and the first 3 secondary end points were rejected for 1 of the doses, one-third of the associated alpha was passed to the other doses (a one-sixth fraction for each dose) to increase the chances of success for the other doses in testing end points in the primary positions of the hierarchy, and the remaining two-thirds of the associated alpha was reserved for testing health outcome end points (MSQ version 2.1, AIM-D) within the same dose. If hypotheses for 3 health outcome end points were rejected within a dose based on the remaining alpha, the alpha for this dose was propagated to the other 2 doses to make full use of the alpha.

Figure 5: Multiple Comparisons Procedure — ADVANCE Study

P = primary; S = secondary.

Source: ADVANCE Statistical Analysis Plan.²⁶

In the ELEVATE study, the overall familywise type I error rate was controlled at the 0.05 level using a fixed sequence procedure for primary and secondary efficacy variables, where once the primary end point for atogepant versus placebo was significant at the 2-sided 0.05 level, the secondary end points were tested sequentially (following the hierarchy outlined in Table 10). Statistical powers for secondary end points were conditional on the success of prior end points in the sequence. All additional secondary and exploratory efficacy end point analyses were performed at the nominal significance level, without adjusting for multiplicity.¹⁵

Sensitivity analyses: In the ADVANCE study, a total of 4 sensitivity analyses for missing data handling were conducted.^13,26

• Analysis of covariance (ANCOVA) model based on a 3-month average of MMDs: The response variable for the ANCOVA model was the change from baseline in a 3-month average of MMDs for each patient. The ANCOVA model included terms for treatment, prior exposure (yes or no) to a migraine prevention medication with proven efficacy, and baseline score. The treatment difference for atogepant doses versus placebo was estimated and reported along with the corresponding 95% CI and nominal P value for superiority testing. This analysis was also termed as supportive analysis.

• Within-group imputation based on observed data: A sensitivity analysis was performed based on imputation using patients from the same treatment group with observed data under the missing at random (MAR) assumption. Missing data for patients who prematurely discontinued were assumed to copy the profile of patients in the same treatment group with observed data.

• Copy-reference approach: The copy-reference approach was performed on the primary end point to assess the robustness of the MMRM analysis to possible violation of the MAR assumption. This sensitivity analysis is 1 type of pattern-mixture models (PMMs), under which data could be missing not at random, with repeated analyses combined via the reference-based multiple imputation procedure. Patients who discontinued in the atogepant groups were assumed to have no treatment effect after the discontinuation. Patients were assumed to copy the profile of the placebo group and missing values were imputed based on the distribution estimated from the placebo group under the MAR using the copy-reference approach.

• MMRM based on primary measures collected during the double-blind and follow-up periods: The off-treatment hypothetical estimand in support of the EU filing served as 1 sensitivity analysis in support of the US filing.

One additional sensitivity analysis for possible violations of the normality assumption was conducted in the ADVANCE trial. The normality test was performed on the residuals that were generated by the same MMRM that was used for the primary efficacy analysis. The residuals are scaled by the inverse Cholesky root of its estimated variance-covariance matrix. The Kolmogorov-Smirnov test for normality was applied to the decorrelated and scaled residuals and the normality test was rejected if the P value from the Kolmogorov-Smirnov test was less than 0.01. If the normality test was rejected, the sensitivity analysis used multiple imputation in conjunction with robust regression to assess the robustness of the primary MMRM analysis to the possible violation of normality assumption.^13,26

In the ELEVATE study, sensitivity analyses on the primary end point for handling missing data were identical to those of the ADVANCE study and included an ANCOVA model based on a 3-month average of the MMDs, a within-group imputation based on observed data, and a copy-reference approach, using the off-treatment hypothetical estimand in support of the EU filing as a sensitivity analysis for the US filing. An additional sensitivity analysis for possible violations of the normality assumption was conducted. As noted, all sensitivity analyses were conducted in the same manner as those of the ADVANCE study described earlier; however, model factors varied with the ELEVATE study, including terms for treatment, region, and number of classes of failed prior prophylactic treatments (2 and > 2) as fixed factors, and baseline MMD as a covariate.¹⁵

Subgroup analysis: Prespecified subgroups in the ADVANCE study were conducted in the mITT population for 2 subgroups of patients based on prior exposure to migraine prevention medication with proven efficacy. One subgroup had prior exposure to migraine prevention medication with proven efficacy (N = 608) and the other subgroup, also referred to as the naive subgroup, did not (N = 265).¹³

Prespecified subgroup analyses for the primary efficacy end point in the ELEVATE study included region (North America and Europe), patients who had baseline migraine days (4 to < 8 and ≥ 8), patients who had failed 2 classes of prior oral prophylactic treatments, patients who had failed 3 or more classes of prior oral prophylactic treatments, and patients who had failed 3 classes of prior oral prophylactic treatments. For each subgroup analysis, treatment effect and treatment comparison were estimated by the LSMs and their difference in LSMs, along with SEs and 95% CIs.¹⁵

Other efficacy analyses: Other efficacy and health outcomes research analyses in the ADVANCE and ELEVATE trials, including the HIT-6, MIDAS, PGIC, PGI-S, WPAI:Migraine, and time point analyses of primary and key secondary end point analyses, were performed at the nominal significance level, without adjusting for multiplicity.^13,15

Safety analyses: Safety parameters in the ADVANCE and ELEVATE trials included AEs, clinical laboratory evaluations, vital sign measurements, ECG parameters, and the C-SSRS tool. All safety analyses were performed using the safety population, which consisted of all participants who took at least 1 dosage of study intervention.^13,15

In both the ADVANCE and ELEVATE studies, an independent data safety monitoring board was established to review unblinded safety data and summary reports, identify any safety issues and trends, and make recommendations to the sponsor, including modification or early termination of the trial if emerging data showed unexpected and clinically significant AEs.^13,15

Study CGP-MD-01

Primary and secondary end point analyses: The primary efficacy end point of change from baseline in mean MMDs across the 12-week treatment period was analyzed using a MMRM. The response variable was the change from baseline to each postbaseline month in MMDs. The model included baseline MMDs as a covariate, treatment group and visit (month) as fixed factors, and treatment-group-by-visit and baseline-by-visit as interaction terms. The analysis was performed based on evaluable postbaseline data using only the observed cases without imputation of missing values. The restricted maximum likelihood method was used. The within-patient correlation was modelled using the unstructured covariance matrix. If the model did not converge, then the compound symmetry covariance structure would be used. The Kenward-Roger approximation was used to estimate denominator degrees of freedom. Contrasts were constructed to obtain the average treatment effects across the 12-week treatment period to compare each atogepant treatment group with the placebo group. All treatment effects and treatment comparisons were estimated by the LSMs and their differences in LSMs, along with their SEs and 95% CIs, and the P value corresponding to the between–treatment group difference.¹⁴

The overall type I error rate for multiple comparisons across active treatment doses and the primary and secondary efficacy parameters was controlled at the 0.05 level. The weighting strategy of the multiple comparisons was designed to allocate initial alpha equally to the once daily and twice daily dose regimens. Within each dosing regimen, individual atogepant doses were tested in a hierarchical order from high to low dose (i.e., for primary efficacy end point, the low dose was tested only if the high dose comparison showed statistical significance). In addition, for a given dose comparison versus placebo, the strategy had the primary end point (change from baseline in mean MMDs) as gatekeeper to the secondary end points (change from baseline in mean MHDs, proportion of patients with at least a 50% reduction in mean MMDs, and change from baseline in mean monthly acute MUDs) so that secondary end points could be tested only if the primary hypothesis of the corresponding dose comparison reached statistical significance. Weighted Bonferroni tests were used for testing the hypotheses.¹⁴

For continuous variables, pairwise comparisons were analyzed using MMRM, with baseline covariates. For variables where data were binary, comparisons between treatment groups were done by pairwise contrasts using logistic regressions for variables with only 1 postbaseline assessment or using a generalized linear mixed model for variables with multiple postbaseline assessments.¹⁴

Sensitivity analyses: In study CGP-MD-01, 2 sensitivity analyses were performed on the primary end point. The first used a PMM approach based on the copy-reference method for missing value imputation using a missing-not-at-random mechanism for missing data to assess the impact of potential deviation from a MAR assumption in the primary analysis. The PMM analysis used the placebo group as the reference. The missing pattern was defined by the patient’s last visit with an observed value. Any intermediate missing values were imputed using the last observation carried forward approach. The missing values in the reference group were imputed using the observed data in that group under the MAR assumption. The missing values in any other treatment group were then imputed using the observed data from that treatment group and the distribution estimated from the reference group. The dataset with missing values imputed were analyzed using an ANCOVA model with treatment group as a factor and baseline value as a covariate for treatment comparison at week 9 to week 12. The imputation of missing values and the analysis were performed multiple times, and the inference was based on the combined estimates using the standard multiple imputation technique.^14,26

The second sensitivity analysis used multiple imputations in conjunction with robust regression to assess the robustness of the primary MMRM analysis with respect to the possibility of a violation of the normality assumption.²⁶

Other efficacy analyses: In general, other efficacy analyses were performed at the nominal significance level, without adjusting for multiplicity. Descriptive statistics were provided by visit for each efficacy variable by treatment group. An analysis of change from baseline in the EQ-5D visual analogue scale score at week 6 and week 12 were limited to descriptive summary statistics.¹⁴

Safety analyses: The safety analyses were performed using the safety population. The safety parameters were AEs and clinical laboratory, vital sign, and ECG parameters, and the C-SSRS tool. For each of the clinical laboratory, vital sign, and ECG parameters, the last nonmissing safety assessment before the initial dose of treatment was used as the baseline for all analyses of that safety parameter. Continuous variables were summarized by the number of patients and mean, SD, median, minimum, and maximum values. Categorical variables were summarized by the number and percentage of patients.¹⁴

An independent data safety monitoring board was established to review unblinded safety data and summary reports, identify any safety issues and trends, and make recommendations to the sponsor, including modification or early termination of the trial if emerging data showed unexpected and clinically significant AEs.¹⁴

Analysis Populations

The following analysis populations were defined in the ADVANCE, CGP-MD-01, and ELEVATE studies:

• the intention-to-treat (ITT) population included all randomized patients

• the safety population included all patients who received at least 1 dosage of study intervention

• the mITT population included all randomized patients who received at least 1 dosage of study intervention, had an evaluable baseline period of eDiary data, and had at least 1 evaluable postbaseline 4-week period of eDiary data during the double-blind treatment period. In study CGP-MD-01, “evaluable” was defined as having at least 20 days of diary data during the 4-week baseline period and as having at least 12 days of diary data for each postbaseline 4-week treatment period.

In the ADVANCE and ELEVATE studies, an additional analysis population was included. The analysis population for an off-treatment hypothetical estimand, which was used as the primary population in support of the EU filing and was defined as all randomized participants who received at least 1 dosage of study treatment, had an evaluable baseline period of eDiary data, and had at least 1 evaluable postbaseline 4-week period (week 1 to week 4, week 5 to week 8, week 9 to week 12) of eDiary data, regardless of whether on study treatment or off study treatment. Analyses from this population were not included in this report.

Protocol Amendments and Deviations

Protocol deviations in the ADVANCE, CGP-MD-01, and ELEVATE studies are summarized in Table 11.

In the ADVANCE trial, the proportion of patients with protocol deviations was similar across groups, ranging from 14.0% of patients to 17.4% of patients. The most frequently reported protocol deviations were prohibited concomitant medications (7.5% overall). There were 3 amendments to the original protocol for the ADVANCE study (dated September 25, 2018): Protocol Amendment 1 (dated November 30, 2018), Protocol Amendment 2 (dated February 25, 2019), and Protocol Amendment 3 (dated May 14, 2020). Protocol Amendment 1 occurred before the enrolment of any patients. The main revisions in Protocol Amendment 2 were to clarify the definition for subgroups. Protocol Amendment 3 included new methods for handling the COVID-19 pandemic to ensure patient safety, and maintaining data integrity and allowing for remote visits for visit 3 to visit 8. Investigators were allowed to conduct an in-person follow-up visit at their discretion if there were safety concerns. Aside from the potential logistical and missing data concerns due to the COVID-19 pandemic, protocol amendments generally had no major impact on the conduct of studies.¹³

In study CGP-MD-01, there was a greater range of protocol deviations across groups, ranging from 7.0% to 17.0%. The most common protocol deviation was the use of prohibited concomitant medication (placebo = 6.5%; atogepant = 7.0%). There were 2 amendments to the original protocol (dated May 9, 2016). Protocol Amendment 1 (dated November 11, 2016) specified the following significant changes: the exclusion of patients who had used injectable mAbs for CGRP and patients who had used benzodiazepines. Significant changes specified in Protocol Amendment 2 (dated September 11, 2017) included the following: allowing the participation of patients with a history of hemiplegic migraine, the revision of the primary and secondary efficacy end points to evaluate treatment effects across the entire 12 weeks of treatment instead of the last 28 days of treatment as well as the addition of sensitivity analyses of the primary end point, and the revision of the multiple comparisons procedure and sample size calculation to reflect a revised primary end point and multiplicity strategy.¹⁴

In the ELEVATE trial, the proportion of patients with any major protocol deviations was similar across groups (| ||||||| || || ||||||). The most common protocol deviation was patients entering the study despite not satisfying the entry criteria (| ||||||| || || |||||||||). The original study protocol for the ELEVATE trial (dated December 17, 2019) was amended 2 times. Protocol Amendment 1 (dated April 3, 2020) included changes to the exclusion criteria, where patients with medication overuse headache were not enrolled; randomization methods, where block randomization was applied with a block size of 6 (3 treatment groups × 2); and the primary and secondary analysis methods, where “region” was added as a factor. Protocol Amendment 2 (dated December 1, 2020) included changes to the study design, where the atogepant 30 mg once daily dose was removed based on the results of the ADVANCE study. In turn, the randomization block size and the sample size determination were also changed. Additional changes included the specification of the first 3 secondary end points, sensitivity analyses of the primary efficacy data, and the addition of various exploratory end points. Both protocol amendments occurred before the first patients’ first visit.¹⁵

Results

Patient Disposition

Table 12 summarizes the disposition of patients enrolled in the ADVANCE and CGP-MD-01 studies. The ADVANCE study was a randomized, double-blind phase III RCT. A total of 2,270 patients were screened for eligibility, and 910 patients were randomized 1:1:1:1 to receive atogepant 10 mg (N = 222), atogepant 30 mg (N = 230), atogepant 60 mg (N = 235), or placebo (N = 223), comprising the ITT population. In total, 86.8% to 90.1% of patients completed the double-blind period of the ADVANCE study. Discontinuations were balanced between groups, with the main reasons for discontinuation in the double-blind treatment period consisting of withdrawal by patient (3.5% to 4.3%), AEs (1.7% to 4.1%), and protocol deviations (1.8% to 3.4%). Only 16.5% to 24.3% of patients entered the follow-up period, with 13.9% to 22.1% of patients completing the follow-up period.¹³

Study CGP-MD-01 was a randomized, double-blind phase II/III RCT. A total of 1,772 patients were screened for eligibility, and 834 patients were randomized 2:1:2:1:2:1 to receive placebo (N = 186), atogepant 10 mg once daily (N = 94), atogepant 30 mg once daily (N = 185), atogepant 60 mg once daily (N = 187), atogepant 30 mg twice daily (N = 89), atogepant 60 mg twice daily (N = 93), comprising the ITT population. Completion rates for the double-blind treatment period were similar across groups (79.6% to 87.7%). The most common reasons for discontinuation were withdrawal of consent, which was numerically higher in the placebo group (10.8%) compared to the atogepant groups (3.2% to 6.4%), and the occurrence of AEs, which was numerically higher in the atogepant groups (3.2% to 5.9%) compared to placebo (2.7%).¹⁴

Table 11: Summary of Protocol Deviations — ADVANCE Study (All Randomized Patients) and CGP-MD-01 and ELEVATE Studies (Intention-to-Treat Population)

IP = investigational product; IRT = interactive response technology; q.d. = once daily; SAE = serious adverse event.

Sources: ADVANCE Clinical Study Report,¹³ CGP-MD-01 Clinical Study Report,¹⁴ and ELEVATE Clinical Study Report.¹⁵

The ELEVATE study was a randomized, double-blind phase III RCT. A total of ||| patients were screened for eligibility. Of these, ||| had failed the screening process, and 315 patients were randomized 1:1 to atogepant 60 mg once daily (N = ||||) or placebo (N = |||), comprising the ITT population. In total, ||||| || ||||| of patients completed the double-blind period of the ELEVATE study. The main reasons for discontinuation (| |||||| || |||||||) in the double-blind treatment period consisted of AEs (| |||||| |||| ||||||), and protocol deviations (| |||||| || |||||||| Only | ||||||| || || ||||||| patients entered the follow-up period, with only | ||||||| from the placebo group not completing the follow-up period due to a withdrawal by the patient.

Exposure to Study Treatments

Exposure to study treatments and the duration of treatment for the ADVANCE, CGP-MD-01, and ELEVATE studies are summarized in Table 13. The mean treatment duration with atogepant and placebo was similar across studies.

The mean duration of treatment in the ADVANCE trial was similar across treatment groups, ranging from |||| || |||| days in the atogepant groups compared with |||| |||| in the placebo group.¹³

In study CGP-MD-01, the mean duration of treatment ranged from |||| || |||| |||| in the atogepant groups compared with |||| |||| in the placebo group.¹⁴

In the ELEVATE study, the mean duration of treatment in the atogepant 60 mg once daily group was |||| |||| |||| |||||| compared to |||| |||| |||| |||||| in the placebo group.

Efficacy

Only those efficacy outcomes and analyses of subgroups identified in the review protocol are reported as follows. Refer to Appendix 3 for detailed efficacy data.

Migraine or Headache Days

Monthly Migraine Days

The primary end point of all included studies was the reduction in mean MMDs across the 12-week treatment period. The mean change from baseline in MMDs for all studies is summarized in Table 14.

For LSM change from baseline in MMDs in the ADVANCE study, a dose-response relationship was observed for the 3 atogepant doses, with each increasing atogepant dose: –3.69 days (95% CI, –4.11 to –3.28 days) for atogepant 10 mg, –3.86 days (95% CI, –4.27 to –3.46 days) for atogepant 30 mg, and –4.20 days (95% CI, –4.60 to –3.80 days) for atogepant 60 mg, compared with –2.48 days (95% CI, –2.90 to –2.07 days) for placebo. Results for the observed change from baseline in mean MMDs were consistent with the imputed values. Each of the 3 atogepant doses demonstrated statistically significant differences compared with placebo in the reduction of mean MMDs across the 12-week treatment period (atogepant 10 mg = –1.21 days [95% CI, –1.78 to –0.64 days; P < 0.0001]; atogepant 30 mg = –1.38 days [95% CI, –1.94 to –0.82 days; P < 0.0001]; atogepant 60 mg = –1.72 days [95% CI, –2.28 to –1.15 days; P < 0.0001]).¹³

For study CGP-MD-01, the mean change in MMDs was generally similar across the atogepant treatment groups (range = –4.00 days with atogepant 10 mg once daily to –3.55 days for atogepant 60 mg once daily) compared to –2.85 days (95% CI, –3.30 to –2.39 days) for placebo. No dose-response relationship was evident. In all cases, decreases in mean MMDs during the treatment period were statistically significantly larger in all atogepant groups compared with placebo (atogepant 10 mg once daily = –1.15 days [95% CI, –1.93 to –0.37 days; P = 0.0039]; atogepant 30 mg once daily = –0.91 days [95% CI, –1.55 to –0.27 days; P = 0.0056]; and atogepant 60 mg once daily = –0.70 days [95% CI, –1.35 to –0.06 days; P = 0.0325]).¹⁴

In the ELEVATE study, the LSM change from baseline at 12 weeks of ||||| |||| |||| |||||| for atogepant 60 mg once daily compared to ||||| |||| |||| |||||| for placebo and the LSM difference in mean change from baseline in MMDs between atogepant 60 mg once daily and placebo was ||||| |||| |||| || ||||| || |||||| | | ||||||| in favour of atogepant.¹⁵

Sensitivity analysis: Results for the sensitivity analyses conducted in the ADVANCE, CGP-MD-01, and ELEVATE studies are summarized in Table 32, Table 34, and Table 35, respectively. In all cases, sensitivity analyses were consistent with the primary analyses, demonstrating statistically significant reductions in mean MMD with atogepant doses across the 12-week treatment periods.¹³

Results for the additional supportive analysis conducted in the ADVANCE and ELEVATE studies of the MMRM based on primary measures collected during the double-blind and follow-up periods (Table 33 and Table 36) were consistent with the primary analysis.¹³

Subgroup analysis: Results for the subgroup analyses in patients with or without prior exposure to migraine prevention therapy in the ADVANCE study are summarized in Table 37 of Appendix 3. In the subgroup of patients who had prior exposure to migraine prevention medication with proven efficacy, results were consistent with the primary analysis — with a dose-response relationship with each increasing atogepant dose with mean change from baseline in MMDs of –3.63 days (95% CI, –4.13 to –3.13 days) for atogepant 10 mg, –3.77 days (95% CI, –4.24 to –3.29 days) for atogepant 30 mg, and –4.42 days (95% CI, –4.91 to –3.94 days) for atogepant 60 mg compared to –2.26 days (95% CI, –2.74 to –1.77 days) for placebo.¹³

A post hoc subgroup analysis by number of prior preventive treatment failures was provided by the sponsor. Results for change from baseline in MMDs in this subgroup are summarized in Table 44. Among patients with 1 or more prior preventive treatment failures (N = 436), and 2 or more prior preventive treatment failures (N = 119), atogepant was associated with a greater change from baseline in MMDs compared with placebo, with the greatest LSM difference versus placebo in the atogepant 60 mg once daily group (≥ 1 = –2.24 [SE = 0.44]; ≥ 2 = –3.12 [SE = 0.88]).¹³

Table 12: Patient Disposition

AE = adverse event; DB = double-blind; ITT = intention to treat; mITT = modified intention to treat; q.d. = once daily.

^aThe off-treatment hypothetical estimand population includes all randomized patients who received at least 1 dosage of study treatment, had evaluable baseline period data, and had at least 1 evaluable postbaseline 4-week period data during the DB treatment period and follow-up period, regardless of whether the patient was on or off study treatment. This population was used for the primary estimand in support of European Union filing.

Sources: ADVANCE Clinical Study Report,¹³ CGP-MD-01 Clinical Study Report,¹⁴ and ELEVATE Clinical Study Report.¹⁵

Table 13: Summary of Treatment Duration — Safety Population

q.d. = once daily; SD = standard deviation.

^aTreatment duration = (last study treatment date – first study treatment date) + 1.

^bn1 = Number of participants within a specific category.

^cParticipant-years = (total treatment duration in days) / 365.25.

Sources: ADVANCE Clinical Study Report,¹³ CGP-MD-01 Clinical Study Report,¹⁴ and ELEVATE Clinical Study Report.¹⁵

Subgroup analysis of the ELEVATE study is summarized by the number of prior oral prophylactic treatment failures in Table 38, and by migraine days at baseline in Table 39. Results by the number of oral prophylactic treatment failures were consistent with the primary analysis, with the LSM difference in mean change from baseline in MMDs between atogepant 60 mg once daily and placebo balanced across the number of prior prophylactic treatment failures (≥ 2 = ||||| |||| |||| || ||||| || ||||||| ≥ 3 = |||| |||| |||| || ||||| || |||||) in favour of atogepant, representing an LSM change from baseline at 12 weeks of ||||| |||| |||| |||||) for atogepant 60 mg once daily compared to |||| |||| |||| |||||| for placebo.¹⁵

For the subgroup analysis by migraine days at baseline, results were also consistent with the primary analysis, with LSM difference in mean change from baseline in MMDs between atogepant 60 mg once daily and placebo of (|||| |||| |||| || ||||| || |||||) for patients with 4 migraine days to fewer than 8 migraine days at baseline, and (||||| |||| |||| || ||||| || |||||) for patients with 8 or more migraine days at baseline.¹⁵

50% Reduction in MMDs

The proportion of patients who achieved a greater than or equal to 50% reduction in the 3-month average of MMDs was a secondary outcome in all studies. Results for a 50% reduction in mean MMDs are summarized in Table 15.

In the ADVANCE study, the OR for the proportion of patients who achieved a greater than or equal to 50% reduction in mean MMDs with atogepant versus placebo was 3.06 (95% CI, 2.05 to 4.56; P < 0.0001) for atogepant 10 mg, 3.53 (95% CI, 2.37 to 5.26; P < 0.0001) for atogepant 30 mg, and 3.82 (95% CI, 2.56 to 5.71; P < 0.0001) for atogepant 60 mg. A greater proportion of patients achieved a greater than or equal to 50% reduction in mean MMDs with atogepant (55.6%, 58.7%, and 60.8% for atogepant 10 mg, 30 mg, and 60 mg, respectively) compared to placebo (29.0%).¹³

In study CGP-MD-01, the OR for the proportion of patients who achieved a 50% or greater reduction in mean MMDs with atogepant versus placebo ranged from 1.42 (95% CI, 1.00 to 2.03) to 1.50 (95% CI, 0.98 to 2.31). The proportion of patients achieving a 50% reduction in mean MMDs in the atogepant groups was 57.6%, 53.3%, and 52.0% in the atogepant 10 mg, atogepant 30 mg, and atogepant 60 mg groups compared with 40.4% in the placebo group.¹⁴

In the ELEVATE study, the proportion of patients in the atogepant 60 mg once daily group versus the placebo group with a 50% or greater reduction in mean MMDs was ||||| || |||||| The OR for the proportion of patients who achieved a 50% or greater reduction in mean MMDs with atogepant 60 mg once daily over placebo was |||| |||| || |||| || ||||| in favour of atogepant. ¹⁵

Table 14: Change From Baseline in Mean Monthly Migraine Days — mITT Population

CI = confidence interval; LSM = least squares mean; mITT = modified intention to treat; MMD = monthly migraine day; MMRM = mixed model of repeated measures; q.d. = once daily; SD = standard deviation; SE = standard error; vs. = versus.

^aThe MMRM for change from baseline included baseline MMDs as a covariate; prior exposure to migraine prevention medications (yes or no), treatment group, and visit (month) as fixed factors; and treatment-group-by-visit and baseline-by-visit as interaction terms, with an unstructured covariance matrix. P values were from the test between the atogepant dose group and the placebo group.

^bThe model includes treatment group and visit as fixed effects, the baseline value as a covariate, and treatment-group-by-visit and baseline-by-visit as interaction terms, with an unstructured covariance matrix. P values are from the test between the atogepant dose group and the placebo group.

^cThe MMRM for change from baseline included baseline MMDs as a covariate; treatment group, visit (month), region, and number of classes of failed prior prophylactic treatments (2 and > 2) as fixed factors; and treatment-group-by-visit and baseline-by-visit as interaction terms, with an unstructured covariance matrix.

Sources: ADVANCE Clinical Study Report,¹³ CGP-MD-01 Clinical Study Report,¹⁴ and ELEVATE Clinical Study Report.¹⁵

Additional responder analysis: The proportions of participants who had a 25% or more, 75% or more, and 100% reduction (improvement) in the 3-month average of MMDs was an additional efficacy outcome in the ADVANCE and ELEVATE studies and is summarized in Table 40. In the ADVANCE trial, the proportion of patients with a 25% or more reduction in 3-month mean MMDs ranged from ||||| || ||||| in the atogepant groups compared with 58.9% in the placebo group. For a 75% or more reduction in MMDs, the proportion of patients ranged from ||||| || ||||| in the atogepant groups compared with 10.7% in the placebo group. The proportion of patients with 100% reductions in 3-month mean MMDs ranged from |||| || |||| in the atogepant groups compared with 0.9% in the placebo group.¹³

In study CGP-MD-01, a 25% or more reduction in MMDs were observed in ||||| || ||||| of patients in the atogepant groups compared to 50.8% of patients in the placebo group at week 1 to week 4, 73.4% to 79.1% for atogepant compared to 67.3% for placebo at week 5 to week 8, and ||||| || ||||| for atogepant compared to ||||| for placebo at week 9 to week 12. Reductions of 75% or more in MMDs were observed in ||||| || ||||| of patients in the atogepant groups compared to ||||| for placebo at week 1 to week 4, ||||| || ||||| for atogepant groups compared to 24.8% for placebo at week 5 to week 8, and ||||| || ||||| for atogepant groups compared to ||||| for placebo at week 9 to week 12. A 100% reduction in MMDs was observed in ||||| || ||||| of patients in the atogepant groups compared to |||| for placebo at week 1 to week 4; ||||| || ||||| for atogepant groups compared to |||| for placebo at week 5 to week 8; and ||||| || ||||| for atogepant groups compared to ||||| for placebo at week 9 to week 12.¹⁴

In the ELEVATE study, the OR for the difference between atogepant 60 mg once daily and placebo in the proportion of patients achieving 25% or more, 75% or more, and 100% reductions in the 3-month mean MMDs was |||| |||||| |||||, ||||| |||||| ||||||, and ||||| |||||| ||||||, respectively, with ||| |||||||, | |||||||, and | |||||| patients in the atogepant 60 mg once daily group compared to |||||||, |||||||, and | |||||| patients in the placebo group achieving 25%, 75%, and 100% reductions, respectively.¹⁵

Subgroup analysis: Subgroup analysis results for the ADVANCE study for the subgroup of patients with or without prior exposure to migraine prevention therapy are summarized in Table 43. Results for subgroup analyses for each of the response categories (≥ 50%, ≥ 75%, and 100%) were consistent with the primary analysis regardless of prior exposure to a migraine prevention medication with proven efficacy.¹³

Results for the unplanned subgroup analysis by the number of prior preventive treatment failures provided by the sponsor for 50% reduction in MMDs are summarized in Table 44. Among patients with 1 or more prior preventive treatment failures (N = |||), and 2 or more prior preventive treatment failures (N = |||), results were consistent with the primary analysis that atogepant was associated with a greater proportion of patients with a 50% reduction in mean MMDs | || ||||| || ||||| || |||||| || | ||||| || ||||| || ||||||.²⁶

Monthly Headache Days

The first secondary end point of the ADVANCE, CGP-MD-01, and ELEVATE studies was the change from baseline in mean MHDs across the 12-week treatment period, which is summarized in Table 16.

In the ADVANCE study, a dose-response relationship with each increasing atogepant dose was observed for the LSM change from baseline in MHDs across the 12-week treatment period: atogepant 10 mg was –3.94 days (||| || ||||| || |||||), atogepant 30 mg was –4.04 days (||| || ||||| || |||||), atogepant 60 mg was –4.23 days (||| || ||||| || |||||), and placebo was –2.52 days (||| || ||||| || |||||). Results for the observed mean change were consistent with the MMRM. All 3 doses of atogepant demonstrated statistically significant reductions in LSM difference in MHDs from baseline to 12 weeks, with the LSM difference versus placebo of –1.42 days (95% CI, –2.03 to –0.81 days; P < 0.0001) for atogepant 10 mg, –1.53 days (95% CI, –2.13 to –0.92 days; P < 0.0001) for atogepant 30 mg, and –1.71 days (95% CI, –2.32 to –1.10 days; P < 0.0001) for atogepant 60 mg.¹³

In study CGP-MD-01, the observed mean change from baseline in MHD ranged from ||||| |||| || ||||| days across the atogepant groups and ||||| days for placebo; however, no dose-related trend was evident in the responses. In all cases, decreases in LSM difference in MHDs during the treatment period were statistically significantly larger in all atogepant groups compared with placebo (atogepant 10 mg once daily = –1.38 days [95% CI, –2.23 to –0.54 days; P = 0.0014]; atogepant 30 mg once daily = –1.24 days [95% CI, –1.94 to –0.55 days; P = 0.0005]; and atogepant 60 mg once daily = –0.94 days [95% CI, –1.64 to –0.24 days; P = 0.0087]).¹⁴

In the ELEVATE trial, the LSM difference between atogepant 60 mg once daily and placebo was ||||| |||| |||| || ||||| || |||||| | | ||||||| in favour of atogepant. The LSM change from baseline was ||||| |||| |||| | ||||| || |||||| for atogepant 60 mg once daily compared to ||||| |||| |||| | ||||| || |||||| for placebo.¹⁵

Subgroup analysis: In the ADVANCE study, subgroup analyses based on prior exposure to migraine therapy are summarized in Table 41. Results were consistent with the primary analysis for all 3 atogepant groups compared to placebo in both the subgroup of patients who had prior exposure to migraine prevention medication with proven efficacy and the naive subgroup.¹³

Results for the unplanned subgroup analysis by number of prior preventive treatment failures provided by the sponsor for change from baseline in MHDs are summarized in Table 44. Among patients with 1 or more prior preventive treatment failures (N = |||), and 2 or more prior preventive treatment failures (N = |||), atogepant was associated with a greater change from baseline in MHDs compared with placebo |||| ||||| |||| ||||| || ||||| |||| ||||| || ||||| |||| |||||| | ||||| |||| ||||| || ||||| |||| ||||| || ||||| |||| |||||).¹³

Monthly Cumulative Headache Hours

Change from baseline in the mean monthly cumulative headache hours was an additional efficacy outcome of the ADVANCE, CGP-MD-01, and ELEVATE studies.

In the ADVANCE study, the LSM reduction from baseline in mean monthly cumulative headache hours across the 12-week treatment period was |||||| ||||| |||| | ||||||| ||||||| for atogepant 10 mg, |||||| ||||| |||| || ||||||| ||||||| for atogepant 30 mg, and |||||| ||||| |||| || ||||||| ||||||| for atogepant 60 mg, compared to |||||| ||||| |||| || ||||||| ||||||| for placebo. The LSM difference versus placebo was |||||| ||||| |||| | ||||||| ||||||| |||||| ||||| |||| || ||||||| ||||||| || |||||| ||||| |||| || ||||||| |||||| in favour of atogepant 10 mg, atogepant 30 mg, and atogepant 60 mg, respectively.¹³

Table 15: Reduction of 50% or More in 3-Month Average of Monthly Migraine Days — mITT Population

CI = confidence interval; mITT = modified intention to treat; OR = odds ratio; q.d. = once daily; vs. = versus.

^aThe OR (95% CI) and P value are based on logistic regression with treatment group, baseline value, and prior exposure (yes or no) to a migraine prevention medication with proven efficacy as explanatory variables.

^bAnalyses were based on a generalized linear mixed model of repeated measures. The model included treatment group and visit as fixed effects, the baseline value as a covariate, and treatment-group-by-visit and baseline-by-visit as interaction terms, with an unstructured covariance matrix. P values were from the test between the atogepant dose group and the placebo group.

^cFor the ELEVATE study, the OR (95% CI) and P value are based on logistic regression with treatment group, region, baseline monthly migraine days, and number of classes of failed prior prophylactic treatments (2 and > 2) as explanatory variables.

Sources: ADVANCE Clinical Study Report,¹³ CGP-MD-01 Clinical Study Report,¹⁴ and ELEVATE Clinical Study Report.¹⁵

In study CGP-MD-01, the change from baseline in the number of cumulative headache hours was measured in a time course manner from week 1 to week 4, week 5 to week 8, and week 9 to week 12. The LSM difference versus placebo in the number of cumulative headache hours ranged from |||||| ||||| |||| || |||||| |||||| || ||||| ||||| |||| | |||||| |||||| for week 1 to week 4, ||||| |||| | ||||||| |||||| || ||||| |||| || ||||||| ||||| in favour of atogepant for week 5 to week 8, and ||||| |||| ||||||| ||||| || ||||| |||| || ||||||| ||||| for week 9 to week 12.¹⁴

In the ELEVATE study, the LSM change from baseline in the number of cumulative headache hours across the 12-week treatment period was |||||| hours (||| || |||||| || ||||||) for atogepant 60 mg once daily compared to |||||| ||||| |||| || |||||| || ||||||. The LSM difference between atogepant and placebo was |||||| |||| || |||||| || |||||| in favour of atogepant.¹⁵

Monthly Moderate to Severe Headache Days

The mean reduction from baseline in mean monthly severe headache days was an additional efficacy outcome of the ADVANCE and CGP-MD-01 studies. In the ADVANCE study, the LSM difference versus placebo in change from baseline in mean monthly severe headache days was ||||| |||| |||| || |||||| |||||| for atogepant 10 mg, ||||| |||| |||| || |||||| |||||| for atogepant 30 mg, and ||||| |||| |||| || |||||| |||||| for atogepant 60 mg. The LSM difference versus placebo for change from baseline in moderate to severe headache days was ||||| |||| |||| || |||||| ||||||| ||||| |||| |||| || |||||| ||||||| || ||||| |||| |||| || |||||| |||||| for atogepant 10 mg, atogepant 30 mg, and atogepant 60 mg, respectively.¹³

In study CGP-MD-01, the change from baseline in the average headache day pain intensity, defined as the worst pain intensity participants reported on any headache day with a scale from 0 (no pain), 1 (mild), and 2 (moderate) to 3 (severe), was measured in a time course manner from week 1 to week 4, week 5 to week 8, and week 9 to week 12. The LSM difference for atogepant versus placebo in change from baseline in the average headache day pain intensity ranged from ||||| |||||| |||| || |||||| |||||| || ||||| |||||| |||| || |||||| |||||| for week 1 to week 4, ||||| |||||| |||| || |||||| |||||| || ||||| |||||| |||| || |||||| ||||| for week 5 to week 8, and ||||| |||||| |||| || ||||| ||||| || |||||| |||||| |||| | |||||| ||||| for week 9 to week 12.¹⁴

In the ELEVATE study, the LSM change from baseline in mean monthly severe headache days across the 12-week treatment period was ||||| |||| |||| || ||||| || |||||| for atogepant 60 mg once daily compared to ||||| |||| |||| || ||||| || |||||| for placebo. The LSM difference between atogepant and placebo was ||||| |||| || ||||| || |||||| in favour of atogepant.¹⁵

Health-Related Quality of Life

Migraine-Specific Quality-of-Life Questionnaire, Version 2.1

Change from baseline at week 12 for the MSQ version 2.1 role function-restrictive domain score was a secondary end point for the ADVANCE and ELEVATE studies and is summarized in Table 17. In the ADVANCE trial, at week 12, the LSM difference change from baseline versus placebo for the 3 atogepant treatment groups was 9.90 points (95% CI, 5.45 points to 14.36 points) for atogepant 10 mg, 10.08 points (95% CI, 5.71 points to 14.46 points) for atogepant 30 mg, and 10.80 points (95% CI, 6.42 points to 15.18 points) for atogepant 60 mg.¹³

Table 16: Change From Baseline in Mean Monthly Headache Days — mITT Population