CADTH Reimbursement Review

Risankizumab (Skyrizi)

Sponsor: AbbVie Corporation

Therapeutic area: Crohn disease

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

Crohn disease (CD) is a chronic form of inflammatory bowel disease (IBD) that can affect any part of the gastrointestinal (GI) tract, but commonly affects the ileum (i.e., small intestine), colon (i.e., beginning of the large intestine), and rectum. Common symptoms experienced by patients with CD include abdominal pain, rectal bleeding, fatigue, vomiting, diarrhea, perianal disease, weight loss, and bloating.^1,2 Complications associated with CD can include malnutrition, weight loss, anemia, bowel obstructions, fistulas, anal fissures, and intra-abdominal and other abscesses and ulcers.^1,3 In addition, patients with colonic CD have been shown to have an increased risk of developing colon cancer.¹ Smoking, a family history of IBD, infectious gastroenteritis, and frequent use of nonsteroidal anti-inflammatory drugs have been identified as risk factors.⁴ For many patients with CD, symptoms are chronic and intermittent, and disease activity and severity can vary widely over time. The predicted prevalence of CD in 2018 was 368 per 100,000 population, which translates to approximately 135,000 people in Canada living with CD.^5,6

Currently, there is no cure for CD. Therapeutic goals include inducing and maintaining clinical and endoscopic remission. Pharmaceutical treatments for CD include aminosalicylates, immunosuppressants, corticosteroids, tumour necrosis factor (TNF) alpha antagonists, interleukin (IL) inhibitors, and integrin inhibitors. Medical management is based on a stepwise approach, with treatments used sequentially and escalated to either newer therapies or higher doses as patients fail to respond to each step of treatment. Not all patients respond to available treatments and their disease may become refractory to the current treatment regimens.

Risankizumab (Skyrizi) is a humanized immunoglobulin G1 monoclonal antibody that binds to the p19 subunit of human interleukin-23 (IL-23) cytokine and inhibits IL-23 signalling, including the release of the proinflammatory cytokine interleukin-17 (IL-17).⁷ Risankizumab is indicated for the treatment of adults with moderately to severely active CD who have had an inadequate response, intolerance, or demonstrated dependence to corticosteroids; or an inadequate response, intolerance, or loss of response to immunomodulators or biologic therapies.⁷ The sponsor-submitted reimbursement criteria of risankizumab is the same as the Health Canada–approved indication. The recommended dose for CD is 600 mg IV infusion at week 0, week 4, and week 8 as induction therapy, followed by 360 mg subcutaneous (SC) injection at week 12 and every 8 weeks thereafter as maintenance therapy.⁷

The objective of this systematic review is to assess the beneficial and harmful effects of risankizumab (60 mg/mL) IV infusion as induction therapy and SC injection (150 mg/mL) as maintenance therapy for the treatment of adults with moderately to severely active CD who have an inadequate response, intolerance, or demonstrated dependence to corticosteroids; or an inadequate response, intolerance, or loss of response to immunomodulators or biologic therapies.

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 1 clinical expert consulted by CADTH for the purpose of this review.

Patient Input

Two patient groups, Crohn’s and Colitis Canada (CCC) and the Gastrointestinal (GI) Society, provided input for this review. CCC’s input was informed by its Impact of Inflammatory Bowel Disease in Canada 2018 report, a survey involving 687 respondents with moderate to severe CD, and interviews with 3 patients with CD who participated in the risankizumab clinical trial. The GI Society’s input was informed by 5 patient surveys involving more than 1,000 participants; interviews with 2 patients with CD who participated in the risankizumab trial; a focus group; a patient round table; phone, email, and social media interactions; and story submissions.

From the patients’ perspective, the inability to predict when the next urgent bowel movement would occur and the inability to control flare-ups had a significant negative impact on the personal and social lives of patients with CD. Both patient groups emphasized the importance of relieving symptoms, achieving remission, improving quality of life, minimizing chronic steroid use, and having access to a variety of effective treatment options.

Clinician Input

Input From Clinical Expert Consulted by CADTH

Unmet Needs

The clinical expert noted the following unmet needs of patients with CD: some patients do not respond to available treatments and some become refractory over time, access to biologic drugs is challenging or limited, and there is a lack of treatment options for fibrostenotic strictures and perianal or fistulizing CD.

The clinical expert noted that risankizumab is not expected to cause a shift in the treatment paradigm; they indicated it would be used in a similar fashion as other biologic treatments for CD, and likely prescribed alone or with a steroid taper or immunomodulator. The expert also noted that risankizumab could be used as first-line treatment or as a later treatment. However, the expert noted that due to a lack of data for fistulizing CD, these patients should try other treatments such as anti-TNF therapy before risankizumab.

The clinical expert commented that patients who are most in need are those with moderate to severe disease who have failed other biologic therapies, although those who are bionaive may have an even better response. Patients best suited should have an established diagnosis of CD based on an ileocolonoscopy with active disease.

The clinical expert noted that the following outcomes are used to determine patient response to treatment: clinical response and/or remission (e.g., improvement in symptoms such as pain, diarrhea), improvement in biomarkers, mucosal healing (e.g., endoscopic improvement), and improved health-related quality of life (HRQoL). The clinical expert noted that discontinuation of treatment should be based on primary or secondary loss of response, or adverse events (AEs) or symptoms that cannot be managed. It was noted by the expert that a gastroenterologist should be required to diagnose, treat, and monitor patients who might receive risankizumab, either in a community or hospital setting.

Clinician Group Input

One clinician group that provided input was the Pan-Canadian Inflammatory Bowel Disease Specialist Group, which consists of specialists in gastroenterology caring for patients with CD. Their input was informed by 16 specialists.

The clinician group noted that the goal of treatment should focus on improving clinical symptoms, endoscopic response, and endoscopic remission. The clinician group stated there is a lack of safe and effective treatments for rapidly improving endoscopic outcomes of CD and maintaining improvement in the long term. It was suggested that risankizumab be used in patients with moderate to severe CD as first-line therapy, as well as second-line therapy for patients experiencing flares or inadequate response to biologics. The clinician group indicated that risankizumab is not suitable for patients with perianal or fistulizing CD, severe peripheral arthritis, uveitis, or a concomitant immune-mediated disease.

The clinician group indicated that administration of risankizumab during the induction phase should occur in a clinic under the supervision of a gastroenterologist. For maintenance therapy, the clinician group indicated patients could self-administer SC injections after training. Aligning with the opinion of the clinical expert consulted by CADTH, the clinician group proposed the following outcomes to determine treatment response with risankizumab: improvements in symptoms (e.g., stool frequency [SF], abdominal pain), a reduction in biomarkers (e.g., C-reactive protein, fecal calprotectin) of inflammatory activity by 3 months of therapy, symptomatic remission, discontinuation of corticosteroids by 6 months of treatment, and improvements in HRQoL. The clinician group indicated risankizumab should be discontinued when symptoms worsen or when there is inadequate response. Drug program input was obtained from the drug programs that participate in the CADTH reimbursement review process. The following were identified as key factors that could potentially impact the implementation of a CADTH recommendation for risankizumab:

• consideration for the initiation of therapy

• consideration for the continuation or renewal of therapy

• consideration of the discontinuation of therapy

• care provision issues.

The clinical expert consulted by CADTH provided advice on the potential implementation issues raised by the drug programs.

Clinical Evidence

Pivotal Studies and Protocol Selected Studies

Description of Studies

Four phase III randomized controlled trials (RCTs) submitted by the sponsor were included in this systematic review: the M15-991 (MOTIVATE) induction study (N = 413), the M16-006 (ADVANCE) induction study (N = 559), the M16-000-substudy 1 (FORTIFY) maintenance substudy 1 (N = 363), and the M20-259 part 1 (SEQUENCE) induction and maintenance ongoing study, || |||. The objectives of the MOTIVATE, ADVANCE, and FORTIFY trials were to evaluate the efficacy and safety of risankizumab in patients with moderately to severely active CD who had an inadequate response, had a loss of response, or were intolerant to either conventional therapy (denoted as non-bio-IR) or biologic therapy (denoted as bio-IR). SEQUENCE aimed to evaluate the comparative efficacy and safety of risankizumab compared to ustekinumab in the same population. Both induction trials were of similar design, except the MOTIVATE study enrolled patients who were bio-IR, and the ADVANCE study enrolled patients who were bio-IR or non-bio-IR. In these 2 trials, eligible patients were randomized to receive risankizumab 600 mg IV administered at week 0, week 4, and week 8 or matching placebo, in a double-blind manner. Patients without clinical response to risankizumab at week 12 entered an additional exploratory open-label 12-week induction period (period 2) and were rerandomized to risankizumab 1,200 mg IV, risankizumab 360 mg SC, or risankizumab 180 mg SC. Clinical responders from the induction trials were eligible to enter the maintenance trial (FORTIFY), as were patients from induction period 2 who achieved clinical response at week 24. Patients who entered the maintenance study were rerandomized to receive blinded risankizumab 360 mg SC or matching placebo every 8 weeks for 52 weeks. The induction and maintenance trials included treatment groups (1,200 mg IV induction and 180 mg SC maintenance doses of risankizumab) that were not aligned with the Health Canada–approved dose; for this reason, these treatment groups were not included in this review. To meet regional regulatory requirements, all 3 trials included 2 protocols denoted as US and outside the US (OUS) that were identical in design but specified different coprimary and key ranked secondary outcomes. Clinical remission and endoscopic response were coprimary outcomes in both protocols; however, the definition of clinical remission in the US protocol was defined as Crohn’s Disease Activity Index (CDAI) score being less than 150, whereas in the OUS protocol, it was defined as SF and abdominal pain score (APS) (together, referred to as SF/APS) clinical remission (defined as average daily SF ≤ 2.8 and not worse than baseline and average daily APS ≤ 1 and not worse than baseline). Key secondary outcomes were similar in both protocols but ranked differently. These included clinical remission, clinical response, enhanced SF/APS clinical response and endoscopic response, endoscopic remission, ulcer-free endoscopy, corticosteroid-free clinical remission, the Functional Assessment of Chronic Illness Therapy–Fatigue (FACIT-F) score, the Inflammatory Bowel Disease Questionnaire (IBDQ) total score, the Short Form (36) Health Survey (SF-36) physical component summary (PCS) and mental component summary (MCS) scores, and safety outcomes.

In the SEQUENCE study, patients were randomized to receive blinded risankizumab 600 mg IV induction at week 0, week 4, and week 8, then risankizumab 360 mg SC maintenance at week 12 and every 8 weeks thereafter or ustekinumab weight-based IV induction dose at week 0 and then ustekinumab 90 mg SC maintenance every 8 weeks thereafter, over 48 weeks. In the SEQUENCE study, part 1, the primary objective was to assess the noninferior rate of clinical remission based on a prespecified interim data lock that was powered by approximately 50% of planned patients (n = 272) who completed their week 24 visit or were prematurely discontinued before week 24. Other exploratory outcomes included clinical response, endoscopic remission, mucosal healing, deep remission, biologic remission, SF-36 PCS and MCS scores, and IBDQ total score.

Patients in the trial populations were predominantly white (77% to 91%), with an approximate mean age of 40 years and a mean CD duration of approximately 8 years to 12 years. In the MOTIVATE study, approximately 48% and 52% of patients were bio-IR of 1 and greater than 1, respectively. In the ADVANCE study, 23% to 30% of patients were bio-IR, 28% to 32% of patients were bio-IR greater than 1, and 42% to 45% of patients were non-bio-IR. Between 29% and 36% of patients across treatment groups were on concomitant corticosteroids and about 19% to 28% of patients were on immunomodulators. In the maintenance trial (FORTIFY), patients’ baseline characteristics were generally comparable to those in the induction trials. In the SEQUENCE study, ||| || ||| || |||||||| ||| |||||| |||||||| ||||||| || |||| |||| || ||||| || | ||| ||| || ||| ||| |||||| ||||||| |||| |. All other key baseline characteristics were generally comparable to the other trials.

Efficacy Results

The key efficacy results from the MOTIVATE, ADVANCE, and FORTIFY studies are summarized in Table 2 and Table 3. The primary outcome for the SEQUENCE study is described in the text.

Clinical Remission

In both induction trials (MOTIVATE and ADVANCE), the coprimary outcome of clinical remission at week 12 for both the US and OUS protocols favoured risankizumab versus placebo. In the MOTIVATE US protocol, the adjusted between-group difference in the CDAI clinical remission rate with risankizumab versus placebo was 22.1% (95% confidence interval [CI], 13.1% to 31.0%; P < 0.001). For the OUS protocol, the adjusted between-group difference in the SF/APS clinical remission rate was 15.2% (95% CI, 6.4% to 24.0%; P = 0.001). In the ADVANCE US protocol, the adjusted between-group difference in the CDAI clinical remission rate with risankizumab versus placebo was 20.7% (95% CI, 12.4% to 29.0%; P < 0.001). For the OUS protocol, the adjusted between-group difference in SF/APS clinical remission was 21.9% (95% CI, 13.8% to 29.9%; P < 0.001). In both trials and protocols, all secondary ranked multiplicity-controlled outcomes — including SF and APS remission at week 12, CDAI clinical remission at week 4, and SF/APS clinical remission at week 4 — favoured risankizumab versus placebo. The results of subgroup analyses by bio-IR status were consistent with the main analysis. The findings were robust to sensitivity analyses using different methods to account for missing data.

In the maintenance trial (FORTIFY), the coprimary outcome of clinical remission at week 52 in both protocols favoured risankizumab versus placebo. For the US protocol, the adjusted between-group difference in the CDAI clinical remission rate with risankizumab was 14.6% (95% CI, 4.3% to 25.0%; P = 0.005). For the OUS protocol, the adjusted between-group difference in the SF/APS clinical remission rate was 15.2% (95% CI, 4.9% to 25.4%); P = 0.004). In both protocols, almost all secondary remission outcomes — including SF and APS remission, maintenance of SF/APS or CDAI clinical remission, SF/APS or CDAI clinical remission with endoscopic response, and SF/APS or CDAI deep remission — favoured risankizumab versus placebo. The evidence was too imprecise to show a difference for corticosteroid-free CDAI or SF/APS clinical remission. However, except for SF/APS clinical remission (US protocol), the secondary outcomes are at an increased risk of type I error (false-positive results) because they were tested after failure of the statistical hierarchy.

In the ongoing SEQUENCE trial, the primary outcome of CDAI clinical remission at week 24 in the intention-to-treat population, the primary efficacy analysis for the SEQUENCE study, part 1 (ITT1H), and the per-protocol population for the interim lock analysis ||||||| risankizumab versus ustekinumab. However, this was based on only ||| of the planned population and the findings are at risk of overestimating the efficacy of |||||||||||| |||||| |||||||||||, although the potential presence and magnitude of the overestimation is unclear.

Clinical Response

In both induction trials and protocols, all the secondary ranked multiplicity-controlled clinical response outcomes favoured risankizumab versus placebo. The between-group adjusted difference in CDAI clinical response at week 12 for risankizumab versus placebo was 23.1% (95% CI, 14.2% to 31.9%) in the ADVANCE study and 29.4% (95% CI, 19.9% to 39.0%) in the MOTIVATE study. The between-group adjusted difference for CDAI clinical response and endoscopic response combined at week 12 for risankizumab versus placebo was 24.5% (95% CI, 18.5% to 30.5%) in the ADVANCE study and 15.0% (95% CI, 8.5% to 21.5%) in the MOTIVATE study. Results of the sensitivity analysis for all outcomes were consistent with the primary analysis.

In the maintenance trial (FORTIFY), the secondary outcomes of CDAI clinical response and SF/APS enhanced clinical response at week 52 were not formally tested due to failure of the statistical hierarchy, although they were supportive of the primary outcomes.

Mucosal Healing and Endoscopic Response

In the induction trials, the coprimary outcome of endoscopic response and secondary outcomes of endoscopic remission and ulcer-free endoscopy at week 12 favoured risankizumab versus placebo. In the MOTIVATE study, the adjusted between-group difference in endoscopic response rate with risankizumab versus placebo was 17.7% (95% CI, 9.9% to 25.4%; P < 0.001). In the ADVANCE study, the adjusted between-group difference in endoscopic response rate was 28.3% (95% CI, 21.2% to 35.4%; P < 0.001). In both trials, results of the sensitivity analysis were consistent with the primary analysis.

In the maintenance trial (FORTIFY), the adjusted between-group difference in the coprimary outcome of endoscopic response at week 52 with risankizumab versus placebo was 27.8% (95% CI, 18.7% to 37.0%; P < 0.001). The ranked secondary outcomes of ulcer-free endoscopy and endoscopic remission were not formally tested due to failure of the statistical hierarchy, but were supportive of the primary outcomes.

Table 2: Summary of Key Results From Induction Trials MOTIVATE and ADVANCE

BL = baseline; CDAI = Crohn’s Disease Activity Index; CI = confidence interval; ITT1A = intention-to-treat population, the primary efficacy analysis for the MOTIVATE, ADVANCE, and FORTIFY studies; OUS = outside the US; SA1 = safety population; SAE = serious adverse event; SES-CD = Simple Endoscopic Score for Crohn’s Disease; SF/APS = stool frequency and abdominal pain score; TEAE = treatment-emergent adverse event; WDAE = withdrawal due to adverse event.

^aThe ITT1A population includes randomized patients in the intention-to-treat population who received at least 1 dose of the study drug during the 12-week induction period, received only one 12-week period of induction, and had a BL eligible SES-CD score of 6 or more (≥ 4 for isolated ileal disease).

^bAcross the strata, 95% CIs for adjusted difference and P value are calculated according to the Cochran-Mantel-Haenszel test adjusted for strata (number of biologics failed, baseline steroid use) for the comparison of the 2 treatment groups. Within each subgroup, 95% CIs for the difference are calculated using normal approximation to the binomial distribution. The calculations are based on nonresponder imputation incorporating multiple imputation to handle missing data due to COVID-19 or nonresponder imputation only if there are no missing data due to COVID-19. Testing was done according to the prespecified statistical hierarchy testing procedure.

^cThe SA1 population includes all patients who received at least 1 dose of the study drug.

Sources: MOTIVATE and ADVANCE Clinical Study Reports.^8,9

Table 3: Summary of Key Results From Maintenance Trial FORTIFY

CDAI = Crohn’s Disease Activity Index; CI = confidence interval; ITT1A = intention-to-treat population, the primary efficacy analysis for the MOTIVATE, ADVANCE, and FORTIFY studies; NRI = nonresponder imputation; OUS = outside the US; SA1 = safety population; SAE = serious adverse event; SC = subcutaneous; SES-CD = Simple Endoscopic Score for Crohn’s Disease; SF/APS = stool frequency and abdominal pain score; TEAE = treatment-emergent adverse event; WDAE = withdrawal due to adverse event.

^aThe ITT1A population includes the randomized patients in the intention-to-treat population who received IV risankizumab for only 1 period of 12 weeks in the induction study MOTIVATE or ADVANCE and at least 1 dose of the study drug in the FORTIFY trial and had eligible SES-CD of 6 or more (≥ 4 for isolated ileal disease) at the baseline of the induction study. Baseline was defined as the baseline visit of the induction study MOTIVATE or ADVANCE for efficacy analyses.

^bFor overall population, 95% CIs for adjusted difference and P value are calculated according to the Cochran-Mantel-Haenszel test adjusted for strata (endoscopic response at week 0 [yes or no], SF/APS clinical remission status at week 0 [yes or no], and last IV dose during the risankizumab induction period for the comparison of 2 treatment groups). The calculations are based on NRI incorporating multiple imputation to handle missing data due to COVID-19 or NRI only if there are no missing data due to COVID-19.

^cThe P value was not adjusted for multiple testing due to failure of the statistical hierarchy (i.e., the type I error rate was not controlled).

^dThe SA1 population includes all patients who received at least 1 dose of the study drug.

Sources: MOTIVATE, ADVANCE, and FORTIFY Clinical Study Reports.^8-10

Harms Results

Evidence from the pivotal trials showed induction therapy (600 mg IV) and maintenance therapy (360 mg SC) with risankizumab seemed generally safe and well tolerated. In the MOTIVATE study, treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), and AEs leading to study drug discontinuation were higher in the placebo group than in the risankizumab group, mainly due to worsening CD. In the ADVANCE induction study, TEAEs occurred with similar frequency in both treatment groups while SAEs and AEs leading to study drug discontinuation occurred with higher frequency in the placebo group. The most common TEAEs with risankizumab (> 2% of patients) during the 12-week induction period were headache, arthralgia, and nasopharyngitis, whereas with placebo, they were worsening CD, headache, and arthralgia. In both induction trials, the most frequently reported TEAE leading to study drug discontinuation was worsening CD. Two deaths were reported, both of which occurred in the ADVANCE study’s placebo group. In the maintenance trial (FORTIFY), TEAEs, SAEs, and AEs leading to discontinuation were similar between treatment groups and induction trials. Across the 3 trials, the incidence of notable harms in treatment groups was comparable and infrequent. In the SEQUENCE study, || |||||||| |||| ||||||| ||||||| |||||||||||| ||| |||||||||||| || |||||||| ||| ||||||||| || ||||||| ||||| || |||| ||||||||| |||||| |||| ||||||||| |||| |||| ||| |||| |||||| || |||| |||||| ||||| ||||||| |||||| |||||||||||||| ||||| |||||||||||| |||||| || |||||| |||| ||||||||.

Critical Appraisal

Internal Validity

The trials used appropriate methods of randomization and allocation concealment via interactive response technology. In general, baseline characteristics of patients appeared balanced between trial groups, indicating that randomization was successful.

There are some concerns related to risk of bias due to deviation from the intended interventions. This is primarily due to performing the analysis on the intention-to-treat population, the primary efficacy analysis for the MOTIVATE, ADVANCE, and FORTIFY studies (ITT1A); this population included randomized patients who received at least 1 dose of the study drug. As this was not a true intention-to-treat (ITT) population, some concerns for bias were introduced in the ADVANCE and MOTIVATE trials (about 10% of patients were not included), and a high risk of potential bias may have been present for the FORTIFY trial (21% of the risankizumab group and 11% of the placebo group were not included). The magnitude and direction of the potential bias cannot be predicted.

For most outcomes, there was minimal concern for missing outcome data. In the induction trials, there was a higher number of discontinuations of the study drug in the placebo groups (10% in the MOTIVATE study and 12% in the ADVANCE study) compared to the risankizumab groups (2% in both the MOTIVATE and ADVANCE studies). In the maintenance trial, discontinuations were similar and just over 10% across groups. For the primary outcomes, acceptable methods were used to impute missing data, and the findings were robust to sensitivity analyses using different methods to account for missing data. There is concern for bias due to large and imbalanced amounts of missing data for the HRQoL and fatigue outcomes, particularly at the 12-week time point. The direction and magnitude of the potential bias is unclear.

Across all trials, most outcomes were subjective (e.g., SF/APS or CDAI clinical remission or response, FACIT-F, IBDQ, SF-36) and collected from patient diaries, except for endoscopic outcomes, which were read centrally by a blinded reviewer. Although the subjective outcomes are prone to risk of bias, the double-blind design of the trials mitigated this risk. There is some risk of unblinding that could have affected the subjective outcomes since dropout rates were higher in the placebo groups, which could allow investigators and patients to make inferences on treatment assignment regardless of blinding. However, the extent of the potential bias is unclear.

Statistical analyses in the 3 trials were prespecified. A hierarchical testing procedure was appropriately used in all 3 trials to account for multiplicity in coprimary and key secondary outcomes. The exploratory outcomes of Crohn’s Symptom Severity (CSS) and 5-Level EQ-5D (EQ-5D-5L) were not adjusted for multiplicity, which limited the ability to draw conclusions regarding these outcomes. In the FORTIFY study, early failure of the statistical hierarchy precluded formal statistical testing of most secondary outcomes. This lack of adjustment for multiplicity may have increased the likelihood of type I error and as such, P values for these outcomes should be considered supportive and not meant as a basis for drawing conclusions.

In the ongoing SEQUENCE trial, there were 2 key limitations with the interim results that are at risk of overestimating the treatment effect in |||||| || ||||||||||||, although the potential presence and magnitude of the overestimation is unclear. There was a considerable amount of missing data for all outcomes since this was an interim analysis where only 50% of patients had reached the time point of interest. There was also bias in the selection of reported results, as the statistical analyses presented for all exploratory outcomes were not described in the statistical analysis plan. The analysis plan only aimed to describe the outcomes descriptively. Because of these limitations, the interim results cannot support definitive conclusions about the efficacy of risankizumab compared to ustekinumab.

External Validity

According to the clinical expert consulted by CADTH, the inclusion and exclusion criteria of the pivotal trials were generally aligned with selection criteria that would be adopted by most clinicians in Canada when identifying suitable candidates for risankizumab. The relative efficacy of risankizumab to other active treatments was not known, given the trial data available. In the MOTIVATE, ADVANCE, and FORTIFY studies, placebo was the comparator while in the SEQUENCE study, ustekinumab was the comparator. Since ustekinumab is not used frequently in Canada, it’s not considered as the most relevant active treatment. The trials included outcomes that were important to patients and clinicians. All outcomes were considered appropriate by the clinical expert, although the Harvey-Bradshaw Index was noted as a more commonly used tool to assess clinical remission in patients with CD in Canada. The clinical expert noted that the time frames used in the trials were appropriate to determine short-term treatment effects with risankizumab; however, they may not be considered sufficient to fully understand the long-term safety for rare events and those that take longer to develop, such as malignancy.

Indirect Comparisons

Description of Studies

The sponsor-submitted indirect treatment comparison (ITC) was a network meta-analysis (NMA)¹¹ assessing the efficacy and safety of risankizumab relative to vedolizumab, ustekinumab, adalimumab, infliximab, and placebo in patients diagnosed with moderately to severely active CD.

The 2 published ITCs identified from the CADTH literature search^12,13 were also NMAs. Barberio et al. evaluated the efficacy of all biologic therapies and small molecules that have been investigated in phase III clinical trials in luminal CD, compared to placebo or each other. Singh et al. determined the relative efficacy and safety of infliximab, adalimumab, certolizumab pegol, vedolizumab, ustekinumab, and risankizumab (either alone or in combination with immunosuppressants) for the treatment of moderate to severe CD in patients with or without previous biologic exposure.

Efficacy and Harms Results

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

As for the NMA conducted by Barberio et al., in the induction phase, both patients naive to biologic therapies and patients exposed to biologic therapies previously who were treated with risankizumab had a lower risk of failing to achieve clinical remission or clinical response compared to placebo and some of the active treatments (e.g., ustekinumab, adalimumab). During the maintenance phase, in most cases the effect estimates were too imprecise to draw conclusions about the efficacy of risankizumab versus placebo or any other active treatments in patients naive to biologic therapies or those exposed to biologic therapies previously. With respect to harms outcomes, the evidence was insufficient to show a difference between risankizumab 600 mg IV versus placebo or other active treatments in the incidence of any AEs or any infection at the induction phase.

As for the NMA conducted by Singh et al., patients naive to biologic therapies and patients with previous biologic exposure who were treated with risankizumab were more likely to achieve clinical remission or clinical response compared to placebo in the induction phase. Risankizumab was also superior to vedolizumab in achieving clinical remission in patients with previous biologic exposure in the induction phase. The effect estimates for efficacy outcomes in the maintenance phase were too imprecise to draw conclusions about the comparison of risankizumab versus placebo or any active treatment. No NMA comparative estimates for harms outcomes were available for risankizumab because they were not connected in the evidence networks.

Critical Appraisal

There were several notable sources of heterogeneity across RCTs included in the sponsor-submitted NMA (e.g., differences in patient characteristics, differences in disease duration in the ||| |||||||||||, differences in the time at which primary outcomes across individual induction trials were accessed). These increase uncertainty in the effect estimates because it is likely that the assumption of exchangeability was violated. The causes of heterogeneity were not explored ||| ||||||||||||| |||||||| |||||||| || ||||||||||||||| || ||| ||||||||||||||||| ||||||. In addition, ||||||||| ||||||||| || ||| ||||| ||||||| |||| ||||| || ||| |||, which does not incorporate heterogeneity across included studies and implied that heterogeneity across included trials had no impact on the magnitude of effect, might yield biased NMA estimates given the notable heterogeneity. Many of the estimates of treatment effects were affected by imprecision. Finally, ||| |||| || |||| |||||||||| || ||| |||||||||| ||||| ||||| ||| ||| ||||||||| |||||| on the internal validity of the NMA effect estimates at the outcome level were not explicitly discussed in the sponsor-submitted NMA.

Given the overlap in the included studies, the potential sources of heterogeneity across included studies are likely to be similar between the sponsor-submitted NMA and the 2 published NMAs identified from the CADTH literature search (i.e., Barberio et al. and Singh et al.). However, neither of the 2 published NMAs adequately discussed or accounted for the heterogeneity issue. Therefore, there was considerable uncertainty in the effect estimates from both studies, and no definitive conclusions could be made.

Other Relevant Evidence

No other relevant evidence was submitted by the sponsor or identified from the literature.

Conclusions

Evidence from 3 double-blind randomized trials (MOTIVATE, ADVANCE, and FORTIFY) showed that compared to placebo, treatment with risankizumab resulted in clinically important improvements in clinical remission and endoscopic response at a 12-week induction period (600 mg IV) and a 52-week maintenance period (360 mg SC) in adults with moderate to severe CD who had inadequate response or were intolerant to prior conventional or biologic therapies. These results addressed key treatment outcomes noted as important by both patients and clinicians. The clinical expert consulted by CADTH considered the benefits of risankizumab on clinical remission and endoscopic response, as well as the resolution of clinical symptoms (e.g., SF and APS remission) and disease activity (e.g., CDAI clinical response), and reductions in endoscopic inflammation (e.g., endoscopic remission, ulcer-free endoscopy) to be clinically meaningful. In the maintenance trial, the secondary outcomes were generally supportive of the induction trials; however, there is some risk of false-positive conclusions due to the outcomes being tested outside the statistical testing hierarchy and/or after failure. In the induction trials, risankizumab treatment was also associated with improvement in HRQoL outcomes that met most identified minimal important differences (MIDs); however, these findings were affected by bias and the CIs include the potential for effects that are not clinically important. The evidence was insufficient to show a difference for change in HRQoL compared to placebo in the maintenance trial. In general, risankizumab seemed safe and well tolerated compared to placebo, but long-term data are needed to further evaluate its efficacy and safety profile. Due to limitations of the preliminary data from the SEQUENCE trial comparing risankizumab to ustekinumab and ITCs, no firm conclusions can be drawn on the relative efficacy and safety of risankizumab compared to other active treatments.

Introduction

Disease Background

CD is a chronic form of IBD that can affect any part of the GI tract, but most commonly affects the ileum (i.e., small intestine), colon (i.e., beginning of the large intestine), and rectum. CD has 3 phenotypes: inflammatory, stricturing, and penetrating (fistulas and abscesses).¹⁴ Common symptoms of CD include abdominal pain, rectal bleeding, fatigue, vomiting, diarrhea, perianal disease, weight loss, and bloating.^1,2 Inflammation associated with CD can also manifest outside the GI tract, affecting the joints, eyes, and skin.¹⁵ Complications associated with CD can include malnutrition, weight loss, anemia, bowel obstructions, fistulas, anal fissures, and intra-abdominal and other abscesses and ulcers.^1,3 In addition, patients with colonic CD have an increased risk of developing colon cancer.¹ Smoking, a family history of IBD, infectious gastroenteritis, and frequent use of nonsteroidal anti-inflammatory drugs have been identified as risk factors for CD.⁴

The diagnosis of CD is based on a combination of clinical evaluation and endoscopic, histological, radiological, and/or biochemical investigations.⁴ An ileocolonoscopy with multiple biopsy specimens is the first-line procedure for diagnosing CD.⁴ The endoscopic hallmark of CD is the patchy distribution of inflammation, with skip lesions, defined as areas of inflammation interposed between normal-appearing mucosa.⁴ Cross-sectional imaging using MRIs and CT enterography and transabdominal ultrasonography are complementary to endoscopy and offer the opportunity to detect and stage inflammatory, obstructive, and fistulizing CD.⁴ The classification of disease severity in CD suggested by the American College of Gastroenterology is provided in Table 4.

For many patients with CD, symptoms are chronic and intermittent, and disease activity and severity can vary widely over time. Some patients may have a continuous and progressive course of active disease, while approximately 20% of patients experience prolonged remission after initial presentation.¹⁵ For patients in remission, relapse rates at 1 year, 2 years, 5 years, and 10 years are estimated at 20%, 40%, 67%, and 76%, respectively.¹⁶ Based on patient group input for this review, CD has a profound effect on physical, emotional, and social well-being.

According to the Canadian Gastro-Intestinal Epidemiology Consortium, the predicted prevalence of CD in 2018 was 368 per 100,000 population, which translates to approximately 135,000 people in Canada living with CD.^5,6 Age groups most likely to be diagnosed with CD are adolescents and those between the ages of 20 years and 30 years.¹

Standards of Therapy

The selection of treatment regimens for CD is based on location, extent, phenotype, and severity of disease.³ According to the clinical expert consulted by CADTH, the therapeutic goals of CD treatment are to induce and maintain clinical remission and reduce the need for long-term corticosteroid use while minimizing side effects. Long-term goals include endoscopic healing, the absence of disability, and the normalizing of HRQoL. Short to intermediate goals include normalizing biomarkers of disease activity (e.g., C-reactive protein, fecal calprotectin). These goals described by the clinical expert are consistent with Canadian and American published clinical practice guidelines.^14,18 Several drug classes are used in the treatment of CD, including aminosalicylates, immunosuppressants (e.g., azathioprine, cyclosporine, methotrexate, 6-mercaptopurine), corticosteroids (e.g., prednisone), TNF alpha antagonists (e.g., infliximab, adalimumab), IL inhibitors, and integrin inhibitors (e.g., vedolizumab).^3,19 With the exception of the TNF alpha antagonists, IL inhibitors, and vedolizumab, all are commonly referred to as conventional therapies. Medical management is based on a stepwise approach, with treatments used sequentially and escalating to either newer therapies or higher doses as patients fail to respond to each step of treatment.²⁰ Most drugs have important adverse effects that may have short-term or long-term consequences.^1,19 Surgery, including total colectomy and ileostomy, may be considered for patients with serious complications or for those who do not respond to medical management.³

The clinical expert consulted by CADTH noted the following unmet needs for patients with CD: not all patients respond to available treatments and their disease may become refractory to the current treatment regimens; to gain access to biologics, patients need to first be refractory to, or have side effects from, less expensive approved medications and assume the risks of these medications (e.g., corticosteroids, immunomodulators); treatment options for perianal or fistulizing CD are lacking; overall response and remission rates in clinical trials are not very high; and medications mostly target moderate to severe CD.

Drug

Risankizumab (Skyrizi) is a humanized immunoglobulin G1 monoclonal antibody that binds to the p19 subunit of human IL-23 cytokine and inhibits IL-23 signalling, including the release of the proinflammatory cytokine IL-17.⁷

Risankizumab has been approved by Health Canada for the treatment of adults with moderately to severely active CD who have had an inadequate response, intolerance, or demonstrated dependence to corticosteroids, or an inadequate response, intolerance, or loss of response to immunomodulators or biologic therapies.⁷ The sponsor-submitted reimbursement request for risankizumab is the same as the Health Canada indication. Risankizumab has been previously approved by Health Canada for the treatment of adult patients with plaque psoriasis,⁷ and was reviewed by CADTH for this indication.

The recommended dose for CD is 600 mg IV infusion at week 0, week 4, and week 8 as induction therapy, followed by 360 mg SC injection at week 12 and every 8 weeks thereafter as maintenance therapy.⁷ Key characteristics of risankizumab and commonly used medical treatments for CD are presented in Table 5.

Table 5: Key Characteristics of Risankizumab, Ustekinumab, Vedolizumab, Infliximab, and Adalimumab

CD = Crohn disease; CS = corticosteroid; IgG1 = immunoglobin G1; IL-12 = interleukin-12; IL-17 = interleukin-17; IL-23 = interleukin-23; q.2.w. = every 2 weeks; q.8.w. = every 8 weeks; q.12.w. = every 12 weeks; SC = subcutaneous; TNF = tumour necrosis factor.

^aHealth Canada indication.

Sources: Product monographs of risankizumab (Skyrizi),⁷ vedolizumab (Entyvio),²¹ infliximab (Remicade and Inflectra),^22,23 adalimumab (Humira),²⁴ and ustekinumab (Stelara).²⁵

Stakeholder Perspectives

Patient Group Input

This section was prepared by CADTH staff based on the input provided by patient groups. The full original patient input received by CADTH has been included in the stakeholder section at the end of this report.

Two patient groups, CCC and the GI Society, provided input for this review. The CCC gathered the information from a report published in 2018 (Impact of Inflammatory Bowel Disease in Canada), a 2022 survey involving 687 respondents with moderate to severe CD, and interviews with 3 patients with CD who participated in a risankizumab clinical trial. The patient input provided by the GI Society was based on surveys and interviews, including a 2015 survey on biologics and biosimilars involving 423 patients with IBD living in Canada; a 2018 survey on unmet needs involving 432 patients with IBD living in Canada; a 2020 survey on the unmet needs of IBD involving 579 respondents; a 2020 survey on biosimilars completed by 145 respondents (most of whom had IBD); a 2022 survey on the IBD patient journey completed by 54 patients with IBD living in Canada; interviews with 2 patients with CD who participated in the risankizumab trial; a 2022 focus group with patients with CD; as well as 1-on-1 conversations with patients with IBD; a patient round table; phone, email, and social media interactions; and story submissions.

Both the CCC and GI Society agreed that being unable to predict when the next urgent bowel movement would occur and the inability to control the flare had a significant negative impact on the personal and social lives of patients with CD. The CCC found that 6 in 10 respondents felt isolated because of having CD.

In terms of experiences with currently available treatments, the CCC stated that there were fewer treatment options available for patients with CD in Canada than in other Western countries, and 6 in 10 respondents feared that their treatment options were running out. Respondents were also expecting more effective treatments to manage their CD. More than 7 out of 10 respondents from the CCC input experienced diarrhea, bloating, and an unpredictable feeling of urgency to use the washroom at least some days, despite being on treatments. In a survey carried out by the GI Society, about 56% of IBD patients thought that the available medications were only somewhat adequate and 20% of IBD patients felt they were not at all adequate.

In terms of experiences with risankizumab, 5 patients with CD who participated in a risankizumab clinical trial valued its effectiveness for relieving symptoms. Furthermore, 3 favoured risankizumab for its convenience, ease of administration, and lack of side effects.

Symptom relief or remission and a subsequent improvement in quality of life were perceived by patients as being important. Specifically, 8 in 10 patients from the CCC input listed unpredictable and frequent bowel movements, pain, and fatigue as the most important factors in CD management. Taking fewer medications and minimizing chronic steroid use were also rated by the respondents from the CCC as important aspects of treatment options.

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 CD.

Unmet Needs

The clinical expert noted unmet needs of patients with CD include that not all patients respond to available treatments and patients become refractory to available treatments. The clinical expert highlighted that overall response and remission rates are not very high. The clinical expert reported that to gain access to biologics, patients need to first be refractory to or experience side effects from less expensive medications and assume the risks of these medications (e.g., corticosteroids, immunomodulators). In addition, the clinical expert noted that there are unmet needs in the treatment of fibrostenotic strictures as medications generally target inflammation, not fibrosis, and treatment options for perianal or fistulizing CD. Lastly, medications in clinical trials mostly target moderate to severe disease.

Place in Therapy

The clinical expert noted that risankizumab is not expected to cause a shift in the treatment paradigm; it would be used in a similar manner to other biologic treatments for CD. Risankizumab is a monoclonal antibody against IL-23; similar to other biologics, it targets the underlying disease process and not just symptoms. Ustekinumab similarly blocks interleukin-12 as well as IL-23 through the shared p40 subunit. IL-23 is a key regulator in the inflammatory pathway in CD. The mechanism of action of risankizumab would likely be similar to ustekinumab. Risankizumab would likely be prescribed alone or with a steroid taper or immunomodulator. The clinical expert believed that further studies are needed to assess if risankizumab would be beneficial in combination with other biologics or for use specifically in fistulizing disease.

The clinical expert also noted that, in their opinion, this medication could be used as first-line treatment or as a later treatment; it would not need to be reserved for those who are intolerant or have contraindications for other biologics. For moderate to severe CD, the clinical expert indicated that patients would not need to try other biologic treatments first. However, due to a lack of data for fistulizing CD, the clinical expert believed that patients with fistulizing CD should try other treatments (namely anti-TNF) before risankizumab.

Patient Population

The clinical expert noted that patients who are most likely to respond to risankizumab are those with moderate to severe luminal CD, and patients who are in most need are those with moderate to severe disease who have failed other biologic therapies, although those who are bionaive may have an even better response. The clinical expert highlighted that patients best suited for treatment with risankizumab would be those who have an established diagnosis of CD based on an ileocolonoscopy with active disease (misdiagnosis is uncommon).

The clinical expert indicated that in their clinical opinion, earlier treatment with biologics may reduce cost, surgery, and hospitalization.

Assessing Response to Treatment

The clinical expert noted the following outcomes are used to determine response to treatment:

• clinical response and/or remission (i.e., improvement in symptoms such as pain, diarrhea, and extraintestinal complications)

• improvement in biomarkers (e.g., C-reactive protein, fecal calprotectin)

• mucosal healing (e.g., endoscopic improvement)

• improved HRQoL.

Discontinuing Treatment

The clinical expert noted that discontinuation of treatment should be based on primary or secondary loss of response, and AEs or symptoms that cannot be managed.

Prescribing Conditions

The clinical expert noted that a specialist (i.e., gastroenterologist) should be required to diagnose, treat, and monitor patients who might receive risankizumab, either in a community or hospital setting.

Clinician Group Input

This section was prepared by CADTH staff based on the input provided by clinician groups. The full original clinician group input received by CADTH has been included in the stakeholder section at the end of this report.

The clinician group input was provided by the Pan-Canadian Inflammatory Bowel Disease Specialist Group, which consists of specialists in gastroenterology from across Canada caring for patients with CD. The clinician group input was based on a discussion held by the Pan-Canadian Inflammatory Bowel Disease Specialist Group involving 16 experts in September 2022. The group reviewed the safety and efficacy data from the risankizumab trial, described the CD burden in Canada, and discussed the unmet treatment needs of CD, and how access to risankizumab could benefit patients and society in the short term and long term.

In addition to relieving clinical symptoms, the clinician group emphasized that the goal of treatment should focus on improvements in endoscopic response, endoscopic remission, and mucosal healing. However, the group stated that such a goal might not be achievable in most patients due to a lack of safe and effective treatments that could rapidly improve endoscopic appearance and maintain improvement in the long term. The group claimed that there is a high rate of surgery and postoperative recurrence in CD despite current available treatment options, such as corticosteroids, immunomodulators, and biologics.

The clinician group recognized and valued the potential of risankizumab to improve both clinical and endoscopic outcomes in patients with CD. They suggested the use of risankizumab in patients with moderate to severe CD as the first-line biologic, as well as in patients still experiencing flares or inadequate response on other existing biologics as a second-line drug. Furthermore, the use of risankizumab was considered not suitable by the clinician group for patients with perianal or fistulizing CD, severe peripheral arthritis, uveitis, or a concomitant immune-mediated disease for which an anti-TNF biologic drug would be more suitable.

The clinician group indicated that the administration of risankizumab during the induction phase should occur in a clinic under the supervision of a gastroenterologist. For maintenance therapy, patients could self-administer the on-body injector after receiving training. Aligning with the opinion of the clinical expert consulted by CADTH, the clinician group proposed several outcomes with which to determine the efficacy of risankizumab in patients with CD, including improvements in symptoms (e.g., SF, abdominal pain), accompanied by a decrease in biomarkers of inflammatory activity (e.g., C-reactive protein, fecal calprotectin) by 3 months of therapy, as well as symptomatic remission and being off corticosteroids by 6 months of treatment. In addition, the group highlighted that HRQoL should also be taken into consideration. If there is a worsening of symptoms or an inadequate response, risankizumab should be discontinued as per the clinician group.

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 6.

Table 6: Summary of Drug Plan Input and Clinical Expert Response

AE = adverse event; APS = abdominal pain score; CD = Crohn disease; CDAI = Crohn’s Disease Activity Index; CDEC = CADTH Canadian Drug Expert Committee; CRP = C-reactive protein; ESR = erythrocyte sedimentation rate; FCP = fecal calprotectin; GI = gastroenterologist; HBI = Harvey-Bradshaw Index; LOR = loss of response; OUS = outside the US; PLA = product listing agreement; PM = product monograph; PSP = patient support program; SC = subcutaneous; SES-CD = Simple Endoscopic Score for Crohn’s Disease; SF = stool frequency; SF/APS = stool frequency and abdominal pain score; TNF = tumour necrosis factor; UC = ulcerative colitis; vs. = versus.

^aSkyrizi Clinical Evidence Summary (page 47).³²

Clinical Evidence

The clinical evidence included in the review of risankizumab is presented in 2 sections. The first section, the systematic review, includes the pivotal studies provided in the sponsor’s submission to CADTH and Health Canada, as well studies selected according to an a priori protocol. The second section includes indirect evidence from the sponsor and indirect evidence from the literature that met the selection criteria specified in the review. No additional relevant studies were identified 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 risankizumab (60 mg/mL) IV infusion (induction) and SC injection (maintenance) for the treatment of adults with moderately to severely active CD who have an inadequate response, intolerance, or demonstrated dependence to corticosteroids, or an inadequate response, intolerance, or loss of response to immunomodulators or biologic therapies.

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 7. Outcomes included in the CADTH review protocol reflect outcomes considered to be important to patients, clinicians, and drug plans.

Table 7: Inclusion Criteria for the Systematic Review

AE = adverse event; CDAI = Crohn’s Disease Activity Index; HRQoL = health-related quality of life; RCT = randomized controlled trial; SAE = serious adverse event; vs. = versus; 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.²⁶

Published literature was identified by searching the following bibliographic databases: MEDLINE All (1946–) via Ovid and Embase (1974–) 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 risankizumab and its synonyms. Clinical trials registries were searched: the US National Institutes of Health’s ClinicalTrials.gov, the WHO’s 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 November 23, 2022. Regular alerts updated the search until the meeting of the CADTH Canadian Drug Expert Committee on March 22, 2022.

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.²⁷ 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. These searches were supplemented by reviewing bibliographies of key papers and through contacts with appropriate experts.

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 7 reports of 4 studies were identified from the literature for inclusion in the systematic review (Figure 1). The included studies are summarized in Table 8.

Figure 1: Flow Diagram for Inclusion and Exclusion of Studies

Table 8: Details of Included Studies

APS = abdominal pain score; BL = baseline; CD = Crohn disease; CDAI = Crohn Disease’s Activity Index; CSS = Crohn’s Symptom Severity; DB = double-blind; EIM = extraintestinal manifestation; EQ-5D-5L = 5-Level EQ-5D; FACIT-F = Functional Assessment of Chronic Illness Therapy–Fatigue; HRQoL = health-related quality of life; IBDQ = Inflammatory Bowel Disease Questionnaire; NR = not reported; OUS = outside the US; PCS = physical component summary; RCT = randomized controlled trial; SC = subcutaneous; SES-CD = Simple Endoscopic Score for Crohn’s Disease; SF = stool frequency; SF-36 = Short Form (36) Health Survey; SF/APS = stool frequency and abdominal pain score; TNF = tumour necrosis factor; UC = ulcerative colitis; vs. = versus; WPAI:CD = Work Productivity and Activity Impairment Questionnaire in Crohn’s Disease.

^aPart 1 is a phase IIIb, multicentre, randomized, efficacy assessor-blinded, parallel-group trial designed to compare the efficacy and safety of risankizumab vs. ustekinumab over 48 weeks in adult patients with moderate to severe CD who have failed anti-TNF therapy. Part 2 of the SEQUENCE study is an open-label long-term extension to evaluate the long-term safety of risankizumab for up to 220 weeks in patients who received risankizumab during part 1 and completed the week 48 visit. Data from patients enrolled before or on January 5, 2022, in part 1 of the SEQUENCE study are available, whereas part 2 is currently unavailable.

^bTo meet regional regulatory requirements, the MOTIVATE, ADVANCE, and FORTIFY studies included 2 protocols (i.e., US and OUS) that were identical in design but specified different coprimary and key secondary outcomes. Secondary outcomes in the US and OUS protocols were similar, focusing on improvements in signs and symptoms of CD, HRQoL, and the healing of the gastrointestinal mucosa.

Sources: MOTIVATE, ADVANCE, FORTIFY, and SEQUENCE Clinical Study Reports.^8-10,31

Description of Studies

Studies MOTIVATE,⁸ ADVANCE,⁹ FORTIFY part 1,¹⁰ and SEQUENCE part 1³¹ are pivotal trials submitted by the sponsor.

MOTIVATE and ADVANCE were both multicentre, randomized, double-blind, placebo-controlled, 12-week, phase III induction trials that aimed to assess the efficacy and safety of risankizumab in adult patients with moderately to severely active CD. Both trials were of similar design, except the MOTIVATE trial enrolled patients who were denoted as bio-IR, whereas the ADVANCE trial enrolled patients who were denoted as non-bio-IR or bio-IR. Clinical responders from the MOTIVATE and ADVANCE studies were eligible to enrol in FORTIFY substudy 1, a multicentre, randomized, placebo-controlled, 52-week, phase III maintenance trial that aimed to evaluate the efficacy and safety of continued risankizumab use versus the withdrawal of risankizumab (i.e., switched to placebo) in patients with moderately to severely active CD. Patients completing the FORTIFY study were eligible to continue in an open-label extension phase that is currently ongoing and not included in this review. The SEQUENCE study is an ongoing, multicentre, randomized, efficacy assessor-blinded, 48-week parallel-group, phase III trial designed to compare the efficacy and safety of risankizumab versus ustekinumab in adult patients with moderate to severe CD who have failed anti-TNF therapy. Only results for the SEQUENCE study, part 1, are included in this review, which consists of an interim data lock that was predetermined to occur when approximately 50% of patients in the risankizumab group had reached week 24 or discontinued the study. Part 2 is an open-label extension to evaluate the long-term safety of risankizumab for up to 220 weeks in patients who received risankizumab during part 1 and completed the week 48 visit. The SEQUENCE study is scheduled to be completed by September 2023.

MOTIVATE and ADVANCE (Induction Studies)

The primary objective of both the MOTIVATE and ADVANCE study was to assess the efficacy and safety of IV risankizumab 600 mg administered at week 0, week 4, and week 8 versus IV placebo as induction therapy in adult patients with moderately to severely active CD (Figure 2). The MOTIVATE trial enrolled patients who were bio-IR, meaning they had inadequate response or intolerance to 1 or more biologic drugs including infliximab, adalimumab, certolizumab, natalizumab, vedolizumab, and ustekinumab (the percentage of patients with exposure to ustekinumab capped at 20% of the study population). The ADVANCE trial enrolled patients who were bio-IR as described in MOTIVATE or were non-bio-IR, meaning they had an inadequate response or were intolerant to conventional therapy including budesonide, beclomethasone, systemic corticosteroids, or immunomodulators, but not to biologic therapy. Each trial included a screening period of up to 35 days, a 12-week induction period (induction period 1), an additional exploratory blinded 12-week prolonged induction period (induction period 2) for patients who did not achieve clinical response at week 12, and a 140-day follow-up period for patients who did not continue in the FORTIFY maintenance trial. Clinical evaluations occurred at baseline and at week 4, week 8, and week 12, or at premature discontinuation. Both trials included treatment groups not aligned with the Health Canada–approved dose (refer to Table 7); these trials are not included in this review.

Enrolled patients were randomly assigned using interactive response technology 1:1 in the MOTIVATE trial (N = 413 patients across 214 sites, including Canada) or 2:1 in the ADVANCE trial (N = 559 patients across 297 sites, including Canada) to receive risankizumab 600 mg IV or placebo IV. There was a total of 17 Canadian sites and a total of 110 patients living in Canada enrolled. Randomization in both trials was stratified by the number of prior biologics failed (1, more than 1 in the MOTIVATE trial or 0, 1, more than 1 in the ADVANCE trial), corticosteroid use at baseline (yes, no), and Simple Endoscopic Score for Crohn’s Disease (SES-CD) score (original, alternative). Patients without clinical response to risankizumab at week 12 entered induction period 2 and were rerandomized 1:1:1 to risankizumab 1,200 mg IV, risankizumab 360 mg SC, or risankizumab 180 mg SC. Patients who did not have a clinical response to placebo at week 12 received risankizumab 1,200 mg IV. During the 12-week or 24-week induction period, initiation or dose changes of concomitant CD medications (e.g., aminosalicylates, oral locally acting steroids, systemic corticosteroids, immunomodulators) was prohibited. Since induction period 2 in both trials was exploratory and did not include the Health Canada–approved dose for induction, only results from the first 12-week induction period are reported in this review.

To meet regional regulatory requirements, both trials included 2 protocols denoted as US and OUS that were identical in design but specified different coprimary and key secondary outcomes. Clinical remission and endoscopic response were coprimary outcomes at week 12 in both the US and OUS protocols; however, the definition of clinical remission differed. In the US protocol, clinical remission was defined as CDAI less than 150 whereas in the OUS protocol, SF/APS clinical remission (defined as having average daily SF ≤ 2.8 and not worse than baseline and average daily APS ≤ 1 and not worse than baseline) was used. The secondary outcomes were similar in both protocols but ranked differently. They included clinical remission, clinical response, fatigue (FACIT-F score), HRQoL (SF-36 PCS score, IBDQ total score), enhanced SF/APS clinical response and endoscopic response, endoscopic remission, and ulcer-free endoscopy. Exploratory outcomes included CSS and EQ-5D-5L scores.

A detailed breakdown of secondary outcomes per protocol is provided in Table 8.

FORTIFY Substudy 1 (Maintenance)

The primary objective of FORTIFY substudy 1 was to evaluate the efficacy and safety of risankizumab SC as maintenance therapy versus placebo (i.e., risankizumab was withdrawn) in patients with moderately to severely active CD who responded to risankizumab IV induction treatment in the MOTIVATE or ADVANCE study (Figure 2). The FORTIFY trial enrolled patients who achieved clinical response at the last visit of either induction period 1 or induction period 2 of the MOTIVATE or ADVANCE study (i.e., achieved SF/APS clinical response defined as ≥ 30% decrease in average daily SF and/or APS and both not worse than baseline of the induction study). Patients were required to have had a baseline of induction eligibility SES-CD score of 6 or more (≥ 4 for isolated ileal disease). The trial included a 52-week maintenance period with a 140-day follow-up (for those not entering the open-label extension), and an open-label extension lasting for up to 220 weeks or until study discontinuation. Only results from the rerandomized portion are reported in this review.

Enrolled patients were rerandomized in a 1:1 ratio using interactive response technology to continue receiving risankizumab 360 mg SC every 8 weeks or to have risankizumab treatment withdrawn (i.e., patients continued to receive placebo SC every 8 weeks to maintain the blind and are hereafter referred to as the placebo SC group). Rerandomization was stratified by endoscopic response (yes, no), SF/APS clinical remission status at last visit of induction (yes, no), and last IV risankizumab dose taken during induction. Similar to the induction trials, the FORTIFY study included a US protocol and an OUS protocol that included the same coprimary outcomes and similar secondary outcomes, ranked differently. A detailed breakdown of secondary outcomes per protocol are provided in Table 8.

SEQUENCE Study, Part 1 (Induction and Maintenance Ongoing)

Part 1 of the SEQUENCE study consists of a 35-day screening period, a 48-week treatment period, and a 140-day follow-up period for patients not participating in part 2. The primary objective of the SEQUENCE study, part 1, interim data lock analysis was to evaluate the noninferiority of risankizumab compared to ustekinumab in inducing clinical remission (defined as CDAI less than 150) at week 24. Patients were randomized 1:1 to risankizumab (600 mg IV at week 0, week 4, and week 8, and then at week 12 to 360 mg SC and every 8 weeks thereafter) or to ustekinumab (weight-based IV induction dose followed by a 90 mg SC maintenance dose at week 8 and every 8 weeks thereafter). Randomization was stratified by the number of anti-TNF failures (1 or fewer, more than 1) and corticosteroid use at baseline (yes, no). Secondary exploratory outcomes included clinical response, clinical remission, endoscopic remission, mucosal healing, deep remission, biologic remission, SF-36 PCS and MCS scores, and IBDQ total score.

Figure 2: Study Design of the MOTIVATE, ADVANCE, and FORTIFY Studies

APS = abdominal pain score; BL = baseline; PBO = placebo; RZB = risankizumab; SC = subcutaneous; SF = stool frequency; SF/APS = stool frequency and abdominal pain; wk = week.

Notes: Patients from the induction studies (M15-991 [the MOTIVATE study] and M16-006 [the ADVANCE study]) who achieved SF/APS clinical response (defined as ≥ 30% decrease in average daily SF and/or average daily APS and both not worse than BL) at week 12 or week 24 could enrol in the maintenance study (M16-000 [the FORTIFY study]). The patient numbers in Figure 2 reflect the number of planned patients for enrolment. Only nonresponders in the PBO group at week 12 who received 12 weeks of RZB 1,200 mg and responded went on to the maintenance study. Responders exposed to 24 weeks of RZB went into the open-label extension.

Source: Skyrizi Clinical Evidence Summary.³²

Figure 3: Study Design of the SEQUENCE Study, Part 1

Q8w = every 8 weeks; RZB = risankizumab; SC = subcutaneous; UST = ustekinumab; wk = week.

Source: SEQUENCE Clinical Study Report.³¹

Populations

Inclusion and Exclusion Criteria

A detailed description of the inclusion and exclusion criteria for each study is provided in Table 8.

MOTIVATE and ADVANCE (Induction Studies)

In both trials, eligible patients were aged 18 years to 80 years (where locally permissible, patients 16 years to younger than 18 years were enrolled) with a confirmed diagnosis of CD for at least 3 months before baseline, and moderately to severely active disease defined by a CDAI score of 220 to 450 at baseline, average daily SF greater than or equal to 4 and/or an average daily APS greater than or equal to 2, and endoscopic evidence of mucosal inflammation documented by an SES-CD score of 6 or more (or 4 or more for isolated ileal disease). In both the MOTIVATE and ADVANCE studies, a limited number of patients with an SES-CD score of 3 to less than 6 were enrolled. In the MOTIVATE study, patients must have been bio-IR for CD, and in the ADVANCE study, patients must have been non-bio-IR or bio-IR for CD.

FORTIFY Substudy 1 (Maintenance Study)

Patients were eligible to enter the FORTIFY trial if they demonstrated clinical response to IV risankizumab induction therapy at week 12 of induction period 1 or at week 24 of induction period 2 in the ADVANCE or MOTIVATE trial. Clinical response was defined as at least a 30% decrease in mean SF of daily values reported for 7 days before the scheduled assessment visit or at least a 30% decrease in mean daily APS, both not worse than baseline of the induction study.

SEQUENCE Study, Part 1 (Induction and Maintenance Ongoing)

Eligible patients were aged 18 to 80 years with a confirmed diagnosis of CD for at least 3 months before baseline, and with moderately to severely active disease defined by a CDAI score of 220 to 450 at baseline, average daily SF greater than and/or equal to 4 or an average daily APS greater than or equal to 2, and endoscopic evidence of mucosal inflammation documented by an SES-CD score of 6 or more (or 4 or more for isolated ileal disease), and had failed 1 or more anti-TNF therapy.

Baseline Characteristics

MOTIVATE and ADVANCE Studies, and FORTIFY Substudy 1

A summary of baseline patient demographics and disease characteristics of ITT1A populations are in Table 9 and Table 10. Overall, key baseline characteristics were generally balanced between treatment groups and trials. Patients in the trial populations were predominantly white (77% to 91%), with an approximate mean age of 40 years, and a mean CD disease duration of approximately 8 years to 12 years. Between 29% and 36% of patients across treatment groups were on concomitant corticosteroids and about 19% to 28% of patients were on immunomodulators. The baseline mean CDAI score was about 310 to 320; however, the proportion of patients with moderate versus severe disease was not reported.

All of the patients in the MOTIVATE study (100%) and almost all of the patients in the ADVANCE study (approximately 99%) had previously taken at least 1 CD-related medication. The most frequently reported prior CD-related medications in the MOTIVATE and ADVANCE studies were adalimumab, infliximab, and vedolizumab. In the MOTIVATE study, approximately 48% and 52% of patients were bio-IR to 1 biologic therapy or greater than 1 biologic therapy, respectively. In the ADVANCE study, 23% to 30% of patients were bio-IR to 1 biologic therapy, 28% to 32% of patients were bio-IR to greater than 1 biologic therapy, and 42% to 45% of patients were non-bio-IR. Across the trials, 12% to 22% of patients had a history of ustekinumab failure and the majority of patients had failed 1 or more anti-TNF therapy (0 to 11% had not failed anti-TNF therapy).

SEQUENCE Study, Part 1

A summary of baseline patient demographics and disease characteristics of the ITT1H population are shown in Table 11.

Demographic characteristics were generally balanced between the treatment groups. Most patients were white and the mean age was approximately 39 years. Disease characteristics were also relatively similar between the treatment groups.

Table 9: Summary of Baseline Characteristics — MOTIVATE, ADVANCE, and FORTIFY Studies, ITT1A Population

APS = abdominal pain score; bio-IR = inadequate response to biologic therapy; BL = baseline; CDAI = Crohn’s Disease Activity Index; hs-CRP = high-sensitivity C-reactive protein; ITT1A = intention-to-treat population, the primary efficacy analysis for the MOTIVATE, ADVANCE, and FORTIFY studies; non-bio-IR = inadequate response to conventional therapy; SC = subcutaneous; SD = standard deviation; SES-CD = Simple Endoscopic Score for Crohn’s Disease; SF = stool frequency; TNF = tumour necrosis factor.

^aThe ITT1A population includes randomized patients who received at least 1 dose of study drug during the 12-week induction period, received only one 12-week period of induction, and had BL eligible SES-CD of 6 or more (≥ 4 for isolated ileal disease).

^bThe ITT1A population included the randomized patients in the intention-to-treat population who received IV risankizumab for only 1 period of 12 weeks in the induction study MOTIVATE or ADVANCE and at least 1 dose of the study drug in the FORTIFY study and had eligible SES-CD of 6 or more (≥ 4 for isolated ileal disease) at the BL of the induction study. BL was defined as the BL visit of the induction study MOTIVATE or ADVANCE for efficacy analyses.

^cAt BL, 125 (14.7%) patients in the ADVANCE study and 80 (14.1%) patients in the MOTIVATE study had isolated ileal disease. Twenty-one patients in the ADVANCE study and 20 patients in the MOTIVATE study had isolated ileal disease at BL with SES-CD of 0 at week 12; none of these was due to the inability to intubate the ileum.

^dThe maximum dose of steroids allowed at BL was 20 mg per day of prednisone (or equivalent), or 9 mg per day of budesonide or 5 mg per day of beclomethasone. The patient had to be in the current course of steroids for 14 days or more before BL and on a stable dose for 7 days or more before BL.

Sources: MOTIVATE, ADVANCE, and FORTIFY Clinical Study Reports.^8-10

Interventions

MOTIVATE and ADVANCE (Induction Studies)

In both trials, patients received risankizumab 600 mg IV or matched placebo IV infusion administered at week 0, week 4, and week 8 as induction therapy, in a double-blinded manner. During the induction period, concomitant CD medications (e.g., aminosalicylates, oral locally acting steroids, systemic corticosteroids, immunomodulators) were allowed but initiating doses, increasing doses, or decreasing doses was prohibited.

FORTIFY Substudy 1 (Maintenance Study)

Patients received either risankizumab 360 mg SC or placebo (i.e., 4 90 mg injections) at week 0, week 8, week 16, week 24, week 32, week 40, and week 48. Each scheduled dose was administered within plus or minus 7 days. Patients who did not respond adequately received open-label risankizumab rescue therapy defined as 1 single 1,200 mg IV infusion followed by 360 mg SC injection, starting at the week 16 visit on the basis of increased symptom activity and confirmation with objective markers of inflammation.

SEQUENCE Study, Part 1 (Induction and Maintenance Ongoing)

Patients received the risankizumab 600 mg IV induction dose administered at baseline, week 4, and week 8, and then at week 12, received a 360 mg SC maintenance dose and every 8 weeks thereafter and completed their last visit at week 24, or received a ustekinumab weight-based IV induction dose at week 0 (a patient weight of 55 kg or less = 260 mg dose; a patient weight of more than 55 kg to 85 kg = 390 mg dose; or a patient weight of more than 85 kg = 520 mg) and then a 90 mg SC maintenance dose at week 8 and every 8 weeks thereafter. Aminosalicylates, immunomodulators, and/or CD-related antibiotics at baseline were allowed but initiating doses, increasing doses, or decreasing doses was prohibited.

Table 10: Summary of Week 0 Disease Characteristics — FORTIFY Study, ITT1A Population

APS = abdominal pain score; CDAI = Crohn’s Disease Activity Index; hs-CRP = high-sensitivity C-reactive protein; ITT1A = intention-to-treat population, the primary efficacy analysis for the MOTIVATE, ADVANCE, and FORTIFY studies; SC = subcutaneous; SD = standard deviation; SES-CD = Simple Endoscopic Score for Crohn’s Disease; SF = stool frequency; SF/APS = stool frequency and abdominal pain score.

^aWeek 0 was defined as the first study visit in the FORTIFY study or the final visit of study MOTIVATE or ADVANCE (week 12 or week 24).

^bThe ITT1A population includes the randomized patients in the intention-to-treat population who received IV risankizumab for only 1 period of 12 weeks in the induction study MOTIVATE or ADVANCE and at least 1 dose of the study drug in the FORTIFY study and had eligible SES-CD of 6 or more (≥ 4 for isolated ileal disease) at the baseline of the induction study.

Source: FORTIFY Clinical Study Report.¹⁰

Table 11: Summary of Baseline Characteristics — SEQUENCE Study, Part 1, ITT1H Population

APS = abdominal pain score; BMI = body mass index; CDAI = Crohn’s Disease Activity Index; hs-CRP = high-sensitivity C-reactive protein; ITT = intention-to-treat; ITT1H = intention-to-treat population, the primary efficacy analysis for the SEQUENCE study, part 1; SD = standard deviation; SES-CD = Simple Endoscopic Score for Crohn’s Disease; SF = stool frequency; TNF = tumour necrosis factor.

^aThe ITT population (denoted as ITT1H) is the primary efficacy population for the primary efficacy outcome of clinical remission (CDAI < 150) at week 24 and is a subset of the ITT1 population. The ITT1 population includes all randomized patients who received at least one dose of study drug during the 12-week induction period. The ITT1H population includes approximately 50% of patients in the ITT1 population who had the opportunity to reach week 24 by the time of the interim lock 1 (i.e., patients who were randomized in the selected risankizumab dose regimen group or ustekinumab group by the predefined enrolment cut-off date of January 5, 2022).

Source: SEQUENCE Clinical Study Report.³¹

Outcomes

A list of efficacy outcomes identified in the CADTH review protocol that were assessed in the included clinical trials is summarized in Table 12. A detailed description and critical appraisal of the outcome measures is provided in Appendix 2, Table 37.

Table 12: Summary of Outcomes of Interest Identified in the CADTH Review Protocol

AE = adverse event; AP = abdominal pain; BL = baseline; CDAI = Crohn’s Disease Activity Index; CSS = Crohn’s Symptom Severity; EQ-5D-5L = 5-Level EQ-5D; FACIT-F = Functional Assessment of Chronic Illness Therapy–Fatigue; IBDQ = Inflammatory Bowel Disease Questionnaire; OUS = outside the US; PCS = physical component summary; SAE = serious adverse event; SF = stool frequency; SF-36 = Short Form (36) Health Survey; SF/APS = stool frequency and abdominal pain score; WDAE = withdrawal due to adverse event.

Sources: Clinical Study Reports for the MOTIVATE,⁸ ADVANCE,⁹ FORTIFY,¹⁰ and SEQUENCE studies.³¹

Clinical Remission

• SF/APS clinical remission was defined as average daily SF (number of liquid or very soft stools) less than or equal to 2.8 and not worse than baseline, and average daily APS (abdominal pain rating components of CDAI) as less than or equal to 1 and not worse than baseline. Average daily SF and the average daily APS were calculated from the patient diary. No MID was identified in the literature for patients with CD.

• CDAI clinical remission was defined as a CDAI score of less than 150. The CDAI is a composite score that includes patient symptoms evaluated over the past 7 days (i.e., abdominal pain, SF, and general well-being) as well as physical and laboratory findings. The items are scored individually and weighted, and do not contribute equally to the overall score. The CDAI score is derived from summing the weighted individual scores of 8 items and ranges from 0 to 600. A higher score indicates more severe disease.^33,34 The thresholds used to define disease severity are in Table 3. The average daily SF, average daily APS, and average daily well-being were calculated from the patient diary. No MID was identified in the literature for patients with CD.

• SF remission was defined as average daily SF of less than or equal to 2.8 and not worse than baseline and was calculated from the patient diary.

• APS remission was defined as an average daily APS of less than or equal to 1 and not worse than baseline, and was calculated from the patient diary.

• Deep remission was defined as a composite of SF/APS or CDAI clinical remission and endoscopic remission, which was defined as a SES-CD score of less than or equal to 4 and at least a 2-point reduction versus baseline with no subscore greater than 1 in any individual variable, as scored by a central reviewer. The SES-CD is a scoring system that assesses 4 endoscopic items, including the size of ulcers, the ulcerated surface, the affected surface, and the presence of narrowing.³⁵ Each item is scored from 0 to 3, with a total score ranging from 0 to 56. Higher scores indicate more severe disease.

• Maintenance of clinical remission was defined as CDAI or SF/APS clinical remission at week 52 among patients with CDAI or SF/APS clinical remission at week 0 in the FORTIFY maintenance trial.

• Biologic remission was defined as CDAI clinical remission and fecal calprotectin of less than or equal to 250 mcg/g or C-reactive protein of less than or equal to 5 mg/L.

Corticosteroid-Free Clinical Remission

• CDAI or SF/APS corticosteroid-free clinical remission was defined as the proportion of patients who discontinued corticosteroid use for 90 days and achieved clinical remission at week 52 among patients taking steroids at the baseline of induction.

Clinical Response

• SF/APS clinical response was defined as a 30% or more decrease in average daily SF and/or a 30% or more decrease in average daily APS and both not worse than baseline. This was calculated based on the patient’s diary.

• CDAI clinical response was defined as a reduction in the CDAI score of 100 or more points from baseline.

• Enhanced SF/APS clinical response was defined as a 60% or more decrease in average daily SF and/or a 35% or more decrease in average daily APS and both not worse than baseline, and/or SF/APS clinical remission. This was calculated based on the patient diary.

Symptoms (Abdominal Pain, Fatigue, Stool Frequency)

• CSS, developed by the sponsor AbbVie, is a 14-item tool that evaluates patient-reported symptoms and impacts associated with CD during the previous week. The total score of CSS, which is calculated by summing the individual item scores, ranges from 14 to 70 with a higher score indicating worse symptoms. A difference in change between groups that exceeds 4 points has been suggested as clinically meaningful.³²

• FACIT-F is a 13-item, patient-reported, fatigue questionnaire that uses a 5-point Likert scale. It assesses tiredness, weakness, and difficulty conducting usual activities as a result of fatigue over the previous week. The total score ranges from 0 (extreme fatigue) to 52 (no fatigue). No MID was identified in the literature for patients with CD.

Mucosal Healing Determined by Histology or Endoscopy

• Endoscopic remission was defined as an SES-CD score of less than or equal to 4 and at least a 2-point reduction versus baseline with no subscore greater than 1 in any individual variable, as scored by a central reviewer.

• Endoscopic response was defined as decrease in an SES-CD score of greater than 50% from baseline (or for patients with isolated ileal disease and a baseline SES-CD score of 4, at least a 2-point reduction from baseline), as scored by a central reviewer. The SES-CD is based on the sum of individual segment values for 4 endoscopic variables (i.e., the presence and size of ulcers, ulcerated surface, affected surface, and the presence of narrowing). Each variable in each segment is scored from 0 to 3 resulting in SES-CD values ranging from 0 to 56, with higher scores indicating more severe disease.

• Ulcer-free endoscopy was defined as an SES-CD ulcerated surface subscore of 0 in patients with an SES-CD ulcerated surface subscore of 1 or more at baseline, as scored by a central reviewer.

• Steroid-free endoscopic remission was defined as endoscopic remission and not receiving steroids in the past 90 days.

• Mucosal healing was defined as an SES-CD ulcerated surface subscore of 0 in patients with an SES-CD ulcerated surface subscore of 1 or more at baseline as scored by a central reviewer.

HRQoL

Change from baseline in HRQoL was assessed via generic or disease-specific instruments: IBDQ total score and SF-36 PCS and MCS. These are detailed in Appendix 2.

• IBDQ is a disease-specific, patient-reported, multidimensional HRQoL questionnaire that has been validated for CD. It comprises 32 Likert-scaled items that cover 4 domains: bowel symptoms, systemic symptoms, emotional function, and social function. Each question is scored on a 7-point scale where 1 corresponds to the poorest function and 7 to the optimum function. The total score ranges from 32 to 224 points with higher scores indicating a better HRQoL. One study proposed that a clinically meaningful improvement is an increase of 16 points or more in the total score or 0.5 points or more per question in patients with CD.³⁶

• SF-36 is a patient-reported, general health status instrument that consists of 8 subdomains: physical function, role-physical (limitations due to physical problems), bodily pain, general health, energy/fatigue, social function, role-emotional (limitations due to emotional problems), and mental health. It also provides 2 component summaries: the PCS score and the MCS score. Each of these 2 component summaries and 8 subdomains is measured on a scale of 0 to 100, with an increase in score indicating improvement in health status. One study reported the MID for SF-36 PCS and MCS scores in patients with CD as a range between 1.6 to 7.0 and 2.3 to 8.7, respectively.

• The EQ-5D-5L is a generic patient-reported, HRQoL outcome measure that may be applied to a variety of health conditions and treatments.³⁷ Higher scores indicate a better HRQoL. No MID was identified in the literature for patients with CD.

Harms

• The harm outcomes assessed were AEs, SAEs, deaths, AEs of special interest (infections, hepatotoxicity, injection-site reactions, hypersensitivity reactions), and withdrawals due to AE. AEs were coded using the Medical Dictionary for Regulatory Activities dictionary. Treatment-emergent AEs were defined as AEs that began or worsened in severity after initiation of the study drug and within 140 days after the last dose of the study drug.

Statistical Analysis

Power Calculation

The power calculation for the MOTIVATE and ADVANCE studies was based on the expected number needed to detect a difference in the coprimary end points of clinical remission and endoscopic response at week 12 between risankizumab and placebo. This approach used historical data from the phase II Study 1311.6 that showed slightly lower event rate and similar treatment difference versus placebo for the endoscopic response rate than the clinical remission rate at week 12. Based on the assumption of a 23.5% clinical remission rate for the risankizumab group and 10% for the placebo group, in the MOTIVATE study, a sample size of 193 patients in each group would have 89% power to detect a difference between groups at week 12 using 2-sided Fisher’s exact test at a significance level of 0.025. Based on the assumption that the week 12 endoscopic response rate would be 17% for the risankizumab group and 5% for the placebo group, this sample size would have 93% power to detect the treatment difference for endoscopic response between the risankizumab group and the placebo group at week 12 using a Fisher’s exact test with a 2-sided alpha of 0.025.

In the ADVANCE study, to detect a clinical remission rate of 27.8% for the risankizumab group and 12% for the placebo group, a sample size of 342 patients for the risankizumab group and 171 patients for the placebo group would have 97% power to detect a treatment difference between groups at week 12 using a Fisher’s exact test at a 2-sided alpha of 0.025. Based on the assumption that the week 12 endoscopic response rate would be 25.5% for the risankizumab group and 8% for the placebo group, this sample size would have 99% power to detect the treatment difference between the risankizumab group and the placebo group at week 12 using a Fisher’s exact test at a 2-sided alpha of 0.025. In addition, the ADVANCE study would have approximately 80% power for the failed biologic therapy subgroup to detect the treatment difference between the risankizumab and placebo groups in clinical remission rates at week 12, with the assumption that the week 12 clinical remission rate would be 24.2% for the risankizumab group and 10% for the placebo group. For the failed conventional therapy subgroup, there would be 72% power to detect the treatment difference for clinical remission rates at week 12 between the risankizumab group and the placebo group, with the assumption that the week 12 clinical remission rate would be 35% for the risankizumab group and 15% for the placebo group.

In FORTIFY substudy 1, for the US protocol, assuming a 46% CDAI clinical remission rate for the risankizumab group and a 28% CDAI clinical remission rate for the placebo group at week 52, a sample size of 150 patients for each group would have 87% power to detect a difference between groups using the Fisher’s exact test at a 2-sided alpha of 0.05. For the OUS protocol, assuming a 38.7% clinical remission rate for the risankizumab group and a 20% clinical remission rate for the placebo group at week 52, a sample size of 150 patients for each group would have 93% power to detect a difference in SF/APS clinical remission rate. Based on the assumption that the week 52 endoscopic response rate would be 32.6% for the risankizumab group and 10% for the placebo group, this sample size would have approximately 95% power to detect the treatment difference between groups for endoscopic response rates at week 52.

In the SEQUENCE study, part 1, the power calculation was based on the assumption of a CDAI clinical remission (less than 150) rate of 45% for the risankizumab group and 29% for the ustekinumab group at week 24, based on phase III trials for ustekinumab and risankizumab. Based on this assumption, a sample size of 129 patients per group would have at least 95% power to determine noninferiority based on a noninferiority margin of 10% at the 0.05, 2-sided significance level. Clinical remission rate assumptions were informed by published results from phase III trials for ustekinumab and the MOTIVATE study. Noninferiority was met if the lower bound of the 95% CI of the adjusted risk difference between risankizumab and ustekinumab was above –10%. The margin of 10% was selected based on the physician’s perspective of the clinical meaningfulness of IBD trial results as per an International Organization for the Study of Inflammatory Bowel Disease survey.³⁸

Multiplicity Considerations

In the MOTIVATE and ADVANCE studies, testing for the difference between treatment groups across the coprimary and secondary end points was performed using a graphical multiplicity adjustment to control the familywise type I error rate at a 2-sided significance level of 0.05. The coprimary end points were first tested, each using a 2-sided significance level of 0.025. If those end points both reached statistical significance, the alpha was allocated to the ranked secondary end points, which were tested sequentially. If these reached statistical significance, the final group of ranked secondary end points was tested using the Holm procedure. All other efficacy end points were tested without control for type I error. The same multiplicity control procedure was used in the FORTIFY trial. The ranked secondary outcomes are described in Table 12.

In the SEQUENCE study, part 1, a single end point was tested (achievement of clinical remission); other end points were intended to be presented descriptively without formal statistical testing.

Statistical Analysis for the Coprimary Efficacy Outcomes

Statistical Model

In the MOTIVATE and ADVANCE studies, the comparisons between risankizumab versus placebo for the coprimary outcomes were performed using the Cochran-Mantel-Haenszel (CMH) test, adjusted by the randomization factors of the number of prior biologics failed (1, greater than 1 in the MOTIVATE study or 0, 1, greater than 1 in the ADVANCE study) and baseline steroid use (yes, no) in the ITT1A population. A CMH-based, 2-sided, 95% CI for the difference between treatment groups was determined. Each primary end point was assigned a 2-sided alpha of 0.025.

In the FORTIFY study, the comparisons between risankizumab and placebo for the coprimary outcomes were performed using the CMH test, adjusted by the week 0 SF/APS clinical remission status and week 0 endoscopic response status (per central review), and the last risankizumab induction dose. A CMH-based, 2-sided, 95% CI for the difference between groups was constructed. Each primary end point was assigned a 2-sided alpha of 0.025.

In the SEQUENCE study, part 1, at interim lock 1 the primary outcome of CDAI clinical remission at week 24 was tested based on the ITT1H population using the CMH test stratified by the number of prior anti-TNF therapy failures (less than or equal to 1, greater than 1) and steroid use at baseline (yes, no). Point estimates and proportions for the difference in proportions between groups were calculated and the CI for the common difference was constructed based on the CMH estimate adjusting for stratification factors.

Data Imputation Methods

In the MOTIVATE, ADVANCE, and FORTIFY studies, the primary approach for handling missing data for the coprimary outcomes was the nonresponder imputation (NRI) approach incorporating multiple imputation for missing data due to COVID-19 infection or logistical restrictions. Patients with missing data for all other reasons were counted as nonresponders. In the FORTIFY trial, patients who received rescue therapy were also counted as nonresponders for categorical outcomes.

In the SEQUENCE study, the primary approach for handling missing data for the primary analysis was also NRI while incorporating multiple imputation to handle missing data due to COVID-19 infection or logistical restrictions due to pandemic and/or geopolitical conflict. Patients with missing data for all other reasons were counted as nonresponders.

Subgroup and Sensitivity Analyses

In the MOTIVATE, ADVANCE, and FORTIFY studies, the subgroup analysis of interest for this review was bio-IR status (bio-IR less than or equal to 1 or greater than 1 in the MOTIVATE study and bio-IR or non-bio-IR in the ADVANCE and FORTIFY studies). This was a prespecified subgroup analysis conducted for the coprimary outcomes using the ITT1A population. Results are shown as the point estimate and 95% CI for treatment differences between the risankizumab group and placebo, without formal statistical testing. No subgroup analyses were reported for the SEQUENCE study, part 1.

Sensitivity analyses for the coprimary outcomes were conducted to provide insight on the robustness of the findings regarding the use of different data imputation methods. First, hybrid multiple imputation was used, where patients who discontinued before week 12 (in the MOTIVATE and ADVANCE studies) and week 52 (in the FORTIFY study) due to lack of efficacy, AEs or received rescue therapy were considered as “not achieved” for the clinical remission or endoscopic response, and patients who discontinued for other reasons were categorized according to multiple imputations. Next, an analysis of observed cases was performed, which excluded those patients with missing data at scheduled assessment visits. In the MOTIVATE and ADVANCE trials, the pattern-mixture model was also used for sensitivity analyses.

In the SEQUENCE study, sensitivity analyses using NRI and multiple imputation separately were conducted as well as an analysis using observed events, which did not impute values for missing evaluations.

Statistical Analysis for Secondary Efficacy Outcomes

Statistical Model

Multiplicity-controlled ranked secondary outcomes of the MOTIVATE, ADVANCE, and FORTIFY studies are summarized in Table 13 and graphical testing procedures are in Appendix 4. In the MOTIVATE and ADVANCE studies, the coprimary and key secondary outcomes were controlled for type I error rate at a 2-sided significance level of 0.05 based on a prespecified hierarchical testing procedure, except for CSS and EQ-5D-5L, which were tested without multiplicity control. Continuous secondary efficacy outcomes with repeat measurements were analyzed using a mixed model of repeated measures (MMRM) model including factors for treatment group, visit, visit by treatment interaction, stratification variables, and the continuous fixed covariates of baseline measurement. The MMRM analysis was considered primary for inferential purposes. Continuous secondary efficacy variables that were collected at only 1 postbaseline visit were analyzed using an analysis of covariance approach based on observed data. Categorical secondary efficacy outcomes were analyzed using the CMH test controlling for stratification variables (i.e., prior biologics failed [1, greater than 1 in the MOTIVATE study or 0, 1, greater than 1 in the ADVANCE study]) and baseline steroid use [yes, no]). A CMH-based, 2-sided, 95% CI for the difference between the risankizumab group and placebo group was determined. In the FORTIFY study, continuous secondary efficacy outcomes with repeated measures were analyzed by an MMRM model whereas outcomes collected at only 1 post–week 0 visit were analyzed using an analysis of covariance model including treatment, stratification factors, and measurements at both induction baseline and week 0. In all trials, the methods of handling missing data were the same as the primary analysis of the coprimary outcomes.

Table 13: Coprimary and Ranked Secondary Outcomes in the MOTIVATE, ADVANCE, and FORTIFY Studies, by Protocol

AP = abdominal pain; BL = baseline; CDAI = Crohn’s Disease Activity Index; FACIT-F = Functional Assessment of Chronic Illness Therapy–Fatigue; IBDQ = Inflammatory Bowel Disease Questionnaire; NA = not applicable; OUS = outside the US; PCS = physical component summary; SF = stool frequency; SF-36 = Short Form (36) Health Survey; SF/APS = stool frequency and abdominal pain score.

Note: The coprimary and key secondary outcomes were controlled for type I error based on a prespecified hierarchical testing procedure.

Sources: MOTIVATE and ADVANCE Clinical Study Reports.^8,9

In the SEQUENCE trial, all secondary outcomes were considered exploratory and statistical testing was not preplanned or controlled for multiplicity. Categorical variables were analyzed using the CMH test stratified by the number of prior anti-TNF therapy failures (≤ 1, > 1) and steroid use at baseline (yes, no). Continuous variables were analyzed using MMRM. The methods of handling missing data were the same as the primary analysis of the primary outcome.

Safety Analysis

In all trials, safety analyses were carried out using the corresponding safety analysis described in the Analysis Populations section. In all safety analyses, patients were analyzed according to treatment received regardless of randomization.

Analysis Populations

MOTIVATE and ADVANCE (Induction Studies)

The primary efficacy analysis population for the 12-week induction period was the ITT1A population (N = 378 for the MOTIVATE study; N = 511 for the ADVANCE study), which included all randomized patients who received at least 1 dose of study drug and who had a baseline-eligible SES-CD score of 6 or more (4 or more for isolated ileal disease). The safety population was denoted as SA1 (N = 413 for the MOTIVATE study; N = 580 for the ADVANCE study). It included all patients who received at least 1 dose of study drug during induction period 1.

FORTIFY Substudy 1 (Maintenance Study)

The primary efficacy analysis for the 52-week maintenance period was the ITT1A population (N = 305), which included rerandomized patients (i.e., patients who received at least 1 dose of study drug) who met eligibility criteria of an SES-CD score of 6 or more (4 or more for isolated ileal disease) at baseline of the induction study and received risankizumab IV for only 1 period of 12 weeks in the induction study. The SA1 population (N = 363) included all patients who received at least 1 dose of study drug in FORTIFY substudy 1.

SEQUENCE Study, Part 1 (Induction and Maintenance Ongoing)

The primary efficacy population for the 24-week interim lock analysis was a subset of all randomized patients (ITT1 population) — the ITT1H population (N = 265). The ITT1H population included approximately 50% of patients in the ITT1 population who reached week 24 (or discontinued) by the time of the interim lock 1. The per-protocol population denoted as PP1H (|| |||) excluded patients from the ITT1H population with major protocol deviations. The SA1 population (|||||) included all patients who received at least 1 dose of study drug by the predefined enrolment cut-off date of January 5, 2022.

Results

Patient Disposition

A summary of patient disposition for the MOTIVATE, ADVANCE, and FORTIFY studies is in Table 14, and in Table 15 for the SEQUENCE study. Details of the screening period were not reported for all trials.

In the MOTIVATE study, 98.1% of patients who received risankizumab 600 mg IV and 89.9% of patients who received placebo completed the 12-week induction period. In the ADVANCE study, 97.9% of patients who received risankizumab 600 mg IV and 87.6% of patients who received placebo completed the 12-week induction period. In both trials, a higher proportion of patients in the placebo group discontinued the study drug during the 12-week induction period. The most common reasons for discontinuation in the placebo groups were due to AEs followed by lack of efficacy, whereas in the risankizumab group, discontinuations were generally low with no 1 primary reason. In the placebo groups, the most frequently reported AE that led to discontinuation of the study drug was worsening CD (6.3% in the MOTIVATE trial and 3.8% in the ADVANCE trial).

In the FORTIFY study, a similar proportion of patients (87.0% to 89.4%) completed the study drug across the 2 treatment groups. The most common reason for discontinuation was lack of efficacy in the withdrawal placebo SC group. In the risankizumab group, lack of efficacy and “other” accounted for 6.8% of the reasons for discontinuation.

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

Table 14: Patient Disposition in the MOTIVATE, ADVANCE, and FORTIFY Studies

ITT = intention-to-treat; ITT1A = intention-to-treat population, the primary efficacy analysis for the MOTIVATE, ADVANCE, and FORTIFY studies; NR = not reported; SC = subcutaneous; SES-CD = Simple Endoscopic Score for Crohn’s Disease.

^aPrimary reason for discontinuation.

^bThe ITT population for the 12-week induction period (denoted as ITT1A) includes randomized patients who received at least 1 dose of study drug during this period and includes the subjects with a baseline-eligible SES-CD of 6 or more (≥ 4 for isolated ileal disease). This was the primary population for efficacy analysis.

^cThe ITT population for substudy 1 included the randomized subjects in the ITT1A set who had an eligible SES-CD score of 6 or more (≥ 4 for isolated ileal disease) at the baseline of the MOTIVATE or ADVANCE study and had received IV risankizumab for only 1 period of 12 weeks in the MOTIVATE or ADVANCE study. This was the primary population for efficacy analysis.

^dThis includes all patients who received at least 1 dose of study medication.

Sources: MOTIVATE, ADVANCE, and FORTIFY Clinical Study Reports.^8-10

Table 15: Patient Disposition in SEQUENCE Study, Part 1^a

CDAI = Crohn’s Disease Activity Index; ITT = intention-to-treat; ITT1H = intention-to-treat population, the primary efficacy analysis for the SEQUENCE study, part 1; NR = not reported; PP = per-protocol; SA1 = safety population; SC = subcutaneous.

^aPatient disposition was derived from the safety population (SA1) (|||||), which includes all patients who received at least 1 dose of study drug (risankizumab or ustekinumab) by the predefined enrolment cut-off date of January 5, 2022.

^bPatients who discontinued the study were counted under each reason given for discontinuation. Therefore, the sum of the counts given for the reasons may be greater than the overall number of discontinuations.

^cThe ITT1H population (|||||) is the primary efficacy population for the primary efficacy outcome of clinical remission (CDAI < 150) at week 24 and is a subset of the ITT1 population. The ITT1 population includes all randomized patients who received at least one dose of study drug during the 12-week induction period. The ITT1H population includes approximately 50% of patients in the ITT1 population who had the opportunity to reach week 24 by the time of the interim lock 1 (i.e., patients who were randomized in the selected risankizumab dose regimen group or ustekinumab group by the predefined enrolment cut-off date of January 5, 2022).

^dThe per-protocol population (PP1H) (|||||) excludes patients from the ITT1H population with major protocol deviations and is the population upon which additional sensitivity analyses were performed to evaluate the impact of major protocol deviations on the primary efficacy outcome at week 24.

^eSafety population 1 (SA1) (|||||) includes all patients who received at least 1 dose of study drug (risankizumab or ustekinumab) by the predefined enrolment cut-off date of January 5, 2022.

Source: SEQUENCE Clinical Study Report.³¹

Exposure to Study Treatments

Details of the extent of exposure to the study drug in the MOTIVATE, ADVANCE, and FORTIFY studies are reported in Table 16, and in Table 17 for the SEQUENCE study.

In the MOTIVATE and ADVANCE trials, mean exposure to risankizumab 600 mg IV and placebo IV was approximately 83.0 days for the 12-week induction period.

In the FORTIFY trial, mean exposure to risankizumab 360 mg SC was 328 days and 309 days for the withdrawal placebo SC group.

|| ||||||||| |||| |||||||| || |||||||||||| ||| || |||||| || || ||| ||||||| ||| ||| |||| || ||||||||||| |||||||||||| ||||||||| |||| ||||| || || |||||

Table 16: Extent of Exposure — MOTIVATE, ADVANCE, and FORTIFY Studies

SA1 = safety population; SC = subcutaneous; SD = standard deviation.

^aThe SA1 population includes all patients who received at least 1 dose of the study drug during the 12-week induction period.

^bThe SA1 population includes all patients who received at least 1 dose of the study drug in FORTIFY maintenance substudy 1.

Sources: MOTIVATE, ADVANCE, and FORTIFY Clinical Study Reports.^{8 to 10}

Table 17: Extent of Exposure — SEQUENCE Trial, ITT1H Population

CDAI = Crohn’s Disease Activity Index; ITT1H = intention-to-treat population, the primary efficacy analysis for the SEQUENCE study, part 1; SC = subcutaneous; SD = standard deviation.

^aThe intention-to-treat population (denoted as ITT1H) is the primary efficacy population for the primary efficacy outcome of clinical remission (CDAI < 150) at week 24 and is a subset of the ITT1 population. The ITT1 population includes all randomized patients who received at least one dose of study drug during the 12-week induction period. The ITT1H population includes approximately 50% of patients in the ITT1 population who had the opportunity to reach week 24 by the time of the interim lock 1 (i.e., patients who were randomized in the selected risankizumab dose regimen group or ustekinumab group by the predefined enrolment cut-off date of January 5, 2022).

Source: SEQUENCE Clinical Study Report.³¹

Efficacy

Only those efficacy outcomes and subgroup analyses identified in the review protocol are reported as follows.

Clinical Remission

MOTIVATE and ADVANCE (Induction Studies)

The coprimary and secondary clinical remission outcomes in the ITT1A population (primary analysis) for both trials and protocols are summarized in Table 18 and Table 21, respectively. In both trials, the coprimary outcome of clinical remission at week 12 for both the US and OUS protocols favoured risankizumab versus placebo. In the MOTIVATE study’s US protocol, the CDAI clinical remission rate with risankizumab was 42.0% versus 19.8% with placebo, with a between-group adjusted difference of 22.1% (95% CI, 13.1% to 31.0%; P < 0.001). For the OUS protocol, the SF/APS clinical remission rate with risankizumab was 34.6% versus 19.3% with placebo, with a between-group adjusted difference of 15.2% (95% CI, 6.4% to 24.0%; P = 0.001). In the ADVANCE study’s US protocol, the CDAI clinical remission rate with risankizumab was 45.2% versus 24.6% with placebo, with a between-group adjusted difference of 20.7% (95% CI, 12.4% to 29.0%; P < 0.001). For the OUS protocol, the SF/APS clinical remission rate with risankizumab was 43.5% versus 21.7% with placebo, with a between-group adjusted difference of 21.9% (95% CI, 13.8% to 29.9%; P < 0.001). In both trials and protocols, all secondary ranked multiplicity-controlled remission-related outcomes — including SF and APS remission at week 12, CDAI clinical remission at week 4, and SF/APS clinical remission at week 4 — favoured risankizumab versus placebo (Table 18).

The results of the bio-IR subgroup analyses for the coprimary outcome of clinical remission were compatible with the primary analysis, and similar between trials. In both trials, results of the sensitivity analysis were consistent with the primary analysis.

FORTIFY Substudy 1 (Maintenance)

The coprimary and secondary clinical remission outcomes in the ITT1A population (i.e., primary analysis of patients who were clinical responders at the end of the MOTIVATE or ADVANCE study) are summarized in Table 19 and Table 22, respectively. In both protocols, the coprimary outcome of clinical remission at week 52 favoured risankizumab versus placebo. For the US protocol, the CDAI clinical remission rate with risankizumab 360 mg SC was 52.2% versus 40.9% with placebo SC, with a between-group adjusted difference of 14.6% (95% CI, 4.3% to 25.0%; P = 0.005). For the OUS protocol, the SF/APS clinical remission rate was 51.8% versus 39.6%, respectively, with a between-group adjusted difference of 15.2% (95% CI, 4.9% to 25.4%; P = 0.004).

In both protocols, SF and APS remission, maintenance of SF/APS or CDAI clinical remission, SF/APS or CDAI clinical remission with endoscopic response, and SF/APS or CDAI deep remission favoured risankizumab versus placebo. The evidence was insufficient to show a between-group difference for CDAI or SF/APS clinical remission with discontinuation of corticosteroid use for 90 days in patients taking steroids at the baseline of the induction study (Table 19). However, due to the adjusted treatment difference for the comparison of risankizumab 180 mg SC versus placebo SC for the coprimary outcome of SF/APS clinical remission (OUS protocol) not achieving statistical significance, the hierarchical testing strategy prevented formal statistical testing of the significance of all subsequent secondary outcomes, including all secondary clinical remission outcomes (i.e., the findings for these outcomes are at increased risk of being false positives). In the US protocol, with the exception of SF/APS clinical remission, the hierarchical testing strategy prevented formal statistical testing of the significance of all subsequent secondary outcomes.

The results of the bio-IR subgroup analyses for the coprimary outcome of clinical remission were consistent with the primary analysis. The results of the sensitivity analysis were consistent with the primary analysis.

The SEQUENCE study, part 1 (induction and maintenance ongoing),|||| ||||||| ||||||| || |||| |||||||| ||||||||| || |||| || || ||| ||||| |||||||||| |||||||| ||||||||| ||| ||| |||||||| |||||||||| |||||||| || ||||| ||| ||| ||||||| |||| |||||||| || ||||| || Table 20| || ||| ||||| |||| |||||||| ||||||||| |||| |||||||||||| ||| || |||||| || || ||| ||||| ||| ||||| |||| ||||||||||| |||||||||||| ||||||||| |||| ||||| || ||| |||| | ||||||| ||||| |||||||| |||||||||| || ||||| |||| ||| |||| || ||||||| | ||||| ||| |||||||||| || ||| |||| |||| |||||||| ||||||||| ||| ||||| ||| |||||| ||||||||||||| |||| | ||||||| ||||| |||||||| |||||||||| || ||||| |||| ||| |||| || |||||| | ||||| ||| |||||||||| ||| ||||| ||||| || ||| ||| || |||| |||||||||| ||| ||||||| |||| ||| |||||||||||||| |||||| || |||| || |||| ||| ||||| ||| |||| |||||||| ||||| |||||||||| |||||||||||||| ||||||| |||||| || |||||||| |||||||||| ||| ||||||||||| |||||||| || |||||| ||||||||| |||| ||| |||||||| ||||||||| || |||| || ||| ||||| || Table 23.

The results of the sensitivity analyses were consistent with the primary analysis.

Table 18: Coprimary Efficacy Outcomes, Clinical Remission — MOTIVATE and ADVANCE Induction Trials, ITT1A Population

Bio-IR = inadequate response to biologic therapy; CDAI = Crohn’s Disease Activity Index; CI = confidence interval; ITT1A = intention-to-treat population, the primary efficacy analysis for the MOTIVATE, ADVANCE, and FORTIFY studies; NA = not applicable; non-bio-IR = inadequate response or intolerance to conventional therapy; NRI-C = nonresponder imputation COVID-19; OUS = outside the US; SF/APS = stool frequency and abdominal pain score.

^aThe 95% CI for response rate is the synthetic result based on Student’s t-distribution procedure if there are missing data due to COVID-19 or based on the normal approximation to the binomial distribution if there are no missing data due to COVID-19.

^bThe 95% CI for risk difference or adjusted risk difference is based on the Cochran-Mantel-Haenszel test.

^cAcross the strata, the 95% CI for adjusted difference and P value are calculated according to the Cochran-Mantel-Haenszel test adjusted for strata (number of biologics failed, baseline steroid use) for the comparison of the 2 treatment groups. Within each subgroup, 95% CIs for the differences are calculated using normal approximation to the binomial distribution. Testing was done according to the prespecified statistical hierarchy testing procedure.

Sources: MOTIVATE and ADVANCE Clinical Study Reports.^8,9

Table 19: Coprimary Efficacy Outcomes, Clinical Remission — FORTIFY Maintenance Trial, ITT1A Population

Bio-IR = inadequate response to biologic therapy; CDAI = Crohn’s Disease Activity Index; CI = confidence interval; ITT1A = intention-to-treat population, the primary efficacy analysis for the MOTIVATE, ADVANCE, and FORTIFY studies; non-bio-IR = inadequate response to conventional therapy; NRI = nonresponder imputation; NRI-C = nonresponder imputation COVID-19; OUS = outside the US; SC = subcutaneous; SF/APS = stool frequency and abdominal pain score.

^aThe withdrawal (placebo SC) group consisted of patients who achieved SF/APS clinical response to IV risankizumab induction therapy and were randomized to receive placebo in the maintenance study.

^bThe 95% CI for response rate is the synthetic result based on Student's t-distribution if there are missing data due to COVID-19 or based on the normal approximation to the binomial distribution if there are no missing data due to COVID-19.

^cRisk difference equals risankizumab minus placebo. Adjusted risk difference is calculated based on the Cochran-Mantel-Haenszel test.

^dFor the overall population, the 95% CI for adjusted difference and P value are calculated according to the Cochran-Mantel-Haenszel test adjusted for strata (endoscopic response at week 0 [yes or no], SF/APS clinical remission status at week 0 [yes or no], and last IV dose during risankizumab induction period for the comparison of 2 treatment groups). The calculations are based on NRI incorporating multiple imputation to handle missing data due to COVID-19 or NRI only if there are no missing data due to COVID-19.

^eAccording to the prespecified graphical testing procedure for the US protocol, SF/APS clinical remission was the only secondary outcome that could be formally tested as a secondary outcome.

Source: FORTIFY Clinical Study Report.¹⁰

Table 20: Clinical Remission at Week 24 — SEQUENCE Study

CI = confidence interval; PP1H = per protocol population; SC = subcutaneous; vs. = versus.

^aThe 95% CI for response rate is based on the normal approximation to the binomial distribution.

^bRate difference equals risankizumab minus ustekinumab. The adjusted risk difference is calculated based on the Cochran-Mantel-Haenszel test.

^c|||||| ||| ||||||| ||| || ||| |||||||| |||||||||| || |||||||||| ||||||||| || ||| ||||||||||||||||||||||| |||| |||||||| ||| |||||| ||||||| || ||||| ||| ||||||| |||||| ||||| |||||||| ||||||| || || | || ||| ||||||| ||| || ||||||||

Source: SEQUENCE Clinical Study Report.³¹

Clinical Response

MOTIVATE and ADVANCE (Induction Studies)

The secondary outcome of clinical response in the ITT1A population (primary analysis) is summarized in Table 21. In both trials and protocols, all of the following secondary ranked multiplicity-controlled clinical response outcomes favoured risankizumab compared with placebo:

• CDAI clinical response at week 4 (US and OUS protocols)

• CDAI clinical response at week 12 (US and OUS protocols)

• SF/APS enhanced clinical response at week 4 (US and OUS protocols)

• SF/APS enhanced clinical response at week 12 (US and OUS protocols)

• CDAI clinical response and endoscopic response at week 12 (US protocol)

• SF/APS enhanced clinical response and endoscopic response at week 12 (OUS protocol).

Results of the sensitivity analysis for all outcomes were consistent with the primary analysis.

FORTIFY Substudy 1 (Maintenance Study)

The secondary outcomes of CDAI clinical response (US and OUS protocols) and SF/APS enhanced clinical response (OUS protocol) at week 52 in the ITT1A population favoured risankizumab versus placebo (Table 22). However, the hierarchical testing strategy prevented formal statistical testing of the significance of these outcomes, and they can be considered to be at increased risk of type I error (false-positive conclusions).

SEQUENCE Study, Part 1 (Induction and Maintenance Ongoing)

||| ||||||||||| ||||||| || |||| |||||||| |||||||| || |||| || || ||| ||||| |||||||||| ||| ||||| |||| |||||||||||| ||| ||||| |||| ||||||||||| ||| |||| ||| ||| || |||||| (Table 23).

Symptoms

MOTIVATE and ADVANCE (Induction Studies)

In both trials, the ranked multiplicity-adjusted secondary outcome FACIT-F scores (US and OUS protocols) at week 12 in the ITT1H population favoured risankizumab versus placebo (Table 26). In the MOTIVATE study, patients in the risankizumab group reported FACIT-F scores that were 2.8 points higher than placebo (95% CI, 0.4 points to 5.1 points; P = 0.02) and in the ADVANCE study, 5.2 points higher than placebo (95% CI, 3.2 points to 7.2 points; P < 0.001), which indicate less fatigue. In the ADVANCE study, patients in the risankizumab group also reported favourable FACIT-F scores at week 4. In the MOTIVATE trial, the evidence was insufficient to show a difference in FACIT-F scores.

In the MOTIVATE and ADVANCE studies, the exploratory outcome of the CSS score in the ITT1A population favoured risankizumab compared to placebo. In the MOTIVATE trial, the least squares mean (LSM) change from baseline at week 12 in the CSS score was –11.0 (standard error [SE] = 0.66) points in the risankizumab group, and –7.5 (SE = 0.70) points in the placebo group, with a between-group adjusted difference in LSM of –3.5 points (95% CI, –5.4 points to –1.6 points). In the ADVANCE trial, the LSM change from baseline at week 12 in CSS score was –11.5 (SE = 0.47) points in the risankizumab group, and –6.0 (SE = 0.69) points in the placebo group, with a between-group adjusted difference in LSM of –5.5 points (95% CI, –7.1 points to –3.9 points).

FORTIFY Substudy 1 (Maintenance Study)

The evidence was insufficient to show a difference between risankizumab and placebo for ranked secondary outcome FACIT-F (US and OUS protocols) scores change from baseline induction at week 52 in the ITT1H population (Table 27).

Table 21: Secondary Clinical Outcomes — MOTIVATE and ADVANCE Induction Trials, ITT1A Population

APS = abdominal pain score; CDAI = Crohn’s Disease Activity Index; CI = confidence interval; ITT1A = intention-to-treat population, the primary efficacy analysis for the MOTIVATE, ADVANCE, and FORTIFY studies; OUS = outside the US; SES-CD = Simple Endoscopic Score for Crohn’s Disease; SF = stool frequency; SF/APS = stool frequency and abdominal pain score.

^aSF remission was defined as average daily SF of 2.8 or less and not worse than baseline.

^bUS analysis plan: Efficacy analyses included randomized patients who received at least 1 dose of study drug during the 12-week induction period and had a baseline-eligible SES-CD score of 6 or more (≥ 4 for isolated ileal disease).

^cAPS remission was defined as an average daily APS of 1 or less and not worse than baseline.

^dCDAI clinical remission was defined as CDAI of less than 150.

^eCDAI clinical response was defined as a reduction of CDAI of 100 points or greater from baseline.

^fOUS analysis plan: Efficacy analyses included randomized patients who received at least 1 dose of study drug during the 12-week induction period and had a baseline-eligible SES-CD score of 6 or more (≥ 4 for isolated ileal disease).

^gSF/APS clinical remission was defined as average daily SF of 2.8 or less and not worse than baseline and an average daily APS of 1 or less and not worse than baseline.

^hSF/APS enhanced clinical response was defined as a 60% or greater decrease in average daily SF and/or a 35% or greater decrease in average daily APS and both not worse than baseline, and/or clinical remission.

^IEndoscopic remission was defined as an SES-CD score of 4 or less and at least a 2-point reduction versus baseline with no subscore greater than 1 in any individual variable, as scored by a central reviewer.

^jUlcer-free endoscopy was defined as an SES-CD ulcerated surface subscore of 0 in patients with an SES-CD ulcerated surface subscore of 1 or more at baseline, as scored by a central reviewer.

^kEndoscopic response was defined as a decrease in the SES-CD score of greater than 50% from baseline (or for patients with isolated ileal disease and a baseline SES-CD score of 4, at least a 2-point reduction from baseline), as scored by a central reviewer.

Sources: MOTIVATE and ADVANCE Clinical Study Reports.^8,9

Table 22: Secondary Clinical Outcomes — FORTIFY Maintenance Trial, ITT1A Population

AP = abdominal pain; APS = abdominal pain score; CDAI = Crohn’s Disease Activity Index; CI = confidence interval; ITT1A = intention-to-treat population, the primary efficacy analysis for the MOTIVATE, ADVANCE, and FORTIFY studies; OUS = outside the US; SC = subcutaneous; SES-CD = Simple Endoscopic Score for Crohn’s Disease; SF = stool frequency; SF/APS = stool frequency and abdominal pain score.

Adjusted treatment difference, 95% CI and P values for comparison of binary end points between risankizumab and placebo were calculated using the Cochran Mantel Haenszel test adjusted for randomization stratification factors (endoscopic response at week 0 [yes or no], clinical remission status at week 0 [yes or no], and by last IV dose during risankizumab induction periods [600 mg]).

^aSF remission was defined as average daily SF of 2.8 or less and not worse than baseline.

^bAP remission was defined as an average daily APS of 1 or less and not worse than baseline.

^cCDAI clinical response was defined as a reduction of CDAI score of 100 points or more from baseline.

^dEnhanced clinical response was defined as a 60% or greater decrease in average daily SF and/or a 35% or greater decrease in the average daily APS and both not worse than baseline, and/or clinical remission.

^eOUS analysis plan: Efficacy analyses included randomized patients who received at least 1 dose of study drug during the 12-week induction period and had a baseline-eligible SES-CD score of 6 or more (≥ 4 for isolated ileal disease).

^fMaintenance of clinical remission was defined as clinical remission at week 52 in patients with clinical remission at week 0.

^gUlcer-free endoscopy was defined as an SES-CD ulcerated surface subscore of 0 in patients with an SES-CD ulcerated surface subscore of 1 or more at baseline, as scored by a central reviewer.

^hEndoscopic remission was defined as an SES-CD score of 4 or less and at least a 2-point reduction versus baseline with no subscore greater than 1 in any individual variable, as scored by a central reviewer.

^ICDAI clinical remission was defined as a CDAI score of less than 150.

^jUS analysis plan: Efficacy analyses included randomized patients who received at least 1 dose of study drug during the 12-week induction period and had a baseline-eligible SES-CD score of 6 or more (≥ 4 for isolated ileal disease).

^kSF/APS clinical remission was defined as average daily SF of 2.8 or less and not worse than baseline of the induction study and an average daily APS of 1 or less and not worse than baseline of the induction study.

^lEndoscopic response was defined as a decrease in the SES-CD score of greater than 50% from baseline (or for patients with isolated ileal disease and a baseline SES-CD score of 4, at least a 2-point reduction from baseline), as scored by a central reviewer.

^mThis consisted of CDAI clinical remission and endoscopic remission.

ⁿThis consisted of SF/APS clinical remission and endoscopic remission.

Source: FORTIFY Clinical Study Report.¹⁰

Table 23: Exploratory Outcomes — SEQUENCE Study, ITT1H Population

APS = abdominal pain score; CDAI = Crohn’s Disease Activity Index; CI = confidence interval; IBDQ = Inflammatory Bowel Disease Questionnaire; ITT1H = intention-to-treat population; LSM = least squares mean; NR = not reported; SC = subcutaneous; SF = stool frequency; SF-36 = Short Form (36) Health Survey; SF/APS = stool frequency and abdominal pain score.

^a||| |||||||| || |||| ||||| |||| ||||||||||| || |||| |||

^b|||||| ||||||||||| |||||||| |||| ||| ||||||| ||| ||||||||||| ||||||||| ||| ||| |||||||| |||| ||| |||||||||| ||| ||||||||||||

Source: SEQUENCE Clinical Study Report.³¹

Mucosal Healing and Endoscopic Response

MOTIVATE and ADVANCE (Induction Studies)

The coprimary outcome of endoscopic response and the secondary outcomes of endoscopic remission and ulcer-free endoscopy in the ITT1A population are summarized in Table 24 and Table 21, respectively. In both trials, the coprimary outcome of endoscopic response at week 12 favoured risankizumab versus placebo. In the MOTIVATE study, the endoscopic response rate with risankizumab was 28.8% versus 11.2% with placebo, with a between-group adjusted difference of 17.7% (95% CI, 9.9% to 25.4%; P < 0.001). In the ADVANCE study, the endoscopic response rate with risankizumab was 40.3% versus 12.0% with placebo, with a between-group adjusted difference of 28.3% (95% CI, 21.2% to 35.4%; P < 0.001). In both trials, the secondary ranked multiplicity-controlled outcomes of endoscopic remission and ulcer-free endoscopy at week 12 favoured risankizumab compared with placebo (Table 24).

The results of subgroup analyses for the coprimary outcome of endoscopic response by bio-IR status was consistent with the primary analysis, and similar across trials. In both trials, results of the sensitivity analysis were consistent with the primary analysis.

FORTIFY Substudy 1 (Maintenance Study)

The coprimary outcome of endoscopic response and the secondary outcomes of ulcer-free endoscopy and endoscopic remission in the ITT1A population are summarized in Table 25 and Table 22, respectively. At week 52, the coprimary outcome of endoscopic response in the risankizumab 360 mg SC group was 46.5% and 22.0% in the withdrawal placebo SC group, with a between-group adjusted difference of 27.8% (95% CI, 18.7% to 37.0%; P < 0.001). The ranked secondary outcomes of ulcer-free endoscopy and endoscopic remission also favoured risankizumab versus placebo (Table 25). However, the hierarchical testing strategy prevented formal statistical testing of all secondary outcomes.

The results of the bio-IR subgroup analysis for the coprimary outcome of endoscopic response were compatible with the primary analysis. In both trials, results of the sensitivity analysis were consistent with the primary analysis.

SEQUENCE Study, Part 1 (Induction and Maintenance Ongoing)

The exploratory outcomes of endoscopic remission and mucosal healing in the ITT1H population are summarized in Table 23. || |||| ||| ||| |||||||| ||||||||||||| |||||||||| ||| |||||||||||| ||| ||||||||||| ||| ||||| ||||| || |||||| ||| |||||||||| ||||||||| ||| ||||| ||||| || |||||| ||| ||||||| |||||||.

Table 24: Endoscopic Response — MOTIVATE and ADVANCE Induction Trials, ITT1A Population

Bio-IR = inadequate response to biologic therapy; CI = confidence interval; ITT1A = intention-to-treat population, the primary efficacy analysis for the MOTIVATE, ADVANCE, and FORTIFY studies; NA = not applicable; non-bio-IR = inadequate response to conventional therapy; NRI-C = nonresponder imputation COVID-19; SES-CD = Simple Endoscopic Score for Crohn’s Disease.

^aEndoscopic response is defined as a decrease in the SES-CD score of greater than 50% from baseline (or for patients with isolated ileal disease and a baseline SES-CD score of 4, at least a 2-point reduction from baseline), as scored by a central reviewer.

^bThe 95% CI for response rate is the synthetic result based on Student’s t-distribution procedure if there are missing data due to COVID-19 or is based on the normal approximation to the binomial distribution if there are no missing data due to COVID-19.

^cThe 95% CI for risk difference or adjusted risk difference based on the Cochran-Mantel-Haenszel test.

^dAcross the strata, the 95% CI for adjusted difference and P value are calculated according to the Cochran-Mantel-Haenszel test adjusted for strata (number of biologics failed, baseline steroid use) for the comparison of the 2 treatment groups. Within each subgroup, 95% CIs for the difference are calculated using normal approximation to the binomial distribution. Testing was done according to the prespecified statistical hierarchy testing procedure.

Sources: MOTIVATE and ADVANCE Clinical Study Reports.^8,9

Table 25: Endoscopic Response — FORTIFY Maintenance Trial, ITT1A Population

Bio-IR = inadequate response to biologic therapy; CI = confidence interval; ITT1A = intention-to-treat population, the primary efficacy analysis for the MOTIVATE, ADVANCE, and FORTIFY studies; non-bio-IR = inadequate response to conventional therapy; NRI = nonresponder imputation; NRI-C = nonresponder imputation COVID-19; SD = standard deviation; SF/APS = stool frequency and abdominal pain score.

^aThe withdrawal (placebo SC) group consisted of patients who achieved SF/APS clinical response to IV risankizumab induction therapy and were randomized to receive placebo in the maintenance study.

^bThe 95% CI for response rate is the synthetic result based on Student's t-distribution if there are missing data due to COVID-19 or based on the normal approximation to the binomial distribution if there are no missing data due to COVID-19.

^cRisk difference equals risankizumab minus placebo. Adjusted risk difference is calculated based on the Cochran-Mantel-Haenszel test.

^dFor overall population, the 95% CI for adjusted difference and P value are calculated according to the Cochran-Mantel-Haenszel test adjusted for strata (endoscopic response at week 0 [yes or no], SF/APS clinical remission status at week 0 [yes or no], and last IV dose during the risankizumab induction period for the comparison of 2 treatment groups). The calculations are based on NRI incorporating multiple imputation to handle missing data due to COVID-19 or NRI only if there are no missing data due to COVID-19.

Source: FORTIFY Clinical Study Report.¹⁰

HRQoL

MOTIVATE and ADVANCE (Induction Studies)

In both trials, scores for ranked multiplicity-adjusted secondary outcomes IBDQ (OUS protocol) and SF-36 PCS (OUS) at week 12 in the ITT1A population favoured risankizumab versus placebo (Table 26). The IBDQ total score in the MOTIVATE study was 12.4 points higher with risankizumab than placebo (95% CI, 5.0 points to 19.8 points; P = 0.001) and in the ADVANCE study, 20.7 points higher with risankizumab than placebo (95% CI, 14.3 points to 27.1 points; P < 0.001), which indicate better HRQoL. The SF-36 PCS score in the MOTIVATE study was 2.22 points higher with risankizumab than placebo (95% CI, 0.58 points to 3.87 points; P = 0.008) and in the ADVANCE study, 2.91 points higher with risankizumab than placebo (95% CI, 1.51 points to 4.31 points; P < 0.001), which indicate better physical health status. In the ADVANCE trial, patients in the risankizumab group also reported favourable HRQoL outcomes at week 4. In the MOTIVATE trial, IBDQ and SF-36 PCS favoured risankizumab versus placebo at week 4. In both trials, results of the SF-36 MCS score at week 12 favoured risankizumab versus placebo; however, it was not adjusted for multiplicity. In both trials, the exploratory outcome EQ-5D-5L score also favoured risankizumab (Table 26).

FORTIFY Substudy 1 (Maintenance)

The evidence was insufficient to show a difference between risankizumab and placebo for ranked secondary outcomes IBDQ (OUS protocol), FACIT-F (US and OUS protocols), and SF-36 PCS (OUS) scores change from baseline induction at week 52 in the ITT1H population (Table 27). For the exploratory outcome EQ-5D-5L score, the evidence was insufficient to show a difference between groups.

SEQUENCE Study, Part 1 (Induction and Maintenance Ongoing)

The exploratory outcomes of IBDQ total score and SF-36 PCS and MCS scores in the ITT1H population are summarized in Table 23. At week 24, ||| |||| |||| ||||| ||||| |||| |||||||| |||| |||||||||||| ||| ||||| ||| ||||| |||| |||||||||||| || |||| ||| ||| |||| ||||| ||| ||| |||||| |||||||||| |||||| |||| |||||||| || ||| |||||||||||| ||||| ||| |||| ||| |||| |||||| |||| ||| |||| || ||| ||||||||||| |||||| ||||||||||||| |||||||| |||||||||| ||| |||| |||||| |||| ||| ||||||||.

Table 26: Secondary and Exploratory Symptom and HRQoL Outcomes — MOTIVATE and ADVANCE Induction Trials, ITT1A Population