CADTH Reimbursement Review

Ozanimod (Zeposia)

Sponsor: Celgene Inc., a Bristol Myers Squibb Company

Therapeutic area: Ulcerative colitis

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.

Introduction

Inflammatory bowel disease (IBD) is a term used to describe disorders that involve chronic inflammation of the digestive tract. There are 2 main types of IBD: Crohn disease and ulcerative colitis (UC). Crohn disease is characterized by inflammation of the lining of the digestive tract, often involving the deep layers of the digestive tract. UC causes inflammation and ulcers in the digestive tract, affecting the innermost lining of the large intestine (colon) and rectum.^1,2 While both diseases are characterized by diarrhea, abdominal pain, rectal bleeding, and weight loss, UC is characterized by blood in the stool with mucus, frequent diarrhea, loss of appetite, and tenesmus (strong urge to use the bathroom without necessarily having a bowel movement).^3,4 The incidence rate for UC in Canada ranges from a low of 8.4 per 100,000 people in Alberta to a high of 21.4 per 100,000 people in Nova Scotia.^5-7 There are an additional 15,000 individuals living with IBD in Canada that are not clearly classified (Crohn disease versus UC).^5-8

Anti-inflammatory drugs are typically used as first-line therapy for mild to moderate UC and include 5-aminosalicylates (5-ASAs) (mesalamine, balsalazide, and olsalazine), sulfasalazine, and corticosteroids. For patients who do not have an adequate response on a 5-ASA or corticosteroid, conventional immunosuppressants such as azathioprine, mercaptopurine, and methotrexate are treatment options. Biologic therapies are the mainstay treatment for patients with moderate to severe UC and are used for induction and maintenance when other treatments have been unsuccessful, or in those who cannot tolerate other treatments. Approximately 5% to 10% of patients with UC may require surgery.⁹ UC surgery typically involves removing the entire colon and rectum and, in most cases, an ileoanal anastomosis procedure is performed. Colectomy is generally reserved for 3 scenarios: development of colorectal dysplasia, complications (e.g., toxic megacolon and/or perforation), and failure of medical therapy.

Ozanimod is an immune modulator that targets the sphingosine 1-phosphate (S1P) 1 receptor (S1P₁) and the S1P 5 receptors (S1P₅) on immune cells. S1P receptors are a specific part of the immune cell that plays an important role in inflammatory conditions such as UC. By binding to the S1P receptors on immune cells, ozanimod is thought to act as a gatekeeper, keeping these cells from moving out of the lymph node and into the circulation, thereby preventing UC inflammation. Ozanimod is administered as an oral capsule, with an initial dosage of 0.23 mg once daily from day 1 to day 4 followed by 0.46 mg once daily from day 5 to day 7. Following the 7-day dose escalation, a stable dose of 0.92 mg once daily is taken orally beginning on day 8.

The objective of this review is to evaluate the beneficial and harmful effects of ozanimod 0.92 mg daily for the treatment of adult patients with moderately to severely active UC who have had an inadequate response, a loss of response, or were intolerant to either conventional therapy or a biologic agent.

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

Patient Input

The patient input received for this review was collected by the Gastrointestinal (GI) Society and Crohn’s and Colitis Canada (CCC). The input provided by the GI Society included more than 1,500 respondents and was sourced from 4 online surveys (2015, 2018, and 2 surveys in 2020) of respondents with IBD, including UC, one-on-one conversations, and phone, email, and social media interactions. The input provided by the CCC came from more than 3,900 respondents with IBD and came from multiple sources, including multiple surveys (late 2017 to early 2018 and 2021) and a phone interview. The CCC input included 8 respondents with experience using Zeposia for UC; all accessed ozanimod through a clinical trial.

Respondents from both the GI Society and the CCC reported that UC has a profound effect on all aspects of life — physically, emotionally, and socially — regardless of whether they are at home, school, or in the workplace. Symptoms associated with UC (such as diarrhea, rectal bleeding, abdominal pain, bloating, cramping, anemia due to blood loss, frequent and urgent bowel movements, and fatigue) not only affect day-to-day living, they also cause anxiety and stress. Respondents from both groups experienced constant concerns about future flare-ups, which can be disrupting. Respondents reported decreased quality of life during periods of active disease, with patients spending a lot of time in the bathroom. Even during periods of remission, respondents reported the need to stay close to a bathroom, thereby limiting their activities. Moreover, due to the perceived stigma of UC, many report hiding their disease from work colleagues, friends, and family. In extreme cases, based on patient input received from the CCC, thoughts of suicide were reported due to the inability to control and cope with the impacts of UC on their personal and social lives, as well as reports of consequences to their career or schooling. Based on the patient input received from the GI Society, only 24% of respondents with IBD reported that the currently available medications are adequate to control their disease. Patient groups indicated that available treatments initially may have helped relieve some of the symptoms, but the treatments were unsuccessful in controlling their symptoms. Respondents reported the need for new and effective treatment options to achieve mucosal healing and reduce or eliminate the debilitating symptoms of UC. Moreover, respondents stressed that sustained remission or treatment response is more important than relieving any 1 symptom.

Clinician Input

Input From the Clinical Experts Consulted by CADTH

The clinical expert consulted by CADTH detailed 4 unmet needs related to therapies for the treatment of UC. First, while currently available therapies are effective, most patients with UC are unable to achieve complete endoscopic remission. As such, better UC therapies are needed to break through the “therapeutic ceiling” of current treatments. Second, it is unknown what the best treatment strategies are for patients with moderate to severe UC. Currently, there are no tools that can predict which patients will respond to which therapy. Third, there is still uncertainty about the ideal long-term therapeutic target and the overall benefits of targeting clinical, endoscopic, and/or histologic remission. Finally, access to coverage for UC treatments presents a major burden to both patients and care providers. Many jurisdictions require the patient’s UC to fail conventional immunosuppressants before biologics are approved.

The clinical expert consulted by CADTH indicated that the novel mechanism of ozanimod would be a valuable addition to the treatment paradigm, since the current therapies for moderate to severe UC are limited. According to the clinical expert, ozanimod may become a first-line advanced therapy among patients whose condition failed to respond to 5-ASAs, given ozanimod’s oral route of administration and efficacy in treating moderate UC. The clinical expert indicated that ozanimod may be considered among patients whose UC has failed other biologic therapies, although the data for its effectiveness after failure of anti–tumour necrosis factor (anti-TNF) therapy are less promising.

Clinician Group Input

No clinician group input was received for this review.

Drug Program Input

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 ozanimod:

• considerations for initiation of therapy

• considerations for continuation or renewal of therapy

• considerations for discontinuation of therapy

• considerations for prescribing of therapy

• generalizability of trial populations to the broader populations in the jurisdictions

• 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 Study

One sponsor-conducted study that met the CADTH review protocol criteria was included in this systematic review. The TRUE NORTH study was a phase III, multicentre, randomized, double-blind, placebo-controlled trial of oral ozanimod as induction and maintenance therapy for adult patients with moderate to severe UC. A total of 645 patients were enrolled across 250 sites from 29 countries in North America (including 8 sites in Canada), Europe, Asia Pacific, South America, and South Africa. The trial consisted of a 10-week induction period followed by a 42-week maintenance period. The induction period was composed of 2 cohorts: cohort 1, in which patients were randomized in a 2:1 ratio to receive either ozanimod 0.92 mg daily (N = 429) or matching placebo (N = 216) in a double-blind fashion, and cohort 2, in which patients received open-label ozanimod 0.92 mg once daily. Patients were evaluated for clinical response and remission at week 10 of the induction period. Patients who had a clinical response to ozanimod at the end of the induction period proceeded to the maintenance period and were re-randomized in a 1:1 ratio to receive either ozanimod 0.92 mg daily (N = 230) or matching placebo (N = 227) in a double-blind fashion. Patients who were randomized to placebo in the induction period and had a clinical response at week 10 continued to receive placebo in the maintenance period.

The primary outcome of the study was clinical remission as measured by the Mayo score, a disease-specific instrument that assesses disease severity and response to treatment in patients with UC. The Mayo scoring system is a combined endoscopic and clinical assessment composed of 4 components: rectal bleeding, stool frequency, Physician’s Global Assessment, and endoscopy findings. Each part is rated from 0 to 3, yielding a total score of 0 to 12. The primary and key secondary end points that relied on the Mayo score were assessed using the 3-component Mayo score, which excludes the Physician’s Global Assessment. The key secondary end points were controlled for multiplicity using a statistical testing hierarchy and each study period was considered an independent study. The primary end point and the following key secondary end points were assessed in both the induction and maintenance periods: clinical response, endoscopic improvement, and mucosal healing. The key secondary end points assessed only in the maintenance period were clinical remission in patients who were in remission at week 10, corticosteroid-free remission, and durability of clinical remission. Other efficacy outcomes included health-related quality of life (HRQoL) outcomes, as assessed by the 5-level EQ-5D (EQ-5D-5L) and the Short Form (36) Health Survey (SF-36), and work productivity, as assessed by the Work Productivity and Activity Impairment Questionnaire – Ulcerative Colitis (WPAI-UC).

Patients who completed the induction period and did not have a clinical response were invited to participate in an optional open-label extension (OLE) study. Patients who completed the maintenance period or those who experienced disease relapse during the maintenance period were also given the opportunity to enter the OLE study.

Nearly 90% of the study patients were white, more than half were male, and the mean age was 42 years. The mean 3-component Mayo score and 4-component Mayo score ranged from 6.6 (standard deviation [SD] = 1.15) to 6.7 (SD = 1.31) and 8.6 (SD = 1.42) to 9.1 (SD = 9.0), respectively, across treatment groups in both study periods. Disease severity as assessed by mucosal appearance at endoscopy was classified as severe in approximately 60% and 50% of patients in the induction period and maintenance period, respectively. All patients had been previously treated with other UC medications. Excluding patients who received placebo during both the induction period and the maintenance period, patients in each treatment group at the start of the induction and maintenance period had previously received the following UC medications: corticosteroids (range, 70% to 78%), oral aminosalicylic acids (97% to 99%), immunomodulators (37% to 46%), azathioprine (30% to 38%), mercaptopurine (less than 10%), methotrexate (less than 6%), anti-TNF biologics (28% to 33%, aside from 44% in the open-label ozanimod group), and non–anti-TNF biologics (14% to 29%).

Efficacy Results

Key efficacy results are presented in Table 2.

Clinical Remission

Clinical remission was measured at week 10 and week 52 using a 7-day scoring algorithm and was defined as a rectal bleeding subscore (RBS) of 0, a stool frequency subscore (SFS) of 0 or 1 (and a decrease of at least 1 point from the baseline SFS), and an endoscopy subscore of 0 or 1 point without friability. The proportion of patients in clinical remission was significantly higher among patients in cohort 1 of the induction period who received ozanimod compared with those who received placebo (18.4% versus 6.0%; difference in proportions of 12.4%; 95% confidence interval [CI], 7.5% to 17.2%; P < 0.0001) at week 10 and among patients who continued to receive ozanimod in the maintenance period compared with those who were re-randomized to placebo (37.0% versus 18.5%; difference in proportions of 18.6%; 95% CI, 10.8% to 26.4%; P < 0.0001).

Clinical Response

Clinical response was measured using a 7-day scoring algorithm and was defined as a reduction from baseline in the 3-component Mayo score of at least 2 points and at least 35%, and a reduction from baseline in the RBS of at least 1 point or an absolute RBS of 0 or 1. The proportion of patients with clinical response was significantly higher with ozanimod compared with placebo during both the induction period (47.8% versus 25.9%; difference in proportions of 21.9%; 95% CI, 14.4% to 29.3%; P < 0.0001) and the maintenance period (60.0% versus 41.0%; difference in proportions of 19.2%; 95% CI, 10.4% to 28.0%; P < 0.0001).

Durable Clinical Remission

The proportion of patients with durable clinical remission, defined as patients in clinical remission at week 10 and at week 52 in all patients who entered the maintenance period, was significantly greater in patients who remained on ozanimod compared with patients re-randomized to placebo (17.8% versus 9.7%; difference in proportions of 8.2%; 95% CI, 2.8% to 13.6%; P = 0.003).

Maintenance of Clinical Remission

The proportion of patients who maintained clinical remission at week 52 in a subset of patients who were in clinical remission at week 10 was greater among those who remained on ozanimod compared with patients re-randomized to placebo in the maintenance period (51.9% versus 29.3%; difference in proportions of 23.9%; 95% CI, 9.1% to 38.6%; P = 0.0025).

Endoscopic Improvement

Endoscopic improvement was defined as an endoscopy subscore of 0 or 1 without friability. A greater proportion of patients randomized to ozanimod had endoscopic improvement compared with patients randomized to placebo at week 10 (27.3% versus 11.6%; difference in proportions of 15.7%; 95% CI, 9.7% to 21.7%; P < 0.0001). At week 52, the proportion of patients with endoscopic improvement was greater in patients who continued on ozanimod compared with those re-randomized to placebo (45.7% versus 26.4%; difference in proportions of 19.4%; 95% CI, 11.0% to 27.7%, P < 0.001).

Mucosal Healing

Mucosal healing was defined as an endoscopy subscore of 0 or 1 without friability and a Geboes score of less than 2. A greater proportion of patients randomized to ozanimod had mucosal healing compared with patients randomized to placebo at week 10 of the induction period (12.6% versus 3.7%; difference in proportions of 8.9%; 95% CI, 4.9% to 12.9%; P < 0. 001). At week 42 of the maintenance period (week 52 of the study), the proportion of patients with mucosal healing was greater in patients who continued on ozanimod compared with those re-randomized to placebo (29.6% versus 14.1%; difference in proportions of 15.6%; 95% CI, 8.2% to 22.9%; P < 0.001).

Corticosteroid-Free Remission

The proportion of patients with corticosteroid-free remission at week 52 (clinical remission while off corticosteroids for at least 12 weeks) was greater among patients who remained on ozanimod compared with those re-randomized to placebo (31.7% versus 16.7%; difference in proportions of 15.2%; 95% CI, 7.8% to 22.6%; P < 0.001).

Harms Results

Key harms results are presented in Table 2.

Table 2: Summary of Key Results From the TRUE NORTH Trial

CI = confidence interval; CMH = Cochran-Mantel-Haenszel; ITT = intention to treat; OZ = ozanimod; PL = placebo; RBS = rectal bleeding subscore; SD = standard deviation; SFS = stool frequency subscore; TEAE = treatment-emergent adverse event; TNF = tumour necrosis factor.

^aProportion of participants in clinical remission at week 10 week of the induction period (ITT population, nonresponder imputation).

^bProportion of participants in clinical remission at week 52 of the total treatment maintenance period (ITT population, nonresponder imputation).

^cClinical remission was measured using the 3-component Mayo score definition using a 7-day scoring algorithm and defined as an RBS of 0 and an SFS of ≤ 1 point (and a decrease of ≥ 1 point from the baseline SFS) and an endoscopy subscore of ≤ 1 point without friability.

^dOdds ratio (active vs. PL), treatment difference, and 2-sided 95% Wald CI and P value for comparison between the cohort 1 OZ group and PL groups are based on the CMH test, stratified by corticosteroid use at screening and prior anti-TNF use (yes or no). For the maintenance period analysis, the comparison between the OZ 1 mg to OZ 1 mg group vs. the OZ 1 mg to PL group is based on the CMH test, stratified by remission status at week 10 and corticosteroid use at week 10 (yes or no).

^eClinical response was measured using the 3-component Mayo score definition using a 7-day scoring algorithm and defined as a reduction from baseline in the 3-component Mayo score of ≥ 2 points and ≥ 35%, and a reduction from baseline in the RBS of ≥ 1 point or an absolute RBS of ≤ 1 point.

Source: Clinical Study Report for the TRUE NORTH study.¹⁰

Adverse Events

During the induction period, at least 1 treatment-emergent adverse event (TEAE) was reported by 40.1% and 38.0% of patients in the cohort 1 ozanimod group and cohort 1 placebo group, respectively. Among patients re-randomized to placebo and those who continued on ozanimod during the maintenance period, 36.6% and 49.1% of patients reported at least 1 TEAE, respectively.

The TEAEs reported by at least 2% of patients in any treatment group during the induction period were anemia, nasopharyngitis, headache, nausea, alanine aminotransferase increase, pyrexia, arthralgia, colitis ulcerative, and upper respiratory tract infection. Of these, anemia, nausea, and pyrexia were not reported by any patients during the maintenance period; the remaining TEAEs were reported by patients in a proportion similar to the induction period. Apart from anemia, which was reported in 4.2% to 5.6% of patients, these TEAEs were reported in less than 4% of any treatment group. The following commonly reported TEAEs were exclusive to re-randomized patients in the maintenance period: gamma-glutamyl transferase increased (0.4% to 3.0%), edema peripheral (2.6%), and herpes zoster (0.4% to 2.2%).

Serious Adverse Events

During the induction period, serious TEAEs were reported by 4.0% and 3.2% of patients in the cohort 1 ozanimod group and cohort 1 placebo group, respectively. The most common serious TEAE reported in the induction period was colitis ulcerative in both treatment groups (approximately 1.4%). Additional serious TEAEs reported in the cohort 1 ozanimod group were anemia (0.9%) and appendicitis (0.2%).

During the maintenance period, 7.9% of the patients re-randomized to placebo and 5.2% of the patients who continued ozanimod reported at least 1 serious TEAE. The serious TEAEs reported in at least 2 patients in the re-randomized placebo group included colitis ulcerative (4% in the re-randomized placebo group and 0.4% in the ozanimod group) and complicated appendicitis (0.9% in the re-randomized placebo group).

Withdrawals Due to Adverse Events

Withdrawal from the study due to TEAEs during the induction period was similar across the treatment groups at approximately 3%. The most common reason for withdrawal due to TEAEs was colitis ulcerative (0.7% in the cohort 1 ozanimod group and 1.9% on the cohort 1 placebo group). Two patients (0.5%) in the cohort 2 ozanimod group discontinued from the study due to bradycardia.

The percentage of patients who withdrew from the study due to TEAEs during the maintenance period was 2.6% among those re-randomized to placebo and 1.3% in patients who remained on ozanimod. Four (1.8%) patients in the group re-randomized to placebo withdrew from the study due to colitis ulcerative.

Mortality

During the study period, only 1 death was reported, which was recorded in the induction period cohort 2 ozanimod group.

Notable Harms

Of the serious or opportunistic infections reported, the only infection reported in at least 2 patients in any treatment group was herpes zoster (0.5% in the induction period cohort 1 ozanimod group; 0.3% in the induction period cohort 2 ozanimod group; 1.7% in the maintenance period ozanimod group). Each of the following infections was reported in 1 patient over all treatment groups and periods: pyelonephritis, vestibular neuronitis, pneumonia influenza, respiratory syncytial virus test positive, urinary tract infection, Clostridium difficile infection, complicated appendicitis, gastroenteritis norovirus, large intestine infection, measles, and yersinia infection.

Macular edema was reported by 1 patient in both the induction period cohort 1 ozanimod group and the maintenance period ozanimod group.

During the induction period, only the cohort 1 ozanimod group reported hepatic effects (0.5% or less of the group), including alanine aminotransferase increased, hepatic enzyme increased, aspartate aminotransferase increased, liver function test increased, and transaminases increased. In the maintenance period, blood bilirubin increase was reported in 1 patient re-randomized to placebo. Among patients who remained on ozanimod, alanine aminotransferase increase, and liver function test increase were each reported in 1 patient.

Lymphopenia was reported in 2 (0.9%) patients in the maintenance period ozanimod group.

Critical Appraisal

The TRUE NORTH trial was limited by differential dropout between treatment groups in the maintenance period and a study design that resulted in an enriched patient population entering the maintenance period. Although approximately 90% of randomized patients completed the induction period, only approximately 50% had a clinical response and continued into the maintenance period. As selection into the maintenance period was based on clinical response, this likely created an enriched patient population that was more likely to benefit from ozanimod treatment compared with the indicated population as a whole. According to the clinical expert consulted by CADTH, this is a common trial design used in UC programs, as it is challenging to keep nonresponders in a long-term study. Furthermore, of those who continued into the maintenance period, the proportion of patients who completed the trial among the patients re-randomized to receive placebo versus those who continued to receive ozanimod was 54.6% and 80%, respectively. Following disease relapse, a greater proportion of patients in the re-randomized placebo group compared with the ozanimod group discontinued the maintenance period to enter the OLE study (35.7% versus 14.8%, respectively). Although the direction of any bias is unclear, it is possible that the differential dropout rate between the 2 treatment groups may have introduced attrition bias in favour of ozanimod.

Patients had the opportunity to enrol in the OLE study where they would receive open-label ozanimod. There was significant study discontinuation due to disease relapse and entry into the OLE study (34% of patients re-randomized from ozanimod to placebo and 14% of patients re-randomized from ozanimod to ozanimod). Additionally, there may be a subset of patients who experience a delayed response to induction therapy, and they would not have been eligible to continue in the maintenance period. All of these factors contribute to the difficulty in assessing the generalizability of the efficacy results.

Indirect Comparisons

Description of Studies

Two indirect treatment comparison (ITC) studies were reviewed. The sponsor-submitted ITC was a systematic review and network meta-analysis (NMA) comparing ozanimod with currently existing medications for the treatment of moderate to severe UC.¹¹ One NMA study (Lasa et al.)¹² that included ozanimod for patients with moderate to severe UC was included from the CADTH literature search.

In the sponsor-submitted ITC, ozanimod was compared with ustekinumab, infliximab, certolizumab, adalimumab, vedolizumab, tofacitinib, golimumab, filgotinib, etrasimod or the biosimilar versions of these therapies, and placebo. Phase II or III randomized controlled trials (RCTs) were included. Clinical response, clinical remission, endoscopic improvement, and safety were evaluated. In the Lasa et al. study, ozanimod was compared with infliximab, adalimumab, golimumab, vedolizumab, ustekinumab, tofacitinib, etrolizumab, upadacitinib, filgotinib, etrasimod, TD-1473, and placebo. Phase III RCTs were included in this report. In the Lasa et al. report, clinical remission and endoscopic improvement were evaluated. Safety outcomes were examined in the 2 ITCs.

In the sponsor-submitted ITC, 22 RCTs were included in the analyses. Bayesian NMAs were performed using random-effects or fixed-effects models in all analyses. Due to the significant heterogeneity observed across the included trials, especially the study designs that are common in UC, adjustments were made to the data in older treat-through trials to more closely resemble modern re-randomized trials in the maintenance phase. The mean age of patients in the induction phase ranged from 34.1 to 44.8 years, and the mean Mayo score ranged from 8.0 to 9.1. The sponsor report noted differences between trials with respect to the percentage of males (range, 42% to 100%), mean C-reactive protein (CRP) level at baseline (range, 7 mg/L to 35.8 mg/L), years since UC diagnosis (range, 3.8 to 14.6 years), extent of disease (left-sided: range, 15% to 63%; extensive: range, 6.6% to 80.8%; other: range, 0 to 63.4%), and use of concomitant steroids (range, 25% to 100%). In the maintenance phase, baseline characteristics were reported only for the re-randomized arms of the re-randomized trials. Patients in maintenance phase trials were mostly similar in terms of age and sex. The mean Mayo score was similar for most trials. In the Lasa et al. report, NMAs were conducted using the multivariate frequentist approach on 23 RCTs. The mean age of patients in the induction phase ranged from 34.4 to 43 years, and females comprised 33.7% to 45.5% of the study populations. Eleven trials required patients to be naive to anti-TNF biologics at study entry. Among studies that allowed but did not require prior therapy with anti-TNF biologics, there was variation in the percentage of patients who did have prior therapy with these drugs (15% to 58%). Reporting of disease duration varied across studies but appear comparable among studies (mean = 3.8 to 14.6 years). Of the 22 studies evaluating maintenance therapy, 10 were done using a treat-straight-through strategy and 12 followed a randomized responders design. Patients in the maintenance phase ranged in mean age from 34.4 to 43 years, and females comprised 33.7% to 47.7% of the study populations.

Efficacy Results

In the sponsor’s report, results from the NMA suggested that for the induction phase, in the overall population, no treatment was favoured when ozanimod was compared with other active treatments for clinical response. Similar results were found for the biologic-naive patients. Among biologic-exposed patients, there was no evidence for a difference between ozanimod and other relevant active treatments, except that ozanimod was favoured over adalimumab (odds ratio [OR] = 3.13; 95% credible interval [CrI], 1.42 to 7.31). For the maintenance phase, in the overall population, results of the NMA showed no evidence for a difference between ozanimod and other active treatments, except that ozanimod had a less favourable clinical response compared with vedolizumab 300 mg every 8 weeks (OR = 0.55; 95% CrI, 0.34 to 0.92), tofacitinib 5 mg (OR = 0.57; 95% CrI, 0.33 to 0.97), and tofacitinib 10 mg (OR = 0.40; 95% CrI, 0.23 to 0.69). For the biologic-naive population, ozanimod had a less favourable clinical response compared with vedolizumab 300 mg every 8 weeks (OR = 0.47; 95% CrI, 0.24 to 0.87), tofacitinib 5 mg (OR = 0.45; 95% CrI, 0.22 to 0.89), and tofacitinib 10 mg (OR = 0.36; 95% CrI, 0.18 to 0.72). For biologic-exposed patients, there was no evidence for a difference between ozanimod and any of the active comparators.

In the sponsor’s report, for the outcome of clinical remission, for the induction phase, no treatment was favoured when ozanimod was compared with other active treatments in the overall population. Similar results were found for the biologic-naive patients. Among biologic-exposed patients, there was no evidence for a difference between ozanimod and other active treatments, except that ozanimod was favoured over adalimumab (OR = 4.19; 95% CrI, 1.56 to 11.49). For the maintenance phase, there was no evidence for a difference between ozanimod and other active treatments, except that ozanimod had a less favourable rate of clinical remission compared with vedolizumab 300 mg every 8 weeks (OR = 0.56; 95% CrI, 0.34 to 0.92), tofacitinib 5 mg (OR = 0.57; 95% CrI, 0.34 to 0.97), and tofacitinib 10 mg (OR = 0.40; 95% CrI, 0.24 to 0.69). For the biologic-naive population, ozanimod had a less favourable rate of clinical remission compared with vedolizumab 300 mg every 8 weeks (OR = 0.47; 95% CrI, 0.25 to 0.88), tofacitinib 5 mg (OR = 0.45; 95% CrI, 0.23 to 0.89) and tofacitinib 10 mg (OR = 0.37; 95% CrI, 0.19 to 0.72). For biologic-exposed patients, there was no evidence for a difference between ozanimod and any of the active comparators. In the Lasa et al. report, no treatment was favoured when ozanimod was compared with other active treatments for induction of clinical remission in the overall population, in biologic-naive patients, and in biologic-exposed patients.

In the sponsor’s report, for the outcome of endoscopic improvement, for the induction phase, the NMA results found there was no evidence for a difference between ozanimod and other active comparators, except that ozanimod was favoured over adalimumab in the overall population (OR = 2.04; 95% CrI, 1.16 to 3.76) and in biologic-naive patients (OR = 2.04; 95% CrI, 1.16 to 3.76). Among biologic-exposed patients, no active treatments were favoured over others for endoscopic improvement. For the maintenance phase, there was no evidence for a difference between ozanimod and other active comparators, except that ozanimod had a less favourable rate of endoscopic improvement compared with vedolizumab 300 mg every 4 weeks (OR = 0.46; 95% CrI, 0.24 to 0.88) and tofacitinib 10 mg (OR = 0.42; 95% CrI, 0.22 to 0.79). For the biologic-naive population, ozanimod had a less favourable rate of endoscopic improvement compared with tofacitinib 10 mg (OR = 0.34; 95% CrI, 0.15 to 0.77). For biologic-exposed patients, there was no evidence for a difference between ozanimod and any of the active comparators. In the Lasa et al. report, the endoscopic improvement results of the ITC suggested that ozanimod was favoured over adalimumab for the overall population (OR = 1.79; 95% CI, 1.07 to 3.01) and in biologic-naive patients (OR = 2.07; 95% CI, 1.14 to 3.74). In biologic-exposed patients, no treatment was favoured over another for induction of endoscopic improvement.

Harms Results

The NMA results showed there was no evidence for a difference between ozanimod and other relevant active treatments in the incidence of any adverse events (AEs), SAEs, and AEs leading to discontinuation for either the induction or maintenance phases. For incidence of serious infections at induction, there was no evidence for a difference between ozanimod and any of the active comparators, except that golimumab was favoured over ozanimod (OR = 0.04; 95% CrI, 0 to 0.79). At maintenance, there was no evidence for a difference between ozanimod and other active treatments in the incidence of serious infections.

Critical Appraisal

A significant concern with the ITCs presented is that the studies included in the analyses were highly heterogeneous in terms of both study design and patient characteristics. One of the major concerns with design heterogeneity in UC trials is how trials transition from the induction to the maintenance phase. In the sponsor-submitted ITC, adjustments were made to the data in older treat-through trials to more closely resemble modern re-randomized trials in the maintenance phase to alleviate the impact of heterogeneity in study design on result interpretation. Different approaches have been adopted to address this heterogeneity, for example, using recalculated data from treat-through studies to mimic a re-randomized trial, or including only re-randomized trials. Results of this sensitivity analysis suggested that exclusion of the recalculated treat-through data did not alter the results from the base-case analyses.

Other significant heterogeneities can be found in the definition of clinical outcomes, timing of study end point evaluation, subgroup definitions, and patients’ baseline characteristics. In the sponsor’s ITC, a number of trial and patient characteristics were considered treatment-effect modifiers. Despite various statistical techniques being employed to lessen the impact of potential clinical heterogeneity on the estimated treatment effect of ozanimod, there is still significant uncertainty in the ITC results. In the Lasa et al. report, patients’ baseline characteristics were not reported in detail; therefore, limited data are available to examine the treatment effect and safety of ozanimod in the study population, particularly in the subgroups of patients who were biologic-naive and biologic-exposed. In addition, there was insufficient analysis conducted to account for trial and clinical heterogeneity, thus limiting the utility and robustness of the results.

In both ITCs, safety data were sparse and available for the overall population only. In addition, wider CrIs are observed due to the low event rate for some of the safety outcomes, such as AEs leading to discontinuation and serious infections; thus, the interpretation of the results is challenging.

Other Relevant Evidence

Description of Studies

The phase III OLE study was summarized to provide additional evidence regarding the long-term safety and efficacy of ozanimod for the treatment of patients with moderately or severely active UC at the time points beyond the TRUE NORTH parent study. The OLE study included patients who completed at least 10 weeks of the induction period without experiencing a clinical response or completed the maintenance period to week 52, or those who experienced disease relapse during the maintenance period of the TRUE NORTH trial.¹³ Of the 824 patients who entered the OLE study from the TRUE NORTH trial, 43.4% were enrolled after completing the induction period, 39.9% entered after completing the maintenance period, and 16.6% entered after discontinuing from the maintenance period.

Efficacy Results

The long-term efficacy of ozanimod as measured in the OLE study found that at week 46, ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||. However, by week 142, the treatment response rates decreased markedly. The results from the OLE study; however, were limited by the relatively small number of patients evaluated at each assessment point. Additionally, there was a high rate of treatment discontinuations (38.6%) during the OLE study, mostly due to lack of response, patient decision, and AEs.

Harms Results

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Critical Appraisal

The OLE was a single-group study that did not include an active or placebo comparison group; without a comparison group, it is not possible to know the true benefit of treatment and it is difficult to interpret results. All efficacy end points were descriptive, as there was no formal statistical testing. Although certain procedures have been performed to maintain blinding to the treatment assignment from the parent trial, the open-label administration of the drug could introduce bias, as knowledge of the treatment may lead patients and investigators to overestimate its potential benefits and harms. The treatment response rates were higher in the patients who were re-randomized to placebo in the TRUE NORTH study. This may be explained by the longer follow-up period for these patients, as they were more likely to discontinue treatment earlier in the original study. The eligibility criteria of the OLE study specified that patients had to complete the induction or maintenance periods of the parent TRUE NORTH study, or discontinue the maintenance period due to disease relapse, which potentially allowed for selection bias. Patients who did not have a treatment response at study entry could discontinue the study treatment if no clinical improvement was observed from the baseline visit of the TRUE NORTH study by week 10. Additionally, there was a high rate of treatment discontinuations |||||||||| during the OLE study, mostly due to lack of response, patient decision, and AEs. This may have resulted in the enrolment of more patients who were better able to tolerate ozanimod and, as a result, there were fewer reports of AEs. The inclusion of patients with no initial response to ozanimod during the TRUE NORTH parent trial (68.2%) is likely to underestimate the benefit observed during this extension study compared with the maintenance period of the parent study. Given that this was an ongoing study, the results were limited to the interim analysis as of March 31, 2020, and there were small numbers of evaluable patients, especially at weeks 96 and 142.

Conclusions

Based on the TRUE NORTH trial, ozanimod was efficacious in achieving induction and maintenance of clinical remission and clinical response in patients with moderately or severely active UC. Moreover, ozanimod was also found to be efficacious in achieving endoscopic improvement, mucosal healing, corticosteroid-free remission, durable clinical remission, and maintenance of clinical remission. However, the generalizability of the results to the real-world setting is limited due to the re-randomization study design and the option for enrolment into an open-label trial during the maintenance period. Based on the available ITCs, it remains uncertain how ozanimod compares with other advanced treatments for moderate to severe UC in efficacy and safety.

Introduction

Disease Background

IBD is a term used to describe disorders that involve chronic inflammation of the digestive tract. There are 2 main types of IBD: Crohn disease and UC. Crohn disease is characterized by inflammation of the lining of the digestive tract, often involving the deep layers of the digestive tract. UC causes inflammation and ulcers in the digestive tract, affecting the innermost lining of the large intestine (colon) and rectum.^1,2 While both diseases are characterized by diarrhea, abdominal pain, rectal bleeding, and weight loss, UC is characterized by blood in the stool with mucus, frequent diarrhea, loss of appetite, and tenesmus (strong urge to use the bathroom without necessarily having a bowel movement).^3,4 While the etiology of UC is not completely understood, there is growing evidence to suggest that genetic and environmental factors may contribute to the irregular immune response that aberrantly recruits activated immune cells to the colon,³ which results in chronic inflammation that damages the colon and causes the UC symptoms. UC generally develops in young adulthood^5-7 and persists throughout life, marked by periods of spontaneous remission and relapse.¹⁴ The most common initial manifestation of UC is bloody diarrhea with or without mucus. In addition to frequent evacuations with blood and mucus, other symptoms include urgency or tenesmus of evacuations, fever, abdominal pain, and weight loss.^3,4

While endoscopic procedures with tissue biopsy are the only way to definitively diagnose UC, the path to a UC diagnosis also includes a review of medical history, a physical exam, and a series of medical tests. Part of the diagnosis process involves laboratory testing of blood and fecal matter to eliminate the possibility that symptoms are being caused by enteric infections from bacteria, viruses, or parasites. In addition, tests to rule out other forms of IBD, such as Crohn disease, are performed.

UC has a worldwide annual incidence rate of 1.2 to 20.3 cases per 100,000 people and a prevalence of 7.6 to 246.0 cases per 100,000 people.³ The highest age-standardized prevalence rate of IBD in 2017 occurred in high-income countries in North America,¹⁵ with Canada having 1 of the highest rates in the world.⁵ Estimated annual incidence rates for UC in Canada range from a low of 8.4 per 100,000 people in Alberta to a high of 21.4 per 100,000 people in Nova Scotia.^5-7 There are an additional 15,000 individuals living with IBD in Canada who do not have a confirmed diagnosis of Crohn disease or UC (termed indeterminate colitis).⁸

The majority of individuals living with UC have a mild to moderate disease course; generally with active disease at diagnosis followed by alternating exacerbations and longer periods of remission.¹⁶ However, an aggressive disease course is experienced in 10% to 15% of patients, with a cumulative risk of relapse of between 70% and 80% at 10 years postdiagnosis.¹⁶ Regardless of severity, UC is associated with high rates of fatigue and sleep difficulties.¹⁶ According to patient input received for this review, the need to be near and the time spent in bathrooms is disruptive to work and social obligations, which in turn has negative physical, emotional, and social impacts. Approximately half of all patients required UC-related hospitalization at some point during the disease course. Moreover, approximately 1.5% of patients with UC are diagnosed with colorectal cancer, typically after prolonged active inflammation. While UC is not associated with an increased risk of all-cause mortality after the first year after diagnosis,¹⁷ gastrointestinal-specific mortality may be increased.^16,17

UC has a tremendous economic and societal burden due to its impact on school, work, and social interaction. In Canada, approximately $1.2 billion is spent on health care utilization costs in patients with IBD, and an estimated indirect cost of $1.5 billion is borne due to loss of work and productivity, disability coverage, and premature retirement or death.^18,19 In fact, the annual cost due to medical absenteeism is approximately $88 million,⁹ while the estimated lifetime lost wages due to premature retirement due to UC is $994,760 per person.⁹ Furthermore, 56% to 74% of people living with IBD in Canada have reported paying out of pocket for complementary and alternative medicines,^20-22 with no difference between patients with Crohn disease and those with UC.²⁰

Standards of Therapy

According to the clinical expert consulted by CADTH for the purpose of this review, the immediate goal of UC treatment is improvement in symptoms (i.e., induction of clinical remission), as patients can be severely affected by rectal bleeding, urgency, and diarrhea. Reduction in biomarkers of inflammation, such as fecal calprotectin, is an intermediate-term goal. Long-term treatment goals, as indicated by the clinical expert, are to induce and maintain endoscopic remission and, possibly, to achieve mucosal healing (a composite of both endoscopic and histologic healing), alter the normal course of the disease (i.e., avoidance of colectomy and hospitalization), and normalize quality of life. These goals are consistent with the recently published Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE)-II consensus guidelines. However, as described by the clinical expert, many patients with UC are left with residual symptoms (most frequently, abnormal stool frequency) even after achieving long-term resolution of rectal bleeding or endoscopic remission.

Anti-inflammatory drugs are typically used as first-line therapy for mild to moderate UC and include 5-ASAs (mesalamine, balsalazide, and olsalazine), sulfasalazine, and corticosteroids. The clinical expert indicated that patients with UC are initially treated with a 5-ASA, with corticosteroids added for induction therapy in patients with more severely active disease. The choice of 5-ASA and its route of administration (e.g., oral or as an enema or suppository) depends on the extent of the colon that is affected. Patients with acute severe UC in hospital typically receive IV corticosteroids. Due to the side effects associated with corticosteroids, they should be reserved for induction therapy and not considered for long-term maintenance therapy.

For patients who do not have an adequate response on a 5-ASA or corticosteroid, conventional immunosuppressants, such as azathioprine, mercaptopurine, and methotrexate, are treatment options. The clinical expert noted that many public drug plans require that, to be eligible for an advanced therapy such as a biologic, the patient’s condition must have failed to respond to conventional immunosuppressants; however, conventional immunosuppressants are generally ineffective as induction therapy and have considerable toxicities.

Biologic therapies are the mainstay treatment for patients with moderate to severe UC. They are used for induction and maintenance when other treatments have been unsuccessful or when patients cannot tolerate other treatments. There are 3 main classes of biologics used to treat UC: anti-TNF drugs (infliximab, adalimumab, and golimumab), anti-integrin drugs (vedolizumab), and anti–interleukin-12 and -23 drugs (ustekinumab). Tofacitinib, a Janus kinase inhibitor, is a small-molecule drug that is also considered an advanced therapy, along with biologics. According to the clinical expert, all of these drugs are effective, and each has its own advantages and disadvantages with respect to safety, convenience, and efficacy. The clinical expert indicated that infliximab is generally used for patients who have acute severe UC in the hospitalized setting. While tofacitinib has excellent efficacy, its safety profile is potentially concerning. Accordingly, tofacitinib has largely been relegated to second-line therapy. Patients who do not have a response to, lose response to, or are intolerant to 1 advanced therapy can move to a different advanced therapy, with consideration for the reason for treatment failure as an important determinant of the choice of second-line drug.

Patients with UC may also be prescribed other medications to manage specific symptoms, which may include antidiarrheal medications, pain relievers, antispasmodics, and iron supplements. The clinical expert consulted by CADTH indicated that while some patients with UC will seek out complementary or alternative medicines, these therapies are generally not effective for the long-term management of moderately to severely active UC.

Approximately 5% to 10% of patients with UC may require surgery.⁹ UC surgery typically involves removing the entire colon and rectum (proctocolectomy) and in most cases, an ileoanal anastomosis (J-pouch) procedure is performed. The procedure involves the construction of a pouch from the end of the small intestine which is then attached directly to the anus to allow for relatively normal evacuation. According to the clinical expert consulted by CADTH, colectomy is generally reserved for 3 scenarios: development of colorectal dysplasia; complications (e.g., toxic megacolon and/or perforation); and failure of medical therapy.

Drug

Ozanimod is an immune modulator that targets the S1P₁ and S1P₅ receptors on immune cells. S1P receptors are a specific part of the immune cell that plays an important role in inflammatory conditions such as UC. By binding to the S1P receptors on immune cells, ozanimod is thought to act as a gatekeeper, keeping these cells from moving out of the lymph nodes and into the circulation.

On April 8, 2022, ozanimod received a Notice of Compliance from Health Canada for the treatment of adult patients with moderately to severely active UC who have had an inadequate response, a loss of response, or were intolerant to either conventional therapy or a biologic drug. Ozanimod has been previously approved by Health Canada for the treatment of adult patients with relapsing-remitting multiple sclerosis to decrease the frequency of clinical exacerbation and has been previously reviewed by CADTH for this indication.

Ozanimod received approval from the FDA in May 2021 for the treatment of moderately to severely active UC in adults.²³ Ozanimod received approval from the European Medicines Agency in May 2020 for the treatment of adult patients with moderately to severely active UC who have had an inadequate response, lost response, or were intolerant to either conventional therapy or a biologic drug.²⁴

Ozanimod is administered as an oral capsule at a dosage of 0.23 mg once daily from day 1 to day 3, 0.46 mg once daily from day 5 to day 7, and 0.92 mg once daily from day 8 onward.

Key characteristics of commonly used medical treatments for UC are presented in Table 3.

Stakeholder Perspectives

Patient Group Input

This section was prepared by CADTH staff based on the input provided by patient groups. The full patient group submissions are included in the Stakeholder Input section at the end of this report.

The patient input received for this review was collected by the GI Society and the CCC. The input provided by the GI Society included more than 1,500 respondents with IBD, including UC, and was sourced from 4 online surveys (conducted in 2015, 2018, and 2 conducted in 2020), one-to-one conversations, and phone, email, and social media interactions. The input provided by the CCC consisted of more than 3,900 respondents with IBD and was sourced from multiple surveys (conducted from late 2017 to early 2018 and in 2021) and a phone interview. The CCC input included 8 respondents with experience using ozanimod for UC; all accessed ozanimod through a clinical trial.

Respondents from both groups reported that UC has had a profound effect on all aspects of their life — physically, emotionally, and socially — regardless of whether they are at home, at school, or in the workplace. Symptoms associated with UC such as diarrhea, rectal bleeding, abdominal pain, bloating, cramping, anemia due to blood loss, frequent and urgent bowel movements, and fatigue not only affect day-to-day living, but also cause anxiety, stress, and isolation. Respondents from both groups experienced constant concerns about future flare-ups, which can be disruptive. Respondents reported decreased quality of life during periods of active disease, with patients spending a lot of time in the bathroom. Even during periods of remission, respondents reported the need to stay close to a bathroom, thereby limiting their activities. Moreover, due to the perceived stigma of UC, many report hiding their disease from work colleagues, friends, and family. In extreme cases, based on patient input received from the CCC, thoughts of suicide were reported due to the inability to control and cope with the impacts of UC on their personal and social lives, as well as consequences on their career or schooling. Based on the patient input received from the GI Society, only 24% of respondents with IBD reported that the currently available medications are adequate to control their disease. Patient groups indicated that available treatments may have helped initially to relieve some of the symptoms, but the treatments were unsuccessful in controlling their symptoms. Respondents reported the need for new and effective treatment options to achieve mucosal healing and reduce or eliminate the debilitating symptoms of UC. Moreover, respondents stressed that sustained remission or treatment response is more important than relieving any 1 symptom.

Six of the 8 respondents who were prescribed ozanimod reported treatment benefits, such as ease of use and improved symptoms and quality of life, with a general sense of feeling healthier and happier. One respondent discontinued use of ozanimod due to multiple side effects, including headache, serious infection, joint pain, and nasopharyngitis. Half of the respondents indicated the ozanimod capsules were difficult to swallow.

Clinician Input

Input From the 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, and 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 UC.

Unmet Needs

The clinical expert consulted by CADTH detailed 4 unmet needs related to therapies for the treatment of UC. First, while currently available therapies are effective, most patients with UC are unable to achieve complete endoscopic remission. As such, better UC therapies are needed to break through the “therapeutic ceiling” of current treatments. Second, it is unknown what the best treatment strategies are for patients with moderate to severe UC. Currently, there is no way to predict which patients will respond to which therapy; as a result, the appropriate sequencing of advanced therapies is unclear. Third, there is still uncertainty about the ideal long-term therapeutic target and the overall benefits of targeting clinical, endoscopic, and/or histologic remission. Finally, although access to advanced therapies is generally excellent in Canada compared with other countries, access to coverage for UC treatments continues to present a major burden to both patients and care providers. Many jurisdictions require the failure of treatment with conventional immunosuppressants before biologics are approved for patients with UC. The clinical expert noted that the current criteria for reimbursement requiring the failure of ineffective conventional immunosuppressants or corticosteroids, which carry a high risk of AEs, create a situation where clinicians are forced to make decisions that may be harmful to their patients to satisfy reimbursement requirements.

Place in Therapy

The clinical expert consulted by CADTH indicated that the novel mechanism of ozanimod would be a valuable addition to the treatment paradigm, since the current therapies for moderate to severe UC are limited. According to the clinical expert, ozanimod may become a first-line advanced therapy among patients whose condition has failed to respond to 5-ASAs, given ozanimod’s oral route of administration and efficacy in treating moderate UC. The clinical expert indicated that ozanimod may be considered among patients whose condition has failed to respond to other biologic therapies, although the data for ozanimod’s effectiveness after anti-TNF failure is less promising.

The clinical expert noted that while the treatment under review addresses the underlying disease process in terms of lymphocyte trafficking, the mechanism of inflammation in UC is extremely complex. Current strategies for using biologic monotherapy in UC only allow targeting of 1 pathway of inflammation, although there are likely dozens contributing to UC inflammation, and preliminary trials suggest combination strategies may potentially be more effective than current treatment options. However, they would come at considerably greater cost and patients may be at higher risk for drug-related AEs.

Patient Population

The drug under review targets patients with UC. The diagnosis of UC is based on clinical, endoscopic, and histopathologic features. Overall, most patients have a distinctive clinical history of bloody diarrhea, urgency, and tenesmus, and the endoscopic appearance of contiguous inflammation from the rectum upward is characteristic. Histopathologic features of chronic mucosal inflammation confirm the diagnosis. The likelihood of misdiagnosis or under-diagnosis is relatively low due to its distinctive clinical features (e.g., fecal urgency, tenesmus, and rectal bleeding), although there may be delays to diagnosis for patients due to delays in endoscopy access.

According to the clinical expert, treatment with ozanimod would be suitable for patients with moderate to severe UC. There may be potentially greater uptake in patients with more moderate UC whose condition has failed to respond to a 5-ASA but who have not initiated treatment with other biologic therapies, or who have active disease as determined by endoscopy. Currently, there are no predictive tools to identify the ideal candidate for the medication under review. The identification of patients best suited for treatment with ozanimod would primarily be based on clinical judgment. Ozanimod may also be used in patients with moderately to severely active UC that has failed to respond to other biologic therapies, although the data are less promising for induction of remission among patients who have experienced treatment failure with an anti-TNF therapy.

The clinical expert did stress that patients with presymptomatic UC should not be treated with any UC medications due to a measurable AE rate, and that there are no tools to determine who will go on to develop UC. In addition, patients with conduction abnormalities, significant liver disease, potential for drug–drug interactions, and ocular disease or diabetes may not be suitable for treatment with ozanimod.

Assessing Response to Treatment

Treatment response is determined through symptomatic assessment, evaluation of stool and blood biomarkers, and endoscopy (with or without histopathology). Response to UC treatment may be indicated by a reduction in symptom severity (e.g., resolution of rectal bleeding, normalization or near normalization of stool frequency, and resolution of fecal urgency), reduction in UC biomarkers such as CRP and fecal calprotectin, and improvement in endoscopy features (e.g., endoscopic improvement within the first 4 to 6 months and complete or near endoscopic remission by 12 months).

The clinical expert acknowledged that other outcomes concerning quality of life, activities of daily living, and work productivity may be important outcomes for patients, but these outcomes have not been historically considered markers of true therapeutic efficacy. While histopathology is also important, it is not currently recommended as a therapeutic target.

According to the clinical expert, symptom response should be assessed within 4 to 12 weeks of initiating treatment, biomarker response assessed within 6 months, and endoscopic response assessed within 1 year (ideally by 6 months). The clinical expert indicated that treatment should be discontinued in patients with no endoscopic response to treatment, and that the decision would not be based on symptoms alone due to discordance between symptoms and endoscopic assessment. Treatment would also be expected to be discontinued if the criteria for a drug-related AE were met. Temporary holds on treatment may be required in extenuating circumstances (e.g., need for surgery, development of infection) but, overall, most patients would continue treatment if a positive response was achieved.

Prescribing Conditions

The clinical expert consulted stressed that among patients with UC, ozanimod should be prescribed by a gastroenterologist.

Clinician Group Input

No clinician group input was received for this review.

Drug Program Input

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

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

CDEC = CADTH Canadian Drug Expert Committee; ECG = electrocardiogram; JAK = Janus kinase; UC = ulcerative colitis.

Clinical Evidence

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

Systematic Review (Pivotal and Protocol-Selected Studies)

Objectives

To perform a systematic review of the beneficial and harmful effects of ozanimod 1.0 mg per day for the treatment of moderately to severely active UC in adult patients who had an inadequate response, a loss of response, or were intolerant to either conventional therapy or biologic drug.

Methods

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

Of note, the systematic review protocol presented subsequently was established before the granting of a Notice of Compliance by Health Canada.

Table 5: Inclusion Criteria for the Systematic Review

AE = adverse event; HRQoL = health-related quality of life; RCT = randomized controlled trial; SAE = serious adverse event; UC = ulcerative colitis; WDAE = withdrawal due to adverse event.

^aThese outcomes were identified as being of particular importance to patients in the input received by CADTH from patient groups.

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.³²

Published literature was identified by searching the following bibliographic databases: MEDLINE All (1946–) through Ovid and Embase (1974–) through 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 National Library of Medicine’s MeSH (Medical Subject Headings), and keywords. The main search concepts were Zeposia (ozanimod). Clinical trial registries were searched: the US National Institutes of Health’s clinicaltrials.gov, the WHO’s International Clinical Trials Registry Platform (ICTRP) 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 February 2, 2022. Regular alerts updated the search until the meeting of the CADTH Canadian Drug Expert Committee (CDEC) on May 25, 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.³³ Included in this search were the websites of regulatory agencies (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. In addition, the sponsor of the drug was contacted for information regarding unpublished studies.

A focused literature search for NMAs dealing with UC was run in MEDLINE All (1946–) on February 2, 2022. No limits were applied to the search.

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

One study was identified from the literature for inclusion in the systematic review (Figure 1). The included study is summarized in Table 6. A list of excluded studies is presented in Appendix 2.

Figure 1: Flow Diagram for Inclusion and Exclusion of Studies

Table 6: Details of Included Studies

ADR = adverse drug reaction; ALC = absolute lymphocyte count; bpm = beats per minute; CRP = C-reactive protein; DB = double blind; ECG = electrocardiogram; EMA = European Medicines Agency; EQ-5D-5L = 5-level EQ-5D; Hgb = hemoglobin; HR = heart rate; HRQoL = health-related quality of life; IgG = immunoglobulin G; PK = pharmacokinetic; SAE = serious adverse event; SF-36 = Short Form (36) Health Survey; TEAE = treatment-emergent adverse event; TNF = tumour necrosis factor; UC = ulcerative colitis; ULN = upper limit of normal; VZV = varicella-zoster virus; WPAI-UC = Work Productivity and Activity Impairment Questionnaire – Ulcerative Colitis.

Note: Two additional reports were included.^23,24

^aOutcome was also assessed at week 10.

Source: Clinical Study Report for the TRUE NORTH study¹⁰ and supplement to Sandborn et al.³⁴

Description of Studies

One sponsor-conducted study which met the CADTH review protocol criteria was included in this systematic review. The TRUE NORTH study was a phase III, multicentre, randomized, double-blind, placebo-controlled trial of oral ozanimod as induction and maintenance therapy for adult patients with moderate to severe UC. A total of 645 patients were enrolled across 250 sites from 29 countries in North America (including 8 sites in Canada), Europe, Asia Pacific, South America, and South Africa. The trial consisted of a 10-week induction period followed by a 42-week maintenance period. The induction period was composed of 2 cohorts: cohort 1, in which patients were randomized in a 2:1 ratio to receive either ozanimod 0.92 mg daily (N = 429) or matching placebo (N = 216) In a double-blind fashion, and cohort 2, in which patients received open-label ozanimod 0.92 mg once daily. Patients were evaluated for clinical response and remission at week 10 of the induction period. Patients who had a clinical response to ozanimod at the end of the induction period proceeded to the maintenance period and were re-randomized in a 1:1 ratio to receive either ozanimod 0.92 mg daily (N = 230) or matching placebo (N = 227) in a double-blind fashion. Patients who were randomized to placebo in the induction period and had a clinical response at week 10 continued to receive placebo in the maintenance period. A schematic of the TRUE NORTH trial is presented in Figure 2.

The primary outcome of the study was clinical remission as measured by the Mayo score, a disease-specific instrument that assesses disease severity and response to treatment in patients with UC. The Mayo scoring system is a combined endoscopic and clinical assessment composed of 4 components: rectal bleeding, stool frequency, Physician’s Global Assessment, and endoscopy findings. Each part is rated from 0 to 3, yielding a total score of 0 to 12. The primary and key secondary end points that relied on the Mayo score were assessed using the 3-component Mayo score, which excludes the Physician’s Global Assessment. The key secondary end points were controlled for multiplicity using a statistical testing hierarchy, and each study period was considered an independent study. The primary end point and the following key secondary end points were assessed in both the induction and maintenance periods: clinical response, endoscopic improvement, and mucosal healing. The key secondary end points assessed only in the maintenance period were clinical remission in patients who were in remission at week 10, corticosteroid-free remission, and durability of clinical remission. Other efficacy outcomes included HRQoL outcomes, as assessed by the EQ-5D-5L and the SF-36, and work productivity, as assessed by the WPAI-UC.

Of note, the study included patients who had received anti-TNF therapy and those who had not. The proportion of patients who had previously received anti-TNF therapy was limited to approximately 30% in cohort 1. Patients who had previously received anti-TNF therapy could begin enrolling into cohort 2 once the proportion of patients in cohort 1 who were experienced with anti-TNF therapy hit the randomization limit of approximately 30%. Those patients who were naive to anti-TNF therapy continued to enrol into cohort 1 and could enrol into cohort 2 only after cohort 1 had been closed to enrolment. The proportion of patients who had previously received anti-TNF therapy was limited to approximately 50% in cohort 2.

Patients who completed the induction period and did not have a clinical response were invited to participate in an optional OLE study (RPC01-3102).¹³ Patients who completed the maintenance period or who experienced disease relapse during the maintenance period were also given the opportunity to enter the OLE study. Disease relapse was defined as having met all of the following criteria: an increase in partial Mayo score of at least 2 points from week 10 and a partial Mayo score of at least 4 points, an endoscopy subscore of at least 2 points, and the exclusion of other potential reasons for an increase in disease activity, such as infection or change in medication.

Randomization at the beginning of both the induction and maintenance periods was stratified. Randomization of patients in cohort 1 of the induction period was stratified by corticosteroid use at screening (yes or no) and prior anti-TNF therapy (yes or no). Re-randomization in the maintenance period was stratified by clinical remission status (as defined by either the 3-component or 4-component Mayo score) at week 10 (yes or no) and corticosteroid use at week 10 (yes or no). Treatment allocation and randomization stratification was centrally allocated across all centres using an interactive voice- and/or web-activated response system.

The first patient visit occurred on August 12, 2015, and the last patient visit occurred on March 27, 2020. Database locks were performed after the completion of blinded treatment for the induction and maintenance periods. The first database lock was executed on June 27, 2019, after all patients in cohort 1 had completed the induction period (week 10). Another database lock was executed on June 15, 2020, after all patients had completed the maintenance period.

There was 1 notable departure from Good Clinical Practice policies and procedures: The paper source documents for 9 patients from a single site were lost after the monitor completed the site close-out visit. All patients who were enrolled at the site were allocated to induction cohort 2 of the open-label study and did not contribute to the induction period efficacy results. Sensitivity analyses of the primary and secondary end points of the maintenance period excluding the 9 patients for which the original source documents were lost were consistent with the primary analyses for the intention-to-treat (ITT) population.

Figure 2: Study Schema for the TRUE NORTH Trial

TNF = tumour necrosis factor.

^a Patients were stratified by prior anti-TNF exposure (yes or no) and corticosteroid use (yes or no) at screening. The randomization in the maintenance period was stratified by clinical remission at week 10 (yes or no) and corticosteroid use at week 10 (yes or no).

Source: Clinical Study Report for TRUE NORTH study.¹⁰

Populations

Inclusion and Exclusion Criteria

The key inclusion and exclusion criteria applied to the TRUE NORTH trial are summarized in Table 6. Briefly, patients eligible for enrolment were adults 18 to 75 years of age with moderately to severely active UC, which was defined as a total Mayo score of 6 to 12, with an endoscopy subscore of 2 or higher, an RBS of 1 or higher, and an SFS of 1 or higher. Patients were required to have received stable dosages of oral aminosalicylates and/or glucocorticoids (prednisone at a dosage of ≤ 20 mg per day or budesonide) for at least 2 weeks before screening endoscopy and to continue receiving the same dosage for the duration of the induction period; the glucocorticoid dose had to be tapered once the patient entered the maintenance period. A documented presence of varicella-zoster virus immunoglobulin G antibody or completed varicella-zoster virus vaccination at least 30 days before randomization was also required. Patients were excluded from the trial if they had a diagnosis of Crohn disease or indeterminate colitis, presence or history of a fistula consistent with Crohn disease, a clinically relevant cardiac condition, or a history of uveitis or macular edema.

Baseline Characteristics

The baseline characteristics of the patients enrolled in the induction period and of those who entered the maintenance period are summarized in Table 7.

Most patients were male. The average age of the patients randomized to receive ozanimod and placebo was 42 and 43 years in the induction and maintenance periods, respectively. Among the patients randomized to receive ozanimod and placebo in both periods, 86% to 89% of patients were white and the mean age at UC diagnosis was 34.4 to 36.0 years.

Table 7: Summary of Baseline Characteristics of Participants in the TRUE NORTH Trial

ITT = intention to treat; OZ = ozanimod; PL = placebo; SD = standard deviation; TNF = tumour necrosis factor; UC = ulcerative colitis.

^aEastern European countries include Belarus, Bulgaria, Croatia, Czech Republic, Georgia, Greece, Hungary, Latvia, Republic of Moldova, Poland, Romania, Russian Federation, Serbia, Slovakia, and Ukraine.

^bWestern European countries include Austria, Belgium, Germany, Italy, the Netherlands, and the UK.

^cThree-component Mayo score is the sum of the rectal bleeding subscore, stool frequency subscore, and the endoscopy subscore.

^dFour-component Mayo Score is the sum of the rectal bleeding subscore, stool frequency subscore, Physician’s Global Assessment subscore, and the endoscopy subscore.

^eDerived from Robarts data.

^fPercentages for patients who were intolerant to or whose condition did not respond to anti-TNF treatment were calculated as a percentage of the number of patients who received prior anti-TNF treatment rather than the total safety population for each treatment group. Primary nonresponse was defined as signs and symptoms of persistently active disease despite an adequate trial of induction treatment with an anti-TNF drug (per the country’s approved label).

^gSecondary nonresponse was defined as recurrence of symptoms during maintenance dosing following prior clinical benefit. Intolerance included inability to achieve doses, dose levels, or treatment durations because of treatment-related side effects and/or laboratory abnormalities. Patients could be classified under more than 1 response category if they received more than 1 prior anti-TNF and experienced a different response to each therapy.

Source: Clinical Study Report for the TRUE NORTH study.¹⁰

The extent of disease was limited to the left side of the colon in approximately 60% of patients in both the induction and maintenance periods. The mean 3-component Mayo score and 4-component Mayo score ranged from 6.6 (SD = 1.15) to 6.7 (SD = 1.31) and 8.6 (SD = 1.42) to 9.1 (SD = 9.0), respectively, across treatment groups in both study periods. Finally, disease severity, as assessed by mucosal appearance at endoscopy, was classified as severe disease in approximately 60% of patients across treatment groups in the induction period, and in approximately 50% of patients across treatment groups in the maintenance period.

All patients were previously treated with other UC medications. Excluding those patients who received placebo during both the induction and maintenance periods, patients in each treatment group at the start of the induction and maintenance periods had previously received the following UC medications: corticosteroids (range, 70% to 78%), oral aminosalicylic acids (range, 97% to 99%), immunomodulators (range, 37% to 46%), azathioprine (range, 30% to 38%), mercaptopurine (less than 10%), methotrexate (less than 6%), anti-TNF biologics (range, 28% to 33%, aside from 44% in the open-label ozanimod group), and non–anti-TNF biologics (14% to 29%).

Interventions

Patients were randomized to receive 1 of 2 interventions: ozanimod or placebo. The ozanimod and placebo capsules were identical in physical appearance. Dose escalation was implemented due to the results of prior phase I and phase II studies that suggested dose escalation resulted in a less profound decrease in heart rate or blood pressure.

On day 1 of the induction period, patients initiated their assigned intervention in accordance with a 7-day dose escalation regimen. From day 1 to day 4, patients received ozanimod 0.23 mg or matching placebo once daily as 1 capsule. From day 5 to day 7, patients received ozanimod 0.46 mg or matching placebo once daily as 2 capsules. From day 8 onward, patients received ozanimod 0.92 mg or matching placebo once daily for 9 weeks as 1 capsule. Patients who received ozanimod in the induction period and continued in the maintenance period were re-randomized to receive ozanimod 0.92 mg once daily for 42 weeks as one 0.92 mg capsule or matching placebo as a single capsule once daily for 42 weeks. Patients from cohort 1 of the induction period who had been randomized to receive placebo and showed a clinical response at week 10 continued to received placebo in the maintenance period in a double-blind manner.

Concomitant Therapy

All treatments, other than ozanimod, taken by the patients on entry into the trial or any time during the study period, including the safety follow-up visit, were regarded as concomitant medications and were documented as such.

Patients who were receiving a 5-ASA or oral corticosteroid at screening were to keep their prescribed dose steady through to week 10. Oral 5-ASA or corticosteroids were not started in patients who were not receiving them at screening. Patients receiving 5-ASA were to maintain a stable dose through week 52 of the maintenance period. For patients who were receiving an oral corticosteroid, steroid tapering was introduced after week 10. Upon entering the maintenance period, tapering proceeded as follows:

• Prednisone greater than 10 mg per day or equivalent: Reduced at a rate of 5 mg per week until a dosage of 10 mg per day (or equivalent) was achieved.

• Prednisone 10 mg per day or equivalent (or once a dosage of 10 mg per day or equivalent was achieved by tapering): Reduced at a rate of 2.5 mg per week until discontinuation.

• Budesonide MMX greater than 9 mg every day: Reduced to 9 mg every other day for 2 weeks and then discontinued.

For patients who were unable to tolerate corticosteroid tapering, the corticosteroid dose was increased and tapering was recommenced within 2 weeks.

Concomitant medications that were prohibited during the induction or maintenance periods and during the observational 30-day safety follow-up visit included:

• treatment during the study with Class Ia or Class III antiarrhythmic drugs or treatment with 2 or more drugs in a combination known to prolong PR interval (e.g., combination of a beta-blocker and verapamil) unless approved by the sponsor’s representative

• biologic therapies, such as abatacept, infliximab, etanercept, adalimumab, anakinra, rituximab, vedolizumab, and golimumab immunosuppressive drugs (e.g., azathioprine, mercaptopurine, cyclosporine, methotrexate)

• any per-rectum therapy, including enemas (e.g., 5-ASA, corticosteroid), other than that required for endoscopy preparation

• antimotility medications

• oral cyclosporine, tacrolimus, sirolimus, or mycophenolate mofetil

• any investigational drug other than the investigational drug specified in this study

• chronic use of nonsteroidal anti-inflammatory drugs (NSAIDs) (occasional use [for headache, arthritis, myalgias, or menstrual cramps, for example] of acetaminophen, NSAIDs, acetaminophen, and ASA up to 325 mg per day was permitted)

• live vaccines or live attenuated vaccines (also not allowed within 4 weeks before randomization)

• IV immunoglobulin or plasmapheresis (also not allowed within 3 months before randomization)

• treatment with D-penicillamine, leflunomide, or thalidomide

• treatment with natalizumab, fingolimod, etrasimod, or tofacitinib

• immunosuppressive drugs that deplete lymphocytes

• breast cancer resistance protein inhibitors (e.g., cyclosporine, eltrombopag)

• monoamine oxidase inhibitors (e.g., selegiline, phenelzine)

• cytochrome P450 2C8 (CYP2C8) inducers (e.g., rifampicin) or inhibitors (e.g., gemfibrozil and clopidogrel)

The following medications were not permitted for use between the 30-day safety follow-up visit and the 90-day safety follow-up visit:

• Class Ia or Class III antiarrhythmic drugs or treatment with 2 or more drugs in a combination known to prolong PR interval (e.g., combination of a beta-blocker and verapamil) were prohibited during the study unless approved by the sponsor’s representative

• natalizumab, fingolimod, and etrasimod

• immunosuppressive drugs that deplete lymphocytes

• monoamine oxidase inhibitors (e.g., selegiline, phenelzine)

• CYP2C8 inducers (e.g., rifampicin) and inhibitors (e.g., gemfibrozil, clopidogrel)

• live vaccines or live attenuated vaccines

Outcomes

A list of efficacy end points identified in the CADTH review protocol that were assessed in the clinical trials included in this review is provided in Table 8. These end points are further summarized subsequently. A detailed discussion and critical appraisal of the clinical instruments and HRQoL measures used in the trial is provided in Appendix 4.

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

EQ-5D-5L = 5-level EQ-5D; HRQoL = health-related quality of life; NR = not reported; SF-36 = Short Form (36) Health Survey; WPAI-UC = Work Productivity and Activity Impairment Questionnaire – Ulcerative Colitis.

Source: Clinical Study Report for the TRUE NORTH study.¹⁰

Clinical Remission

Clinical remission was the primary efficacy end point in the TRUE NORTH study and was expressed as the proportion of patients who were in clinical remission. Clinical remission was defined according to the 3- and 4-component Mayo score based on a 7-day scoring algorithm.^1,35

The Mayo score is a disease-specific, physician-measured instrument that assesses disease severity and response to treatment in patients with UC. The Mayo scoring system is a combined endoscopic and clinical scale used to assess the severity of UC.^1,35 In its complete form, the Mayo score is composed of 4 components: rectal bleeding, stool frequency, Physician’s Global Assessment, and endoscopy findings. Each part is rated from 0 to 3, yielding a total score of 0 to 12.

Clinical remission was measured at the conclusion of the induction period at week 10 and at the conclusion of the maintenance period at week 52. The definitions of clinical remission were as follows:

• Clinical remission based on the 3-component Mayo score was defined as an RBS of 0 and an SFS of 1 or less with a decrease of 1 or more points from the baseline SFS and an endoscopy subscore of 1 or less.

• Clinical remission based on the 4-component Mayo score was defined as a score of 2 or less with no individual subscore of greater than 1 point.

To determine the endoscopy subscore for the Mayo score, endoscopy recordings were centrally read by a gastroenterologist blinded to treatment assignment.

Clinical Response

Clinical response was a key secondary efficacy end point of the TRUE NORTH study and was expressed as the proportion of patients who had a clinical response. Clinical response was also defined according to 3- and 4-component Mayo scores based on a 7-day scoring algorithm. Clinical response was assessed at the conclusion of the induction period at week 10 and at the conclusion of the maintenance period at week 52. The definitions of clinical response were as follows:

• Clinical response based on the 3-component Mayo score was defined as a reduction from baseline in the 3-component score of 2 or more points and 35% or greater, and a reduction in RBS of 1 or more points from baseline or an absolute RBS of less than 1 point.

• Clinical response in the 4-component Mayo score was defined as a reduction from baseline in the 4-component score of 3 or more points and more than 30%, and a reduction in RBS of more than 1 point from baseline or an absolute RBS of 1 point or less.

Rectal Bleeding

RBS was a post hoc exploratory end point in the TRUE NORTH study and was expressed as the change from baseline in the RBS of the Mayo score. RBS was reported for baseline, week 2, week 4, week 5, week 6, week 8, and week 10 of the induction period.

Endoscopic Improvement

Endoscopic improvement was a key secondary outcome in the TRUE NORTH study and was expressed as the proportion of patients with endoscopic improvement. Endoscopic improvement was defined as an endoscopy subscore of 1 or less without friability. Endoscopic improvement was assessed at the conclusion of the induction period at week 10 and at the conclusion of the maintenance period at week 52.

Corticosteroid-Free Remission

Corticosteroid-free remission was a key secondary outcome of the maintenance period in the TRUE NORTH study and expressed as the proportion of patients with corticosteroid-free remission. Corticosteroid-free remission was defined as being in clinical remission at 52 weeks while off corticosteroids for at least 12 weeks.

Mucosal Healing

Mucosal healing was a key secondary outcome in the TRUE NORTH study and expressed as the proportion of patients with mucosal healing. Mucosal healing was assessed using the endoscopy subscore of the Mayo score and the Geboes index score.^36,37

The Geboes score is a 6-item instrument that classifies histological changes into 1 of 6 grades (grade 0 to grade 5). Each grade is assessed on a 4-point scale and given equal weight, as follows: “no abnormality,” “mild abnormality,” “mild/moderate diffuse or multifocal abnormalities,” and “severe diffuse or multifocal abnormalities.” The higher the score, the greater the inflammation.

Mucosal healing was defined as an endoscopy subscore of 1 point or less without friability and a Geboes index score of less than 2 (no neutrophils in the epithelial crypts or lamina propria and no increase in eosinophils, no crypt destruction, and no erosion ulcerations of granulation tissue). Mucosal healing was assessed at week 10 of the induction period and at week 42 of the maintenance period (week 52 of the study).

Durable Clinical Remission

Durable clinical remission was a key secondary outcome of the maintenance period in the TRUE NORTH study and expressed as the proportion of patients in clinical remission at week 10 and at week 52 in all patients who entered the maintenance period.

Maintenance of Remission

The maintenance of remission was a key secondary outcome of the maintenance period in the TRUE NORTH study and expressed as the proportion of patients with clinical remission at week 52 in a subset of patients in remission at week 10.

Histologic Remission

Histologic remission was classified as an “other efficacy end point” in the TRUE NORTH study. Histologic remission was assessed using the Geboes index score and was expressed as the proportion of patients with histologic remission. Histologic remission was defined as a Geboes index score of less than 2 (no neutrophils in the epithelial crypts or lamina propria and no increase in eosinophils, no crypt destruction, and no erosion ulcerations of granulation tissue). Histologic remission was assessed at the conclusion of the induction period at week 10 and at the conclusion of the maintenance period at week 52.

HRQoL

HRQoL in the TRUE NORTH study was classified as an “other efficacy end point” and was assessed using 2 instruments: the SF-36 and the EQ-5D-5L. HRQoL outcomes were expressed as the change from baseline to week 10, and from baseline to week 52.

The SF-36 is a generic self-reported health assessment questionnaire that has been used in clinical trials to study the impact of chronic disease on HRQoL. The SF-36 consists of 8 domains: physical functioning, role limitations due to physical health problems, bodily pain, general health, vitality, social functioning, role limitations due to emotional health problems, and mental health. The SF-36 also provides 2 component summaries: the Physical Component Summary (PCS) and the Mental Component Summary (MCS), which are scores created by aggregating the 8 domains.³⁸ The PCS and MCS and individual domains are each measured on a scale of 0 to 100, with increasing score indicating improvement in health status.³⁸

The EQ-5D-5L is a generic self-reported HRQoL outcome measure that may be applied to a variety of health conditions and treatments.³⁹ The first component of the EQ-5D-5L assesses 5 dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression.³⁹ It is a descriptive system that classifies respondents (aged ≥ 12 years) based on these 5 dimensions. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems, and extreme problems. The EQ-5D-5L has 5 possible levels for each dimension and respondents are asked to choose the level that reflects their health state for each of the 5 dimensions.³⁹ The second component of the EQ-5D-5L is a 20 cm visual analogue scale (EQ VAS) that has end points labelled 0 and 100, with respective anchors of “worst imaginable health state” and “best imaginable health state.” Respondents are asked to rate their health by drawing a line from an anchor box to the point on the EQ VAS that best represents their health on that day. The EQ-5D-5L index score is generated by applying a multiattribute utility function to the descriptive system.⁴⁰ Different utility functions are available that reflect the preferences of specific populations (e.g., US or UK). Scores less than 0 represent health states that are valued by society as being worse than dead, while scores of 0 and 1.00 are assigned to the health states “dead” and “perfect health,” respectively.

Work Productivity

Work productivity was classified as an “other efficacy end point” in the TRUE NORTH study and was assessed using the WPAI-UC.^41,42 Work productivity was measured at week 10 and week 52.

The WPAI-UC is a self-administered 6-item questionnaire with a 7-day recall period that measures the impact of health problems on absenteeism (percentage of work time missed due to UC), presenteeism (percentage of impairment due to UC while working), percentage of overall work impairment due to UC (combined absenteeism and presenteeism), and percentage of daily activity impairment.^41,42 The WPAI-UC scores from all domains are expressed as percentages (0% to 100%) of impairment, with lower values indicating less impairment due to the health problem.⁴¹

Safety

The primary safety outcomes assessed in TRUE NORTH were:

• TEAEs

• serious adverse events (SAEs)

• TEAEs leading to discontinuation of the investigational drug

• TEAEs of special interests, including bradycardia and heart conduction abnormalities, pulmonary effects, hepatic effects, macular edema, malignancies, and serious or opportunistic infections

• changes from baseline for clinical laboratory measures, vital signs, and ECG and pulmonary function tests.

Statistical Analysis

Efficacy Analysis

For the purpose of statistical analyses, the induction period and the maintenance period were treated as 2 independent studies. For the induction period, the efficacy end points were formally examined with statistical hypothesis tests conducted on the efficacy results obtained from the patients randomized and dosed in cohort 1. Cohort 2 was open-label and did not contain a control group; therefore, all cohort 2 efficacy end points were summarized and described without statical hypothesis testing. For the maintenance period, patients (in either cohort 1 or cohort 2 and with a clinical response based on either the 3-component or 4-component Mayo score at week 10) who were re-randomized to either ozanimod or placebo contributed to the ITT population.

The statistical analysis of efficacy end points conducted in the TRUE NORTH trial is summarized in Table 9.

Table 9: Statistical Analysis of Efficacy End Points

ANCOVA = analysis of covariance; EQ-5D-5L = 5-level EQ-5D; MI = multiple imputation; NR = not reported; NRI = nonresponder imputation; SF-36 = Short Form (36) Health Survey; TNF = tumour necrosis factor; WPAI-UC = Work Productivity and Activity Impairment Questionnaire – Ulcerative Colitis.

Source: Clinical Study Report for the TRUE NORTH study.¹⁰

Sample Size Determination

For cohort 1 of the induction period, a sample size of approximately 600 patients randomized in a 2:1 ratio (400 received ozanimod 1 mg and 200 received placebo) was planned. The sample size was determined to provide at least 90% power to detect a difference of 10% between groups in the proportion of patients with clinical remission based on a 2-sided Fisher exact test at an alpha of 0.05. Sample size determination was based on the results from a previous study of ozanimod 1 mg (RPC01 to 201) that anticipated that at least 16% of patients in the ozanimod group and approximately 6% of patients in the placebo group would be in clinical remission at the end of the induction period.

The sample size for cohort 2 of the induction period was also based on the same phase II study cited previously, which anticipated that at least 60% of patients treated with ozanimod would have a clinical response at the end of the induction period. Assuming a 5% dropout rate, enrolment of approximately 900 patients into the induction period, of which 700 would receive ozanimod, was planned. This was to ensure approximately 420 patients would have a clinical response to ozanimod so that approximately 400 patients could potentially be enrolled into the maintenance period. Therefore, an addition of approximately 300 patients receiving ozanimod 1 mg was planned for enrolment into cohort 2.

For the maintenance period, a placebo remission rate of 16% at week 52 was assumed based on a prior study.⁴³ A sample size of 400 patients (200 patients per treatment group) was determined, based on a 2-sided Fisher exact test at alpha = 0.05, to provide 90% power to detect a statistically significant improvement in a remission rate of 14% or higher. To account for a 5% rate of patients who had a clinical response to induction therapy with ozanimod not entering the maintenance period, approximately 420 patients with a clinical response to ozanimod were required at the end of the induction period.

Primary Efficacy Analysis

The primary analysis of the proportion of patients in clinical remission at week 10 and week 52 was carried out on the ITT population using a 2-sided Cochran-Mantel-Haenszel test at the 5% level of significant, stratified by corticosteroid use at screening (yes or no) and prior anti-TNF use (yes or no). Patients who met the criteria for treatment failure were imputed using nonresponder imputation (NRI).

Treatment of patients was considered to have failed if any of the following occurred:

• a protocol-prohibited change in medications, including:

  • postbaseline initiation of or an increase in the total daily dose level higher than the maximum dose taken between the screening and baseline visit of the following:

    • corticosteroids or 5-ASA dose to treat UC

    • a prolonged course of system corticosteroids of longer than 14 days for treatment of disease other than UC

    • immune-suppressing therapy, including initiation of mercaptopurine, azathioprine, anti-TNF drugs, vedolizumab, or tofacitinib

• a colectomy (partial or total) or ostomy

• discontinuation of ozanimod or placebo due to lack of therapeutic effect before the week 10 or week 52 efficacy evaluation.

The primary analysis was repeated on the per-protocol (PP) population and on key subgroups of the ITT population. These were considered sensitivity (supportive) analyses and were not subject to familywise type I error control.

Secondary and Other Efficacy Analysis

The secondary end points were tested in order using a hierarchical testing procedure to control the overall type I error rate for multiple end points. If the primary end point was statistically significant, the proportion of patients with a clinical response at week 10 and week 52 was tested at the 5% significance level. This testing procedure continued through each of the key secondary end points until the end point failed to reach statistical significance, after which subsequent key secondary end points were considered exploratory. The end points listed as other efficacy end points were tested in a nonhierarchical fashion without adjustments for multiplicity.

All key secondary and other efficacy end points expressed as proportions of patients were tested using the same type of Cochran-Mantel-Haenszel test as specified for the primary end point, with treatment failures imputed as nonresponders (refer to Table 9). All efficacy end points expressed as changes from baseline were analyzed with an analysis of covariance (ANCOVA) model adjusted for the baseline response parameter of interest, corticosteroid use at screening, and prior anti-TNF use.

Safety Analyses

All safety analyses were carried out on the safety population.

Sensitivity Analysis

A sensitivity analysis of the primary efficacy end point (clinical remission) based on a 14-day scoring algorithm was performed to support the primary analysis. Sensitivity analyses were conducted for the primary end point and the secondary end point of clinical response, with the use of observed-cases analysis (assumption of data missing completely at random) and with the use of multiple imputation (assumption of data missing at random).

Subgroup Analyses

Predefined subgroup analyses were performed for the primary and key secondary end points. The relevant subgroup analyses were conducted for the induction and maintenance periods: corticosteroid use at screening (yes or no), prior anti-TNF use (yes or no), extent of colitis (left-sided versus extensive), and moderate UC status at baseline (4-component Mayo score 6 to 10, yes or no).

Missing Data

For the proportion-based primary and key secondary efficacy end points, patients with missing week 10 and/or missing week 52 efficacy data were considered nonresponders using NRI. Sensitivity analyses around missing data could include tipping-point analysis, missing data imputed using multiple imputation, and analysis of observed cases with no imputation. For continuous efficacy end points, analyses were performed using observed cases with no imputation.

Analysis Populations

All patient populations were defined and documented before database lock. The following analysis populations were used in the statistical analysis: ITT population, PP population, and safety population.

The ITT populations were used as the primary population for all efficacy parameters. Patients were analyzed according to their randomized group. For each treatment group in the induction period, the ITT population included all randomized (cohort 1) or enrolled (cohort 2) patients who received at least 1 dose of the study drug. For the maintenance period, the ITT population included all randomized patients who received at least 1 dose of the study drug in the maintenance period.

The PP populations consisted of all patients in the ITT population who adhered to the protocol. Patients were excluded from the PP populations if they violated the eligibility criteria or significantly deviated from the study plan. Specific reasons for exclusion from these populations were documented before database lock and included, but were not limited to, investigational drug noncompliance greater than 20%, receiving an incorrect investigational drug for more than 1 week in the induction period or more than 1 month in the maintenance period, and missing more than 2 visits while still on the study.

The safety populations consisted of all patients who received at least 1 dose of the investigational drug. The safety populations were used for all summaries of safety data. Patients randomized to receive any amount of ozanimod were summarized in the ozanimod group; otherwise, they were to be summarized in the placebo group.

Results

Patient Disposition

Details of patient disposition in the induction period and maintenance period are summarized in Table 10.

A total of 1,831 patients were screened for entry into the study’s induction period. Of those, 1,012 were enrolled into the TRUE NORTH study, including 645 patients in cohort 1 (429 randomized to ozanimod and 216 to placebo) and 367 patients in cohort 2 (all treated with ozanimod). Most ozanimod-treated patients in cohort 1 (93.5%) and cohort 2 (88.3%) completed the induction period, with 54.3% and 61.0% continuing to the maintenance period, and 37.1% and 21.5% enrolled in the OLE study, respectively. Among the placebo-treated patients in cohort 1, 88.9% completed the induction period, 55.6% enrolled in the OLE following the induction period, and 31.9% continued into the maintenance period.

The most frequently reported reason for withdrawal from the induction period among patients in cohort 1 in descending order were AEs and withdrawal by patients in the ozanimod treatment group and lack of efficacy, withdrawal by patients, and AEs in the placebo treatment group. The most frequently reported reasons for study withdrawal among patients in cohort 2 of the induction period were withdrawal by patient, AEs, and lack of efficacy. A total of 526 patients were treated during the maintenance period of the study, including 230 patients who were randomized to ozanimod 1 mg, 227 who were re-randomized from ozanimod 1 mg to placebo, and 69 who continued on placebo. The completion rate for the maintenance period was 80% for the patients continuously treated with ozanimod, approximately 55% for those re-randomized from ozanimod 1 mg to placebo, and approximately 65% for the patients continuously treated with placebo. Most patients who completed the maintenance period enrolled in the OLE study.

The most frequently reported reason for discontinuing from the trial during the maintenance period was disease relapse. Disease relapse was reported in 13.5% of patients continuously treated with ozanimod, approximately 33.9% in those re-randomized from ozanimod to placebo, and approximately 29% among the patients continuously treated with placebo.

In total, 824 of the 1,012 patients who entered TRUE NORTH went on to enrol in the OLE study.¹³

Protocol Deviations

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Table 10: Patient Disposition

ITT = intention to treat; NA = not applicable; OLE = open-label extension; OZ = ozanimod; PL = placebo; PP = per protocol.

^aPercentages are based on the number of patients in the randomized population (cohort 1) divided by the enrolled population (cohort 2 and maintenance period).

^bPercentages are based on the number of patients dosed.

^cTo continue into the maintenance period, patients were required to be in clinical response as assessed by the 3- or 4-component Mayo.

^dPatients who discontinued from the induction period were withdrawn from the study.

^eOther reasons include leaving the country; lost to follow-up; sponsor withdrew patients due to prolonged breast cancer chemotherapy; early term visit was 90 days after last dose, so a 90-day follow-up visit was not needed; and wife wanted to get pregnant.

Source: Clinical Study Report for the TRUE NORTH study.¹⁰

Table 11: Redacted

Note: This table has been redacted as per the sponsor’s request.

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Exposure to Study Treatments

Extent of Exposure

In the induction period, the mean duration of exposure to ozanimod and placebo in cohort 1 was 10.4 (SD = 1.7) weeks and 10.3 (SD = 2.2) weeks, respectively. In the maintenance period, the mean duration of exposure to the investigational drug was 37.6 (SD = 11.3) weeks in patients re-randomized to ozanimod and 30.8 (SD = 14.8) weeks to patients re-randomized to placebo.

Concomitant Medications

Common concomitant medications for patients in both the induction and maintenance periods included medications used for endoscopies, such as propofol, midazolam, and macrogol 4000.

All patients enrolled in the trial were required to be treated with other concomitant therapies, including aminosalicylates. Indeed, mesalazine and sulfasalazine were taken by a total of 71% and 13% of patients, respectively.

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In total, corticosteroids for systemic use were used in approximately 31% of patients in the induction period and in 31.7% of patients re-randomized in the maintenance period. Prednisone was the most commonly used corticosteroid and its use across the treatment periods was as follows:

• Induction period: 18.1% of patients in the cohort 1 ozanimod group, 16.1% of patients in the placebo group, and 17.6% in the cohort 2 ozanimod group.

• Maintenance period: 15.9% of patients who remained on placebo, 14.1% of patients who were re-randomized to placebo, and 17.0% who remained on ozanimod.

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Table 12: Redacted

Note: This table has been redacted as per the sponsor’s request.

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Efficacy

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

For the induction period, only cohort 1 data (double-blind ozanimod once daily or placebo) was used to assess the efficacy end points. As cohort 2 did not have a placebo control, no inferential statistics were conducted; instead, descriptive statistics are provided in the tables.

Clinical Remission

Clinical remission, as defined by the 3-component and 4-component Mayo in both the induction and maintenance periods, is summarized in Table 13.

Table 13: Proportion of Patients With Clinical Remission as Measured by the Mayo Score in the TRUE NORTH Trial

CI = confidence interval; CMH = Cochran-Mantel-Haenszel; DBL = database lock; ITT = intention to treat; OZ = ozanimod; PL = placebo; RBS = rectal bleeding subscore; SFS = stool frequency subscore; TNF = tumour necrosis factor.

Note: Patients with any RBS, SFS, or endoscopy subscores missing at week 10 and week 52 were classified as not being in clinical remission.

^aProportion of patients in clinical remission at week 10 of the induction period (ITT population, nonresponder imputation).

^bProportion of patients in clinical remission at week 42 of the treatment maintenance period (week 52 of the study) (ITT population, nonresponder imputation).

^cClinical remission was measured using the 3-component Mayo score using a 7-day scoring algorithm and defined as an RBS of 0 and an SFS of ≤ 1 point (and a decrease of ≥ 1 point from the baseline SFS) and an endoscopy subscore ≤ 1 point without friability.

^dOdds ratio (active vs. PL), treatment difference, and 2-sided 95% Wald CI and P value for comparison between the cohort 1 OZ group and PL group are based on the CMH test, stratified by corticosteroid use at screening and prior anti-TNF use (yes or no). For the maintenance period analysis, the comparison between the OZ 1 mg to OZ 1 mg group vs. the OZ 1 mg to PL group is based on the CMH test, stratified by remission status at week 10 and corticosteroid use at week 10 (yes or no).

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Source: Clinical Study Report for the TRUE NORTH study.¹⁰

Three-Component Mayo Score

The proportion of patients in clinical remission in the cohort 1 ozanimod group versus the cohort 1 placebo group at week 10 of the induction period, based on the 3-component Mayo definition using a 7-day scoring algorithm, was 18.4% and 6.0%, respectively; this represents a statistically significant difference in proportion between the groups of 12.4% (95% CI, 7.5% to 17.2%; P < 0.001). The odds of being in clinical remission at week 10 of the induction period among patients in cohort 1 were greater in patients who received ozanimod compared with those who received placebo (OR = 3.59; 95% CI, 1.94 to 6.64).

The proportion of patients in clinical remission based on the 3-component Mayo definition using a 7-day scoring algorithm in the patients who were re-randomized to placebo and in those who remained on ozanimod at week 52 of the maintenance period was 18.5% and 37.0%, respectively; representing a statistically significant difference in proportion between the groups of 18.6% (95% CI, 10.8% to 26.4%; P < 0.001). The odds of achieving clinical remission at week 52 of the induction period were greater in patients who remained on ozanimod compared with those re-randomized to placebo (OR = 2.76; 95% CI, 1.77 to 4.29).

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Sensitivity Analysis

In both the induction and maintenance periods, the results of the sensitivity analyses for the primary end point (using observed cases only, multiple imputation, and PP analysis) were consistent with the main results. At week 10, a statistically significantly higher proportion of patients in the cohort 1 ozanimod group were in clinical remission compared with the placebo group when sensitivity analyses were performed using observed cases (21.2% versus 7.6%; difference in proportion of 13.7%; 95% CI, 8.0 to 19.4; P < 0.0001), multiple imputation (20% versus 7.4%; difference in proportion of 12.6%; 95% CI, 7.4% to 17.8%, P < 0.0001) and the PP population (18.2% versus 6.1%; difference in proportion of 12.1%; 95% CI, 7.3% to 17.0%; P < 0.0001).

At week 52, a statistically significantly higher proportion of patients in the re-randomized ozanimod group were in clinical remission compared with the re-randomized placebo group when sensitivity analyses were performed using observed cases (54.1% versus 38.2%; difference in proportion of 17.2%; 95% CI, 5.5 to 28.8; P < 0.005), multiple imputation (44.0% versus 26.1%; difference in proportion of 17.9%; 95% CI, 7.7% to 28.2%, P = 0.0009) and the PP population (37.9% versus 18.6%; difference in proportion of 19.1%; 95% CI, 11.2% to 27.1%; P < 0.0001).

Subgroup Analysis

The subgroup analyses of the proportion of patients in clinical remission at week 10 and week 52 as defined by the 3-component Mayo score based on prior use of anti-TNF, disease severity, and disease extent are summarized in Table 14.

In the induction period, treatment effect was greater in patients with no prior use of anti-TNF, moderate UC, and left-sided disease.

Durable Clinical Remission

Results pertaining to the proportion of patients with durable clinical remission (patients in clinical remission at week 10 and at week 52 among all patients who entered the maintenance period) are summarized in Table 15.

At week 42 of the maintenance period (week 52 of the study), the proportion of patients with durable remission in the patients re-randomized to placebo versus those who remained on ozanimod was 9.7% and 17.8%, respectively; this represents a statistically significant difference in proportion between the groups of 8.2% (95% CI, 2.8% to 13.6%; P = 0.003). The odds of durable remission at week 52 among patients who remained on ozanimod were greater compared with those who were re-randomized to placebo (OR = 2.65; 95% CI, 1.38 to 5.06).

Table 14: Proportion of Patients in Clinical Remission^a Based on Prior Use of Anti-TNF, Disease Severity, and Disease Extent in the TRUE NORTH Trial

CI = confidence interval; CMH = Cochran-Mantel-Haenszel; ITT = intention to treat; RBS = rectal bleeding subscore; SFS = stool frequency subscore. TNF = tumour necrosis factor; UC = ulcerative colitis.

^aClinical remission is defined as an RBS of 0 and an SFS of ≤ 1 point (and a decrease of ≥ 1 point from the baseline SFS) and an endoscopy subscore of ≤ 1 point without friability.

^bOdds ratio (active vs. placebo), treatment difference, 2-sided 95% Wald CI and P value for comparison between the active and placebo groups are based on the CMH test, stratified by corticosteroid use at screening and prior anti-TNF use (yes or no).

^cP values < 0.05 are considered nominally significant because no multiplicity adjustment was applied.

^dModerate UC was defined as a 4-component Mayo score of 6 to 10.

Source: Clinical Study Report for the TRUE NORTH study.¹⁰

Table 15: Proportion of Patients With Durable Clinical Remission^a in the Maintenance Period of the TRUE NORTH Trial

CI = confidence interval; CMH = Cochran-Mantel-Haenszel; ITT = intention to treat; RBS = rectal bleeding subscore; SFS = stool frequency subscore; TNF = tumour necrosis factor.

Note: Patients with any RBS, SFS, or endoscopy subscores missing at week 10 or week 52 are classified as not having durable clinical remission.

^aDurable clinical remission was defined as an RBS of 0 and an SFS of ≤ 1 point (and a decrease of ≥ 1 point from the baseline SFS) and an endoscopy subscore of ≤ 1 point without friability at weeks 10 and 52.

^bProportion of patients in clinical remission at week 42 of the treatment maintenance period (week 52 of the study) (ITT population, nonresponder imputation).

^cOdds ratio (active vs. placebo), treatment difference, and 2-sided 95% Wald CI and P value for comparison between the cohort 1 ozanimod group and placebo group are based on the CMH test, stratified by corticosteroid use at screening and prior anti-TNF use (yes or no). For the maintenance period analysis, the comparison between the ozanimod 1 mg to ozanimod 1 mg group vs. the ozanimod 1 mg to placebo group is based on the CMH test, stratified by remission status at week 10 and corticosteroid use at week 10 (yes or no).

Source: Clinical Study Report for the TRUE NORTH study.¹⁰

The subgroup analysis of the proportion of patients who had durable remission at week 52 based on prior use of anti-TNF, disease severity, and disease extent is summarized in Appendix 3.

Maintenance of Clinical Remission

Results pertaining to the proportion of patients who maintained remission at week 52 in the subset of patients who were in remission at week 10 are summarized in Table 16.

At week 42 of the maintenance period (week 52 of the study) in the subset of patients who were in remission at week 10, the proportion of patients who were in remission among those re-randomized to placebo versus those who remained on ozanimod was 29.3% and 51.9%, respectively, representing a statistically significant difference in proportion between the groups of 23.9% (95% CI, 9.1% to 38.6%; P = 0.0025). The odds of maintaining remission at week 52 among patients who remained on ozanimod were greater compared with those who were re-randomized to placebo (OR = 2.88; 95% CI, 1.45 to 5.74).

There was no difference in the proportion of patients in clinical remission at week 52 in the subset of patients in clinical remission at week 52 between those re-randomized to placebo compared with those re-randomized to ozanimod when using observed cases only. The other sensitivity analyses for maintenance of clinical remission were consistent with the main analysis.

Table 16: Proportion of Patients With Maintenance of Remission^a During the Maintenance Period of the TRUE NORTH Trial

CI = confidence interval; CMH = Cochran-Mantel-Haenszel; ITT = intention to treat; RBS = rectal bleeding subscore; SFS = stool frequency subscore; TNF = tumour necrosis factor.

Note: Patients with any RBS, SFS, or endoscopy subscores missing at week 52 are classified as not maintaining remission.

^aClinical remission at week 10 and week 52 was defined as an RBS of 0 and an SFS of ≤ 1 point (and a decrease of ≥ 1 point from the baseline SFS) and an endoscopy subscore of ≤ 1 point without friability.

^bOdds ratio (active vs. placebo), treatment difference, and 2-sided 95% Wald CI and P value for comparison between the cohort 1 ozanimod group and placebo group are based on the CMH test, stratified by corticosteroid use at screening and prior anti-TNF use (yes or no). For the maintenance period analysis, the comparison between the ozanimod 1 mg to ozanimod 1 mg group vs. the ozanimod 1 mg to placebo group is based on the CMH test, stratified by remission status at week 10 and corticosteroid use at week 10 (yes or no).

Source: Clinical Study Report for the TRUE NORTH study.¹⁰

The subgroup analysis of the proportion of patients who had maintained remission at week 52 based on prior use of anti-TNF, disease severity, and disease extent is summarized in Appendix 3.

Clinical Response

Clinical response, as defined by the 3-component and 4-component Mayo, in both the induction and maintenance periods is summarized in Table 17.

Three-Component Mayo Score

The proportion of patients with a clinical response based on the 3-component Mayo definition using a 7-day scoring algorithm in the cohort 1 ozanimod group versus the cohort 1 placebo group at week 10 of the induction period was 47.8% and 25.9%, respectively, representing a statistically significant difference in proportion between the groups of 21.9% (95% CI, 14.4% to 29.3%; P < 0.0001). The odds of being in clinical response at week 10 of the induction period among patients in cohort 1 were greater in patients who received ozanimod compared with those who received placebo (OR = 2.67; 95% CI, 1.86 to 3.84).

The proportion of patients with a clinical remission based on the 3-component Mayo definition using a 7-day scoring algorithm in patients who were re-randomized to placebo versus those who remained on ozanimod at week 42 of the maintenance period (week 52 of the study) was 41.0% and 60.0%, respectively, representing a statistically significant difference in proportion between the groups of 19.2% (95% CI, 10.4% to 28.0%). The odds of achieving clinical remission at week 52 were 2.3 times greater in patients who remained on ozanimod compared with those re-randomized to placebo (OR = 2.27; 95% CI, 1.54 to 3.33).

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Table 17: Proportion of Patients in Clinical Response as Measured by the Mayo Score in the TRUE NORTH Trial

CI = confidence interval; CMH = Cochran-Mantel-Haenszel; DBL = database lock; ITT = intention to treat; OZ = ozanimod; PL = placebo; RBS = rectal bleeding subscore; SFS = stool frequency subscore; TNF = tumour necrosis factor.

Note: P values < 0.05 are considered nominally significant because no multiplicity adjustment was applied.

^aProportion of patients in clinical response at week 10 of the induction period (ITT population, nonresponder imputation).

^bProportion of patients in clinical response at week 42 of the treatment maintenance period (week 52 of the study) (ITT population, nonresponder imputation).

^cOdds ratio (active vs. PL), treatment difference, and 2-sided 95% Wald CI and P value for comparison between the cohort 1 OZ group and PL group are based on the CMH test, stratified by corticosteroid use at screening and prior anti-TNF use (yes or no). For the maintenance period analysis, the comparison between the OZ 1 mg to OZ 1 mg group vs. the OZ 1 mg to PL group is based on the CMH test, stratified by remission status at week 10 and corticosteroid use at week 10 (yes or no).

Source: Clinical Study Report for the TRUE NORTH study.¹⁰

The subgroup analyses of the proportion of patients who experienced clinical response at week 10 and week 52, as defined by the 3-component Mayo score based on prior use of anti-TNF, disease severity, and disease extent, are summarized in Appendix 3.

Rectal Bleeding

Rectal bleeding was an exploratory outcome assessed only in the induction period. Change in RBS from baseline over the induction period is illustrated in Figure 3. Symptomatic improvement in RBS was observed 1 week after completing the required 7-day dose escalation at week 2 in the cohort 1 ozanimod group, and continued to improve, with increasing separation from placebo through to week 10. Compared with the cohort 1 placebo group, a greater reduction from baseline in the least squares mean for the RBS was observed in the cohort 1 ozanimod group at all postbaseline time points.

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Figure 3: Plot of Least Squares Mean Estimate of Change in RBS From Baseline^a

ITT = intention to treat; LSM = least squares mean; RBS = rectal bleeding score; RPC1063 = ozanimod.

Note: Ozanimod change is indicated by a solid line and change score in the placebo group is indicated by the dotted line. Error bars denote standard error.

^a Cohort 1 induction period, ITT population, observed data.

Source: Clinical Study Report for TRUE NORTH.¹⁰

Table 18: Redacted

Note: This table has been redacted as per the sponsor’s request.

Endoscopic Remission

Endoscopic remission was not measured in this study.

Endoscopic Improvement

Results pertaining to the proportion of patients who achieved endoscopic improvement at week 10 of the induction period and week 42 of the maintenance period (week 52 of the study) are summarized in Table 19. Endoscopic remission was defined as an endoscopy subscore for the Mayo score of 1 or less without friability.

The proportion of patients with endoscopic improvement at week 10 of the induction period was 27.3% and 11.6%, respectively; representing a statistically significant difference in proportion between the groups of 15.7% (95% CI, 9.7% to 21.7%; P < 0.0001). The odds of endoscopic improvement at week 10 of the induction period among patients in cohort 1 were greater in patients who received ozanimod compared with those who received placebo (OR = 2.88; 95% CI, 1.80 to 4.59).

At week 42 of the maintenance period (week 52 of the study), the proportion of patients with endoscopic improvement in the group re-randomized to placebo versus the group that remained on ozanimod was 26.4% and 45.7%, respectively; representing a statistically significant difference in proportion between the groups of 19.4% (95% CI, 11.0% to 27.7%; P < 0.001). The odds of endoscopic improvement at week 52 among patients who remained on ozanimod were greater compared with those who were re-randomized to placebo (OR = 2.48; 95% CI, 1.65 to 3.72).

Table 19: Proportion of Patients With Endoscopic Improvement^a in the TRUE NORTH Trial

CI = confidence interval; CMH = Cochran-Mantel-Haenszel; ITT = intention to treat; OZ = ozanimod; PL = placebo; RBS = rectal bleeding subscore; SFS = stool frequency subscore; TNF = tumour necrosis factor.

Note: Patients with missing endoscopy subscores at week 10 and week 52 were classified as not having endoscopic improvement.

^aEndoscopic improvement is defined as an endoscopy subscore of ≤ 1 point without friability.

^bProportion of patients in endoscopic remission at week 10 of the induction period (ITT population, nonresponder imputation).

^cProportion of patients in endoscopic remission at week 52 of the total treatment maintenance period (ITT population, nonresponder imputation).

^dOdds ratio (active vs. placebo), treatment difference, and 2-sided 95% Wald CI and P value for comparison between the cohort 1 OZ group and PL group are based on the CMH test, stratified by corticosteroid use at screening and prior anti-TNF use (yes or no). For the maintenance period analysis, the comparison between the OZ 1 mg to OZ 1 mg group vs. the OZ 1 mg to PL group is based on the CMH test, stratified by remission status at week 10 and corticosteroid use at week 10 (yes or no).

Source: Clinical Study Report for the TRUE NORTH study.¹⁰

The subgroup analysis of the proportion of patients who experienced endoscopic improvement at week 10 and week 52 based on prior use of anti-TNF, disease severity, and disease extent is summarized in Appendix 3.

Mucosal Healing

Results pertaining to the proportion of patients with mucosal healing at week 10 of the induction period and week 42 of the maintenance period (week 52 of the study) are summarized Table 20. Mucosal healing was defined as a Mayo score endoscopy subscore of 1 or less without friability and a Geboes index score of 2 or less.

The proportion of patients with mucosal healing in the cohort 1 ozanimod group versus the cohort 1 placebo group at week 10 of the induction period was 12.6% and 3.7%, respectively; representing a statistically significant difference in proportion between the groups of 8.9% (95% CI, 4.9% to 12.9%; P < 0.001). The odds of mucosal healing at week 10 of the induction period among patients in cohort 1 were greater in patients who received ozanimod compared with those who received placebo (OR = 3.77; 95% CI, 1.76 to 8.07).

At week 42 of the maintenance period (week 52 of the study), the proportion of patients with mucosal healing in the group re-randomized to placebo versus the group that remained on ozanimod was 14.1% and 29.6%, respectively; representing a statistically significant difference in proportion between the groups of 15.6% (95% CI, 8.2% to 22.9%; P < 0.001). The odds of mucosal healing at week 52 among patients who remained on ozanimod were greater compared with those who were re-randomized to placebo (OR = 2.64; 95% CI, 1.64 to 4.26).

The subgroup analysis of the proportion of patients who experienced mucosal healing at week 10 and week 52 based on prior use of anti-TNF, disease severity, and disease extent is summarized in Appendix 3.

Need for Colectomy

Need for colectomy was not measured in this study.

Histologic Remission

Results pertaining to the proportion of patients who achieved histologic remission at week 10 of the induction period and week 42 of the maintenance period (week 52 of the study) are summarized in Table 21. Histologic remission was based on a Geboes index score of 2.0 or less.

The proportion of patients in histologic remission in the cohort 1 ozanimod group versus the cohort 1 placebo group at week 10 of the induction period was 18.2% and 7.4%, respectively, representing a difference in proportion between the groups of 10.8% (95% CI, 5.8% to 15.8%). The odds of histologic remission at week 10 of the induction period among patients in cohort 1 were greater in patients who received ozanimod compared with those who received placebo (OR = 2.80; 95% CI, 1.59 to 4.93).

At week 42 of the maintenance period (week 52 of the study), the proportion of patients in histologic remission among those re-randomized to placebo versus those who remained on ozanimod was 16.3% and 33.5%, respectively, representing a difference in proportion between the groups of 17.3% (95% CI, 9.6% to 24.9%). The odds of being in histologic remission at week 52 among patients who remained on ozanimod was higher by more than twofold compared with those who were re-randomized to placebo (OR = 2.68; 95% CI, 1.70 to 4.23).

Corticosteroid-Free Remission

Results pertaining to corticosteroid-free remission, which was only assessed at week 42 of the maintenance period (week 52 of the study), are summarized in Table 22. Corticosteroid-free remission was defined as clinical remission while off corticosteroids for at least 12 weeks.

At week 52, the proportion of patients with corticosteroid-free remission in the group re-randomized to placebo versus the group that remained on ozanimod was 16.7% and 31.7%, respectively; representing a statistically significant difference in proportion between the groups of 15.2% (95% CI, 7.8% to 22.6%; P < 0.001). The odds of being in corticosteroid-free remission at week 42 of the maintenance period (week 52 of the study) among patients who remained on ozanimod were greater compared with those who were re-randomized to placebo (OR = 2.56; 95% CI, 1.60 to 4.09).

Table 20: Proportion of Patients With Mucosal Healing^a in the TRUE NORTH Trial

CI = confidence interval; CMH = Cochran-Mantel-Haenszel; ITT = intention to treat; OZ = ozanimod; PL = placebo; RBS = rectal bleeding subscore; SFS = stool frequency subscore; TNF = tumour necrosis factor.

Note: Patients with a missing endoscopy subscore or missing Geboes index score at week 10 and week 52 were classified as not having mucosal healing.

^aMucosal healing is defined as an endoscopy subscore of ≤ 1 point without friability and a Geboes index score of < 2.0 (no neutrophils in the epithelial crypts or lamina propria and no increase in eosinophils, no crypt destruction, and no erosions, ulcerations, or granulation tissue).

^bProportion of patients in mucosal healing at week 10 of the induction period (ITT population, nonresponder imputation).

^cProportion of patients in mucosal healing at week 42 of the treatment maintenance period (week 52 of the study) (ITT population, nonresponder imputation).

^dOdds ratio (active vs. PL), treatment difference, and 2-sided 95% Wald CI and P value for comparison between the cohort 1 OZ group and PL group are based on the CMH test, stratified by corticosteroid use at screening and prior anti-TNF use (yes or no). For the maintenance period analysis, the comparison between the OZ 1 mg to OZ 1 mg group vs. the OZ 1 mg to PL group is based on the CMH test, stratified by remission status at week 10 (yes or no) and corticosteroid use at week 10 (yes or no).

Source: Clinical Study Report for the TRUE NORTH study.¹⁰

Table 21: Proportion of Patients in Histologic Remission^a in the TRUE NORTH Trial

CI = confidence interval; CMH = Cochran-Mantel-Haenszel; ITT = intention to treat; OZ = ozanimod; PL = placebo; RBS = rectal bleeding subscore; SFS = stool frequency subscore; TNF = tumour necrosis factor.

Note: Patients with a missing Geboes index score at week 10 and week 52 were classified as not being in histologic remission.

^aHistologic remission is defined as a Geboes index score of < 2.0 (no neutrophils in the epithelial crypts or lamina propria and no increase in eosinophils, no crypt destruction, and no erosions, ulcerations, or granulation tissue).

^bProportion of patients in clinical remission at week 10 of the induction period (ITT population, nonresponder imputation).

^cProportion of patients in clinical remission at week 42 of the maintenance period (week 52 of the study) (ITT population, nonresponder imputation).

^dOdds ratio (active vs. PL), treatment difference, and 2-sided 95% Wald CI and P value for comparison between the cohort 1 OZ and PL group are based on the CMH test, stratified by corticosteroid use at screening and prior anti-TNF use (yes or no). For the maintenance period analysis, the comparison between the OZ 1 mg to OZ 1 mg group vs. the OZ 1 mg to PL group is based on the CMH test, stratified by remission status at week 10 (yes or no) and corticosteroid use at week 10 (yes or no).

Source: Clinical Study Report for the TRUE NORTH study.¹⁰

Table 22: Proportion of Patients in Corticosteroid-Free Remission^a During the Maintenance Period in the TRUE NORTH Trial

CI = confidence interval; CMH = Cochran-Mantel-Haenszel; ITT = intention to treat; RBS = rectal bleeding subscore; SFS = stool frequency subscore; TNF = tumour necrosis factor.

Note: Patients with any of RBS, SFS, and endoscopy subscores missing at week 52 were classified as not being in corticosteroid-free remission.

^aCorticosteroid-free remission is defined as clinical remission (which is defined as an RBS of 0 and an SFS of ≤ 1 point (and a decrease of ≥ 1 point from the baseline SFS) and an endoscopy subscore of ≤ 1 point) at week 52 while off corticosteroids for ≥ 12 weeks.

^bProportion of patients in clinical remission at week 42 of the maintenance period (week 52 of the study) (ITT population, nonresponder imputation).

^cOdds ratio (active vs. placebo), treatment difference, and 2-sided 95% Wald CI and P value for comparison between the cohort 1 ozanimod group and placebo groups are based on the CMH test, stratified by corticosteroid use at screening and prior anti-TNF use (yes or no). For the maintenance period analysis, the comparison between the ozanimod 1 mg to ozanimod 1 mg group vs. the ozanimod 1 mg to placebo group is based on the CMH test, stratified by remission status at week 10 (yes or no) and corticosteroid use at week 10 (yes or no).

Source: Clinical Study Report for the TRUE NORTH study.¹⁰

The subgroup analysis of the proportion of patients who achieved corticosteroid-free remission at week 52 based on prior use of anti-TNF, disease severity, and disease extent is summarized in Appendix 3.

Depression and Anxiety

Depression and anxiety were not directly measured in the TRUE NORTH trial.

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Harms

Only those harms identified in the review protocol are reported subsequently. Refer to Table 23 for detailed harms data.

Table 23: Summary of Harms in the TRUE NORTH Trial

AE = adverse event; AESI = adverse effect of special interest; MedDRA = Medical Dictionary for Regulatory Activities; NR = not reported; OZ = ozanimod; PL = placebo; TEAE = treatment-emergent adverse event.

Note: A TEAE is defined as any AE with a date of first onset or date of worsening in severity on or after the date of the first induction period dose, excluding those with onset after the date of the first maintenance period dose. Patients with multiple events reported for the same summary level are counted only once. Percentages are based on the number of patients in the safety population.

TEAEs were coded using MedDRA version 22.1.

Source: Clinical Study Report for the TRUE NORTH study.¹⁰

Adverse Events

During the induction period, at least 1 TEAE was reported by 40.1% and 38.0% of patients in the cohort 1 ozanimod group and cohort 1 placebo group, respectively. Among patients re-randomized to placebo versus those who continued on ozanimod during the maintenance period, 36.6% and 49.1% of patients reported at least 1 TEAE, respectively.

The TEAEs reported by at least 2% of patients in any treatment group during the induction period were: anemia, nasopharyngitis, headache, nausea, alanine aminotransferase increase, pyrexia, arthralgia, colitis ulcerative, and upper respiratory tract infection. Of these, anemia, nausea, and pyrexia were not reported by any re-randomized patients during the maintenance period, with the remaining TEAEs reported by a similar proportion of patients as in the induction period. Apart from anemia, which was reported in 4.2% to 5.6% of patients, these TEAEs were reported in less than 4% of any treatment group. The following commonly reported TEAEs were exclusive to re-randomized patients in the maintenance period: gamma-glutamyl transferase increased (0.4% to 3.0%), edema peripheral (2.6%), and herpes zoster (0.4% to 2.2%).

Serious Adverse Events

During the induction period, serious TEAEs were reported by 4.0% and 3.2% of patients in the cohort 1 ozanimod group versus the cohort 1 placebo group, respectively. The most common serious TEAE reported in the induction period was colitis ulcerative in both treatment groups (approximately 1.4%). Additional serious TEAEs reported in the cohort 1 ozanimod group were anemia (0.9%) and appendicitis (0.2%).

During the maintenance period, 7.9% of patients re-randomized to placebo and 5.2% of patients who continued ozanimod reported at least 1 serious TEAE. The serious TEAEs reported in at least 2 patients in the re-randomized placebo group included colitis ulcerative (4% in the re-randomized placebo group and 0.4% in the ozanimod group) and complicated appendicitis (0.9% in the re-randomized placebo group).

Withdrawals Due to Adverse Events

Withdrawal from the study due to TEAEs during the induction period was similar across the treatment groups at approximately 3%. The most common reason for withdrawal due to TEAEs was colitis ulcerative (cohort 1 ozanimod: 0.7%; cohort 1 placebo: 1.9%). Two (0.5%) patients in the cohort 2 ozanimod group discontinued from the study due to bradycardia.

The percentage of patients who withdrew from the study due to TEAEs during the maintenance period was 2.6% among those re-randomized to ozanimod versus 1.3% in patients who remained on ozanimod. Four (1.8%) patients in the group re-randomized to placebo withdrew from the study due to colitis ulcerative.

Mortality

During the study period, only 1 death was reported, which was recorded in the induction period cohort 2 ozanimod group.

Notable Harms

Of the serious or opportunistic infections reported, the only 1 reported in at least 2 patients in any treatment group was herpes zoster (induction period cohort 1 ozanimod: 0.5%; induction period cohort 2 ozanimod: 0.3%; maintenance period ozanimod: 1.7%). Each of the following infections were reported in 1 patient over all treatment groups and periods: pyelonephritis, vestibular neuronitis, pneumonia influenza, positive respiratory syncytial virus test, urinary tract infection, Clostridioides difficile infection, complicated appendicitis, gastroenteritis norovirus, large intestine infection, measles, and yersinia infection.

Macular edema was reported by 1 patient in each of the induction period cohort 1 ozanimod group and the maintenance period ozanimod group.

During the induction period, only the cohort 1 ozanimod group reported hepatic effects (0.5% or less of the group), including alanine aminotransferase increased, hepatic enzyme increased, aspartate aminotransferase, liver function test increased, and transaminases increased. In the maintenance period, an increase in blood bilirubin was reported in 1 patient re-randomized to placebo. Among the patients who remained on ozanimod, alanine aminotransferase increase and liver function test increase were each reported in 1 patient.

Lymphopenia was reported in 2 patients (0.9%) in the maintenance period ozanimod group.

Critical Appraisal

Internal Validity

The TRUE NORTH trial employed appropriate methods for blinding, treatment allocation, and randomization. The treatment groups were well balanced during both study periods. The use of separate induction and maintenance studies was consistent with European Medicines Agency guidelines and similar to other studies assessing other medications for the treatment of UC.

Outcomes were objectively obtained with validated instruments that have been similarly used in other UC trials, and the process to carry out outcome measurements was well described and assessed in blinded fashion. There appears to be a low risk of bias due to the selection of the reported results, and the results presented followed the prespecified analysis plan. As described earlier, the study protocol underwent several amendments, which were all well addressed and unlikely to affect the end results or imply bias due to patient selection.

The TRUE NORTH trial was limited by several study design issues. Although approximately 90% of randomized patients completed the induction period, only approximately 50% had a clinical response and continued into the maintenance period. Furthermore, of those who continued into the maintenance period, the proportion of patients who completed the trial among patients re-randomized to receive placebo versus those who continued to receive ozanimod was 54.6% and 80%, respectively. Moreover, a greater proportion of patients in the re-randomized placebo group discontinued the maintenance period of the trial to enter the OLE study compared with the ozanimod group (35.7% versus 14.8%). Study withdrawal due to disease relapse was based on a prespecified definition of disease relapse that included an objective, blinded, centrally read endoscopic assessment. These patients would have been considered nonresponders in the efficacy analyses. Although the direction of any bias is unclear, it is possible that the differential dropout rate between the 2 treatment groups may have introduced attrition bias in favour of ozanimod.

Regarding the statistical analysis, the study was powered to assess the outcome of clinical remission and clinical response. All analyses were performed using the ITT method, ensuring that the prognostic balance created from randomization was maintained. Patients who stopped or deviated from the intervention were properly accounted for in the ITT approach. The key secondary efficacy end points were addressed using the multiplicity hierarchical testing procedure which controlled for type I error. Missing data pertaining to the primary and secondary outcomes were addressed using NRI. While the NRI approach may be considered appropriate, as patients who discontinue treatment are assigned no treatment benefit, it may cause a biased estimation in certain situations. Sensitivity analyses were conducted around missing data using tipping-point analysis, multiple imputation, and analysis of observed cases with no imputation to confirm study results. Results were generally found to be consistent. Since missing data for continuous end points were not imputed and there were large proportions of discontinuations in each period, results for the HRQoL outcomes and the WPAI-UC were at considerable risk of bias, potentially in favour of ozanimod.

Several subgroup analyses were performed to examine the consistency of the treatment effect observed for the primary and key secondary efficacy end points. However, proper interpretation of all subgroups was not possible due to the lack of sample size considerations for these subgroups and their absence from the statistical testing hierarchy. The subgroups were underpowered to detect significant effect modification by subgroups of interest according to the CADTH review protocol, such as prior anti-TNF use and disease severity, though the results suggested (as shown by inconsistency in statistical significance between the subgroups) a differential treatment effect for these subgroups, particularly for the primary end point.

External Validity

The demographic and disease characteristics of the study population were considered by the clinical expert to be generally reflective of the relevant population with UC in Canada.

Disease Extent and Severity

While the disease extent favoured left-sided colitis, the disease severity was considered high, with most patients having an endoscopy subscore of 3, which is reflective of moderate to severe disease activity and typical of the relevant patient population in Canada, as noted by the clinical expert consulted by CADTH.

Race

Approximately 90% of enrolled patients were white. This proportion of white patients in IBD clinical trials is commonplace, mainly due to heavy recruitment from North American and European centres.⁴⁴ While there may be some genetic polymorphisms that influence treatment response by race, none are routinely used in clinical practice nor related to ozanimod, according to the clinical expert.

Age

The lack of representation of patients over the age of 65 has little impact on the generalizability of the trial. According to the clinical expert consulted by CADTH, patients with IBD are generally younger in age, which is evident, given that the mean age at UC diagnosis among study patients was approximately 35 years. In addition, other treatments with a more favourable side effect profile are typically used among older patients with UC. Finally, older patients are more likely to be on other medications or have cardiac and/or ocular comorbidities that would be contraindications for ozanimod. It should also be noted that the product monograph for Zeposia states, “Health Canada has not authorized Zeposia for maintenance treatment of UC in patients ≥ 65 years of age.”²⁵

Enriched Patient Population

The trial criterion that directed entry into the maintenance period, clinical response, likely created an enriched patient population. Consequently, the patients who entered the maintenance period may be more likely to benefit from treatment with ozanimod than the general population in the real-world setting. According to the clinical expert consulted by CADTH, this is the common trial design used in UC programs, as it is challenging to keep nonresponders in a long-term study. Additionally, there may be a subset of patients who experience a delayed response to induction therapy. Indeed, a recent phase III upadacitinib program found that approximately half of the patients with UC who did not respond during an initial 8-week induction did respond with an extended 16-week induction period. This added another layer of difficulty to assess the generalizability of efficacy results from this 2-stage, enrichment design trial.

Availability of Open-Label Ozanimod Upon Relapse

Patients had the opportunity to enrol in the OLE study, where they would receive ozanimod upon disease relapse during the maintenance period. Indeed, there was significant study discontinuation due to disease relapse and entry into the OLE study (34% of patients re-randomized from ozanimod to placebo and 14% of patients re-randomized from ozanimod to ozanimod); these patients were imputed as nonresponders for the primary and key secondary end points. It is possible that the proportions of patients discontinuing double-blind treatment from the main trial who then receive open-label ozanimod upon disease relapse may not reflect the proportions of discontinuations of ozanimod treatment in the real world, where patients are not blinded to their treatment.

Response to Prior UC Treatment

The observed failure rate of prior UC treatment at baseline was a function of the clinical trial design. For example, compared with the general population with UC, 75% of patients with UC do not experience treatment failure with steroids. According to the clinical expert consulted by CADTH, in the confines of the inclusion and exclusion criteria for clinical trials in moderate to severe UC that require the failure of conventional treatment, the failure rates observed in TRUE NORTH are expected. Similarly, the failure rate for biologic treatment was capped by the trial design.

Prohibited Concomitant Medications

According to the clinical expert consulted by CADTH, the concomitant medications prohibited during the study period and/or during the observations follow-up period through the 30-day safety follow-up visit would not limit the trial results to be generalized to the UC patient population in practice. This is mainly because the general population with UC tends to be otherwise young, healthy individuals whose condition has failed to respond to biologic therapies before treatment with ozanimod, or who would be using biologic therapies after the failure of treatment with ozanimod rather than concomitantly.

Treatment Regimen

The study protocol did not include rectal therapy and required corticosteroid tapering during the study period, creating a treatment regimen that is harsher than in clinical practice. Therefore, the treatment regimen in the TRUE NORTH trial may not be representative of clinical practice, where patients may be kept on the drug longer by using rectal therapy or corticosteroids to ameliorate symptoms while waiting for a response. Of note, patients who could not taper corticosteroids were not considered to have experienced treatment failure; rather, tapering was reset or paused.

Indirect Evidence

Objectives and Methods for the Summary of Indirect Evidence

As there was no direct evidence comparing ozanimod with other active therapies for the treatment of moderate to severe UC in adult patients, a review of indirect evidence was undertaken.

The sponsor submitted an ITC in patients with moderate to severe UC.¹¹ CADTH also conducted a literature search to identify potentially relevant ITCs in this patient population. A focused literature search for NMAs dealing with UC was run in MEDLINE All (1946–) on February 2, 2022. No limits were applied to the search. Titles, abstracts, and full-text articles were screened for inclusion by 1 reviewer based on the population, intervention, comparator, and outcome criteria outlined in Table 5. Two studies (Lasa et al. [2022]¹² and Burr et al. [2021]⁴⁵) describing NMAs of the efficacy and safety of biologics and small-molecule drugs, including ozanimod, for patients with moderate to severe UC were identified. The 2 published ITCs assessed the same biologic drugs and small-molecule drugs, except that in the Lasa et al. ITC, etrasimod and TD-1473 were also included. Both ITCs used the same statistical methods in data analyses and the findings were similar. Therefore, the Lasa et al. ITC has been summarized and appraised in this review.

The objective of this section is to summarize and critically appraise the sponsor-submitted ITC and the Lasa et al. report.

Description of Indirect Comparison

Both ITCs included a systematic review of the literature to identify trials investigating ozanimod or comparator interventions in patients with moderate to severe UC, and an NMA that compared ozanimod with other active treatments.

In the sponsor-submitted ITC, ozanimod was compared with ustekinumab, infliximab, certolizumab, adalimumab, vedolizumab, tofacitinib, golimumab, filgotinib, etrasimod, or the biosimilar versions of these therapies, and placebo. Phase II or III RCTs were included. Clinical response, clinical remission, and endoscopic improvement were evaluated based on subgroups of patients who were biologic-naive or biologic-exposed, and also in the induction and maintenance phases of drug administration.

In the Lasa et al. report, ozanimod was compared with infliximab, adalimumab, golimumab, vedolizumab, ustekinumab, tofacitinib, etrolizumab, upadacitinib, filgotinib, etrasimod, TD-1473, and placebo. Only phase III RCTs were included in this report. In the Lasa et al. report, clinical remission, endoscopic improvement, and steroid-free remission were evaluated (“clinical response” was withdrawn as an outcome of interest in an amendment to the protocol in 2021). Results of clinical remission and endoscopic improvement were reported separately for the subgroups of biologic-naive and biologic-exposed patients during the induction phase and the maintenance phase.

Safety outcomes were examined in the 2 ITCs.

Table 24: Study Selection Criteria and Methods for ITCs