Impact of Steroid Weaning Regimens on Outcomes in Clinical Trials of Ulcerative Colitis

Lead Investigator: Neeraj Narula, Hamilton Health Sciences
Title of Proposal Research: Impact of Steroid Weaning Regimens on Outcomes in Clinical Trials of Ulcerative Colitis
Vivli Data Request: 7656
Funding Source: None
Potential Conflicts of Interest: Neeraj Narula holds a McMaster University Department of Medicine Internal Career Award. Neeraj Narula has received honoraria from Janssen, Abbvie, Takeda, Pfizer, Merck, Lupin and Ferring. None of the listed conflicts of interest are aware of or are involved in this research.

Summary of the Proposed Research:

Ulcerative colitis (UC) is a type of inflammatory bowel disease that affects the large intestine. Patients with UC experience symptoms such as diarrhea, rectal bleeding, abdominal pain, and urgency. Patients with severe disease or those who lack response to corticosteroids are candidates for biologic and small molecule treatments.

Vedolizumab and adalimumab are two biologic therapies that have been approved for the treatment of moderate-to-severe UC on the strength of several placebo-controlled trials demonstrating efficacy and ability to maintain response, including ACT 1 (NCT00036439) and ACT 2 (NCT00096655), ULTRA 2 (NCT00408629), and GEMINI 1 (NCT00783718). Recently, the VARSITY trial (NCT02497469) was a head-to-head trial that demonstrated the superiority of vedolizumab to adalimumab in moderate-to-severe UC. Golimumab is another biologic therapy that demonstrated efficacy in PURSUIT (NCT00488631), which was a placebo-controlled trial. In addition to biologic therapies, small molecule therapies are a treatment option that has recently emerged. Tofacitinib was recently approved on the strength of the placebo-controlled OCTAVE trials (NCT01465763, NCT01458951, and NCT01458574).

The Mayo Score is a tool that is used in clinical practice and trials to determine the severity of UC and is comprised of several patient-reported and endoscopic sub-scores, including stool frequency, rectal bleeding, endoscopic findings, and physician’s global assessment. Each subscore is scored from 0 to 3, with higher scores indicating greater disease severity. The total Mayo Score ranges from 0 to 12, while the partial Mayo Score excludes the endoscopic subscore and thus ranges from 0 to 9. The Mayo Score is widely used in clinical trials for UC to evaluate primary endpoints, such as clinical remission (CR). Corticosteroid-free CR is also an important endpoint and is often included as part of co-primary or secondary endpoints.

Patients enrolled in trials often require corticosteroids at the time of entry to manage their symptoms. Corticosteroid use can reduce symptoms that indicate active disease and therefore its use can impact outcomes in clinical trials. However, protocols for managing steroids during trials vary. In the VARSITY trial, steroid tapering was adaptive and up to the physician’s discretion. Other trials implement a fixed steroid tapering protocol that must be strictly adhered to. Although trials must transparently document steroid tapering protocols, there remains a lack of consistent or standardized tapering definitions across trials. Therefore, it remains unclear what impact steroid tapering protocols have on trial outcomes.

The primary objective of this study is to evaluate whether differences in steroid tapering regimen between clinical trials influenced one-year corticosteroid-free CR among patients with steroid use at baseline. The secondary objectives of this study include CR at one-year and corticosteroid-free CR among all patients, regardless of baseline steroid use.

Patient-level data from ULTRA 2, GEMINI 1, VARSITY, and OCTAVE is being requested from Vivli. Patient-level data from ACT 1, ACT 2, and PURSUIT is being requested from the YODA Project.

Patients may benefit from the knowledge generated from this study as it may inform criteria for steroid tapering protocols in clinical trials. By extention, knowledge generated from this study may help patients better understand how concomitant use of steroids may impact their likelihood of achieving favourable outcomes in the future.

Statistical Analysis Plan:

In GEMINI 1, OCTAVE, and PURSUIT, patients who received active therapy during the induction phase were re-randomized to receive placebo or continue active therapy during maintenance based on clinical response. Data from these trials will be aggregated to form two cohorts: 1) re-randomized to active therapy and 2) re-randomized to placebo. In ACT 1, ACT 2, ULTRA 2 and VARSITY, patients were randomized to active therapy or placebo for the entire duration of the trial. Data from these trials will be aggregated to form a cohort of participants who were treated-straight-through with active therapy. One-year was a common timepoint across all trials. An indicator variable will be used to distinguish between trials.

GEMINI 1 and ULTRA 2 had similar steroid weaning protocols, with an incremental decrease by 5mg every week starting at week 6 until 10mg, with subsequent decreases of 2.5mg per week. Similarly, ACT 1, ACT 2, and OCTAVE had similar tapering regimens (decrease by 5mg every week starting at week 8 (week 5 for OCTAVE) followed by a decrease of 2.5mg per week by 20mg). The maximum steroid doses allowed varied between trials but ranged from 20-40mg. In VARSITY, steroid tapering began at week 6 but was adaptive at the discretion of the physician, with the ability to increase steroid dose if the first attempt at weaning was unsuccessful.

The primary analysis will be conducted as intention-to-treat, where patients with missing data will be assumed to not have achieved the outcomes of interest. A separate case analysis will be conducted where patients with missing outcome data (e.g. one year Mayo Score) will be excluded from the primary analysis.

Descriptive statistics will be calculated to compare the rate of achievement of outcomes between groups. Logistic regression will used to assess the treatment effect on the outcome of interest. Univariate analyses will be conducted to identify associations between covariates and the outcome of interest, and any variables with a p-value < 0.10 will be included in the multivariate model.
Continuous variables will be presented as means (and standard deviations [SD] or as medians and interquartile ranges [IQR]), if the data is skewed. Binary variables will be presented as proportions or percentages. Descriptive statistics will be used to summarize baseline demographics, disease characteristics and outcome parameters of included patients. Differences between groups will be compared using the Mann-Whitney U test or chi-squared test. Data will be analyzed using Stata, which is available on the Vivli secure platform. Additionally, to account for differences in treatment, models will be adjusted for treatment arm.

Requested Studies:

A Randomized, Placebo-controlled, Double-blind Trial to Evaluate the Safety and Efficacy of Infliximab in Patients With Active Ulcerative Colitis
Data Contributor: Johnson & Johnson
Study ID: NCT00036439
Sponsor ID: CR004777

A Multicenter, Randomized, Double-blind, Placebo-controlled Study of the Human Anti-TNF Monoclonal Antibody Adalimumab for the Induction and Maintenance of Clinical Remission in Subjects With Moderately to Severely Active Ulcerative Colitis
Data Contributor: AbbVie
Study ID: NCT00408629
Sponsor ID: M06-827

A Phase 3, Randomized, Placebo-Controlled, Blinded, Multicenter Study of the Induction and Maintenance of Clinical Response and Remission by MLN0002 in Patients With Moderate to Severe Ulcerative Colitis
Data Contributor: Takeda
Study ID: NCT00783718
Sponsor ID: C13006

A Randomized, Double-Blind, Double-Dummy, Multicenter, Active-Controlled Study to Evaluate the Efficacy and Safety of Vedolizumab IV Compared to Adalimumab SC in Subjects With Ulcerative Colitis
Data Contributor: Takeda
Study ID: NCT02497469
Sponsor ID: MLN0002-3026

A Phase 3 Multicenter, Randomized, Placebo-controlled, Double-blind Study to Evaluate the Safety and Efficacy of Golimumab Maintenance Therapy, Administered Subcutaneously, in Subjects With Moderately to Severely Active Ulcerative Colitis
Data Contributor: Johnson & Johnson
Study ID: NCT00488631
Sponsor ID: CR014179

A Multicentre, Randomized, Double-blind, Placebo-controlled, Parallel-group Study Of Oral Cp-690,550 As An Induction Therapy In Subjects With Moderate To Severe Ulcerative Colitis
Data Contributor: Pfizer Inc.
Study ID: NCT01465763
Sponsor ID: A3921094

A Multicentre, Randomized, Double-blind, Placebo-controlled, Parallel-group Study Of Oral Cp-690,550 As An Induction Therapy In Subjects With Moderate To Severe Ulcerative Colitis.
Data Contributor: Pfizer Inc.
Study ID: NCT01458951
Sponsor ID: A3921095

A Multicentre, Randomized, Double-blind, Placebo-controlled, Parallel-group Study Of Oral Cp-690,550 As A Maintenance Therapy In Subjects With Ulcerative Colitis
Data Contributor: Pfizer Inc.
Study ID: NCT01458574
Sponsor ID: A3921096

Public Disclosures

1. Narula, N., Hamam, H., Wong, E.C., Marshall, J.K., Jairath, V., Hanauer, S.B., Reinisch, W. and Dulai, P.S., 2024. P689 Adaptive steroid tapering impedes corticosteroid-free remissions compared to forced tapering in UC clinical trials. Journal of Crohn’s and Colitis, 18(Supplement_1), pp.i1308-i1308. Doi: 10.1093/ecco-jcc/jjad212.0819
2. Narula, N., Hamam, H., Liu, J., Wong, E.C., Marshall, J.K., Jairath, V., Hanauer, S.B., Reinisch, W. and Dulai, P.S., 2024. Adaptive steroid tapering impedes corticosteroid-free remissions compared to forced tapering in clinical trials of ulcerative colitis. Journal of Crohn’s and Colitis, p.jjae092. Doi : 10.1093/ecco-jcc/jjae092