A Multicenter, Randomized, Double-blind Placebo-controlled Study of the Human Anti-TNF Monoclonal Antibody Adalimumab for the Induction of Clinical Remission in Subjects With Moderately to Severely Active Ulcerative Colitis
Overview
- Phase
- Phase 3
- Intervention
- Not specified
- Conditions
- Ulcerative Colitis
- Sponsor
- Abbott
- Enrollment
- 576
- Locations
- 80
- Primary Endpoint
- Proportion of Participants With Clinical Remission Per Mayo Score at Week 8
- Status
- Completed
- Last Updated
- 15 years ago
Overview
Brief Summary
The objective of this study is to assess the efficacy and safety of adalimumab for the induction of clinical remission in subjects with moderately to severely active ulcerative colitis.
Detailed Description
This was a Phase 3, multicenter, randomized, double-blind (DB), placebo-controlled trial designed to evaluate the efficacy and safety of the human anti-TNF monoclonal antibody adalimumab for the induction of clinical remission in participants with moderately to severely active ulcerative colitis (UC). Adult participants with moderate to severe UC (Mayo score of 6 to 12 points with endoscopy subscore of 2 to 3 points), confirmed by colonoscopy with biopsy or by flexible sigmoidoscopy with biopsy, were enrolled at 80 sites worldwide. The study enrolled 576 participants, including 186 participants under the original protocol and protocol Amendments 1 and 2, and 390 participants under protocol Amendments 3 and 4. Participants enrolled in the study prior to Amendment 3 were randomized in a 1:1 ratio to receive adalimumab or placebo during the 12-week DB induction period. Participants received 4 injections of adalimumab 40 mg (160 mg) or 4 injections of placebo at Baseline (Week 0), followed by 2 injections of adalimumab 40 mg (80 mg) or 2 injections of placebo at Week 2, followed by 1 injection of adalimumab 40 mg or placebo at Weeks 4 and 6. At Week 8, participants randomized to placebo received 4 injections of adalimumab 40 mg (160 mg) followed by 2 injections of adalimumab 40 mg (80 mg) at Week 10. Participants randomized to adalimumab received 3 injections of placebo and 1 injection of adalimumab 40 mg at Week 8 and 1 injection of placebo and 1 injection of adalimumab 40 mg at Week 10. All participants continued to receive 1 injection of open-label (OL) adalimumab 40 mg every other week beginning at Week 12 up to Week 52 (or the early termination visit). Starting at Week 14, participants who had inadequate responses to treatment (as defined using partial Mayo scores) were permitted to dose escalate to adalimumab 40 mg weekly. Participants with persistent inadequate response while on weekly treatment could be discontinued from the study at the discretion of the investigator. In August 2007, the study design was amended to incorporate an additional adalimumab induction dosing arm of 80/40 mg. Earlier that year, both 160/80-mg and 80/40-mg induction regimens had been approved in the EU as induction treatment for Crohn's disease. The adalimumab induction dosing regimen of 80/40 mg was therefore included so that both of these approved induction regimens would be evaluated for the induction of remission of UC. Participants enrolled in the study after Amendment 3 were randomized in a 1:1:1 ratio to receive adalimumab (1 of 2 regimens) or placebo during the 8-week DB induction period. Participants received DB therapy from Baseline until Week 8 and OL therapy from Week 8 until the end of the study. In the first adalimumab dosing arm (adalimumab 80/40), participants received 2 injections of adalimumab 40 mg (80 mg) and 2 injections of placebo at Baseline followed by 1 injection of adalimumab 40 mg and 1 injection of placebo at Week 2, and 1 injection of adalimumab 40 mg every other week thereafter. In the second adalimumab DB induction dosing arm (adalimumab 160/80), participants received 4 injections of adalimumab 40 mg (160 mg) at Baseline followed by 2 injections of adalimumab 40 mg (80 mg) at Week 2, and 1 injection of adalimumab 40 mg every other week thereafter. Participants randomized to placebo received 4 injections of placebo at Baseline followed by 2 injections of placebo at Week 2, and 1 injection of placebo at Weeks 4 and 6. Beginning at Week 8, but after the Week 8 study assessments had been completed, all participants received 1 injection of OL adalimumab 40 mg every other week until Week 52 or early termination. Starting at Week 12, participants who had inadequate responses to treatment (as defined using partial Mayo scores) were permitted to dose escalate to adalimumab 40 mg weekly. Participants with persistent inadequate response while on weekly treatment could be discontinued from the study at the discretion of the investigator. For the analysis of efficacy parameters during the DB Period through Week 8, only participants randomized under Protocol Amendment 3 or later were considered ("Efficacy Analysis Set - Induction" in the participant flow). For the analysis of efficacy parameters during the OL Period through Week 52, all randomized participants (under any version of the protocol) who received at least 1 dose of study drug were considered ("Efficacy Analysis Set - Maintenance" in the participant flow). For the analysis of safety parameters, all participants who received at least 1 dose of study drug were considered ("Safety Analysis Set" in the participant flow). Twelve ranked secondary variables during the DB Period through Week 8 were to be tested in a hierarchical order to account for multiple testing. These variables are identified as "Ranked Secondary Endpoints" in the results section below. Additionally, non-ranked secondary variables during the OL Period through Week 52 were tested and are presented after the ranked secondary endpoints in the results section below.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Male and female participants \>= 18 years of age
- •Diagnosis of ulcerative colitis for greater than 90 days prior to Baseline
- •Diagnosis of active ulcerative colitis confirmed by colonoscopy with biopsy or flexible sigmoidoscopy with biopsy during the Screening Period, with exclusion of infection
- •Active UC with a Mayo score of 6 to 12 points and endoscopy subscore of 2 to 3 points, despite concurrent treatment with at least 1 of the following (oral corticosteroids or immunosuppressants or both as defined below):
- •Stable oral corticosteroid dose (prednisone dose of \>= 20 mg/day or equivalent) for at least 14 days prior to Baseline or stable oral corticosteroid dose (prednisone of \< 20 mg/day) for at least 40 days prior to Baseline.
- •At least a consecutive 90 day course of azathioprine or 6-mercaptopurine (6 MP) prior to Baseline, with a dose of azathioprine \>= 1.5 mg/kg/day or 6 MP \>= 1 mg/kg/day (rounded to the nearest available tablet formulation), or a dose that is the highest tolerated by the participant (e.g., due to leukopenia, elevated liver enzymes, nausea) during that time. Participant was to be on a stable dose for at least 28 days prior to Baseline.
- •Concurrent therapy was not required for participants who were previously treated with corticosteroids or immunosuppressants (azathioprine or 6-MP) during the previous 5 years and, in the judgment of the investigator, have failed to respond to or could not tolerate their treatment.
- •Had to be able to self-administer or has caregiver who can reliably administer subcutaneous injections.
- •Had to be able and willing to give written informed consent and to comply with the requirements of this study protocol.
- •Female had to be either not of childbearing potential, defined as postmenopausal for at least 1 year or surgically sterile (bilateral tubal ligation, bilateral oophorectomy or hysterectomy), or of childbearing potential and practicing an approved method of birth control throughout the study and for 150 days after last dose of study drug. Examples of approved methods of birth control included the following:
Exclusion Criteria
- •History of subtotal colectomy with ileorectostomy or colectomy with ileoanal pouch, Koch pouch, or ileostomy for ulcerative colitis or is planning bowel surgery.
- •Received infliximab or any other anti-TNF agent or any biological therapy in the past.
- •Received previous treatment with adalimumab or previous participation in an adalimumab clinical study.
- •Received cyclosporine, tacrolimus, or mycophenolate mofetil within 30 days prior to Baseline.
- •Received intravenous corticosteroids within 14 days prior to Screening or during the Screening Period.
- •Received therapeutic enema or suppository, other than required for endoscopy, within 14 days prior to the Screening endoscopy and during the remainder of the Screening Period.
- •Current diagnosis of fulminant colitis and/or toxic megacolon.
- •Participants with disease limited to the rectum (ulcerative proctitis).
- •Current diagnosis of indeterminate colitis.
- •Current diagnosis and/or history of Crohn's disease.
Outcomes
Primary Outcomes
Proportion of Participants With Clinical Remission Per Mayo Score at Week 8
Time Frame: Week 8
Clinical remission per Mayo score is defined as a total Mayo score \<= 2 and no individual subscore \> 1. The Mayo Score is a discrete ordinal scale ranging from 0 (normal or inactive disease) to 12 (severe disease) and is a composite of 4 subscores: Stool Frequency Subscore, Rectal Bleeding Subscore, Endoscopy Subscore, and Physician's Global Assessment Subscore, each of which ranges from 0 (normal) to 3 (severe disease).
Secondary Outcomes
- Ranked Secondary Endpoint #1: Proportion of Participants With Clinical Response Per Mayo Score at Week 8 (Adalimumab 160/80/40 Versus Placebo).(Week 8)
- Ranked Secondary Endpoint #2: Proportion of Participants With Mucosal Healing at Week 8 (Adalimumab 160/80/40 Versus Placebo).(Week 8)
- Ranked Secondary Endpoint #3: Proportion of Participants With Rectal Bleeding Subscore Indicative of Mild Disease (<= 1) at Week 8 (Adalimumab 160/80/40 Versus Placebo).(Week 8)
- Ranked Secondary Endpoint #5: Proportion of Participants With Stool Frequency Subscore Indicative of Mild Disease (<= 1) at Week 8 (Adalimumab 160/80/40 Versus Placebo).(Week 8)
- Ranked Secondary Endpoint #4: Proportion of Participants With Physician's Global Assessment Subscore Indicative of Mild Disease (<= 1) at Week 8 (Adalimumab 160/80/40 Versus Placebo).(Week 8)
- Ranked Secondary Endpoint #6: Proportion of Participants With Clinical Response Per Mayo Score at Week 8 (Adalimumab 80/40 Versus Placebo).(Week 8)
- Ranked Secondary Endpoint #7: Proportion of Participants With Mucosal Healing at Week 8 (Adalimumab 80/40 Versus Placebo).(Week 8)
- Ranked Secondary Endpoint #8: Proportion of Participants With Rectal Bleeding Subscore Indicative of Mild Disease (<= 1) at Week 8 (Adalimumab 80/40 Versus Placebo).(Week 8)
- Ranked Secondary Endpoint #9: Proportion of Participants With Physician's Global Assessment Subscore Indicative of Mild Disease (<= 1) at Week 8 (Adalimumab 80/40 Versus Placebo).(Week 8)
- Ranked Secondary Endpoint #10: Proportion of Participants With Stool Frequency Subscore Indicative of Mild Disease (<= 1) at Week 8 (Adalimumab 80/40 Versus Placebo).(Week 8)
- Ranked Secondary Endpoint #11: Proportion of IBDQ Responders at Week 8 (Adalimumab 160/80/40 Versus Placebo).(Week 8)
- Ranked Secondary Endpoint #12: Proportion of IBDQ Responders at Week 8 (Adalimumab 80/40 Versus Placebo).(Week 8)
- Proportion of Participants With Clinical Remission Per Mayo Score at Week 52(Week 52)
- Proportion of Participants With Clinical Remission Per Partial Mayo Score at Week 52(Week 52)
- Proportion of Participants With Clinical Response Per Mayo Score at Week 52(Week 52)
- Proportion of Participants With Clinical Response Per Partial Mayo Score at Week 52(Week 52)
- Proportion of Participants With Mucosal Healing at Week 52(Week 52)
- Proportion of Participants With Rectal Bleeding Subscore Indicative of Mild Disease (<= 1) at Week 52(Week 52)
- Proportion of Participants With Physician's Global Assessment Subscore Indicative of Mild Disease (<= 1) at Week 52(Week 52)
- Proportion of Participants With Stool Frequency Subscore Indicative of Mild Disease (<= 1) at Week 52(Week 52)
- Proportion of Participants With Clinical Remission Per Mayo Score at Week 52 Among Participants Who Were Systemic Corticosteroid-free at Week 52(Week 52)