A Study of Adalimumab in Japanese Subjects With Moderately to Severely Active Ulcerative Colitis

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to assess the efficacy and safety of adalimumab in Japanese subjects with moderately to severely active ulcerative colitis (UC).

Detailed Description
-----------------
Patients who meet all of the inclusion criteria and none of the exclusion criteria are randomized 1:1:1 to receive subcutaneous injections of adalimumab at either 160/80 mg at Week 0/2 and 40 mg every other week (eow) starting at Week 4 to Week 50, 80/40 mg at Week 0/2 and 40 mg eow starting at Week 4 to Week 50, or placebo eow starting at Week 0 to Week 50 under the double-blind condition. At or after Week 8, participants who have inadequate response during the double-blind period can switch to the rescue arm, where participants from the placebo group initially receive adalimumab 160 mg and 80 mg 2 weeks later and those from the adalimumab group receive adalimumab 40 mg initially and 2 weeks later under double-blind conditions. All participants in the rescue arm then receive 40 mg adalimumab eow until Week 50. Participants who complete the 52-week double-blind period receive open-label adalimumab 40 mg eow starting at Week 52 and continuing until the end of the study. Participants who have an inadequate response or disease flare can dose escalate to 80 mg eow at or after Week 60. Participants who dose escalate to 80 mg eow and continue to have an inadequate response or disease flare are withdrawn from the study.

Official Title
-----------------
A Multi-Center, Randomized, Double-Blind, Placebo-controlled Study of Adalimumab in Japanese Subjects With Moderately to Severely Active Ulcerative Colitis.

Conditions
-----------------
Ulcerative Colitis

Intervention / Treatment
-----------------
* Biological: adalimumab
* Drug: placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Diagnosis of ulcerative colitis for greater than 90 days prior to Baseline. Active ulcerative colitis with a Mayo Score of 6-12 points at Baseline and endoscopy subscore of 2-3 during the Screening Period, despite concurrent treatment with at least one of the following (oral corticosteroids or immunosuppressants or both as defined below): Stable oral corticosteroid dose (prednisolone dose of ≥ 20 mg/day or equivalent) for at least 14 days prior to Baseline or stable oral corticosteroid dose (prednisolone of 5 to less than 20 mg/day) for at least 40 days prior to Baseline. And/or At least a consecutive 90-day course of azathioprine or 6-mercaptopurine (6-MP) prior to Baseline, with a dose of azathioprine ≥ 50 mg/day or 6-MP ≥ 30 mg/day, or a dose that was the highest tolerated by the patient. Exclusion Criteria: History of subtotal colectomy with ileorectostomy or colectomy with ileoanal pouch, Koch pouch, or ileostomy for ulcerative colitis or was planning bowel surgery. Patients with disease limited to the rectum. Indeterminate colitis and/or Crohn's disease. Received any biological therapy (including infliximab) in the past. History of tuberculosis or malignancy. Pregnant women. Patients with positive C. difficile stool assay at Screening. Current diagnosis of fulminant colitis and/or toxic megacolon.

Ages Eligible for Study
-----------------
Minimum Age: 15 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Participants received placebo subcutaneous injections every 2 weeks for 52 weeks. From Week 8, participants with an inadequate response could switch to rescue therapy, where they initially received adalimumab 160 mg, 80 mg 2 weeks later, and then 40 mg every other week. Participants who completed the 52-week double-blind period received open-label adalimumab 40 mg every other week, with the possibility to escalate to 80 mg every other week, until drug approval. | Biological: adalimumab<br> <br> * Other names: ABT-D2E7 Humira;Drug: placebo<br> <br> |
| Experimental: Adalimumab 80 mg/40 mg<br>Participants received adalimumab 80 mg on Day 1, 40 mg at Week 2 and 40 mg every other week from Week 4 to Week 50, via subcutaneous injection. From Week 8, participants with an inadequate response could switch to rescue therapy, where they received adalimumab 40 mg every other week. Participants who completed the 52-week double-blind period received open-label adalimumab 40 mg every other week, with the possibility to escalate to 80 mg every other week, until drug approval. | Biological: adalimumab<br> <br> * Other names: ABT-D2E7 Humira;|
| Experimental: Adalimumab 160 mg/80 mg<br>Participants received adalimumab 160 mg on Day 1, 80 mg at Week 2 and 40 mg every other week from Week 4 to Week 50, via subcutaneous injection. From Week 8, participants with an inadequate response could switch to rescue therapy, where they received adalimumab 40 mg every other week. Participants who completed the 52-week double-blind period received open-label adalimumab 40 mg every other week, with the possibility to escalate to 80 mg every other week, until drug approval. | Biological: adalimumab<br> <br> * Other names: ABT-D2E7 Humira;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Clinical Remission at 8 Weeks | Clinical remission was defined as a Mayo score ≤ 2 with no individual subscore > 1. The Mayo score is a composite score of ulcerative colitis disease activity calculated as the sum of four subscores: Stool Frequency Subscore (SFS), based on the participant's diary and scored from zero (normal number of stools) to three (5 or more stools than normal); Rectal Bleeding Subscore (RBS), based on the participant's diary and scored from zero (no blood) to three (blood only passed); Endoscopy Subscore (ESS), based on colonoscopy or sigmoidoscopy and scored from zero (normal or inactive disease) to three (severe disease, spontaneous bleeding, ulceration); Physician's Global Assessment (PGA) subscore, based on the physician's overall assessment, and scored from zero (normal) to three (severe disease). The total Mayo score ranges from 0 to 12 points, with higher scores representing more severe disease. | Week 8 | 
| Percentage of Participants With Clinical Remission at 52 Weeks | Clinical remission was defined as a Mayo score ≤ 2 with no individual subscore > 1. The Mayo score is a composite score of ulcerative colitis disease activity calculated as the sum of four subscores: Stool Frequency Subscore (SFS), based on the participant's diary and scored from zero (normal number of stools) to three (5 or more stools than normal); Rectal Bleeding Subscore (RBS), based on the participant's diary and scored from zero (no blood) to three (blood only passed); Endoscopy Subscore (ESS), based on colonoscopy or sigmoidoscopy and scored from zero (normal or inactive disease) to three (severe disease, spontaneous bleeding, ulceration); Physician's Global Assessment (PGA) subscore, based on the physician's overall assessment, and scored from zero (normal) to three (severe disease). The total Mayo score ranges from 0 to 12 points, with higher scores representing more severe disease. | Week 52 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Clinical Remission at 8, 32, and 52 Weeks | Clinical remission was defined as a Mayo score ≤ 2 with no individual subscore > 1. The Mayo score is a composite score of ulcerative colitis disease activity calculated as the sum of four subscores: Stool Frequency Subscore (SFS), based on the participant's diary and scored from zero (normal number of stools) to three (5 or more stools than normal); Rectal Bleeding Subscore (RBS), based on the participant's diary and scored from zero (no blood) to three (blood only passed); Endoscopy Subscore (ESS), based on colonoscopy or sigmoidoscopy and scores from zero (normal or inactive disease) to three (severe disease, spontaneous bleeding, ulceration); Physician's Global Assessment (PGA) subscore, based on the physician's overall assessment, and scored from zero (normal) to three (severe disease). The total Mayo score ranges from 0 to 12 points, with higher scores representing more severe disease. | Weeks 8, 32, and 52 | 
| Percentage of Participants With a Clinical Response | A clinical response was defined as a decrease in Mayo score of ≥ 3 points and ≥ 30% from Baseline PLUS a decrease in the Rectal Bleeding Subscore (RBS) ≥ 1 or an absolute RBS of 0 or 1. The Mayo score is a composite score of ulcerative colitis disease activity calculated as the sum of four subscores: Stool Frequency Subscore, based on the participant's diary and scored from zero (normal number of stools) to three (5 or more stools than normal); Rectal Bleeding Subscore, based on the participant's diary and scored from zero (no blood) to three (blood only passed); Endoscopy Subscore, based on colonoscopy or sigmoidoscopy and scored from zero (normal or inactive disease) to three (severe disease, spontaneous bleeding, ulceration); Physician's Global Assessment subscore, based on the physician's overall assessment, and scored from zero (normal) to three (severe disease). The total Mayo score ranges from 0 to 12 points, with higher scores representing more severe disease. | Baseline and Weeks 8, 32, and 52 | 
| Percentage of Participants With Mucosal Healing | Mucosal healing was defined as an endoscopy subscore of ≤ 1 and was assessed using flexible sigmoidoscopy performed at Weeks 8, 32, and 52. The endoscopy subscore ranges from zero to three as follows: 0 = Normal or inactive disease, 1 = Mild disease (erythema, decreased vascular pattern, mild friability), 2 = Moderate disease (marked erythema, absent vascular pattern, friability, erosions), 3 = Severe disease (spontaneous bleeding, ulceration). | Weeks 8, 32, and 52 | 
| Percentage of Participants With Rectal Bleeding Subscore Indicative of Mild Disease (≤ 1) | Rectal bleeding was assessed from the participant's diary, taking the worst score from the 3 days prior to each study visit. The rectal bleeding subscore ranges from zero to three, according to the following scale: 0 = no blood seen, 1 = streaks of blood with stool less than half the time, 2 = obvious blood with stool most of the time, 3 = blood alone passed. | Weeks 8, 32, and 52 | 
| Percentage of Participants With Physician's Global Assessment Subscore Indicative of Mild Disease (≤ 1) | The Physician's Global Assessment Subscore acknowledges the three other subscores (Stool Frequency, Rectal Bleeding, and Endoscopy), the participant's daily record of abdominal discomfort and functional assessment, and other observations such as physical findings and the participant's performance status. Possible scores range from zero to three as follows: 0 = Normal (other subscores are 0), 1 = Mild disease (other subscores are mostly 1), 2 = Moderate disease (other subscores are 1 to 2), 3 = Severe disease (other subscores are 2 to 3). | Weeks 8, 32, and 52 | 
| Percentage of Participants With Stool Frequency Subscore Indicative of Mild Disease (≤ 1) | Stool frequency was assessed from the participant's diary, taking the worst score from the 3 days prior to each study visit. The stool frequency subscore ranges from zero to three, according to the following scale: 0 = Normal number of stools for this participant, 1 = 1-2 stools more than normal, 2 = 3-4 stools more than normal, 3 = 5 or more stools more than normal. | Weeks 8, 32, and 52 | 
| Percentage of Inflammatory Bowel Disease Questionnaire (IBDQ) Responders | An inflammatory bowel disease questionnaire responder was defined as a participant with at least a 16-point increase from Baseline in total Inflammatory Bowel Disease Questionnaire (IBDQ) score. The IBDQ is a 32-item questionnaire consisting of 4 dimensions: bowel-related symptoms, systemic function, social function, and emotional status. The responses to each question within each domain range from 1 (significant impairment) to 7 (no impairment), with the total score ranging from 32 (very poor) to 224 (perfect health-related quality of life). | Baseline and Weeks 8, 32, and 52 | 
| Number of Participants With Adverse Events up to Week 8 | An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. The investigator assessed the relationship of each event to the use of study drug as either probably related, possibly related, probably not related or not related. A serious adverse event is an event that results in death, is life-threatening, requires or prolongs hospitalization, results in a congenital anomaly, persistent or significant disability/incapacity or is an important medical event that, based on medical judgment, may jeopardize the participant and may require medical or surgical intervention to prevent any of the outcomes listed above. For more details on adverse events please see the Adverse Event section below. | 8 weeks | 
| Number of Participants With Adverse Events up to Week 52 | An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. The investigator assessed the relationship of each event to the use of study drug as either probably related, possibly related, probably not related or not related. A serious adverse event is an event that results in death, is life-threatening, requires or prolongs hospitalization, results in a congenital anomaly, persistent or significant disability/incapacity or is an important medical event that, based on medical judgment, may jeopardize the participant and may require medical or surgical intervention to prevent any of the outcomes listed above. For more details on adverse events please see the Adverse Event section below. | 52 weeks | 
| Number of Participants With Adverse Events During the Adalimumab Treatment Period | An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. The investigator assessed the relationship of each event to the use of study drug as either probably related, possibly related, probably not related or not related. A serious adverse event is an event that results in death, is life-threatening, requires or prolongs hospitalization, results in a congenital anomaly, persistent or significant disability/incapacity or is an important medical event that, based on medical judgment, may jeopardize the participant and may require medical or surgical intervention to prevent any of the outcomes listed above. For more details on adverse events please see the Adverse Event section below. | 221 weeks | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Ulcerative Colitis