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

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

Status

Completed

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT00853099

Enrollment

274

Registered

2009-03-02

Start date

2009-02-28

Completion date

2013-08-31

Last updated

2014-09-05

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Ulcerative Colitis

Keywords

Ulcerative Colitis

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 Participants who dose escalate to 80 mg eow and continue to have an inadequate response or disease flare are withdrawn from the study.

Interventions

BIOLOGICALadalimumab

DRUGplacebo

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

DOUBLE (Subject, Investigator)

Eligibility

Sex/Gender

ALL

Age

15 Years to No maximum

Healthy volunteers

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.

Design outcomes

Primary

Measure	Time frame	Description
Percentage of Participants With Clinical Remission at 8 Weeks	Week 8	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.
Percentage of Participants With Clinical Remission at 52 Weeks	Week 52	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.

Secondary

Measure	Time frame	Description
Percentage of Participants With Mucosal Healing	Weeks 8, 32, and 52	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).
Percentage of Participants With Rectal Bleeding Subscore Indicative of Mild Disease (≤ 1)	Weeks 8, 32, and 52	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.
Percentage of Participants With Physician's Global Assessment Subscore Indicative of Mild Disease (≤ 1)	Weeks 8, 32, and 52	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).
Percentage of Participants With Stool Frequency Subscore Indicative of Mild Disease (≤ 1)	Weeks 8, 32, and 52	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.
Percentage of Participants With Clinical Remission at 8, 32, and 52 Weeks	Weeks 8, 32, and 52	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.
Number of Participants With Adverse Events up to Week 8	8 weeks	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.
Number of Participants With Adverse Events up to Week 52	52 weeks	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.
Number of Participants With Adverse Events During the Adalimumab Treatment Period	221 weeks	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.
Percentage of Inflammatory Bowel Disease Questionnaire (IBDQ) Responders	Baseline and Weeks 8, 32, and 52	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).
Percentage of Participants With a Clinical Response	Baseline and Weeks 8, 32, and 52	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.

Countries

Japan

Participant flow

Participants by arm

Arm	Count
Placebo 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.	96
Adalimumab 80 mg/40 mg 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.	87
Adalimumab 160 mg/80 mg 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.	90
Total	273

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002	FG003
Double-blind + Open-label Periods	Adverse Event	0	0	0	47
Double-blind + Open-label Periods	Lack of Efficacy	0	0	0	74
Double-blind + Open-label Periods	Other	0	0	0	6
Double-blind + Open-label Periods	Withdrawal by Subject	0	0	0	20
Double-blind Period	Adverse Event	7	9	13	0
Double-blind Period	Lack of Efficacy	14	17	16	0
Double-blind Period	Mistreated with rescue study drug	0	0	1	0
Double-blind Period	Other	0	0	1	0
Double-blind Period	Withdrawal by Subject	2	3	0	0

Baseline characteristics

Characteristic	Placebo	Adalimumab 80 mg/40 mg	Adalimumab 160 mg/80 mg	Total
Age, Continuous	41.3 years STANDARD_DEVIATION 13.56	44.4 years STANDARD_DEVIATION 15.04	42.5 years STANDARD_DEVIATION 14.56	42.7 years STANDARD_DEVIATION 14.38
Mayo score	8.5 scores on a scale STANDARD_DEVIATION 1.56	8.5 scores on a scale STANDARD_DEVIATION 1.42	8.6 scores on a scale STANDARD_DEVIATION 1.44	8.5 scores on a scale STANDARD_DEVIATION 1.47
Region of Enrollment Japan	96 participants	87 participants	90 participants	273 participants
Sex: Female, Male Female	26 Participants	37 Participants	29 Participants	92 Participants
Sex: Female, Male Male	70 Participants	50 Participants	61 Participants	181 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk
deaths Total, all-cause mortality	— / —	— / —	— / —	— / —
other Total, other adverse events	51 / 96	47 / 87	60 / 90	235 / 266
serious Total, serious adverse events	13 / 96	14 / 87	10 / 90	90 / 266

Outcome results

Primary

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.

Time frame: Week 52

Population: Full analysis set. Non-responder imputation (NRI) was used, where all missing remission values and values after the start of rescue treatment were considered as non-remission.

Arm	Measure	Value (NUMBER)
Placebo	Percentage of Participants With Clinical Remission at 52 Weeks	7.3 percentage of participants
Adalimumab 80 mg/40 mg	Percentage of Participants With Clinical Remission at 52 Weeks	26.4 percentage of participants
Adalimumab 160 mg/80 mg	Percentage of Participants With Clinical Remission at 52 Weeks	20.0 percentage of participants

Primary

Percentage of Participants With Clinical Remission at 8 Weeks

Time frame: Week 8

Population: The full analysis set includes all patients who received at least 1 dose of study drug any time during the first 52 weeks and with at least 1 efficacy measurement after the first dose of study medication. Non-responder imputation (NRI) was used, where all missing values and values after the start of rescue treatment were considered non-remission.

Arm	Measure	Value (NUMBER)
Placebo	Percentage of Participants With Clinical Remission at 8 Weeks	11.5 percentage of participants
Adalimumab 80 mg/40 mg	Percentage of Participants With Clinical Remission at 8 Weeks	13.8 percentage of participants
Adalimumab 160 mg/80 mg	Percentage of Participants With Clinical Remission at 8 Weeks	10.0 percentage of participants

Secondary

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.

Time frame: 221 weeks

Population: The safety analysis set.

Arm	Measure	Group	Value (NUMBER)
Placebo	Number of Participants With Adverse Events During the Adalimumab Treatment Period	Any adverse event	261 participants
Placebo	Number of Participants With Adverse Events During the Adalimumab Treatment Period	Any AE at least possibly drug related	142 participants
Placebo	Number of Participants With Adverse Events During the Adalimumab Treatment Period	Any serious adverse event	90 participants
Placebo	Number of Participants With Adverse Events During the Adalimumab Treatment Period	Any AE leading to discontinuation of study drug	37 participants

Secondary

Number of Participants With Adverse Events up to Week 52

Time frame: 52 weeks

Population: The safety analysis set.

Arm	Measure	Group	Value (NUMBER)
Placebo	Number of Participants With Adverse Events up to Week 52	Any adverse event	67 participants
Placebo	Number of Participants With Adverse Events up to Week 52	Any AE at least possibly drug related	17 participants
Placebo	Number of Participants With Adverse Events up to Week 52	Any serious adverse event	12 participants
Placebo	Number of Participants With Adverse Events up to Week 52	Any AE leading to discontinuation of study drug	5 participants
Adalimumab 80 mg/40 mg	Number of Participants With Adverse Events up to Week 52	Any AE leading to discontinuation of study drug	5 participants
Adalimumab 80 mg/40 mg	Number of Participants With Adverse Events up to Week 52	Any adverse event	68 participants
Adalimumab 80 mg/40 mg	Number of Participants With Adverse Events up to Week 52	Any serious adverse event	14 participants
Adalimumab 80 mg/40 mg	Number of Participants With Adverse Events up to Week 52	Any AE at least possibly drug related	23 participants
Adalimumab 160 mg/80 mg	Number of Participants With Adverse Events up to Week 52	Any AE leading to discontinuation of study drug	12 participants
Adalimumab 160 mg/80 mg	Number of Participants With Adverse Events up to Week 52	Any AE at least possibly drug related	32 participants
Adalimumab 160 mg/80 mg	Number of Participants With Adverse Events up to Week 52	Any serious adverse event	10 participants
Adalimumab 160 mg/80 mg	Number of Participants With Adverse Events up to Week 52	Any adverse event	75 participants

Secondary

Number of Participants With Adverse Events up to Week 8

Time frame: 8 weeks

Population: The Safety Analysis Set includes all participants who received at least one dose of study medication.

Arm	Measure	Group	Value (NUMBER)
Placebo	Number of Participants With Adverse Events up to Week 8	Any adverse event	45 participants
Placebo	Number of Participants With Adverse Events up to Week 8	Any AE at least possibly drug related	10 participants
Placebo	Number of Participants With Adverse Events up to Week 8	Any serious adverse event	7 participants
Placebo	Number of Participants With Adverse Events up to Week 8	Any AE leading to discontinuation of study drug	4 participants
Adalimumab 80 mg/40 mg	Number of Participants With Adverse Events up to Week 8	Any AE leading to discontinuation of study drug	0 participants
Adalimumab 80 mg/40 mg	Number of Participants With Adverse Events up to Week 8	Any adverse event	49 participants
Adalimumab 80 mg/40 mg	Number of Participants With Adverse Events up to Week 8	Any serious adverse event	2 participants
Adalimumab 80 mg/40 mg	Number of Participants With Adverse Events up to Week 8	Any AE at least possibly drug related	14 participants
Adalimumab 160 mg/80 mg	Number of Participants With Adverse Events up to Week 8	Any AE leading to discontinuation of study drug	6 participants
Adalimumab 160 mg/80 mg	Number of Participants With Adverse Events up to Week 8	Any AE at least possibly drug related	12 participants
Adalimumab 160 mg/80 mg	Number of Participants With Adverse Events up to Week 8	Any serious adverse event	4 participants
Adalimumab 160 mg/80 mg	Number of Participants With Adverse Events up to Week 8	Any adverse event	40 participants

Secondary

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).

Time frame: Baseline and Weeks 8, 32, and 52