Study of Adalimumab Treatment for Induction and Maintenance of Clinical Remission in Subjects With Crohn's Disease

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety of adalimumab for treatment of patients with moderate to severe Crohn's Disease (CD) and to measure the effects of treatment on patient general well-being, health-related quality of life (QoL), fistula healing, CD-related extra-intestinal manifestations, work performance, and overall activity.

Detailed Description
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This is an open-label, multi-center, study designed to evaluate the safety and efficacy of adalimumab on inducing and maintaining clinical remission in subjects with moderate to severe Crohn's Disease. Approximately 1000 subjects with a diagnosis of moderate to severe Crohn's Disease (Harvey Bradshaw Index score >= 7) will be enrolled at approximately 200 sites within Europe. Enrollment will be dependent on meeting all screening criteria. Study medication will be administered by subcutaneous injection. At Baseline (Week 0), all subjects will receive a dose of 160 mg adalimumab. At Week 2, all subjects will receive a dose of 80 mg adalimumab. Starting at Week 4, all subjects will begin receiving injections of adalimumab 40 mg every other week and will continue every other week dosing through Week 20 except in the case of disease flare or non-response. Starting at Week 12, subjects who experience a disease flare (flare is defined by an increase in the Harvey Bradshaw Index >=3 and a total Index score of >=7 when compared to Week 4) or are not responding to adalimumab treatment (non-response is defined as a decrease in the Harvey Bradshaw Index by fewer than 3 points compared to Baseline) will be permitted to increase study therapy to adalimumab 40 mg every week. If the subject continues to demonstrate a lack of improvement on every week adalimumab therapy, they may be withdrawn from the study. Prior to Week 8 subjects will not be allowed to increase or decrease Crohn's specific concomitant medications except in the event of concomitant Crohn's treatment-related toxicities assessed as moderate to severe. Changes in concomitant medications at/after Week 8 will be at the Investigator's discretion. Subjects will be evaluated for safety and efficacy at Baseline (Week 0), Weeks 2, 4, 8, 12, and 20, and at unscheduled visits. Efficacy evaluations include HBI, Short Inflammatory Bowel Disease Questionnaire (SIBDQ), Work Productivity Activity Index (WPAI) questionnaire, fistula counts, health care resource utilization (HCRU), and evaluation of CD-related extra-intestinal manifestations (EIMs). Safety assessments include vital signs, physical examination, general laboratory analyses, urinalysis, and monitoring of adverse events (AEs).

Official Title
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A Multi-Center, Open-Label Study of the Fully Human Anti-TNF Monoclonal Antibody Adalimumab for the Induction and Maintenance of Clinical Remission in Subjects With Moderate to Severe Crohn's Disease

Conditions
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Crohn's Disease

Intervention / Treatment
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* Biological: adalimumab
* Biological: adalimumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of moderate to severe Crohn's Disease confirmed by endoscopy or radiologic evaluation for greater than 4 months (16 weeks) Inadequate response to conventional therapy for Crohn's Disease Subjects >=18 and <=75 years of age and in good health (Investigator discretion) with a recent stable medical history Harvey Bradshaw Index score of 7 or higher Exclusion Criteria: Subject considered by the investigator, for any reason, to be an unsuitable candidate for the study Subject who has had surgical bowel resections within the past 6 months or is planning any resection at any time point while enrolled in the study Female subject who is pregnant or breast-feeding or considering becoming pregnant Previous treatment with adalimumab or previous participation in an adalimumab clinical study Subject considered by the investigator, for any reason, to be an unsuitable candidate for the study Subjects with any prior exposure to Tysabri® (natalizumab) Subjects on prednisone >40 mg/day (or equivalent), subjects on budesonide >9 mg/day, or subjects who are taking prednisone and budesonide concurrently at Baseline

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Open Label<br> | Biological: adalimumab<br>* Adalimumab 40 mg Every Other Week dosing<br>* Other names: Humira;Biological: adalimumab<br>* Adalimumab 40 mg Every Week dosing if participant experiences a disease flare or is not responding to treatment. A disease flare is defined as an increase of 3 points or more on the HBI compared to the Baseline score and a total HBI score of 7 or higher. Non-response is defined as a decrease by fewer than 3 points in the HBI compared to Baseline.<br>* Other names: Humira;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants in Clinical Remission at Treatment Week 20. Clinical Remission Defined as Harvey Bradshaw Index (HBI) Score Less Than 5. | 5-items that assess general well-being, abdominal pain, diarrhea, abdominal mass, and complications. Score is total of 1) subject well-being (0=very well; 4=terrible); 2) abdominal pain (0=none; 3=severe); 3) diarrhea (number of time per day); 4) abdominal mass (0=none; 3=definite and tender); 5) complications (number). Maximum total score for HBI is not specified, is dependent on number of diarrhea times each day and number of complications. Clinical remission = HBI less than 5. Highest total score at Baseline was 47. Missing data were imputed using non-responder imputation (NRI). | Week 20 of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Who Were Responders at Week 20 of Treatment. A Responder Was Defined as a Participant Who Had a Decrease of 3 or More on the HBI. | 5-items that assess general well-being, abdominal pain, diarrhea, abdominal mass, and complications. Score is total of 1) subject well-being (0=very well; 4=terrible); 2) abdominal pain (0=none; 3=severe); 3) diarrhea (number of time per day); 4) abdominal mass (0=none; 3=definite and tender); 5) complications (number). Participants who had a decrease from Baseline of at least 3 points in HBI total score were considered responders. Missing data were imputed using non-responder imputation (NRI). | Week 20 of treatment | 
| Number of Participants Who Had a Reduction in Number of Draining Fistulas of at Least 50% From Baseline to Week 20 | A count of the number of cutaneous fistulas draining was performed during each physical examination. Among participants who had draining fistulas at Baseline, the number of participants who had a reduction in the number of draining fistulas of at least 50% from Baseline to Week 20 of treatment was determined. Fistulas were classified as abdominal or perianal. | Week 20 of treatment | 
| Number of Participants Who Had Extra-intestinal Manifestations (EIM) at Baseline and Resolution by Week 20. | Number of participants who had EIM at baseline and had resolution of those manifestations at Week 20. EIM were skin lesions, eye lesions, joint complaints, CD-related hepatic disease, thrombosis, and nephrolithiasis. EIMs were determined by physical examination. | Week 20 of treatment | 
| Mean Change in Total Score of Short Inflammatory Bowel Disease Questionnaire (SIBDQ) From Baseline to Week 20 | 10-item assessment of health-related quality of life (QoL) in patients with inflammatory bowel disease. Participant marks an option from 1 to 7 for each item. For some items, 1=None of the time; for other items, 1=All of the time. Value for all items are summed. Total score=10 to 70; a high score=good quality of life (QoL). An increase in score indicates improvement. An absolute change in the SIBDQ score of 9 is considered a minimum clinically important difference (MCID) for a patient. | Week 20 of treatment | 
| Mean Change in Percent Work Time Missed Due to Crohn's Disease From Baseline to Week 20 of Treatment | Percent Work Time Missed (Absenteeism) due to CD is one component of the Work Productivity and Activity Impairment (WPAI) Questionnaire. Score of 0% = no impairment. A decrease in the mean indicates improvement. | Week 20 of treatment | 
| Mean Change in Percent Impairment While Working From Baseline to Week 20 of Treatment | Percent impairment while working is a component of the Work Productivity and Activity Impairment measure. A score of 0% = no impairment. A decrease in mean score indicates lessening of impairment. | Week 20 of treatment | 
| Mean Change in Overall Work Productivity and Activity Impairment Score From Baseline to Week 20 | 6-items that assess impairment in work productivity and daily activity during the 7 days before the assessment. It measures the percentage of overall impairment in work productivity and daily activity due to CD. A WPAI score of 0% = no impairment and a score of 100% = total loss of work productivity or activity. An absolute change in WPAI score of 7% is considered the minimum clinically important difference (MCID). | Week 20 of treatment | 
| Mean Change in Activity Impairment Score From Baseline to Week 20 | Daily activity is one component of the Work Productivity and Activity Impairment Questionnaire. 0% = no impairment. A decrease in the mean indicates improvement. | Week 20 of treatment |