Trial Comparing Infliximab and Infliximab and Azathioprine in the Treatment of Patients With Crohn's Disease na�ve to Both Immunomodulators and Biologic Therapy (Study of Biologic and Immunomodulator Naive Patients in Chrohn's Disease: SONIC

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to assess the safety and effectiveness of three different treatments for patients with Crohns disease who have not responded to previous treatment with a group of drugs commonly used to treat Crohn's Disease (5-ASA) and corticosteroids. Patients will receive either infliximab (a drug used to treat autoimmune diseases) or azathioprine (an immunosuppressant or drug used to suppress the immune system) or a combination of both for up to 34 weeks. This research study will involve approximately 500 patients. The main study involves up to 34 weeks (approximately 8 months). A study extension of an additional 20 weeks (approximately 5 months) is optional for patients who successfully complete the main study. A country-specific study extension of open label infliximab treatment for an additional 1 year is optional for patients who successfully complete the main study extension.

Detailed Description
-----------------
Crohns disease is characterized by inflammation (the changes that happen when tissues in the body are injured) and ulceration (open sores) of the intestines. Crohns disease is treated with medications that decrease inflammation, and reduce diarrhea, abdominal pain and other symptoms of Crohns disease. In addition, Crohns disease can be treated with medications that suppress the immune system (the body system involved in inflammation and infections) or with surgery. This study will investigate the effectiveness of infliximab and azathioprine in the treatment of patients with moderate-to-severe Crohns disease. Infliximab is currently approved by the FDA for the treatment of both Crohns disease and rheumatoid arthritis. Azathioprine, which is an investigational drug, has not been approved by the FDA for the treatment of Crohns disease, but it is a well-established therapy that has been used for many years to treat Crohns disease. This study seeks to determine whether infliximab, azathioprine, or the combination of both drugs would be the most appropriate treatment for Crohns disease patients who have not responded well to certain drugs called 5-ASA drugs (e.g. Asacol, Pentasa, sulfasalazine) and/or require frequent treatment with corticosteroids. This research study will involve approximately 500 patients. Patients may participate in the main study for up to 34 weeks (approximately 8 months). During the main study, patients will be asked to visit the study center for 10 visits. If patients enroll into the extension of the study, the total time for participation may be up to 54 weeks (approximately 13 months). Patients enrolled in the Study Extension will be asked to visit the study center for an additional 5 visits. A country-specific (EU and Israel only), prospective, multi-center, open-label extension of the study will further evaluate the long-term safety and efficacy of scheduled maintenance therapy with infliximab in patients with Crohns Disease. Patients who have completed treatment through Week 50 in the SONIC main study and who, in the opinion of the investigator, would benefit from infliximab treatment may enter the open-label extension. Patients will be randomly assigned to one of three treatment groups (either infliximab plus placebo capsules, infliximab plus azathioprine, or azathioprine plus placebo infusions - there is no possibility of being assigned to placebo only in this trial - patients will receive one or both of these medications) at the beginning of the study. Oral medication will be taken daily. There are 5 infusion (which will be either infliximab or placebo) visits during the main study.

Official Title
-----------------
Multicenter, Randomized, Double-Blind, Active Controlled Trial Comparing REMICADE� (Infliximab) and REMICADE Plus Azathioprine to Azathioprine in the Treatment of Patients With Crohn's Disease Naive to Both Immunomodulators and Biologic Therapy

Conditions
-----------------
Crohn Disease

Intervention / Treatment
-----------------
* Biological: infliximab infusion; AZA placebo caps
* Other: infliximab (IFX) infusion; azathioprine (AZA) caps
* Drug: infliximab (IFX) placebo infusion; azathioprine (AZA) caps


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Diagnosis of Crohns Disease for at least 6 weeks Moderate to severe disease activity (CDAI >= 220 and <=450) No history of azathioprine, 6-MP (6 Mercaptopurine), or biologic treatments Are either: Corticosteriod-dependent, OR considered for a 2nd (or greater) course of corticosteriod, OR 5-ASA failures, Or Budesonide failures Exclusion Criteria: History of abdominal surgery within the last 6 months Have an ostomy or stoma [An operation to create an opening from an area inside the body to the outside] Are pregnant, nursing, or planning pregnancy (both men and women) Serious simultaneous illness that could interfere with study participation Use of any investigational drug within 30 days Have a concomitant diagnosis or any history of congestive heart failure Weigh more than 140 kilograms (or 310 pounds)

Ages Eligible for Study
-----------------
Minimum Age: 21 Years
Maximum Age: 99 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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 003<br>infliximab (IFX) infusion; azathioprine (AZA) caps AZA daily 2.5 mg/kg/day and IFX infusions 5 mg/kg at weeks 0, 2, 6, 14, and 22 | Other: infliximab (IFX) infusion; azathioprine (AZA) caps<br>* AZA daily 2.5 mg/kg/day and IFX infusions 5 mg/kg at weeks 0, 2, 6, 14, and 22<br>|
| Experimental: 001<br>infliximab (IFX) placebo infusion; azathioprine (AZA) caps AZA daily 2.5 mg/kg/day and placebo IFX infusions at weeks 0, 2, 6, 14, and 22 | Drug: infliximab (IFX) placebo infusion; azathioprine (AZA) caps<br>* AZA daily 2.5 mg/kg/day and placebo IFX infusions at weeks 0, 2, 6, 14, and 22<br>|
| Experimental: 002<br>infliximab infusion; AZA placebo caps Infliximab 5 mg/kg at weeks 0, 2, 6, 14, and 22 and placebo AZA capsules | Biological: infliximab infusion; AZA placebo caps<br>* Infliximab 5 mg/kg at weeks 0, 2, 6, 14, and 22 and placebo AZA capsules<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Corticosteriod-free Clinical Remission | Corticosteroid-free clinical remission is defined as a Crohn's Disease Activity Index (CDAI) less than (<) 150 in participants who have not received any dose of systemic corticosteroids (prednisone or equivalent) for greater than or equal to (>=) 3 weeks and have not received budesonide at a dose > 6 milligram per day (mg/day) for >= 3 weeks. The total CDAI score ranges from 0 - 600. The lower the CDAI score, the better (i.e., 0 is better and 600 is worse). | Week 26 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Mucosal Healing | Complete absence of mucosal ulcerations in the colon and terminal ileum as assessed by video endoscopy. | Week 26 | 
| Percentage of Participants With Corticosteroid-free Clinical Remission (Study Extension) | Corticosteroid-free clinical remission is defined as a Crohn's Disease Activity Index (CDAI) < 150 who have not received any dose of systemic corticosteroids (prednisone or equivalent) for >= 3 weeks and have not received budesonide at a dose > 6 milligram per day (mg/day) for >= 3 weeks. The total CDAI score ranges from 0 - 600. The lower the CDAI score, the better (i.e., 0 is better and 600 is worse). | Week 50 | 
| Percentage of Participants With Clinical Remission (Main Study) | Clinical remission is defined as a CDAI < 150, compared to baseline (Week 0) | Weeks 2, 6, 10, 18 and 26 | 
| Percentage of Participants With Clinical Remission (Study Extension) | Clinical remission is defined as a CDAI < 150, compared to baseline (Week 0) | Weeks 34, 42 and 50 | 
| Percentage of Participants With Clinical Response Over Time (Main Study) | Clinical response, defined as a >=100-point decrease in CDAI from Baseline. | Weeks 2, 6, 10, 18, 26 | 
| Percentage of Participants With Clinical Response Over Time (Study Extension) | Clinical response, defined as a >=100-point decrease in CDAI from Baseline. | Weeks 34, 42, 50 | 
| Change From Baseline in Inflammatory Bowel Disease Questionnaire (IBDQ) Total Score at Weeks 2, 6, 10, 18 and 26 (Main Study) | Quality of life as measured by the Inflammatory Bowel Disease Questionnaire (IBDQ). The IBDQ is a 32- item questionnaire and the total IBDQ score can range from 32 (very poor) to 224 (perfect). | Baseline and Weeks 2, 6, 10, 18, 26 | 
| Average Corticosteroid Use | Average daily dose of systemic corticosteroid concomitant medications(prednisone or equivalent) | Weeks 2, 6, 10, 18 and 26 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Crohn's Disease, infliximab, azathioprine, Remicade, SONIC