NIH Substudy of AIN457 (Anti-IL-17 Monoclonal Antibody) for Treatment of Moderate to Severe Crohn's Disease

Not Applicable

Terminated

Conditions: Colitis
Crohn's Disease
Inflammatory Bowel Disease

Interventions: Other: Immunologic Monitoring

Registration Number: NCT00936585

Lead Sponsor: National Institutes of Health Clinical Center (CC)

Brief Summary: The objective of this NIH-specific substudy is immunologic monitoring of cytokine and immune cell responses in subjects undergoing treatment with AIN457 (human monoclonal anti-human interleukin-17A) for moderate to severe Crohn's disease. Recent data suggests that interleukin-17 (IL-17) is an important mediator of inflammation in certain animal models of Crohn's disease, and treatment aimed at blocking the IL-23-IL-17 axis can ameliorate the inflammatory changes. In addition, elevated expression of IL-l7 has been found in the gut tissue of patients with active Crohn's disease. This substudy will measure changes in cytokine production, relevant RNA expression, and immune cell populations (in the periphery and lamina propria) for correlation with clinical outcomes in order to explore the mechanisms of therapeutic response.

Detailed Description: Purpose:

* Crohn's disease is an inflammatory bowel disease with major symptoms such as diarrhea and abdominal pain when the disease is in an active stage.

* AIN457 is a protein developed by NOVARTIS that is used to stop the action of Interleukin-17 (IL-17), a protein made by the body that contributes to many different kinds of inflammatory diseases, including Crohn's disease. AIN457 is being developed for the potential treatment of various inflammatory diseases like rheumatoid arthritis and psoriasis, but has not been tested for suitability in people with Crohn's disease.

Objectives:

* The main objective of the NIH substudy is to obtain additional blood and gut biopsy tissue for monitoring biochemical changes in immune variables in response to study drug or placebo.

* The main objective of the main multicenter study (sponsored by NOVARTIS) is to determine whether AIN457 is safe and effective in the treatment of Crohn's disease, and if effective, how long the effect will remain.

Eligibility:

- Important eligibility criteria to consider for patients to be enrolled in the AIN457 trial include:

Inclusion criteria:

* Male or female; 18-75 years old

* Diagnosis of Crohn's disease for at least 3 months prior to screening

* Moderate to severe active Crohn's disease at baseline, defined as: CDAI greater than or equal to 220 and less than or equal to 450

* Active disease despite prior treatment with stable dose of corticosteroids for 2 weeks, or immunosuppressant for at least 3 months (e.g. methotrexate, azathioprine).

Exclusion criteria:

* Subjects with symptoms associated with active bowel stricturing disease and pre-stenotic dilation on radiography.

* Fistulizing disease if complicated by sepsis and/or untreated abscess.

* Subjects with multiple bowel surgeries and clinically important short bowel syndrome defined as an inability to maintain caloric intake.

* Prior therapy with rituximab.

* Receiving corticosteroids dose equivalent to a \> 40mg dose of prednisone per day.

* Subjects demonstrating clinical improvement due to other Crohn's therapy.

* Subjects with active or history of clinically significant cardiac abnormalities.

Design:

* For the NIH substudy, additional blood will be drawn and a colonoscopy will be performed before the first infusion and after the second infusion.

* The multicenter study plans to enroll seventy-two (72) subjects with moderate to severe active Crohn's disease that is not controlled by corticosteroids, immunosuppressant (e.g. methotrexate or purine metabolites) or anti-inflammatory treatment (e.g. 5-ASA). At baseline visit, if the eligibility of the subject is confirmed, the subject will be randomized (2:1 ratio) to receive either AIN457 or placebo administered as a 2 hours intravenous infusion. A total of two infusions will be given on day 1 and day 22 respectively.

* After infusions there will be a follow-up period of up to 18 weeks.

* Once this study is completed, an extension study will be conducted that will offer access to AIN457. Patients who complete the current study may be eligible to enter the extension study and receive therapy with AIN457.