A Study of Safety and Effectiveness of Ustekinumab in Patients With Moderate to Severe Active Crohn's Disease Who Have Been Previously Treated With Anti-TNF Therapy

Study Overview
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Brief Summary
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A medical research study in adult patients who have moderate to severe Crohn's disease designed to determine whether or not treatment with an experimental drug called ustekinumab (or CNTO1275) is safe or not and to determine if the treatment will reduce the symptoms of Crohn's disease.

Detailed Description
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In Crohn's disease there is inflammation (changes in body tissue which normally happen during injury or infection) and or ulceration (open sores) in the intestines.This occurs because the immune system (the part of the body that fights off infection) has an abnormal and overactive response against the intestine and bowel tissues of the body. Crohn's disease is usually treated with medications that either directly decrease inflammation or decrease the general activity of the immune system to improve the diarrhea, abdominal pain, and other symptoms of Crohn's Disease. Ustekinumab antibodies (natural substances made by your immune system to stick to and help remove foreign materials in your body that cause diseases) have been created to stick to and block the activity of two of the immune substances thought to cause abnormal inflammation of Crohn's disease. Patients who are eligible and who have received Remicade, Humira, or Cimzia and failed or been intolerant to one of these drugs will be randomized to either active drug (ustekinumab) or placebo. All patients will be randomized (like flipping a coin) at week 0 to be in one of 4 groups. At week 0 the study drug will be given by IV administration and at weeks 8 and 16 by subcutaneous injection. There will be 11 study visits in total and the study will continue until week 36. Blood and stool samples will be collected and studied, questionnaires to check on how you are doing in terms of your disease will be completed, an Electrocardiogram (EKG) obtained, safety evaluations conducted and diary cards distributed to be completed during the entire study. One of 4 groups: Grp 1-placebo, Grp 2-active drug 1mg/kg IV, Grp 3-active drug 3mg/kg IV, Grp 4-active drug 6mg/kg IV. Based on the clinical response status at Week 6, patients from Grps 2, 3 and 4 will be re-randomized at week 8 to receive either placebo or 90 mg SC at both weeks 8 and 16 and patients from Grp 1 will receive placebo at Week 8 and Week 16 or a 270 mg SC injection at Week 8 and 90 mg SC at Week 16.

Official Title
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A Phase 2b, Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel Group Study to Evaluate the Efficacy and Safety of Ustekinumab Therapy in Subjects With Moderately to Severely Active Crohn's Disease Previously Treated With TNF Antagonist Therapy

Conditions
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Crohn's Disease

Intervention / Treatment
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* Drug: Placebo (IP)
* Drug: Ustekinumab 1mg/kg (IP)
* Drug: Ustekinumab 3 mg/kg (IP)
* Drug: Ustekinumab 6 mg/kg (IP)
* Drug: Placebo IV - Responder - Placebo SC (MP)
* Drug: Placebo IV - Nonresponder - Ustekinumab 270/90 mg SC (MP)
* Drug: Ustekinumab IV - Responder - Placebo SC (MP)
* Drug: Ustekinumab IV - Responder - Ustekinumab 90mg SC (MP)
* Drug: Ustekinumab IV - Nonresponder - Placebo SC (MP)
* Drug: Ustekinumab IV - Nonresponder - Ustekinumab 90mg SC (MP)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Must have Crohn's disease or fistulizing Crohn's disease of at least 3 months duration Must have received Remicade, adalimumab or Cimzia at a dose approved for the treatment of Crohn's disease Must have failed or been intolerant to Remicade, Humira or Cimzia for treatment of Crohn's disease Must be 18 years of age or older Must have active Crohn's disease according to the Crohn's Disease Activity Index (CDAI > =220 and < =450). Exclusion Criteria: Patients who have had any kind of bowel resection, diversions or placement of a stoma within 6 months Are pregnant, nursing or planning pregnancy (both men and women) while enrolled in the study or within 1 year after receiving study agent Patients who have received Remicade, Humira or Cimzia < =8 weeks before the first administration of study drug Patients with certain complications of Crohn's disease that would make it hard to assess response to study drug Patients with a history of or ongoing chronic or recurrent infectious disease.

Ages Eligible for Study
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Minimum Age: 18 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: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo (IP)<br> | Drug: Placebo (IP)<br>* Induction phase (Week 0-8) (IP) - Placebo IV group<br>|
| Experimental: Ustekinumab 1mg/kg (IP)<br> | Drug: Ustekinumab 1mg/kg (IP)<br>* Induction phase (Week 0-8) (IP) - Ustekinumab 1 mg/kg IV group<br>|
| Experimental: Ustekinumab 3 mg/kg (IP)<br> | Drug: Ustekinumab 3 mg/kg (IP)<br>* Induction phase (Week 0-8) (IP) - Ustekinumab 3mg/kg IV group<br>|
| Experimental: Ustekinumab 6 mg/kg (IP)<br> | Drug: Ustekinumab 6 mg/kg (IP)<br>* Induction phase (Week 0-8) (IP) - Ustekinumab 6mg/kg IV group<br>|
| Placebo Comparator: Placebo IV - Responder - Placebo SC (MP)<br> | Drug: Placebo IV - Responder - Placebo SC (MP)<br>* Maintenance phase (Week 8-36) (MP) - Receiving Placebo IV at Week 0 - Responder at week 6 - Receiving Placebo SC at Week 8 and Week 16<br>|
| Placebo Comparator: Placebo IV - Nonresponder - Ustekinumab 270/90 mg SC<br> | Drug: Placebo IV - Nonresponder - Ustekinumab 270/90 mg SC (MP)<br>* Maintenance phase (Week 8-36) (MP) - Receiving Placebo IV at Week 0 - Nonresponder at week 6 - Receiving Ustekinumab 270 mg SC at Week 8 and 90 mg at Week 16<br>|
| Placebo Comparator: Ustekinumab IV - Responder - Placebo SC (MP)<br> | Drug: Ustekinumab IV - Responder - Placebo SC (MP)<br>* Maintenance phase (Week 8-36) (MP) - Receiving Ustekinumab IV at Week 0 - Responder at week 6 - Receiving Placebo SC at Week 8 and Week 16<br>|
| Experimental: Ustekinumab IV - Responder - Ustekinumab 90mg SC (MP)<br> | Drug: Ustekinumab IV - Responder - Ustekinumab 90mg SC (MP)<br>* Maintenance phase (Week 8-36) (MP) - Receiving Ustekinumab IV at Week 0 - Responder at week 6 - Receiving Ustekinumab 90 mg SC at Week 8 and Week 16<br>|
| Placebo Comparator: Ustekinumab IV - Nonresponder - Placebo SC (MP)<br> | Drug: Ustekinumab IV - Nonresponder - Placebo SC (MP)<br>* Maintenance phase (Week 8-36) (MP) - Receiving Ustekinumab IV at Week 0 - Nonresponder at week 6 - Receiving Placebo SC at Week 8 and Week 16<br>|
| Experimental: Ustekinumab IV - Nonresponder - Ustekinumab 90mg SC (MP)<br> | Drug: Ustekinumab IV - Nonresponder - Ustekinumab 90mg SC (MP)<br>* Maintenance phase (Week 8-36) (MP) - Receiving Ustekinumab IV at Week 0 - Nonresponder at week 6 - Receiving Ustekinumab 90 mg SC at Week 8 and Week 16<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Clinical Response at Week 6 | As measured by the Crohn's Disease Activity Index (CDAI). CDAI scores range from 0 points (minimal disease activity) to over 600 points (severe disease activity). Clinical response was defined as a reduction from baseline of ≥ 100 points. Participants with a baseline CDAI of ≥ 220 to ≤ 248 were considered to be in clinical response if a CDAI score of < 150 was attained. | Baseline to Week 6 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Clinical Remission at Week 6 | As measured by a CDAI score of < 150 points. | Baseline to Week 6 | 
| Number of Participants With Clinical Response at Week 4 | As measured by the CDAI. Clinical response was defined as a reduction from baseline of ≥ 100 points. Participants with a baseline CDAI of ≥ 220 to ≤ 248 were considered to be in clinical response if a CDAI score of < 150 was attained. | Baseline to Week 4 | 
| Number of Participants With Clinical Response at Week 8 | As measured by the CDAI. Clinical response was defined as a reduction from baseline of ≥ 100 points. Participants with a baseline CDAI of ≥ 220 to ≤ 248 were considered to be in clinical response if a CDAI score of < 150 was attained. | Baseline to Week 8 | 
| Number of Participants With Clinical Remission at Week 8 | As measured by a CDAI score of < 150 points. | Baseline to Week 8 | 
| Number of Participants With Clinical Remission at Week 22 (Among Responders From Week 6) | As measured by a CDAI score of < 150 points. | Baseline to Week 22 | 
| Number of Participants With Clinical Response at Week 22 (Among Responders From Week 6) | As measured by the CDAI. Clinical response was defined as a reduction from baseline of ≥ 100 points. Participants with a baseline CDAI of ≥ 220 to ≤ 248 were considered to be in clinical response if a CDAI score of < 150 was attained. | Baseline to Week 22 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Interleukin-12, Inflammation, Research study, Ustekinumab, CNTO1275, Interleukin-23