A Study of the Safety and Efficacy of Ustekinumab (CNTO 1275) in Participants With Crohn's Disease

Study Overview
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Brief Summary
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The purpose of this study is to examine the safety and efficacy of CNTO 1275 in participants with active Crohn's Disease.

Detailed Description
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This is a multicenter, randomized study of IL-12p40 (CNTO 1275), hereafter referred to as ustekinumab, in 2 populations of participants with moderately to severely active Crohn's disease of at least 6 weeks duration. A total of approximately 120 volunteers will participate in this study in Canada, Belgium, and the United States. Two separate groups of participants (Population 1 and Population 2) will be evaluated. The primary population of participants (Population 1) will consist of approximately 100 participants with Crohn's disease despite treatment with standard Crohn's disease medications (includes agents to decrease intestinal inflammation such as 5-ASA medications such as PENTASA, ASACOL), corticosteroids such as prednisone and/or other drugs known to suppress the immune system called immunomodulators such as azathioprine, 6-mercaptopurine, methotrexate, infliximab or adalimumab [marketed under the trade name of HUMMIRA]). Participants in Population 1 will be randomly assigned (assigned by chance, like flipping a coin) to double-blind treatment (participants and study staff will not know the identity of the treatments) with ustekinumab and placebo (inactive substance) in 1 of 4 treatment groups as follows: (1) 4 weeks of treatment with ustekinumab 90 mg followed by 4 weeks of treatment with placebo injected subcutaneously (SC, under the skin), (II) 4 weeks of placebo followed by 4 weeks of ustekinumab 90 mg injected SC, (III) 1 intravenous (IV, in the vein) infusion of ustekinumab 4.5 mg/kg followed by 1 IV infusion of placebo, and (IV) 1 IV infusion of placebo followed by 1 IV infusion of ustekinumab 4.5 mg/kg. Population 2 consists of approximately 20 participants who failed to respond to previous therapy with infliximab (trade name REMICADE), a type of antibody that decreases inflammation in patients with moderate to severe Crohn's disease). All participants in Population 2 will receive open-label (un-blinded) treatment with ustekinumab 4.5 mg/kg administered SC for 4 weeks or as one IV infusion. Placebo will not be given to participants in Population 2. The duration of the study for each participant is 28 weeks (not including a screening period of up to 2 weeks) with participants returning at Week 54 to have blood samples collected to assess the concentration of ustekinumab and antibodies to ustekinumab. Adverse events (side-effects) as a measure of safety and tolerability and results from routine laboratory tests will be monitored and reported throughout the study from the time that informed consent is documented up to 3 days after the final blood sample collection at Week 54. Note: doses of ustekinumab used in the study were adjusted by a factor of 0.9 to be consistent with the corrected absorptivity constant for ustekinumab. Therefore, ustekinumab doses of 100 mg and 5 mg/kg previously stated in the study protocol have been restated as 90 mg and 4.5 mg/kg, respectively. No change was made to the amount of ustekinumab given to participants in this study.

Official Title
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A Multicenter, Randomized, Phase 2a Study of Human Monoclonal Antibody to IL-12p40 (CNTO 1275) in Subjects With Moderately to Severely Active Crohn's Disease

Conditions
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Crohn Disease

Intervention / Treatment
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* Drug: Ustekinumab 90 mg
* Drug: Ustekinumab 4.5 mg/kg
* Drug: Placebo SC
* Drug: Placebo IV


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Have moderately to severly active Crohn's disease or fistulizing Crohn's disease for at least 6 weeks' duration with a Crohn's disease activity index (CDAI) score of >=220 and <=450 In Population 1, participants must have had active disease despite treatment with 5-ASA compounds, antibiotics, corticosteroids, and/or immunomodulators, including anti-TNF agents. In Population 2, participants must have had active disease and have failed to respond to infliximab at the maximum approved dose and treatment regimen for Crohn's disease as defined in the US package insert. Exclusion Criteria: Have local manifestations of Crohn's disease such as strictures, abscesses, or other disease complications for which surgery might be indicated Had intra-abdominal surgery within 6 months prior to entering the study Have received treatment with parenteral nutrition (ie, introduction of nutrition into the body via a route other than the mouth) (total parenteral nutrition [TPN]) within 6 weeks of baseline

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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Population 1: Placebo SC followed by ustekinumab SC<br>Placebo injected subcutaneously (SC) once a week for 4 weeks (Weeks 0-3) during Intervention Period 1 followed by ustekinumab 90 mg SC once a week for 4 weeks (Weeks 8-11) during Intervention Period 2. | Drug: Ustekinumab 90 mg<br>* one 90 mg SC injection each week for 4 weeks (Weeks 0-3 during Intervention Period 1 or Weeks 8-11 during Intervention Period 2 for Population 1 or Weeks 0-3 during Intervention Period 1 for Population 2)<br>* Other names: CNTO 1275;Drug: Placebo SC<br>* one SC injection each week for 4 weeks (Weeks 0-3 in Intervention Period 1 or Weeks 8-11 in Intervention Period 2 for Population 1 or at Weeks 0-3 in Intervention Period 1 for Population 2)<br>|
| Experimental: Population 1: Ustekinumab SC followed by Placebo SC:<br>Ustekinumab 90 mg injected subcutaneously (SC) once a week for 4 weeks (Weeks 0-3) during Intervention Period 1 followed by ustekinumab 90 mg SC once a week for 4 weeks (Weeks 8-11) during Intervention Period 2. | Drug: Ustekinumab 90 mg<br>* one 90 mg SC injection each week for 4 weeks (Weeks 0-3 during Intervention Period 1 or Weeks 8-11 during Intervention Period 2 for Population 1 or Weeks 0-3 during Intervention Period 1 for Population 2)<br>* Other names: CNTO 1275;Drug: Placebo SC<br>* one SC injection each week for 4 weeks (Weeks 0-3 in Intervention Period 1 or Weeks 8-11 in Intervention Period 2 for Population 1 or at Weeks 0-3 in Intervention Period 1 for Population 2)<br>|
| Experimental: Population 1: Placebo IV followed by ustekinumab IV<br>Placebo given as 1 intravenous (IV) infusion at Week 0 during Intervention Period 1 and ustekinumab 4.5 mg/kg given as one IV infusion at Week 8 during Intervention Period 2. | Drug: Ustekinumab 4.5 mg/kg<br>* one IV infusion of 4.5 mg/kg over a period of not less than 2 hours at Week 0 in Intervention Period 1 or Week 8 in Intervention Period 2 for Population 1 or at Week 0 in Intervention Period 1 for Population 2<br>* Other names: CNTO 1275;Drug: Placebo IV<br>* one IV infusion over a period of not less than 2 hours at Week 0 in Intervention Period 1 for Population 1 and Population 2 or at Week 8 in Intervention Period 2 for Population 1<br>|
| Experimental: Population 1: Ustekinumab IV followed by Placebo IV:<br>Ustekinumab 4.5 mg/kg given as one intravenous(IV) infusion at Week 0 during Intervention Period 1 followed by placebo given as one IV infusion at Week 8 during Intervention Period 2. | Drug: Ustekinumab 4.5 mg/kg<br>* one IV infusion of 4.5 mg/kg over a period of not less than 2 hours at Week 0 in Intervention Period 1 or Week 8 in Intervention Period 2 for Population 1 or at Week 0 in Intervention Period 1 for Population 2<br>* Other names: CNTO 1275;Drug: Placebo IV<br>* one IV infusion over a period of not less than 2 hours at Week 0 in Intervention Period 1 for Population 1 and Population 2 or at Week 8 in Intervention Period 2 for Population 1<br>|
| Experimental: Population 2: Ustekinumab SC<br>Ustekinumab 90 mg injected subcutaneously (SC) once a week at Weeks 0-3 during Intervention Period 1. No intervention given during Intervention Period 2. | Drug: Ustekinumab 90 mg<br>* one 90 mg SC injection each week for 4 weeks (Weeks 0-3 during Intervention Period 1 or Weeks 8-11 during Intervention Period 2 for Population 1 or Weeks 0-3 during Intervention Period 1 for Population 2)<br>* Other names: CNTO 1275;|
| Experimental: Population 2: Ustekinumab IV<br>Ustekinumab 4.5 mg given as one intravenous (IV) infusion at Week 0 during Intervention Period 1. No intervention given during Intervention Period 2. | Drug: Ustekinumab 4.5 mg/kg<br>* one IV infusion of 4.5 mg/kg over a period of not less than 2 hours at Week 0 in Intervention Period 1 or Week 8 in Intervention Period 2 for Population 1 or at Week 0 in Intervention Period 1 for Population 2<br>* Other names: CNTO 1275;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants in Population 1 With a Clinical Response at Week 8 | The table below provides the number of participants in Population 1 with a clinical response at Week 8 defined as a reduction from baseline in the CDAI (Crohn's disease activity index) score of >= 25% and >= 70 points at Week 8. A reduction in CDAI score correlates with improvement in the severity of illness. The CDAI is derived as a weighted sum of 8 different Crohn's disease related variables: extra-intestinal manifestations, abdominal mass, weight, hematocrit, total number of liquid stools (or bags emptied for participants with a stoma), abdominal pain/cramping, use of antidiarrheal drug(s) and/or opiates, and general well being. The primary endpoint analysis was based on the comparison between the combined SC and IV Placebo and combined SC and IV ustekinumab treatment groups in Population 1. | Week 8 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants in Population 2 With a Clinical Response at Week 8 | The table below provides the number of participants in Population 2 with a clinical response at Week 8 defined as a reduction from baseline in the CDAI (Crohn's disease activity index) score of >= 25% and >= 70 points at Week 8. A reduction in CDAI score correlates with improvement in the severity of illness. The CDAI is derived as a weighted sum of 8 different Crohn's disease related variables: extra-intestinal manifestations, abdominal mass, weight, hematocrit, total number of liquid stools (or bags emptied for participants with a stoma), abdominal pain/cramping, use of antidiarrheal drug(s) and/or opiates, and general well-being. | Week 8 | 
| Number of Participants in Population 1 With Clinical Remission at Week 8 | The table below shows the number of participants in Population 1 with clinical remission at Week 8 defined a CDAI (Crohn's disease activity index) score < 150 points at Week 8. A reduction in CDAI score correlates with improvement in the severity of illness. The CDAI is derived as a weighted sum of 8 different Crohn's disease related variables: extra-intestinal manifestations, abdominal mass, weight, hematocrit, total number of liquid stools (or bags emptied for participants with a stoma), abdominal pain/cramping, use of antidiarrheal drug(s) and/or opiates, and general well-being. | Week 8 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Crohn Disease, Biologic, Infusion, Injection, CNTO 1275, Ustekinumab, C01275, IL-12p40