A Study to Evaluate the Safety and Efficacy of Ustekinumab in Patients With Moderately to Severely Active Crohn's Disease Who Have Failed or Are Intolerant to Tumor Necrosis Factor (TNF) Antagonist Therapy (UNITI-1)

Study Overview
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Brief Summary
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This study (UNITI-1) will compare the effects (both positive and negative) of an initial treatment with ustekinumab to placebo over 8 weeks, in patients with moderately to severely active Crohn's disease who have either failed or could not tolerate at least one TNF-antagonist medications in the past (specifically, infliximab, adalimumab, or certolizumab pegol).

Detailed Description
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This study (CNTO1275CRD3001 or UNITI-1) examines ustekinumab (an antibody medication that inhibits the inflammatory proteins IL-12 and IL-23) versus a placebo (otherwise identical except without the ustekinumab antibody) given intravenously (by an IV) in adults with moderately to severely active Crohn's disease who previously did not respond to, lost response to, or could not tolerate TNF-antagonist medications (specifically, infliximab, adalimumab or certolizumab pegol). Ustekinumab (also known as Stelara) is approved as a treatment for the skin condition of moderate to severe plaque-type psoriasis, but this study will examine if ustekinumab can provide benefit in Crohn's disease and also assess for any risks or side effects. Both the positive and negative outcomes of IV placebo versus two different doses of IV ustekinumab will be tracked and compared over eight weeks, in approximately 703 patients. Patients enrolling in this study will be assigned to one of the 3 treatment groups by chance (randomly, like rolling dice), and all will receive a single IV administration of study agent at the first study visit (after the screening period), and then will be asked to return for 3 additional visits through Week 8. Patients who complete this study through the Week 8 visit and remain eligible can enter the maintenance study (CNTO1275CRD3003 or IM-UNITI'' [NCT01369355]), where they will receive additional study agent, including the administration of ustekinumab in patients who receive placebo in this study and have not had improvement in their Crohn's disease. Patients who do not enter the CNTO1275CRD3003 study will have a final safety follow-up visit approximately 20 weeks after they received study agent when they entered into this study at the Week 0 visit. .All patients will receive a single intravenous (IV) administration of study drug (either placebo or ustekinumab) at the first (week 0) visit when they enter the study.There are 3 treatment groups: Group 1: Placebo; Group 2: ustekinumab 130 mg, Group 3: weight-range based ustekinumab doses approximating ustekinumab 6 mg/kg: 260 mg (weight <= 55 kg), 390 mg (weight > 55 kg and <= 85 kg), and 520 mg (weight > 85 kg).

Official Title
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A Phase 3, Randomized, Double-blind, Placebo-controlled, Parallel-group, Multicenter Study to Evaluate the Safety and Efficacy of Ustekinumab Induction Therapy in Subjects With Moderately to Severely Active Crohn's Disease Who Have Failed or Are Intolerant to TNF Antagonist Therapy (UNITI-1)

Conditions
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Crohn's Disease, Colitis, IBD, Inflammatory Bowel Disease

Intervention / Treatment
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* Drug: Group 2 ustekinumab 130 mg
* Drug: Group 3: ustekinumab approximately 6 mg/kg
* Drug: Group 1: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Have Crohn's disease of at least 3 months' duration with colitis, ileitis, or ileocolitis, confirmed at some time in the past by radiography, histology, or endoscopy Have active Crohn's disease, defined as a baseline Crohn's Disease Activity Index (CDAI) score of >= 220 and <= 450 Have received infliximab, adalimumab, or certolizumab pegol at a dose approved for the treatment of Crohn disease and did not respond initially (ie, primary nonresponse) Or responded initially but then lost response with continued therapy (ie, secondary nonresponse) Or were intolerant to the medication Have screening laboratory test results within protocol-specified parameters. Exclusion Criteria: Patients who have had any kind of bowel resection within 6 months Are pregnant or planning pregnancy (both men and women) while enrolled in the study or for 20 weeks after receiving study agent Patients who have received infliximab, adalimumab or certolizumab pegol < = 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 Patients who have previously received a biologic agent targeting IL-12 or IL-23, including but not limited to ustekinumab (CNTO 1275) or briakinumab (ABT-874)

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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: 001<br>Group 1: Placebo Form=solution for injection route=intravenous use in a single dose. | Drug: Group 1: Placebo<br>* Form=solution for injection, route=intravenous use, in a single dose.<br>|
| Experimental: 002<br>Group 2 ustekinumab 130 mg Type=exact unit=mg number=130 form=solution for injection route= intravenous use in a single dose. | Drug: Group 2 ustekinumab 130 mg<br>* Type=exact, unit=mg, number=130, form=solution for injection, route= intravenous use, in a single dose.<br>|
| Experimental: 003<br>Group 3: ustekinumab approximately 6 mg/kg Type=range unit=mg/kg number=6 form=solution for injection route= intravenous use in a single dose.weight-range based ustekinumab doses approximating ustekinumab 6 mg/kg: 260 mg (weight <= 55 kg) 390 mg (weight > 55 kg and <= 85 kg) and 520 mg (weight > 85 kg). | Drug: Group 3: ustekinumab approximately 6 mg/kg<br>* Type=range, unit=mg/kg, number=6, form=solution for injection, route= intravenous use, in a single dose.weight-range based ustekinumab doses approximating ustekinumab 6 mg/kg: 260 mg (weight <= 55 kg), 390 mg (weight > 55 kg and <= 85 kg), and 520 mg (weight > 85 kg).<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 | Clinical response at Week 6 was defined as a reduction from baseline in the Crohn's Disease Activity Index score of greater than or equal (>=) 100 points (in general, CDAI score ranges from 0 to approximately 600; higher score indicates higher disease activities). Participants with a baseline CDAI score of > = 220 to less than or equal (< =) 248 were considered to be in clinical response if a CDAI score of less than (<) 150 was attained. A CDAI score of less than 150 indicates clinical remission. A decrease in CDAI score over time indicates improvement in disease activity. | Baseline and Week 6 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants in Clinical Remission at Week 8 | Clinical remission is defined as a CDAI score of less than (<) 150 points at Week 8. | Baseline and Week 8 | 
| Number of Participants in Clinical Response at Week 8 | Clinical response at Week 8 was defined as a reduction from baseline in the Crohn's Disease Activity Index (CDAI) score of greater than or equal (>=) 100 points. Participants with a baseline CDAI score of > = 220 to less than or equal (< =) 248 were considered to be in clinical response if a CDAI score of less than (<) 150 was attained. A CDAI score of less than 150 indicates clinical remission. A decrease in CDAI score over time indicates improvement in disease activity. | Baseline and Week 8 | 
| Number of Participants With Crohn's Disease Activity Index (CDAI) 70-point Response at Week 6 | 70-point response is defined as at least 70 points reduction in CDAI score. The CDAI score is used to quantify the symptoms of participants with Crohn's Disease. A decrease in CDAI over time indicates improvement in disease activity. | Baseline and Week 6 | 
| Number of Participants With CDAI 70-point Response at Week 3 | 70-point response is defined as at least 70 points reduction in CDAI score. The CDAI score is used to quantify the symptoms of participants with Crohn's Disease. A decrease in CDAI over time indicates improvement in disease activity. | Baseline and Week 3 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ustekinumab, moderately to severely active Crohn's Disease, tumor necrosis factor, Stelara, Crohn, Crohn's, IBD, UNITI