A Study to Evaluate the Safety and Efficacy of Ustekinumab Maintenance Therapy in Patients With Moderately to Severely Active Crohn's Disease (IM-UNITI)

Study Overview
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Brief Summary
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The primary purpose of this study is to evaluate the efficacy and safety of 2 maintenance regimens of ustekinumab administered subcutaneously to patients with moderately to severely active Crohn's disease who responded to treatment with intravenous ustekinumab in studies CNTO1275CRD3001 and CNTO1275CRD3002, compared to subcutaneously administered placebo.

Detailed Description
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The main purpose of this study is to determine whether additional ustekinumab treatment is beneficial in patients with moderately to severely active Crohn's disease who initially had a clinical response to IV ustekinumab in one of the 2 initial induction studies (the CNTO1275CRD3001 [UNITI-1] or CNTO1275CRD3002 [UNITI-2] induction studies). The maintenance treatment will be injections in the skin (given subcutaneously, or SC) of 90 mg ustekinumab either every 8 weeks or 12 weeks, and the effects (both the benefits and any side effects or adverse events) will be compared to SC placebo injections (otherwise identical except without ustekinumab). Patients who responded to IV ustekinumab in the UNITI-1 (NCT01369329) or UNITI-2 (NCT01369342) induction studies will be put into one of these 3 groups by chance (randomly, like rolling dice). The study will be double-blinded (so that neither patients nor study personnel know the identity of the assigned treatment). Patients who are randomized to either SC placebo or 90mg ustekinumab SC every 12 weeks who experience worsening in their Crohn's Disease symptoms (per the study loss of response criteria) will have their treatment adjusted so that they will instead start to receive 90mg ustekinumab SC every 8 weeks. All patients from the UNITI-1 or UNITI-2 studies (in addition to the patients described above who responded to IV ustekinumab) will be eligible to enter this study, provided the Week 8 visit in those trials was completed and study requirements are still met. Patients who are not in clinical response to IV placebo or ustekinumab in UNITI-1 or UNITI-2 will receive both IV and SC study agent at the first visit of this study (week 0). Patients previously receiving IV placebo will receive ustekinumab 130 mg IV at week 0 (and SC placebo), and patients previously receiving IV ustekinumab will receive 90 mg ustekinumab SC at week 0 (as well as IV placebo). If these patients are in clinical response 8 weeks later, they will receive 90 SC ustekinumab at that week8 visit, and will continue to receive Ustekinumab (every 8 weeks for participants not in response to IV Ustekinumab and every 12 weeks for participants not in response to IV Placebo) throughout the rest of the study (provided they otherwise remain eligible). Patients in clinical response to IV placebo induction dosing will continue to receive SC placebo. The main part of this study, also called the maintenance portion, will last 44 weeks. After week 44, all participants who are continuing to do well will be eligible to continue to receive study agent in the second part of the study, a long term extension where the study agent will continue to be administered up to week 252. Participants who discontinue study agent, either during the study, or after week 252, will be asked to return for a final safety follow-up visit 20 weeks after they last received study agent. Patients in response to IV ustekinumab will be randomized to receive either placebo (Group 1), Ustekinumab 90 mg SC every 12 weeks (Group 2), or Ustekinumab 90mgSC every 8 weeks (Group 3). If patients in Groups 1 or 2 lose response, they will cross over to receive ustekinumab 90mg every 8 weeks. Other populations (nonresponders to prior IV ustekinumab or IV placebo) will receive ustekinumab at Week0 (either 90mg SC or 130mg IV, respectively) and continue SC ustekinumab if in response at Week 8, Placebo IV responders will continue to receive Placebo SC q4w.

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 Maintenance Therapy in Subjects With Moderately to Severely Active Crohn's Disease

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

Intervention / Treatment
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* Drug: Placebo SC
* Drug: Placebo IV
* Drug: Ustekinumab 90 mg SC q8w
* Drug: Ustekinumab 130 mg IV
* Drug: Ustekinumab 90 mg SC q12w


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients who received study agent at the start of study CNTO1275CRD3001 or CNTO1275CRD3002 and completed the Week 8 visit. Exclusion Criteria: Patients who underwent a Crohn's disease-related surgery since the start of induction study CNTO1275CRD3001 or CNTO1275CRD3002 Patients who started a protocol prohibited medication since the start of studies CNTO1275CRD3001 and CNTO1275CRD3002 Patients with protocol-specified changes to their concomitant medications due to Crohn's disease (due to lack of efficacy) since the start of studies CNTO1275CRD3001 and CNTO1275CRD3002

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 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>Participants who were responders to Intravenous (IV) infusion of ustekinumab induction will be randomized to receive a single dose of placebo subcutaneously (SC) every 4 weeks (q4w). | Drug: Placebo SC<br>* Placebo will be administered subcutaneously.<br>|
| Experimental: 002<br>Participants who were responders to IV ustekinumab induction will be randomized to receive a single dose of ustekinumab 90 milligram (mg) SC every 12 weeks (q12w). | Drug: Ustekinumab 90 mg SC q12w<br>* Ustekinumab 90 mg will be administered as subcutaneously every 12 weeks (q12w) through Week 40.<br>|
| Experimental: 003<br>Participants who were responders to IV ustekinumab induction will be randomized to receive a single dose of ustekinumab 90 mg SC every 8 weeks (q8w). | Drug: Ustekinumab 90 mg SC q8w<br>* Ustekinumab 90 mg will be administered subcutaneously every 8 weeks (q8w) through Week 40.<br>|
| Experimental: 004<br>Participants who were nonresponders to IV ustekinumab induction will receive a single dose of ustekinumab 90 mg SC and one placebo IV at week 0, if then respond will continue to receive one ustekinumab 90 mg SC q8w. | Drug: Placebo IV<br>* Placebo will be administered as a single Intravenous infusion at week 0.<br>Drug: Ustekinumab 90 mg SC q8w<br>* Ustekinumab 90 mg will be administered subcutaneously every 8 weeks (q8w) through Week 40.<br>|
| Experimental: 005<br>Participants who were nonresponders to IV placebo induction will receive a single dose of ustekinumab 130 mg IV and one placebo SC at week 0, if then respond will continue to receive one ustekinumab 90 mg SC at week 8 then q12w. | Drug: Placebo SC<br>* Placebo will be administered subcutaneously.<br>Drug: Ustekinumab 130 mg IV<br>* Ustekinumab 130 mg will be administered as a single intravenous infusion at week 0.<br>Drug: Ustekinumab 90 mg SC q12w<br>* Ustekinumab 90 mg will be administered as subcutaneously every 12 weeks (q12w) through Week 40.<br>|
| Placebo Comparator: 006<br>Participants who were responders to IV placebo induction will receive one dose of placebo SC q4w. | Drug: Placebo SC<br>* Placebo will be administered subcutaneously.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Clinical Remission at Week 44 | Clinical remission at Week 44 was defined as a Crohn's Disease Activity Index (CDAI) score of <150 points (in general, CDAI score ranges from 0 to approximately 600; higher score indicates higher disease activities). CDAI was assessed by collecting information on 8 different Crohn's disease-related variables (extra-intestinal manifestations, abdominal mass, weight, hematocrit, total number of liquid stools, abdominal pain/cramping, use of antidiarrheal drug(s) and/or opiates, and general well-being). A decrease in CDAI over time indicates improvement in disease activity. | Week 44 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Clinical Response at Week 44 | Clinical response at Week 44 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. | Week 44 | 
| Number of Participants in Clinical Remission at Week 44 Among Participants in Clinical Remission to Ustekinumab at Week 0 of Maintenance Study | Clinical remission at week 44 was defined as a CDAI score of < 150 points among participants in clinical remission to ustekinumab at week 0 of maintenance study. | Week 44 | 
| Number of Participants With Corticosteroid-free Remission at Week 44 | Corticosteroid-free remission at Week 44 was defined as a CDAI score of <150 points without receiving corticosteroids at Week 44. | Week 44 | 
| Number of Participants in Clinical Remission at Week 44 in the Subset of Participants Who Were Refractory or Intolerant to Tumor Necrosis Factor (TNF) Antagonist Therapy | Clinical remission at Week 44 was defined as a CDAI score of <150 points in the subset of participants who were refractory or Intolerant to tumor necrosis factor antagonist therapy. | Week 44 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Ustekinumab, Stelara, Moderately to severely active Crohn's Disease, IBD, Crohn's, UNITI, colitis, IL-12, IL-23