A Study to Evaluate Efficacy and Safety of Ustekinumab Re-induction Therapy in Participants With Moderately to Severely Active Crohn's Disease

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 a single intravenous (IV) re-induction dose of approximately 6 milligram per kilogram (mg/kg) ustekinumab in participants with secondary loss of response (LoR) to subcutaneous (SC) every 8 Weeks (q8w) 90 mg ustekinumab maintenance therapy.

Detailed Description
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This study compares the efficacy and safety of a single weight-tiered based IV re-induction dose of approximately 6 mg/kg ustekinumab versus continuing with regular SC q8w 90 mg ustekinumab administration. It consists of screening (5 weeks); treatment period (Week 0 to 24); and safety follow up visit (20 weeks after last dose). The primary hypothesis is that a single IV re-induction dose of ustekinumab is superior to continuing with regular SC q8w maintenance treatment as measured by clinical response after 16 weeks of treatment. Study assessments will include Crohn's disease activity index (CDAI), video ileocolonoscopy, patient-reported outcomes (PROs), laboratory evaluations, biomarkers, review of concomitant medications and adverse events (AEs), and evaluation of serum concentrations of study agent as well as development of antibodies to study agent. All participants will be randomly assigned to receive either ustekinumab IV re-induction or regular SC q8w 90 mg ustekinumab injection at baseline in a double dummy design. No participants will be treated with placebo only.

Official Title
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A Phase 3b, Randomized, Double-blind, Multicenter Study to Evaluate the Safety and Efficacy of Intravenous Re-induction Therapy With Ustekinumab in Patients With Moderately to Severely Active Crohn's Disease

Conditions
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Crohn Disease

Intervention / Treatment
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* Drug: Ustekinumab approximately 6 mg/kg (IV)
* Drug: Placebo (SC)
* Drug: Placebo (IV)
* Drug: Ustekinumab 90 mg (SC) Group 1
* Drug: Ustekinumab 90 mg (SC) Group 2


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: A history of Crohn's disease or fistulizing Crohn's disease of at least 3 months' duration, with colitis, ileitis, or ileocolitis, confirmed at any time in the past by radiography, histology, and/or endoscopy Currently receiving subcutaneous 90 mg every 8 weeks (q8w) ustekinumab maintenance therapy and initially responded to ustekinumab induction therapy, administered according to the local label, followed by secondary loss of response (LoR) to ustekinumab. Secondary LoR to ustekinumab is defined as active disease at study baseline, proven by a Crohn's Disease Activity Index (CDAI) score of greater than or equal to (>=) 220 and <=450 with at least one of the following: Elevated C-reactive protein (CRP) (>3.0 milligram per liter [mg/L]); and/or elevated Fecal calprotectin (fCal) >250 milligram per kilogram [mg/kg]); and/or endoscopy (performed less than or equal to (<=) 3 months before baseline) with evidence of active Crohn's disease, (defined as one or more ulcerations in the ileum and/or colon) Participants receiving either oral 5-aminosalicylic acid (5-ASA) compounds, oral corticosteroids (for example {e.g.}, prednisone, budesonide) at a prednisone-equivalent dose of <=40 mg/day or <=9 mg/day of budesonide, antibiotics used as the primary treatment of Crohn's disease, or conventional immunomodulators (i.e., azathioprine [AZA], 6-mercaptopurine [6-MP], or methotrexate [MTX]) are permitted providing the doses indicated are stable before baseline or have been discontinued before baseline within the protocol defined durations Exclusion Criteria: Complications of Crohn's disease, such as symptomatic strictures or stenoses, short gut syndrome, or any other manifestation that might be anticipated to require surgery, could preclude the use of the CDAI to assess response to therapy, or would possibly confound the ability to assess the effect of treatment with ustekinumab Currently has or is suspected to have an abscess. Recent cutaneous and perianal abscesses are not exclusionary if drained and adequately treated at least 3 weeks before baseline (or 8 weeks before baseline for intra-abdominal abscesses) provided there is no anticipated need for any further surgery. Participants with active fistulas may be included if there is no anticipation of a need for surgery and there are currently no abscesses identified Any kind of bowel resection within 6 months or any other intra-abdominal surgery within 3 months before baseline A draining (i.e., functioning) stoma or ostomy Received ustekinumab intravenous re-induction after the initial weight-tiered-based IV induction dose of ustekinumab Any known history of shortened frequency of SC dose administration (<q8w) for a secondary loss of response where the participant did not, in the opinion of the treating physician, benefit from the dose interval shortening

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 |
| --- | --- |
| Experimental: Group 1: Ustekinumab (IV re-induction)<br>Participants who experience a secondary loss of response (LoR) to 90 mg ustekinumab maintenance treatment, administered subcutaneously every 8 weeks (q8w) will receive a weight-tiered based ustekinumab IV re-induction dose of approximately 6 mg/kg and matching placebo subcutaneously at Week 0. At Weeks 8 and 16, all participants will receive SC maintenance injections of 90 mg ustekinumab. Participants will resume their standard-of-care therapy at Week 24 at the discretion of the treating physician. | Drug: Ustekinumab approximately 6 mg/kg (IV)<br>* Participants will receive ustekinumab approximately 6mg/kg intravenously at Week 0.<br>* Other names: STELARA;Drug: Placebo (SC)<br>* Participants will receive SC injection of placebo at Week 0.<br>Drug: Ustekinumab 90 mg (SC) Group 1<br>* Participants will receive SC injection of ustekinumab 90 mg at Weeks 8 and 16.<br>* Other names: STELARA;|
| Active Comparator: Group 2: Ustekinumab (Continuous q8w SC maintenance)<br>Participants who experience a secondary LoR to 90 mg ustekinumab maintenance treatment, administered subcutaneously q8w will receive ustekinumab 90 mg subcutaneously and matching placebo intravenously at Week 0. At Weeks 8 and 16, all participants will receive SC maintenance injections of 90 mg ustekinumab. Participants will resume their standard-of-care therapy at Week 24 at the discretion of the treating physician. | Drug: Placebo (IV)<br>* Participants will receive IV infusion of placebo at Week 0.<br>Drug: Ustekinumab 90 mg (SC) Group 2<br>* Participants will receive SC injection of ustekinumab 90 mg at Weeks 0, 8 and 16.<br>* Other names: STELARA;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Clinical Response at Week 16 | Clinical response was defined as greater than or equal to (>=) 100-point reduction from baseline in Crohn's disease activity index (CDAI) score or a CDAI score < 150 points. CDAI is validated multi-item measure of severity of illness derived as weighted sum of 8 different Crohn's disease (CD)-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). The last 4 variables were scored over 7 days by participant on diary card. In general, CDAI score ranges from 0 to approximately 600; higher score=higher disease activities. Participants who had prohibited CD-related surgery, prohibited concomitant medication changes or discontinued study agent due to lack of efficacy or adverse event indicated to be of worsening CD prior to designated analysis timepoint were considered not to be in clinical response, regardless of their CDAI score. | Week 16 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Clinical Remission at Weeks 8, 16, and 24 | Percentage of participants with clinical remission at Weeks 8, 16, and 24 were reported. Clinical remission was defined as CDAI score of <150 points. CDAI is a validated multi-item measure of severity of illness derived as weighted sum of 8 different CD-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). The last 4 variables were scored over 7 days by participant on diary card. In general, CDAI score ranges from 0 to approximately 600; higher score=higher disease activities. Participants who had prohibited CD-related surgery, prohibited concomitant medication changes or discontinued study agent due to lack of efficacy or adverse event indicated to be of worsening CD prior to designated analysis timepoint were considered not to be in clinical remission, regardless of their CDAI score. | Weeks 8, 16, and 24 | 
| Percentage of Participants With Clinical Response at Weeks 8 and 24 | Clinical response was defined as a >=100-point reduction from the baseline in CDAI score or a CDAI score <150 point. The CDAI is a validated multi-item measure of severity of illness 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, abdominal pain/cramping, use of antidiarrheal drug(s) and/or opiates, and general well-being). The last 4 variables were scored over 7 days by the participant on a diary card. In general, CDAI score ranges from 0 to approximately 600; higher score indicates higher disease activities. Participants who had prohibited CD-related surgery, prohibited concomitant medication changes or discontinued study agent due to lack of efficacy or adverse event indicated to be of worsening CD prior to designated analysis timepoint were considered not to be in clinical response, regardless of their CDAI score. | Weeks 8 and 24 | 
| Percentage of Participants With Normalization of C-reactive Protein (CRP) and/or Normalization of Fecal Calprotectin (fCal) Concentration at Weeks 16 and 24 | Percentage of participants with normalization at Weeks 16 and 24, among participants with elevated CRP and/or fCal at baseline were reported. Participants were considered to be normalized if at least one biomarker (fCal or CRP) was normalized. Normalized CRP=CRP value less than or equal to (<=) 3 milligrams per liter(mg/L). Normalized fCal concentrations was defined as <=250 micrograms per gram(mcg/g). When either CRP or FCal value was abnormal at baseline and value of same parameter normalizes at designated analysis timepoint, participants were considered to be normalized at designated analysis timepoint. Participants who had prohibited CD-related surgery, prohibited concomitant medication changes, or discontinued study agent due to lack of efficacy or adverse event indicated to be of worsening CD prior to designated analysis timepoint are considered not to be normalized. Participants who had insufficient data at designated analysis timepoint had their last value carried forward. | Weeks 16 and 24 | 
| Percentage of Participants With Treatment-emergent Adverse Events (TEAEs) | An adverse event was any untoward medical occurrence in a clinical study participant administered a medicinal (investigational or non-investigational) product. An adverse event does not necessarily have a causal relationship with the treatment. TEAEs were adverse events with onset during the intervention phase or that were a consequence of a pre-existing condition that had worsened since baseline. Any AE occurring at or after the initial administration of study agent through the end of the trial was considered to be treatment emergent. In this outcome measure, TEAEs including all AEs irrespective of being serious or non-serious AE are reported. | From baseline (Week 0) up to Week 36 | 
| Percentage of Participants With Treatment-emergent Serious Adverse Events (TESAEs) | A serious adverse event (SAE) was an adverse event resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly; a suspected transmission of any infectious agent via a medicinal product; medically important. TESAEs were adverse events with onset during the intervention phase or that are a consequence of a pre-existing condition that had worsened since baseline. Any AE occurring at or after the initial administration of study agent through the end of the trial was considered to be treatment emergent. | From baseline (Week 0) up to Week 36 | 
| Percentage of Participants With Treatment-emergent Infections | Percentage of participants with treatment-emergent infections were reported. Any infection occurring at or after the initial administration of study agent through the end of the trial was considered to be treatment emergent. | From baseline (Week 0) up to Week 36 | 
| Percentage of Participants With Treatment-emergent Serious Infections | Percentage of participants with treatment-emergent serious infections was reported. Any infection occurring at or after the initial administration of study agent through the end of the trial was considered to be treatment emergent. | From baseline (Week 0) up to Week 36 | 
| Change From Baseline in Clinical Laboratory Values for Hematology (Hemoglobin) and Chemistry (Albumin, Total Protein) | Change from baseline in clinical laboratory values for hematology (hemoglobin) and chemistry (albumin, total protein) was reported. | Baseline, Weeks 8, 16, 24 | 
| Change From Baseline in Clinical Laboratory Values for Hematology (Hematocrit) | Change from baseline in clinical laboratory values for hematology (hematocrit) was reported. | Baseline, Weeks 8, 16, 24 | 
| Change From Baseline in Clinical Laboratory Values for Hematology (Total White Blood Cell [WBC], Neutrophils, Absolute Lymphocyte, Eosinophils, Platelets) | Change from baseline in clinical laboratory values for hematology (total WBC, neutrophils, absolute lymphocyte, eosinophils, platelets) was reported. | Baseline, Weeks 8, 16, 24 | 
| Change From Baseline in Clinical Laboratory Values for Chemistry (Alkaline Phosphatase, Alanine Transaminase [ALT], Aspartate Transaminase [AST]) | Change from baseline in clinical laboratory values for chemistry (alkaline, ALT, AST) was reported. | Baseline, Weeks 8, 16, 24 | 
| Change From Baseline in Clinical Laboratory Values for Chemistry (Total Bilirubin, Direct Bilirubin, Creatinine) | Change from baseline in clinical laboratory values for chemistry (total bilirubin, direct bilirubin, creatinine) was reported. | Baseline, Weeks 8, 16, 24 | 
| Change From Baseline in Clinical Laboratory Values for Chemistry (Sodium, Potassium, Chloride, Blood Urea Nitrogen [BUN]/Urea, Calcium, Phosphate) | Change from baseline in clinical laboratory values for chemistry (sodium, potassium, chloride, BUN/urea, calcium, phosphate) was reported. | Baseline, Weeks 8, 16, 24 |