Safety and Efficacy of Adalimumab Versus Ustekinumab for One Year

Study Overview
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Brief Summary
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The purpose of this study is to compare the efficacy of treatment with ustekinumab or adalimumab in biologic naive participants with moderately-to-severely active Crohn's disease (CD) who have previously failed or were intolerant to conventional therapy (corticosteroids and/or immunomodulators, such as azathioprine, 6-mercaptopurine, or methotrexate), as measured by clinical remission at one year.

Detailed Description
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This study compares the safety and efficacy of ustekinumab versus adalimumab. It will consist of screening (within 1- 5 weeks prior to Week 0), treatment phase (Weeks 0 to 52), and follow-up phase (up to Week 76). The primary hypothesis is that ustekinumab is superior to adalimumab as measured by clinical remission after one year of treatment. Study assessments will include Crohn's disease activity index (CDAI), video ileocolonoscopy; CD-related healthcare utilization; 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 randomly be assigned to receive either ustekinumab or adalimumab. No participants will be treated with placebo only.

Official Title
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A Phase 3b, Multicenter, Randomized, Blinded, Active-Controlled Study to Compare the Efficacy and Safety of Ustekinumab to That of Adalimumab in the Treatment of Biologic Naïve Subjects With Moderately-to-Severely Active Crohn's Disease

Conditions
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Crohn Disease

Intervention / Treatment
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* Biological: Placebo for Ustekinumab
* Biological: Placebo for Adalimumab
* Biological: Ustekinumab (6 mg/kg)
* Biological: Ustekinumab (90 mg)
* Biological: Adalimumab (40 mg)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Has Crohn's Disease (CD) or fistulizing CD of at least 3 months' duration, with colitis, ileitis, or ileocolitis, confirmed at some time in the past by radiography, histology, and/or endoscopy Has moderately-to-severely active CD with a baseline Crohn's disease activity index (CDAI) score of greater than or equal to (>=) 220 and less than or equal to (<=) 450 Has one or more ulceration on screening ileocolonoscopy (which by definition, would result in an Simple Endoscopic Score for Crohn's Disease [SES-CD] of at least 3) Has failed or was intolerant to conventional therapy (corticosteroids, azathioprine [AZA], 6-mercaptopurine [6-MP] and/or methotrexate [MTX]) at adequate doses or is corticosteroid dependent Has not previously received an approved biologic for Crohn's Disease (i.e., infliximab, adalimumab, certolizumab pegol, ustekinumab, natalizumab, vedolizumab or approved biosimilars of these agents) Participants on oral corticosteroids (e.g., prednisone, budesonide) at a prednisone-equivalent dose of <=40 or milligram/day (mg/day) or <=9 mg/day of budesonide are budesonide <=9 mg/day are permitted if doses are stable for 3 weeks prior to baseline Participants on AZA, 6-MP, or MTX at screening (or recently prior), must discontinue these medications at least 3 weeks prior to baseline Exclusion Criteria: Has complications of CD that are likely to require surgery or would confound the ability to assess the effect of ustekinumab or adalimumab treatment using the CDAI, such as: active stoma; short-gut syndrome and severe or symptomatic strictures or stenosis 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 prior to baseline, or 8 weeks prior for intra-abdominal abscesses, if 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 present Has had any kind of bowel resection within 6 months prior to baseline or other intra-abdominal surgery or a hospital admission for bowel obstruction within 3 months prior to baseline Has a stool culture or other examination positive for an enteric pathogen, including Clostridium difficile toxin, in the last 4 months unless a repeat examination is negative and there are no signs of ongoing infection with that pathogen Has received a Bacillus Calmette-Guerin (BCG) vaccination within 12 months or any other live bacterial or live viral vaccination within 2 weeks of baseline Has a history of, or ongoing, chronic or recurrent infectious disease, including but not limited to, chronic renal infection, chronic chest infection, recurrent urinary tract infection (eg, recurrent pyelonephritis or chronic nonremitting cystitis), or infected skin wounds or ulcers

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)<br>Participants will receive intravenous (IV) infusion of ustekinumab (approximately 6 milligram/kilogram [mg/kg]) and 4 subcutaneous (SC) injections of placebo for adalimumab at Week 0, followed by 2 SC injections of placebo at Week 2. From Week 4 to Week 56, participants will self-administer one SC injection of ustekinumab 90 milligram (mg) every 8 weeks (q8w) starting at Week 8 and placebo adalimumab at the other designated every 2 weeks (q2w) dosing intervals. | Biological: Placebo for Ustekinumab<br>* Participants will receive placebo as SC injection to blind adalimumab.<br>Biological: Ustekinumab (6 mg/kg)<br>* Participants will receive ustekinumab 6 mg/kg (weight based dosing) as IV infusion.<br>* Other names: Stelara;Biological: Ustekinumab (90 mg)<br>* Participants will self-administer SC injection of ustekinumab 90 mg.<br>* Other names: Stelara;|
| Active Comparator: Group 2 (Adalimumab)<br>Participants will receive IV infusion of placebo for ustekinumab and 4 SC injections of adalimumab (each 40 mg, total dose 160 mg) at Week 0, followed by 2 SC injections of adalimumab (each 40 mg, total dose 80 mg) at Week 2. From Week 4 to Week 56, participants will self-administer 1 SC injection of adalimumab 40 mg q2w. | Biological: Placebo for Adalimumab<br>* Participants will receive placebo as IV infusion to blind ustekinumab.<br>Biological: Adalimumab (40 mg)<br>* Participants will self-administer multiple SC injections of adalimumab (each 40 mg) and will receive total dose of 160 mg at Week 0, 80 mg at Week 2, and 40 mg q2w from Week 4 to 56.<br>* Other names: Humira;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Clinical Remission at Week 52 | Percentage of participants with clinical remission at Week 52 were assessed. Clinical remission was defined as a Crohn's Disease Activity Index (CDAI) score of less than (<) 150 points (in general, CDAI score ranges from 0 to approximately 600; higher score indicates higher disease activities). 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. | Week 52 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Corticosteroid-free Remission at Week 52 | Percentage of participants with Corticosteroid-free remission at Week 52 were assessed. Corticosteroid-free remission was defined as CDAI score <150 points at Week 52 and not taking any corticosteroids for at least 30 days prior to Week 52. The CDAI score is used to quantify the symptoms of participants with Crohn's Disease. CDAI score ranges from 0 to approximately 600; higher score indicates higher disease activities. A decrease in CDAI over time indicates improvement in disease activity. | Week 52 | 
| Percentage of Participants With Clinical Response at Week 52 | Percentage of participants with clinical response at Week 52 were assessed. Clinical response at Week 52 was defined as a reduction from baseline in the CDAI score of greater than or equal (>=) 100 points. The CDAI score is used to quantify the symptoms of participants with Crohn's Disease. CDAI score ranges from 0 to approximately 600; higher score indicates higher disease activities. A decrease in CDAI over time indicates improvement in disease activity. | Week 52 | 
| Percentage of Participants in Patient Reported Outcome (PRO)-2 Symptom Remission at Week 52 | PRO2 evaluated 2 patient-reported symptoms: the frequency of liquid or soft stools (total number of soft/liquid stools in the last 7 days) and abdominal pain (on a 4-point scale where 0 = none, 1 = mild, 2 = moderate, 3 = severe). A weekly score was calculated for the liquid or soft stool frequency and a separate weekly score was calculated for abdominal pain, in each case based on daily symptom reporting. PRO-2 symptom remission was defined as an abdominal pain (AP) mean daily score at or below 1 and also stool frequency (SF) mean daily score at or below 3, that is, AP <=1 and SF <=3. PRO2 is a composite index consisting of weighted scoring of both variables. PRO-2 scores range from 0 to no upper limit with higher scores indicating more severe disease. | Week 52 | 
| Percentage of Participants With Clinical Remission at Week 16 | Percentage of participants with clinical remission (defined as CDAI <150 points) at Week 16 were assessed. Clinical remission was defined as a CDAI score of < 150 points (in general, CDAI score ranges from 0 to approximately 600; higher score indicates higher disease activities). 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. | Week 16 | 
| Percentage of Participants With Endoscopic Remission at Week 52 | Percentage of participants with endoscopic remission at Week 52 were assessed. Endoscopic remission was defined as Simple Endoscopic Score for Crohn's Disease (SES-CD) score less than or equal to (<=) 3, or SES-CD =0 for participants who entered the study with a SES-CD =3 at Week 52. The SES-CD evaluates 4 endoscopic variables (ulcer size, proportion of the surface area that is ulcerated, proportion of the surface area affected, and stenosis) each rated from 0 (best) to 3 (worst) in 5 segments evaluated during ileocolonoscopy (ileum, right colon, transverse colon, left colon, and rectum). The score for each endoscopic variable is the sum of values obtained for each segment. The SES-CD total is the sum of the 4 endoscopic variable scores from 0 to 56, where higher scores indicate more severe disease. | Week 52 | 
| Percentage of Participants With Clinical Remission Through Week 52 | Percentage of participants with clinical remission at each postbaseline visit through Week 52 were reported. Clinical remission was defined as a CDAI score of <150 points (in general, CDAI score ranges from 0 to approximately 600; higher score indicates higher disease activities). 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. | Weeks 2, 8, 16, 24, 32, 40, 48, and 52 | 
| Percentage of Participants With Clinical Response Through Week 52 | Percentage of participants with clinical response at each postbaseline visit through Week 52 were reported. Clinical response through Week 52 was defined as a reduction from baseline in the CDAI score of >=100 points. The CDAI score is used to quantify the symptoms of participants with Crohn's Disease. CDAI score ranges from 0 to approximately 600; higher score indicates higher disease activities. A decrease in CDAI over time indicates improvement in disease activity. | Weeks 2, 8, 16, 24, 32, 40, 48, and 52 | 
| Percentage of Participants With Durable Clinical Response at Week 52 | Percentage of participants with durable clinical response at Week 52 were reported. Durable clinical response was defined as CDAI score decreased at least 100 from baseline or CDAI <150 at Week 52 and was >= 80% of all visits between Week 16 and Week 52. The CDAI score is used to quantify the symptoms of participants with Crohn's Disease. CDAI score ranges from 0 to approximately 600; higher score indicates higher disease activities. A decrease in CDAI over time indicates improvement in disease activity. | Week 52 | 
| Percentage of Participants With Durable Clinical Remission at Week 52 | Percentage of participants with durable clinical remission at Week 52 were reported. Clinical remission was defined as CDAI score <150 at Week 52 and was >= 80% of all visits between Week 16 and Week 52. The CDAI score is used to quantify the symptoms of participants with Crohn's Disease. CDAI score ranges from 0 to approximately 600; higher score indicates higher disease activities. A decrease in CDAI over time indicates improvement in disease activity. | Week 52 | 
| Percentage of Participants With Abdominal Pain (AP) Improvement Through Week 52 | Percentage of participants with AP improvement through Week 52 were reported. AP improvement was defined as at least 1 point or greater improvement in mean daily CDAI AP score (ranges from 0 to 3 where higher score indicates severity of pain) from baseline, or a mean score of zero among participants with mean AP>0 at baseline, compared at each visit through Week 52. | Weeks 2, 8, 16, 24, 32, 40, 48, and 52 | 
| Percentage of Participants With Reduction in Frequency of Diarrhea Through Week 52 | Number of participants with reduction in frequency of diarrhea were reported. Reduction in frequency of diarrhea was defined as a reduction of at least 3 (or a mean number <1) in SF (that is, mean daily number of liquid or very soft stools from CDAI score [ranges from 0 to 3 where higher score indicates severity of pain] in the week prior to the visit) from baseline, among subjects with mean SF >1 at baseline, compared at each visit through Week 52. | Weeks 2, 8, 16, 24, 32, 40, 48, and 52 | 
| Percentage of Participants With Clinical and Biomarker Remission at Weeks 8, 16 and 52 | Percentage of participants with clinical and biomarker remission was defined as the percentage of participants with CDAI <150, CRP <= 3 mg/L, and also fecal calprotectin <=250 micrograms per gram (mcg/g). The CDAI score is used to quantify the symptoms of participants with Crohn's Disease. CDAI score ranges from 0 to approximately 600; higher score indicates higher disease activities. A decrease in CDAI over time indicates improvement in disease activity. | At Weeks 8, 16 and 52 | 
| Percentage of Participants With Adverse Events (AEs) | Percentage of participants with AE were reported. An AE is any untoward medical occurrence in a participant participating in a clinical study that does not necessarily have a causal relationship with the pharmaceutical/biological agent under study. | Up to Week 52 and up to Week 76 | 
| Percentage of Participants With Infections | Percentage of participants with infections were reported. | Up to Week 52 and up to Week 76 | 
| Percentage of Participants With Serious Infections | Percentage of participants with serious infections were reported. | Up to Week 52 and up to Week 76 | 
| Percentage of Participants With Serious Adverse Events (SAEs) | Percentage of participants with SAEs were reported. A SAE is any AE that results in: death, persistent or significant disability/incapacity, requires inpatient hospitalization or prolongation of existing hospitalization, is life-threatening experience, is a congenital anomaly/birth defect and may jeopardize participant and/or may require medical or surgical intervention to prevent one of the outcomes listed above. Coronavirus disease 2019 (COVID-19) related adverse events are adverse events with any of the following preferred terms COVID-19, Asymptomatic COVID-19, Suspected COVID-19, COVID-19 pneumonia, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) test positive or with a reported term containing the string COVI. | Up to Week 52 and up to Week 76 | 
| Percentage of Participants With Anti-drug Antibodies | Percentage of participants with anti-drug antibodies were reported. Serum samples were assessed for anti-drug antibodies. Anti-drug assays were performed for ustekinumab and adalimumab. | Up to Week 52 |