A Study To Assess The Efficacy And Safety Of PF-04236921 In Subjects With Crohn's Disease Who Failed Anti-TNF Therapy

Study Overview
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Brief Summary
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This is a proof of concept study to determine the efficacy and safety of a monoclonal antibody with three doses versus placebo. Subjects will be randomized to a treatment and the dose will be delivered subcutaneously twice, 4 weeks apart. All subjects will have moderate to severe refractory Crohn's Disease.

Official Title
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A Double-blind, Randomized, Placebo-controlled, Dose-ranging Study To Evaluate The Efficacy And Safety Of Pf-04236921 In Subjects With Crohn's Disease Who Are Anti-tnf Inadequate Responders (Andante)

Conditions
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Crohn's Disease

Intervention / Treatment
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* Drug: PF-04236921 SC injection
* Drug: PF-04236921 SC injection
* Drug: PF-04236921 SC injection


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects must have failed or are intolerant to anti TNFs hsCRP greater or equal to 5.0 mg/L Ulcerations demonstrated by colonoscopy as defined by SES CD assessment performed within 8 weeks of study entry (screening) and able to retrospectively complete the SES-CD or colonoscopy performed during screening Exclusion Criteria: Pregnant or breastfeeding women Crohn's Disease with active fistulae or abscess History of diverticulitis or symptomatic diverticulosis Abnormality in hematology or chemistry profiles at screening

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo- SC injection<br> | Drug: PF-04236921 SC injection<br>* Placebo delivered SC, 2 doses separated by 4 weeks<br>|
| Experimental: Drug Dose level 1 - SC injection<br> | Drug: PF-04236921 SC injection<br>* Drug dose level 1 delivered SC, 2 doses separated by 4 weeks<br>|
| Experimental: Drug Dose level 2 - SC injection<br> | Drug: PF-04236921 SC injection<br>* Drug dose level 2 delivered SC, 2 doses separated by 4 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Crohn's Disease Activity Index (CDAI)-70 Response Rate at Week 8 in Participants Who Received Placebo, PF-04236921 10 mg and PF-04236921 50 mg | CDAI-70 response was defined as a decrease in CDAI score of 70 or greater from baseline. The proportions of participants with CDAI-70 response at Week 8 were compared between placebo and PF-04236921 10 mg/50 mg. CDAI is used to quantify the symptoms of patients with Crohn's Disease. CDAI evaluates 8 Crohn's disease-related variables during a 1-week assessment period, yielding a composite score greater than or equal to (>=) 0 and without an upper limit. Many clinical trials use the endpoint for response as a 70 or greater point decrease in CDAI and clinical remission is often defined as a CDAI score below 150. The Outcome included a Generalized linear mixed model analyses which incorporated longitudinal data for each subject, and the same model is used for estimate (least squares mean) and statistical analysis (mean difference). | Baseline and Week 8 | 
| The CDAI-70 Response Rate at Week 8 in Participants Who Received Placebo and PF-04236921 200 mg | CDAI-70 response was defined as a decrease in CDAI score of 70 or greater from baseline. The proportions of participants with CDAI-70 response at Week 8 were compared between placebo and PF-04236921 200 mg. CDAI is used to quantify the symptoms of patients with Crohn's Disease. CDAI evaluates 8 Crohn's disease-related variables during a 1-week assessment period, yielding a composite score >=0 and without an upper limit. Many clinical trials use the endpoint for response as a 70 or greater point decrease in CDAI and clinical remission is often defined as a CDAI score below 150. The Outcome included a Generalized linear mixed model analyses which incorporated longitudinal data for each subject, and the same model is used for estimate (least squares mean) and statistical analysis (mean difference). Since the inputs in the model included different Analysis Population than in Outcome Measure 1, that will yield different estimates for placebo for the two different models. | Baseline and Week 8 | 
| The CDAI-70 Response Rate at Week 12 in Participants Who Received Placebo, PF-04236921 10 mg and PF-04236921 50 mg | CDAI-70 response was defined as a decrease in CDAI score of 70 or greater from baseline. The proportions of participants with CDAI-70 response at Week 12 were compared between placebo and and PF-04236921 10 mg/50 mg. CDAI is used to quantify the symptoms of patients with Crohn's Disease. CDAI evaluates 8 Crohn's disease-related variables during a 1-week assessment period, yielding a composite score >=0 and without an upper limit. Many clinical trials use the endpoint for response as a 70 or greater point decrease in CDAI and clinical remission is often defined as a CDAI score below 150. The Outcome included a Generalized linear mixed model analyses which incorporated longitudinal data for each subject, and the same model is used for estimate (least squares mean) and statistical analysis (mean difference). | Baseline and Week 12 | 
| The CDAI-70 Response Rate at Week 12 in Participants Who Received Placebo and PF-04236921 200 mg | CDAI-70 response was defined as a decrease in CDAI score of 70 or greater from baseline. The proportions of participants with CDAI-70 response at Week 12 were compared between placebo and PF-04236921 200 mg. CDAI is used to quantify the symptoms of patients with Crohn's Disease. CDAI evaluates 8 Crohn's disease-related variables during a 1-week assessment period, yielding a composite score >=0 and without an upper limit. Many clinical trials use the endpoint for response as a 70 or greater point decrease in CDAI and clinical remission is often defined as a CDAI score below 150. The Outcome included a Generalized linear mixed model analyses which incorporated longitudinal data for each subject, and the same model is used for estimate (least squares mean) and statistical analysis (mean difference). Since the inputs in the model included different Analysis Population than in Outcome Measure 3, that will yield different estimates for placebo for the two different models. | Baseline and Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The CDAI-70 Response Rate Over Time in Participants Who Received Placebo, PF-04236921 10 mg and PF-04236921 50 mg | CDAI-70 response was defined as a decrease in CDAI score of 70 or greater from baseline. The proportions of participants with CDAI-70 response were compared between placebo and PF-04236921 10 mg/50 mg. CDAI is used to quantify the symptoms of patients with Crohn's Disease. CDAI evaluates 8 Crohn's disease-related variables during a 1-week assessment period, yielding a composite score >=0 and without an upper limit. Many clinical trials use the endpoint for response as a 70 or greater point decrease in CDAI and clinical remission is often defined as a CDAI score below 150. The Outcome included a Generalized linear mixed model analyses which incorporated longitudinal data for each subject, and the same model is used for estimate (least squares mean) and statistical analysis (mean difference). | Baseline and Weeks 2, 4, 6, and 10 | 
| The CDAI-70 Response Rate Over Time in Participants Who Received Placebo and PF-04236921 200 mg | CDAI-70 response was defined as a decrease in CDAI score of 70 or greater from baseline. The proportions of participants with CDAI-70 response were compared between placebo and PF-04236921 200 mg. CDAI is used to quantify the symptoms of patients with Crohn's Disease. CDAI evaluates 8 Crohn's disease-related variables during a 1-week assessment period, yielding a composite score >=0 and without an upper limit. Many clinical trials use the endpoint for response as a 70 or greater point decrease in CDAI and clinical remission is often defined as a CDAI score below 150. The Outcome included a Generalized linear mixed model analyses which incorporated longitudinal data for each subject, and the same model is used for estimate (least squares mean) and statistical analysis (mean difference). Since the inputs in the model included different Analysis Population than in Outcome Measure 5, that will yield different estimates for placebo for the two different models. | Baseline and Weeks 2, 4, 6, and 10 | 
| The CDAI Remission Rate Over Time in Participants Who Received Placebo, PF-04236921 10 mg and PF-04236921 50 mg | CDAI remission rate was defined as an absolute CDAI score less than (<) 150. The proportions of participants with CDAI remission were compared between placebo and PF-04236921 10 mg/50 mg. CDAI is used to quantify the symptoms of patients with Crohn's Disease. CDAI evaluates 8 Crohn's disease-related variables during a 1-week assessment period, yielding a composite score >=0 and without an upper limit. Many clinical trials use the endpoint for response as a 70 or greater point decrease in CDAI and clinical remission is often defined as a CDAI score below 150. The Outcome included a Generalized linear mixed model analyses which incorporated longitudinal data for each subject, and the same model is used for estimate (least squares mean) and statistical analysis (mean difference). | Baseline and Weeks 2, 4, 6, 8, 10, and 12 | 
| The CDAI Remission Rate Over Time in Participants Who Received Placebo and PF-04236921 200 mg | CDAI remission rate was defined as an absolute CDAI score <150. The proportions of participants with CDAI remission were compared between placebo and PF-04236921 200 mg. CDAI is used to quantify the symptoms of patients with Crohn's Disease. CDAI evaluates 8 Crohn's disease-related variables during a 1-week assessment period, yielding a composite score >=0 and without an upper limit. Many clinical trials use the endpoint for response as a 70 or greater point decrease in CDAI and clinical remission is often defined as a CDAI score below 150. The Outcome included a Generalized linear mixed model analyses which incorporated longitudinal data for each subject, and the same model is used for estimate (least squares mean) and statistical analysis (mean difference). Since the inputs in the model included different Analysis Population than in Outcome Measure 7, that will yield different estimates for placebo for the two different models. | Baseline and Weeks 2, 4, 6, 8, 10, and 12 | 
| The CDAI-100 Response Rate Over Time in Participants Who Received Placebo, PF-04236921 10 mg and PF-04236921 50 mg | CDAI-100 response was defined as a decrease in CDAI score of 100 or greater from baseline. The proportions of participants with CDAI-100 response at Week 12 were compared between placebo and PF-04236921 10 mg/50 mg. CDAI is used to quantify the symptoms of patients with Crohn's Disease. CDAI evaluates 8 Crohn's disease-related variables during a 1-week assessment period, yielding a composite score >=0 and without an upper limit. Many clinical trials use the endpoint for response as a 70 or greater point decrease in CDAI and clinical remission is often defined as a CDAI score below 150. The Outcome included a Generalized linear mixed model analyses which incorporated longitudinal data for each subject, and the same model is used for estimate (least squares mean) and statistical analysis (mean difference). | Baseline and Weeks 2, 4, 6, 8, 10, and 12 | 
| The CDAI-100 Response Rate Over Time in Participants Who Received Placebo and PF-04236921 200 mg | CDAI-100 response was defined as a decrease in CDAI score of 100 or greater from baseline. The proportions of participants with CDAI-100 response at Week 12 were compared between placebo and PF-04236921 200 mg. CDAI is used to quantify the symptoms of patients with Crohn's Disease. CDAI evaluates 8 Crohn's disease-related variables during a 1-week assessment period, yielding a composite score >=0 and without an upper limit. Many clinical trials use the endpoint for response as a 70 or greater point decrease in CDAI and clinical remission is often defined as a CDAI score below 150. The Outcome included a Generalized linear mixed model analyses which incorporated longitudinal data for each subject, and the same model is used for estimate (least squares mean) and statistical analysis (mean difference). Since the inputs in the model included different Analysis Population than in Outcome Measure 9, that will yield different estimates for placebo for the two different models. | Baseline and Weeks 2, 4, 6, 8, 10, and 12 | 
| Change From Baseline in CDAI Score Over Time in Participants Who Received Placebo, PF-04236921 10 mg and PF-04236921 50 mg | CDAI evaluates 8 Crohn's disease-related variables during a 1-week assessment period, yielding a composite score >=0 and without an upper limit, and higher score indicate more severe disease. The Outcome included a Linear mixed model analyses which incorporated longitudinal data for each subject, and the same model is used for estimate (least squares mean) and statistical analysis (mean difference). | Baseline and Weeks 2, 4, 6, 8, 10, and 12 | 
| Change From Baseline in CDAI Score Over Time in Participants Who Received Placebo and PF-04236921 200 mg | CDAI evaluates 8 Crohn's disease-related variables during a 1-week assessment period, yielding a composite score >=0 and without an upper limit, and higher score indicate more severe disease. The Outcome included a Linear mixed model analyses which incorporated longitudinal data for each subject, and the same model is used for estimate (least squares mean) and statistical analysis (mean difference). Since the inputs in the model included different Analysis Population than in Outcome Measure 11, that will yield different estimates for placebo for the two different models. | Baseline and Weeks 2, 4, 6, 8, 10, and 12 | 
| Percentages of Participants With Confirmed Positive Anti-drug Antibodies (ADAs) | The percentage of participants with confirmed positive ADA was summarized for each treatment arm. ADA positive was defined as ADA titer defined as ADA titer (ie, the reciprocal of the highest dilution that gives a value equivalent to the cut point of the assay) >= 4.32. | At baseline (Day 1) and at Weeks 4, 8, 12, 16, 24, 32 and 40 | 
| Percentages of Participants With Confirmed Positive Neutralizing Antibodies (NAbs) | The percentage of participants with confirmed positive NAbs was summarized for each treatment arm. Only ADA positive samples were analyzed for Nab. A multi-tiered approach was utilized to detect NAbs. NAb serum samples were screened at tier one, and those found presumptively NAb positive was further tested with the confirmatory assay (tier two). The percentage of subjects with confirmed positive NAbs was summarized for each treatment. | At baseline (Day 1) and at Weeks 4, 8, 12, 16, 24, 32 and 40 | 
| Serum PF-04236921 Concentration Over Time |  | Day 1 (predose), and at Weeks 2, 4 (Day 28, predose), 8, 10, 12, 16, 20, 24, 28, 32, 36, and 40 | 
| Number of Participants Who Withdrew From the Study Due to Treatment-emergent Adverse Events (AEs) | An AE was any untoward medical occurrence without regard to causality in a participant who received study drug. Treatment-emergent were events between first dose of treatment and up to 28 days after last dose that were absent before treatment or that worsened relative to pretreatment state. | Induction period: from Week 0 (Day 1) through Week 12; follow-up period: from Week 12 (or discontinuation from the induction period) through last subject visit (up to 28 weeks after completion of or discontinuation from the 12-week induction period) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Crohn's Disease, safety, efficacy, pharmacokinetics, pharmacodynamics, Crohn's Disease Activity Index (CDAI)