A Study To Investigate Safety And Efficacy Of CP-690,550 For Induction Therapy In Subjects With Moderate To Severe Crohn's Disease

Study Overview
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Brief Summary
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This study investigates safety and efficacy of CP-690,550 in adult patients with moderate to severe Crohn's disease. The study hypothesis is that at least one dose of the tested drug is more effective than placebo (inactive drug).

Official Title
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A Randomized, Double-Blind, Placebo-Controlled, Parallel Group, Multi-Centre Study To Investigate The Safety And Efficacy Of CP-690,550 For Induction Therapy In Subjects With Moderate To Severe Crohn's Disease

Conditions
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Crohn's Disease

Intervention / Treatment
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* Drug: Placebo
* Drug: CP-690,550
* Drug: CP-690,550


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female subjects between the ages of 18 and 75 years at screening (upper age limit will be 64 years in India and 65 years in the Netherlands). Subjects with clinical diagnosis of Crohn's disease for at least 6 months prior to screening. Subjects with active moderate to severe ileal, ileocolic, or colonic CD defined by a baseline score of Crohn's Disease Activity Index (CDAI) of 220 to 450 at baseline. Exclusion Criteria: Diagnosis of indeterminate colitis, ulcerative colitis (UC), or clinical findings suggestive of UC. Subjects diagnosed with Crohn's disease but without previous exposure to treatment (i.e., treatment-naïve). Subjects receiving the following treatment for Crohn's disease: Azathioprine, 6-mercaptopurine or methotrexate within 2 weeks prior to baseline. Anti-TNFα therapy within 8 weeks prior to baseline. Interferon therapy within 8 weeks prior to baseline. Cyclosporine, mycophenolate, or tacrolimus within 4 weeks prior to baseline. Intravenous corticosteroids within 2 weeks prior to baseline.

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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo BID<br> | Drug: Placebo<br>* oral tablets twice daily<br>|
| Experimental: 5mg BID<br> | Drug: CP-690,550<br>* oral tablets twice daily<br>|
| Experimental: 10mg BID<br> | Drug: CP-690,550<br>* oral tablets twice daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants in Clinical Remission (as Defined by a Crohn's Disease Activity Index [CDAI] Score of Less Than [<] 150 Points) at Week 8 | Clinical remission was a CDAI < 150 points. CDAI is a composite index consisting of a weighted scoring of 8 disease variables: number of liquid or very soft stools, extent of abdominal pain, general well-being, occurrence of extra-intestinal symptoms, need for antidiarrheal drugs, presence of abdominal masses, hematocrit, and body weight. CDAI score was based partly on entries (7 days before evaluation) from participant's diary kept while on study. CDAI scores range from 0 to approximately 600, higher score indicates higher disease activity. The 15 mg BID treatment group was closed to further enrolment early on in the study by Protocol Amendment 5 after only 16 participants were enrolled into this group. Therefore, the efficacy analysis was not performed for this group because the results may be difficult to interpret due to the small sample size. | Week 8 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tofacitinib Plasma Concentrations From 0 to 2 Hours Post Dose on Day 1 and at Week 8/Early Termination (ET) Visit | Plasma samples were collected from participants for the determination of tofacitinib concentrations. Only samples from tofacitinib-treated participants were subsequently analyzed. Plasma concentration data are summarized by nominal sample collection times specified in the protocol, and actual sample collection times may be different. | Pre-dose, 20 minutes, 40 minutes, 1 hour, and 2 to 3 hours post-dose on Day 1 and Week 8/ET visit | 
| EQ-5D Visual Analogue Scale (VAS) Scores at Baseline and Week 8/ET Visit | EQ-5D is a participant rated questionnaire to assess health-related QoL in terms of a single index value. The VAS component rates current health state on a scale from 0 millimeters (mm) (worst imaginable health state) to 100 mm (best imaginable health state); higher scores indicate a better health state. | Baseline, Week 8/ET visit | 
| C-Reactive Protein (CRP) Serum Concentrations at Weeks 2, 4, and 8 | The test for CRP is a laboratory measurement for evaluation of an acute phase reactant of inflammation through the use of an ultrasensitive assay. A decrease in the level of CRP indicates reduction in inflammation and therefore improvement. | Weeks 2, 4, and 8 | 
| Calprotectin Fecal Concentrations at Weeks 2, 4, and 8 | Fecal calprotectin is an inflammatory marker for the gastrointestinal tract and considered as a measurement of neutrophil migration to the gastrointestinal tract. Higher values indicate more serious inflammation. | Weeks 2, 4, and 8 | 
| CDAI Scores at Weeks 2, 4, and 8 | CDAI is a composite index consisting of weighted scoring of 8 disease variables: number of liquid or very soft stools, extent of abdominal pain, general well-being, occurrence of extra-intestinal symptoms, need for antidiarrheal drugs, presence of abdominal masses, hematocrit, and body weight. CDAI scores range from 0 to approximately 600 points, higher score indicates higher disease activity. | Weeks 2, 4, and 8 | 
| Percentage of Participants in Clinical Remission (CDAI <150) at Weeks 2 and 4 | Clinical remission was a CDAI <150 points. CDAI is a composite index consisting of a weighted scoring of 8 disease variables: number of liquid or very soft stools, extent of abdominal pain, general well-being, occurrence of extra-intestinal symptoms, need for antidiarrheal drugs, presence of abdominal masses, hematocrit, and body weight. CDAI score was based partly on entries (7 days before evaluation) from participant's diary kept while on study. CDAI scores range from 0 to approximately 600, higher score indicates higher disease activity. The 15 mg BID treatment group was closed to further enrolment early on in the study by Protocol Amendment 5 after only 16 participants were enrolled into this group. Therefore, the efficacy analysis was not performed for this group because the results may be difficult to interpret due to the small sample size. | Weeks 2 and 4 | 
| Percentage of Participants Achieving Clinical Response-70 (as Defined by a Decrease in CDAI Score of at Least 70 Points From Baseline) at Weeks 2, 4, and 8 | Clinical response-70 was defined as a reduction in CDAI score from baseline of at least 70 points. CDAI is a composite index consisting of weighted scoring of 8 disease variables: number of liquid or very soft stools, extent of abdominal pain, general well-being, occurrence of extra-intestinal symptoms, need for antidiarrheal drugs, presence of abdominal masses, hematocrit, and body weight. CDAI scores range from 0 to approximately 600 points, higher score indicates higher disease activity. The 15 mg BID treatment group was closed to further enrolment early on in the study by Protocol Amendment 5 after only 16 participants were enrolled into this group. Therefore, the efficacy analysis was not performed for this group because the results may be difficult to interpret due to the small sample size. | Baseline, Weeks 2, 4, and 8 | 
| Percentage of Participants Achieving Clinical Response-100 (as Defined by a Decrease in CDAI Score of at Least 100 Points From Baseline) at Weeks 2, 4, and 8 | Clinical response-100 was defined as a reduction in CDAI score from baseline of at least 100 points. CDAI is a composite index consisting of weighted scoring of 8 disease variables: number of liquid or very soft stools, extent of abdominal pain, general well-being, occurrence of extra-intestinal symptoms, need for antidiarrheal drugs, presence of abdominal masses, hematocrit, and body weight. CDAI scores range from 0 to approximately 600 points, higher score indicates higher disease activity. The 15 mg BID treatment group was closed to further enrolment early on in the study by Protocol Amendment 5 after only 16 participants were enrolled into this group. Therefore, the efficacy analysis was not performed for this group because the results may be difficult to interpret due to the small sample size. | Baseline, Weeks 2, 4, and 8 | 
| Percentage of Participants Achieving Either Clinical Response-100 or Clinical Remission (CDAI<150) at Weeks 2, 4, and 8 | Clinical response-100 was defined as a reduction in CDAI score from baseline of at least 100 points. Clinical remission was a CDAI < 150 points. CDAI is a composite index consisting of weighted scoring of 8 disease variables: number of liquid or very soft stools, extent of abdominal pain, general well-being, occurrence of extra-intestinal symptoms, need for antidiarrheal drugs, presence of abdominal masses, hematocrit, and body weight. CDAI scores range from 0 to approximately 600 points, higher score indicates higher disease activity. The 15 mg BID treatment group was closed to further enrolment early on in the study by Protocol Amendment 5 after only 16 participants were enrolled into this group. Therefore, the efficacy analysis was not performed for this group because the results may be difficult to interpret due to the small sample size. | Baseline, Weeks 2, 4, and 8 | 
| Inflammatory Bowel Disease Questionnaire (IBDQ) Total Score and Domain Scores (Bowel Function, Emotional Status, Systemic Symptoms, and Social Function) at Baseline and Week 8/ET Visit | The IBDQ is a psychometrically validated patient reported outcome (PRO) instrument for measuring disease-specific quality of life (QOL) in participants with inflammatory bowel disease (IBD). IBDQ consists of 32 items, each item score ranged from 1 (worst possible response) to 7 (best possible response). The 32 items are grouped into 4 domains: bowel function, emotional status, systemic symptoms and social function. The 4 domains are scored as follows: bowel symptoms 10 to 70; systemic symptoms 5 to 35; emotional function 12 to 84; social function 5 to 35. For each domain, a higher score indicates better QOL. Total score is the sum of each item score, and ranged from 32 to 224 with a higher score indicating a better QOL. Positive change in total score indicated improvement in QOL. | Baseline, Week 8/ET visit | 
| Change From Baseline IBDQ Total Score and Domain Scores (Bowel Function, Emotional Status, Systemic Symptoms, and Social Function) at Week 8/ET Visit Using Analysis of Covariance (ANCOVA) | IBDQ is a validated PRO instrument for measuring QOL in IBD consisting of 32 items scored from 1 (worst response) to 7 (best response). 32 items are grouped into 4 domains scored as follows: bowel symptoms 10 - 70; systemic symptoms 5 - 35; emotional function 12 - 84; social function 5 - 35. For each domain, higher score indicates better QOL. Total score is the sum of each item score, & ranged from 32 to 224 with a higher score indicating better QOL. Positive change in total score indicated improvement in QOL. Adjusted means were derived from an ANCOVA model with baseline value as covariate, treatment group & prior use of anti-tumor necrosis factor (TNF) alpha (α) treatments as factors. The 15 mg BID treatment group was closed to further enrolment early in the study by Protocol Amendment 5 after only 16 participants were enrolled in this group. Therefore, the efficacy analysis was not performed for this group as the results may be difficult to interpret due to the small sample size. | Baseline, Week 8/ET visit | 
| Percentage of Participants With an IBDQ Total Score of Greater Than or Equal to (≥) 170 at Week 8/ET Visit | The IBDQ is a psychometrically validated PRO instrument for measuring disease-specific QOL in participants with IBD. IBDQ consists of 32 items, each item score ranged from 1 (worst possible response) to 7 (best possible response). Total score is the sum of each item score, and ranged from 32 to 224 with a higher score indicating a better QOL. Positive change in total score indicated improvement in QOL. | Week 8/ET visit | 
| Percentage of Participants With ≥16 Point Increase From Baseline in IBDQ Total Score at Week 8/ET Visit | The IBDQ is a psychometrically validated PRO instrument for measuring disease-specific QOL in participants with IBD. IBDQ consists of 32 items, each item score ranged from 1 (worst possible response) to 7 (best possible response). Total score is the sum of each item score, and ranged from 32 to 224 with a higher score indicating a better QOL. Positive change in total score indicated improvement in QOL. | Week 8/ET visit | 
| Percentage of Participants With a Response to the Patient-Reported Treatment Impact Assessment (PRTI) at Week 8/ET Visit by Category | The IBD Patient Reported Treatment Impact Modified (PRTI) questionnaire comprises 3 individual questions administered to the participant: participant satisfaction with study treatment; participant preference for study drug over prior treatment (this question on participant preference for study drug is prefaced by a simple question of previous treatment/s for IBD received in order to place the preference question into context) and participant willingness to re-use the study treatment again. Each of these questions (except the question on previous treatment, which is informational only) is scored on a 5 point Likert scale. PSA = Patient Satisfaction Assessment; PPTA = Patient Previous Treatment Assessment; PPA = Patient Preference Assessment; PWA = Patient Willingness Assessment. | Week 8/ET visit | 
| Short Form 36 Health Survey (SF-36) Component and Domain Scores at Baseline and Week 8/ET Visit | The component and domain scores were scored using the United States (US) 1998 general population norms. The resulting norm-based T scores for both the SF-36 version 2 and SF-36 health domain scales and component summary measures have means of 50 and standard deviations of 10. Higher scores indicate better health-related QOL. | Baseline, Week 8/ET visit | 
| Change From Baseline SF-36 Component and Domain Scores at Week 8/ET Visit Using ANCOVA | The component and domain scores were scored using the US 1998 general population norms. The resulting norm-based T scores for both the SF-36 version 2 and SF-36 health domain scales and component summary measures have means of 50 and standard deviations of 10. Higher scores indicate better health-related QOL. Adjusted means were derived from the ANCOVA model with baseline value as a covariate, treatment group and prior use of anti-TNF alpha treatments as factors. The 15 mg BID treatment group was closed to further enrolment early on in the study by Protocol Amendment 5 after only 16 participants were enrolled into this group. Therefore, the efficacy analysis was not performed for this group because the results may be difficult to interpret due to the small sample size. | Baseline, Week 8/ET visit | 
| EuroQoL 5 Dimensions Questionnaire (EQ-5D) Utility Scores at Baseline and Week 8/ET Visit | EQ-5D is a participant rated questionnaire to assess health-related QoL in terms of a single utility score. Health State Profile component assesses level of current health for 5 domains: mobility, self-care, usual activities, pain and discomfort, and anxiety and depression; 1 indicates better health state (no problems); 3 indicates worst health state (confined to bed). Scoring formula developed by EuroQol Group assigns a utility value for each domain in the profile. Score is transformed and results in a total score range from -0.594 to 1.000; a higher score indicates a better health state. | Baseline, Week 8/ET visit | 
| Change From Baseline EQ-5D Utility Scores at Week 8/ET Visit Using ANCOVA | EQ-5D is a participant rated questionnaire to assess health-related QoL via a single utility score. Health State Profile component assesses level of current health for 5 domains: mobility, self-care, usual activities, pain & discomfort, anxiety & depression; 1 = better health state (no problems); 3 = worst health state (confined to bed). Scoring formula developed by EuroQol Group assigns a utility value for each domain. Score is transformed to a total score ranging from -0.594 to 1.000; higher score indicates better health state. Adjusted means were derived from the ANCOVA model with baseline value as a covariate, treatment group & prior use of anti-TNFα treatments as factors. The 15 mg BID treatment group was closed to further enrolment early on in the study by Protocol Amendment 5 after only 16 participants were enrolled into this group. Therefore, the efficacy analysis was not performed for this group because the results may be difficult to interpret due to the small sample size. | Baseline, Week 8/ET visit | 
| Change From Baseline EQ-5D VAS Scores at Week 8/ET Visit Using ANCOVA | EQ-5D is a participant rated questionnaire to assess health-related QoL in terms of a single index value. The VAS component rates current health state on a scale from 0 millimeters (mm) (worst imaginable health state) to 100 mm (best imaginable health state); higher scores indicate a better health state. Adjusted means were derived from the ANCOVA model with baseline value as a covariate, treatment group & prior use of anti-TNF alpha treatments as factors. The 15 mg BID treatment group was closed to further enrolment early on in the study by Protocol Amendment 5 after only 16 participants were enrolled into this group. Therefore, the efficacy analysis was not performed for this group because the results may be difficult to interpret due to the small sample size. | Baseline, Week 8/ET visit |