A Study of Tofacitinib in Patients With Ulcerative Colitis in Stable Remission

Study Overview
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Brief Summary
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This study is a follow up study for subjects with Ulcerative Colitis (UC) in stable remission designed to evaluate flexible dosing of CP-690,550.

Official Title
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A PHASE 3B/4, MULTI-CENTER, DOUBLE-BLIND, RANDOMIZED, PARALLEL GROUP STUDY OF TOFACITINIB (CP-690,550) IN SUBJECTS WITH ULCERATIVE COLITIS IN STABLE REMISSION

Conditions
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Ulcerative Colitis

Intervention / Treatment
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* Drug: CP-690,500 5 mg
* Drug: CP-690,550 10 mg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Currently enrolled in Study A3921139 receiving CP-690,550 10 mg BID for at least 2 years consecutively. In stable remission on CP-690,550 10 mg BID Agree to use highly effective contraception Negative pregnancy test Comply with visits, treatments, lab tests, diary and other study procedures Signed and dated informed consent document. Exclusion Criteria: Subjects who were initially assigned to tofacitinib 10 mg BID at baseline of Study A3921139 whose tofacitinib dose was reduced to 5 mg BID due to safety or efficacy. Presence of indeterminate colitis, microscopic colitis, ischemic colitis, infectious colitis or findings suggestive of Crohn's disease Likely to require surgery for ulcerative colitis during study Expected to receive any prohibited medication Expected to receive live or attenuated virus vaccination during study Women who are pregnant or breastfeeding or planning to become pregnant during the study Evidence of colonic malignancy or any dysplasia Acute or chronic medical or psychiatric condition that may increase risk of participation Investigator site staff member Subjects likely to be uncooperative or unable to comply with study procedures Participation in other studies involving investigational drugs during study Subjects with any of the following risk factors for pulmonary embolism at baseline as defined by EMA's PRAC: has heart failure; has inherited coagulation disorders; has had venous thromboembolism, either deep venous thrombosis or pulmonary embolism; is taking combined hormonal contraceptives or hormone replacement therapy; has malignancy (association is strongest with cancers other than non-melanoma skin cancers); is undergoing major surgery

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: CP-690,550 5 mg<br>CP-690,550 5 mg tablet by mouth twice a day (BID) | Drug: CP-690,500 5 mg<br>* CP-690,550 5 mg tablet BID<br>|
| Experimental: CP-690,550 10 mg<br>CP-690,550 10 mg BID | Drug: CP-690,550 10 mg<br>* CP-690,550 10 mg tablet BID<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Remission Based on Modified Mayo Score at Month 6 | Remission as per modified mayo score was defined as an endoscopic subscore of 0 or 1, stool frequency subscore of 0 or 1, and rectal bleeding subscore of 0 at Month 6. Modified mayo score consisted of 3 components: stool frequency subscore, rectal bleeding subscore and endoscopic subscore: higher scores for each score = more severe disease. These scores were summed up to give a total modified mayo score range of 0 to 9; where higher scores indicating more severe disease. | Month 6 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Loss of Remission Based on Modified Mayo Score Using Kaplan-Meier Method | Time to loss of remission(flare): time from first drug administration until time of meeting loss of remission criteria based on modified mayo score. Loss of remission: meeting at least (>=)1 criteria: increase from Baseline in rectal bleeding subscore by >=1 point and increase in endoscopic subscore by >=1 point; increase from Baseline in rectal bleeding subscore by >=2 points and endoscopic subscore >0; increase in stool frequency subscore by >=2 points and increase in endoscopic subscore by >=1 point; increase in endoscopic subscore by >=2 points. Modified mayo score included 3 components: stool frequency, rectal bleeding and endoscopic subscores: Modified mayo score included 3 components: stool frequency, rectal bleeding and endoscopic subscores, each subscore graded from 0 to 3 with higher scores for each score=more severe disease. All scores summed up to give total modified mayo score range from 0 to 9; higher scores=more severe disease. | Up to Month 42 | 
| Number of Participants With Remission Based on Modified Partial Mayo Score at Months 1, 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39 and 42 | Remission as per modified partial mayo score was defined as stool frequency subscore of 0 or 1, and rectal bleeding sub score of 0 at the specified time points. Modified partial mayo scores consisted of 2 components: stool frequency and rectal bleeding: each subscore graded from 0 to 3 with higher scores for each score = more severe disease. These scores were summed up to give a total modified partial mayo score range of 0 to 6; where higher scores indicating more severe disease. | Months 1, 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39 and 42 | 
| Number of Participants With Remission Based on Total Mayo Score at Months 6, 18, 30 and 42 | Remission as per total mayo score was defined by a total mayo score of 2 points or lower, with no individual subscore exceeding 1 point and a rectal bleeding subscore of 0. Mayo score is an instrument designed to measure disease activity of UC. It consisted of 4 subscores: stool frequency, rectal bleeding, findings of flexible sigmoidoscopy and physician global assessment (PGA), each subscore graded from 0 to 3 with higher scores indicating more severe disease. PGA included 3 criteria: participant's recollection of abdominal discomfort, general sense of wellbeing and other observations such as physical findings and performance status. Individual subscores were summed up to give a total mayo score range of 0 to 12, where higher scores indicating more severe disease. | Months 6, 18, 30 and 42 | 
| Number of Participants With Remission Based on Partial Mayo Score at Months 1, 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39 and 42 | Remission as per partial mayo score was defined as partial mayo score of 2 points or lower, with no individual subscore exceeding 1 point and a rectal bleeding subscore of 0. Partial mayo score was an instrument designed to measure disease activity of UC without endoscopy. It consisted of 3 subscores: stool frequency, rectal bleeding and PGA with each subscore graded from 0 to 3 with higher scores indicating more severe disease. PGA included 3 criteria: participant's recollection of abdominal discomfort, general sense of wellbeing and other observations such as physical findings and performance status. Individual subscores were summed up to give a total partial mayo score range from 0 (normal or inactive disease) to 9 (severe disease) with higher scores indicating more severe disease. | Months 1, 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39 and 42 | 
| Number of Participants With Remission Based on Modified Mayo Score at Months 18, 30 and 42 | Remission as per modified mayo score was defined as an endoscopic subscore of 0 or 1, stool frequency subscore of 0 or 1, and rectal bleeding subscore of 0. Modified mayo score consisted of 3 components: stool frequency subscore, rectal bleeding subscore and endoscopic subscore: higher scores for each score = more severe disease. These scores were summed up to give a total modified mayo score range of 0 to 9; where higher scores indicating more severe disease. | Months 18, 30 and 42 | 
| Change From Baseline in Modified Mayo Score at Month 6 | Modified mayo score is an instrument designed to measure disease activity of UC. Modified mayo scores consisted of 3 subscores: stool frequency, rectal bleeding and endoscopic subscore, each subscore graded from 0 to 3 with higher scores indicating more severe disease. These individual scores were summed up to give a total modified mayo score range of 0 to 9, where higher scores indicated more severe disease. | Baseline, Month 6 | 
| Change From Baseline in Modified Mayo Score at Months 18, 30 and 42 | Modified mayo score is an instrument designed to measure disease activity of UC. Modified mayo scores consisted of 3 subscores: stool frequency, rectal bleeding and endoscopic subscore, each subscore graded from 0 to 3 with higher scores indicating more severe disease. These individual scores were summed up to give a total modified mayo score range of 0 to 9, where higher scores indicated more severe disease. | Baseline, Months 18, 30 and 42 | 
| Change From Baseline in Modified Partial Mayo Score at Months 1, 3 and 6 | Modified partial mayo scores consisted of 2 subscores: stool frequency and rectal bleeding with each subscore graded from 0 to 3 with higher scores indicating more severe disease. Individual subscores were summed up to give a total Modified partial mayo score ranges from 0 (normal or inactive disease) to 6 (severe disease) with higher scores indicating more severe disease. | Baseline, Months 1, 3 and 6 | 
| Change From Baseline in Modified Partial Mayo Score at Months 9, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39 and 42 | Modified partial mayo scores consisted of 2 subscores: stool frequency and rectal bleeding with each subscore graded from 0 to 3 with higher scores indicating more severe disease. Individual subscores were summed up to give a total modified partial mayo score range from 0 (normal or inactive disease) to 6 (severe disease) with higher scores indicating more severe disease. | Baseline, Months 9, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39 and 42 | 
| Change From Baseline in Total Mayo Score at Month 6 | Mayo score is an instrument designed to measure disease activity of UC. It consisted of 4 subscores: stool frequency, rectal bleeding, findings of flexible sigmoidoscopy and PGA, each sub score graded from 0 to 3 with higher scores indicating more severe disease. PGA included 3 criteria: participant's recollection of abdominal discomfort, general sense of wellbeing and other observations such as physical findings and performance status. Individual subscores were summed up to give a total mayo score range of 0 to 12, where higher scores indicating more severe disease. | Baseline, Month 6 | 
| Change From Baseline in Total Mayo Score at Months 18, 30 and 42 | Mayo score is an instrument designed to measure disease activity of UC. It consisted of 4 subscores: stool frequency, rectal bleeding, findings of flexible sigmoidoscopy and PGA, each sub score graded from 0 to 3 with higher scores indicating more severe disease. PGA included 3 criteria: participant's recollection of abdominal discomfort, general sense of wellbeing and other observations such as physical findings and performance status. Individual subscores were summed up to give a total mayo score range of 0 to 12, where higher scores indicating more severe disease. | Baseline, Months 18, 30 and 42 | 
| Change From Baseline in Partial Mayo Score at Months 1, 3 and 6 | Partial mayo score was an instrument designed to measure disease activity of UC without endoscopy. It consisted of 3 subscores: stool frequency, rectal bleeding and PGA with each subscore graded from 0 to 3 with higher scores indicating more severe disease. PGA included 3 criteria: participant's recollection of abdominal discomfort, general sense of wellbeing and other observations such as physical findings and performance status. Individual subscores were summed up to give a total partial mayo score range from 0 (normal or inactive disease) to 9 (severe disease) with higher scores indicating more severe disease. | Baseline, Months 1, 3 and 6 | 
| Change From Baseline in Partial Mayo Score at Months 9, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39 and 42 | Partial mayo score was an instrument designed to measure disease activity of UC without endoscopy. It consisted of 3 subscores: stool frequency, rectal bleeding and PGA with each subscore graded from 0 to 3 with higher scores indicating more severe disease. PGA included 3 criteria: participant's recollection of abdominal discomfort, general sense of wellbeing and other observations such as physical findings and performance status. Individual subscores were summed up to give a total partial mayo score ranges from 0 (normal or inactive disease) to 9 (severe disease) with higher scores indicating more severe disease. | Baseline, Months 9, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39 and 42 | 
| Number of Participants With Mucosal Healing at Months 6, 18, 30 and 42 | Mucosal healing in participants was defined as the mayo endoscopic subscore of 0 or 1. The Mayo endoscopic subscore consisted of the findings of centrally read flexible sigmoidoscopy, graded from 0 to 3 with higher scores indicated more severe disease. | Months 6, 18, 30 and 42 | 
| Number of Participants With Clinical Response Based on Mayo Score at Months 6, 18, 30 and 42 | Clinical response was defined as a decrease from baseline in mayo score of at least 3 points and at least 30 percent, with an accompanying decrease in the rectal bleeding subscore of at least 1 point or an absolute rectal bleeding subscore of 0 or 1. Mayo score is an instrument designed to measure disease activity of UC. It consisted of 4 subscores: stool frequency, rectal bleeding, findings of flexible sigmoidoscopy and PGA, each sub score graded from 0 to 3 with higher scores indicating more severe disease. PGA included 3 criteria: participant's recollection of abdominal discomfort, general sense of wellbeing and other observations such as physical findings and performance status. Individual subscores were summed up to give a mayo score range of 0 to 12, where higher scores indicating more severe disease. | Months 6, 18, 30 and 42 | 
| Change From Baseline in Fecal Calprotectin at Months 1, 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39 and 42 | Change from baseline in fecal calprotectin (in micrograms per gram [mcg/g]) was reported. | Baseline, Months 1, 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39 and 42 | 
| Change From Baseline in High Sensitivity C-Reactive Protein (Hs-CRP) Level at Months 1, 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39 and 42 | Change From baseline in hs-CRP level (in milligrams per liter [mg/L]) is reported. | Baseline, Months 1, 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39 and 42 | 
| Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | An AE was any untoward medical occurrence in a participant who received investigational product without regard to possibility of causal relationship. SAE was an AE 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; medically important events. A treatment emergent AE was defined as an event that emerged during the treatment period that was absent before treatment or worsened during the treatment period relative to the pretreatment state. AEs included both serious and all non-serious adverse events (irrespective of frequency threshold used to report other AEs in safety section). | Baseline up to 43 months | 
| Number of Participants With Serious Infections | Serious infections were defined as any infections (viral, bacterial, and fungal) requiring parenteral antimicrobial therapy, hospitalization for treatment, or meeting other criteria that require the infection to be classified as serious adverse event. SAE was an AE 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; medically important events. | Baseline up to 43 months | 
| Number of Participants With Clinical Laboratory Abnormalities | Abnormality criteria: Hematology: hemoglobin(Hg): <0.8* lower limit of normal (LLN); hematocrit: <0.8*LLN; lymphocytes: <0.8* LLN; lymphocytes/leukocytes: <0.8*LLN; erythrocytes: <0.8*LLN; erythrocytes mean corpuscular volume: <0.9*LLN; erythrocytes mean corpuscular Hg: <0.9*LLN; reticulocytes, reticulocytes/erythrocytes:>1.5* upper limit of normal (ULN); neutrophils, neutrophils/leukocytes: >1.2*ULN; basophils/leukocytes, eosinophils, eosinophils/leukocytes, monocytes/leukocytes: >1.2*ULN; leukocyte esterase: >=1; Clinical chemistry: bicarbonate:<0.9*LLN, bilirubin: >1.5*ULN; indirect bilirubin: >1.5* ULN; aspartate aminotransferase(AT): >3.0*ULN; alanine AT: >3.0*ULN; gamma glutamyl transferase: >3.0* ULN; creatine kinase: >2.0*ULN; potassium: >1.1*ULN; blood urea nitrogen: >1.3*ULN; creatinine: >1.3*ULN; urate: >1.2*ULN; cholesterol: >1.3*ULN; HDL-cholesterol: <0.8* LLN; LDL-cholesterol: >1.2*ULN; triglycerides: >1.3*ULN; glucose: >1.5*ULN; and urine Hg >=1. | Baseline up to 27 months | 
| Number of Participants With Clinically Significant Laboratory Abnormalities Leading to Study Treatment Discontinuation | Laboratory abnormalities leading to study treatment discontinuation: 2 sequential neutrophil counts <750 neutrophils per cubic millimeter (mm^3); 2 sequential lymphocyte counts <500 lymphocytes/mm^3; 2 sequential hemoglobin <8.0 grams per deciliter; 2 sequential platelet counts <75000 platelets/mm^3; 2 sequential AST or ALT elevations >=3*ULN with at least one total bilirubin value >=2*ULN; 2 sequential AST or ALT elevations >=3*ULN accompanied by signs or symptoms consistent with hepatic injury; 2 sequential AST or ALT elevations >=5*ULN; 2 sequential increases in creatinine >50% and >0.5 milligrams per deciliter over A3921139 baseline; 2 sequential CK elevations >10*ULN unless the causality is known not to be medically serious (eg, exercise induced). | Baseline up to 43 months | 
| Number of Participants With Vital Sign Abnormalities | Vital signs abnormality criteria included: 1) a) diastolic blood pressure (DBP) of (less than) <50 millimeter of mercury (mmHg), b) change greater than equal to (>=) 20 mmHg increase, c) change >=20 mmHg decrease; 2) a) systolic blood pressure (SBP) of <90 mmHg, b) change >=30 mmHg increase, c) change >=30 mmHg decrease; 3) a) pulse rate value of <40 beats per minute (bpm), b) pulse rate >120 bpm. Only those categories in which at least 1 participant had data were reported. | Baseline up to 43 months | 
| Number of Participants With Clinically Significant Physical Examinations Abnormalities | Physical examination included assessment of the weight, general appearance, eyes, mouth, lungs, heart, abdomen, musculoskeletal, extremities, skin and lymph nodes. Clinical significance was assessed by the Investigator. | Baseline up to 43 months | 
| Number of Participants With Opportunistic Infections, All Malignancy, Gastrointestinal Perforation and Cardiovascular Events Adjudicated by Adjudication Committee | Number of participants with adjudicated opportunistic infections including herpes zoster (non-adjacent or >2 adjacent dermatomes); all malignancies including non-melanoma skin cancer; gastrointestinal perforation and cardiovascular events including pulmonary embolism and cerebrovascular accident, adjudicated by adjudication committee were reported. | Baseline up to 43 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ulcerative colitis, inflammatory bowel disease