Study to Compare Oral PF-06651600, PF-06700841 and Placebo in Subjects With Moderate to Severe Ulcerative Colitis

Study Overview
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Brief Summary
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The purpose of this study is to determine whether PF-06651600 and PF-06700841 are effective in treatment of moderate to severe ulcerative colitis.

Official Title
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A PHASE 2B, DOUBLE-BLIND, RANDOMIZED, PLACEBO-CONTROLLED, PARALLEL GROUP, DOSE RANGING STUDY OF ORAL PF-06651600 AND PF-06700841 AS INDUCTION AND CHRONIC THERAPY IN SUBJECTS WITH MODERATE TO SEVERE ULCERATIVE COLITIS

Conditions
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Ulcerative Colitis

Intervention / Treatment
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* Drug: PF-06651600 or Placebo
* Drug: PF-06700841 or Placebo
* Drug: PF-06700841
* Drug: PF-06651600


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of ulcerative colitis for greater than/equal to 3 months. Moderate to severe active ulcerative colitis Inadequate response to, loss of response to, or intolerance to at least one conventional therapy for UC. Exclusion Criteria: Pregnant or breastfeeding Clinical findings suggestive of Crohn's Disease History of bowel surgery within 6 months

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 |
| --- | --- |
| Experimental: PF-06651600 Drug Dose Level 1<br>Delivered orally for 8 weeks | Drug: PF-06651600 or Placebo<br>* Delivered orally for 8 weeks.<br>|
| Experimental: PF-06651600 Drug Dose Level 2<br>Delivered orally for 8 weeks | Drug: PF-06651600 or Placebo<br>* Delivered orally for 8 weeks.<br>|
| Experimental: PF-06651600 Drug Dose Level 3<br>Delivered orally for 8 weeks. | Drug: PF-06651600 or Placebo<br>* Delivered orally for 8 weeks.<br>|
| Placebo Comparator: PF-06651600 Placebo<br>Delivered orally for 8 weeks. | Drug: PF-06651600 or Placebo<br>* Delivered orally for 8 weeks.<br>|
| Experimental: PF-06700841 Drug Dose Level 1<br>Delivered orally for 8 weeks | Drug: PF-06700841 or Placebo<br>* Delivered orally for 8 weeks.<br>|
| Experimental: PF-06700841 Drug Dose Level 2<br>Delivered orally for 8 weeks. | Drug: PF-06700841 or Placebo<br>* Delivered orally for 8 weeks.<br>|
| Experimental: PF-06700841 Drug Dose Level 3<br>Delivered orally for 8 weeks. | Drug: PF-06700841 or Placebo<br>* Delivered orally for 8 weeks.<br>|
| Placebo Comparator: PF-06700841 Placebo<br>Delivered orally for 8 weeks. | Drug: PF-06700841 or Placebo<br>* Delivered orally for 8 weeks.<br>|
| Experimental: PF-06651600 Drug Dose Level 4<br>Delivered orally for 24 weeks. | Drug: PF-06651600<br>* Delivered orally for 24 weeks.<br>|
| Experimental: PF-06700841 Drug Dose Level 4<br>Delivered orally for 24 weeks. | Drug: PF-06700841<br>* Delivered orally for 24 weeks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total Mayo Score at Week 8 (Induction Period) | The Mayo score is a tool designed to measure disease activity for ulcerative colitis. The Mayo scoring system ranges from 0 to 12 points and consists of 4 subscores, which are stool frequency, rectal bleeding, findings on endoscopy and physician's global assessment. Each subscore graded 0 to 3 with the higher score indicates more severe disease activity and lower score denotes improvement of disease activity as measured by the total Mayo score. | Week 8 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With AEs, SAEs and Discontinuation Due to AEs (Chronic Period) | An AE was an untoward medical occurrence in a participant who received study treatment without regard to possibility of causal relationship. An SAE was an AE resulting in any of the following outcomes: death, life-threatening experience, initial or prolonged inpatient hospitalization, persistent or significant disability/incapacity, congenital anomaly/birth defect. Treatment-emergent AEs were those with initial onset or that worsen in severity after the first dose of study medication. All AEs mentioned below are treatment-emergent AEs. | From Week 8 up to Week 32 | 
| Number of Participants With Laboratory Test Abnormalities (Chronic Period) | The number of participants with a laboratory abnormality meeting the pre-specified criteria defined in the study protocol while on study treatment or during lag time are reported here. Baseline is defined as the last measurement prior to receiving study treatment. Laboratory data included hematology test, serum chemistry test, C-creative protein and viral surveillance. | From Week 8 to Week 32 | 
| Number of Participants With Laboratory Test Abnormalities-hematology (Chronic Period) | The number of participants with a laboratory abnormality meeting specified criteria while on study treatment or during lag time are reported here. Baseline is defined as the last measurement prior to receiving study treatment. The list of hematology test parameters were as follows: hemoglobin, hematocrit, red blood cell count, platelet count, white blood cell count, total neutrophils (absolute, Abs), eosinophils (Abs), monocytes (Abs), basophils (Abs), lymphocytes (Abs), prothrombin time (PT)/international normalized ratio (INR)/partial thromboplastin time (PTT), and reticulocytes (% and Abs). Percentages are displayed for the laboratory tests having a category with greater or equal to 1 evaluable participant. | From Week 8 to Week 32 | 
| Number of Participants With Abnormal Vital Signs Data (Chronic Period) | The vital signs data included the single sitting blood pressure, pulse rate and temperature. The criteria of vital sign abnormality are indicated below. | From Week 8 to Week 32 | 
| Number of Participants With Abnormal ECG Findings (Chronic Period) | The number of participants with abnormal ECG findings during the chronic period (from Week 9 to Week 32) are reported below. | Week 8 to Week 32 | 
| Number of Participants With Serious Infections (Chronic Period) | Serious infections was defined as any infection (for example, viral, bacterial, and fungal) requiring hospitalization or parenteral antimicrobials. | Week 8 to Week 32 | 
| Number of Participants With Laboratory Test Abnormalities-clinical Chemistry (Chronic Period) | The number of participants with a laboratory abnormality meeting specified criteria while on study treatment or during lag time are reported here. Baseline is defined as the last measurement prior to receiving study treatment. The list of serum chemistry test parameters were as follows: blood urea nitrogen, creatinine, cystatin C, glucose, calcium, sodium, potassium, gamma glutamyl transferase, chloride, aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin, direct bilirubin, alkaline phosphatase, uric acid, albumin, total protein, creatine kinase (CK), total cholesterol, triglycerides, high-density lipoproteins (HDL), and low-density lipoprotein (LDL). | Week 8 to Week 32 | 
| Number of Participants With Laboratory Test Abnormalities-urinalysis (Chronic Period) | The number of participants with a laboratory abnormality meeting specified criteria while on study treatment or during lag time are reported here. Baseline is defined as the last measurement prior to receiving study treatment. The list of urinalysis test parameters were as follows:pH, glucose (qual), protein (qual), blood (qual), ketones, nitrites, leukocyte esterase, microscopy, and spot urine albumin/creatinine ratio. The criteria of laboratory abnormality is defined as one of the following conditions was met: 1)associated with accompanying symptoms;2)Test result requires additional diagnostic testing or medical/surgical intervention;3)Test result leads to a change in study dosing (outside of any protocol specified dose adjustments) or discontinuation from the study, significant additional concomitant drug treatment, or other therapy;4)Test result is considered to be an AE by the investigator or sponsor. | Week 8 to Week 32 | 
| Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) and Discontinuation Due to AEs (All-causalities) (Induction Period) | An AE was an untoward medical occurrence in a participant who received study treatment without regard to possibility of causal relationship. An SAE was an AE resulting in any of the following outcomes: death, life-threatening experience, initial or prolonged inpatient hospitalization, persistent or significant disability/incapacity, congenital anomaly/birth defect. Treatment-emergent AEs were those with initial onset or that worsen in severity after the first dose of study medication. All AEs mentioned below are treatment-emergent AEs. | From Day 1 up to Week 8 | 
| Number of Participants With Laboratory Test Abnormalities (Induction Period) | The number of participants with a laboratory abnormality meeting the pre-specified criteria defined in the study protocol while on study treatment or during lag time are reported here. Baseline is defined as the last measurement prior to receiving study treatment. Laboratory data included hematology test, serum chemistry test, C-creative protein and viral surveillance. The criteria of laboratory abnormality is defined as one of the following conditions was met: 1)associated with accompanying symptoms;2)Test result requires additional diagnostic testing or medical/surgical intervention;3)Test result leads to a change in study dosing (outside of any protocol specified dose adjustments) or discontinuation from the study, significant additional concomitant drug treatment, or other therapy;4)Test result is considered to be an AE by the investigator or sponsor. | From Day 1 up to Week 8 | 
| Number of Participants With Laboratory Test Abnormalities-hematology (Induction Period) | The number of participants with a laboratory abnormality meeting specified criteria while on study treatment or during lag time are reported here. Baseline is defined as the last measurement prior to receiving study treatment. The list of hematology test parameters were as follows: hemoglobin, hematocrit, red blood cell count, platelet count, white blood cell count, total neutrophils (absolute, Abs), eosinophils (Abs), monocytes (Abs), basophils (Abs), lymphocytes (Abs), prothrombin time (PT)/international normalized ratio (INR)/partial thromboplastin time (PTT), and reticulocytes (% and Abs). Percentages are displayed for the laboratory tests having a category with greater or equal to 1 evaluable participant. | From Day 1 up to Week 8 | 
| Number of Participants With Laboratory Test Abnormalities-clinical Chemistry (Induction Period) | The number of participants with a laboratory abnormality meeting specified criteria while on study treatment or during lag time are reported here. Baseline is defined as the last measurement prior to receiving study treatment. The list of serum chemistry test parameters were as follows: blood urea nitrogen, creatinine, cystatin C, glucose, calcium, sodium, potassium, gamma glutamyl transferase, chloride, aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin, direct bilirubin, alkaline phosphatase, uric acid, albumin, total protein, creatine kinase (CK), total cholesterol, triglycerides, high-density lipoproteins (HDL), and low-density lipoprotein (LDL) | From Day 1 up to Week 8 | 
| Number of Participants With Laboratory Test Abnormalities- Urinalysis (Induction Period) | The number of participants with a laboratory abnormality meeting specified criteria while on study treatment or during lag time are reported here. Baseline is defined as the last measurement prior to receiving study treatment. The list of urinalysis test parameters were as follows:pH, glucose (qual), protein (qual), blood (qual), ketones, nitrites, leukocyte esterase, microscopy, and spot urine albumin/creatinine ratio. The criteria of laboratory abnormality is defined as one of the following conditions was met: 1)associated with accompanying symptoms;2)Test result requires additional diagnostic testing or medical/surgical intervention;3)Test result leads to a change in study dosing (outside of any protocol specified dose adjustments) or discontinuation from the study, significant additional concomitant drug treatment, or other therapy;4)Test result is considered to be an AE by the investigator or sponsor. | From Day 1 up to Week 8 | 
| Number of Participants With Abnormal Vital Signs Data (Induction Period) | The vital signs data included the single sitting blood pressure, pulse rate and temperature. The criteria of vital sign abnormality are indicated below. | From screening to Week 8 | 
| Number of Participants With Abnormal Electrocardiogram (ECG) Findings (Induction Period) | The number of participants with abnormal ECG findings during the induction period (from Day 1 to Week 8) are reported below. The criteria of test abnormality is defined as one of the following conditions was met: 1)associated with accompanying symptoms;2)Test result requires additional diagnostic testing or medical/surgical intervention;3)Test result leads to a change in study dosing (outside of any protocol specified dose adjustments) or discontinuation from the study, significant additional concomitant drug treatment, or other therapy;4)Test result is considered to be an AE by the investigator or sponsor. | From screening to Week 8 | 
| Number of Participants With Serious Infections (Induction Period) | Serious infections was defined as any infection (for example, viral, bacterial, and fungal) requiring hospitalization or parenteral antimicrobials including Listeria encephalitis, Pneumonia, Viral infection. | From Day 1 up to Week 8 | 
| Percentage of Participants Achieving Remission Based on Total Mayo Score at Week 8 (Induction Period) | The Mayo Score is a tool designed to measure disease activity for ulcerative colitis. The Mayo scoring system ranges from 0 to 12 points and consists of 4 subscores, which are stool frequency, rectal bleeding, findings on endoscopy and physician's global assessment. Each subscore graded 0 to 3 with the higher score indicating more severe disease activity. Clinical remission was defined as total Mayo score of 2 points or lower, with no individual subscore exceeding 1 point and a rectal bleeding subscore of 0. | Week 8 | 
| Percentage of Participants Achieving Improvement in Endoscopic Appearance Based on Total Mayo Score at Week 8 (Induction Period) | The Mayo Score is a tool designed to measure disease activity for ulcerative colitis. The Mayo scoring system ranges from 0 to 12 points and consists of 4 subscores, which are stool frequency, rectal bleeding, findings on endoscopy and physician's global assessment. Each subscore graded 0 to 3 with the higher score indicating more severe disease activity. Improvement in endoscopic subscore appearance was defined at Mayo endoscopic subscore of ≤1. | Week 8 | 
| Percentage of Participants Achieving Clinical Response Based on Total Mayo Score at Week 8 (Induction Period) | The Mayo Score is a tool designed to measure disease activity for ulcerative colitis. The Mayo scoring system ranges from 0 to 12 points and consists of 4 subscores, which are stool frequency, rectal bleeding, findings on endoscopy and physician's global assessment. Each subscore graded 0 to 3 with the higher score indicating more severe disease activity. Clinical response was defined as decrease from baseline in total Mayo score of at least 3 points and at least 30%, with an accompanying decrease in the subscore for rectal bleeding of at least 1 point or absolute subscore for rectal bleeding of 0 or 1. | Week 8 | 
| Percentage of Participants Achieving Endoscopic Remission Based on Total Mayo Score at Week 8 (Induction Period) | The Mayo Score is a tool designed to measure disease activity for ulcerative colitis. The Mayo scoring system ranges from 0 to 12 points and consists of 4 subscores, which are stool frequency, rectal bleeding, findings on endoscopy and physician's global assessment. Each subscore graded 0 to 3 with the higher score indicating more severe disease activity. Endoscopic remission was defined as endoscopic subscore of 0. | Week 8 | 
| Percentage of Participants Achieving Symptomatic Remission Based on Total Mayo Score at Week 8 (Induction Period) | The Mayo Score is a tool designed to measure disease activity for ulcerative colitis. The Mayo scoring system ranges from 0 to 12 points and consists of 4 subscores, which are stool frequency, rectal bleeding, findings on endoscopy and physician's global assessment. Each subscore graded 0 to 3 with the higher score indicating more severe disease activity. Symptomatic remission was defined as total Mayo score of 2 points or lower, with no individual subscore exceeding 1 point, and both rectal bleeding and stool frequency subscores of 0. | Week 8 | 
| Percentage of Participants Achieving Deep Remission Based on Total Mayo Score at Week 8 (Induction Period) | The Mayo Score is a tool designed to measure disease activity for ulcerative colitis. The Mayo scoring system ranges from 0 to 12 points and consists of 4 subscores, which are stool frequency, rectal bleeding, findings on endoscopy and physician's global assessment. Each subscore graded 0 to 3 with the higher score indicating more severe disease activity. Deep remission was defined as total Mayo score of 2 points or lower, with no individual subscore exceeding 1 point and a zero on both endoscopic and rectal bleeding subscore. | Week 8 | 
| Partial Mayo Score and Change From Baseline at Weeks 2, 4 and 8 (Induction Period) | The Mayo Score is a tool designed to measure disease activity for ulcerative colitis. The Mayo scoring system ranges from 0 to 12 points and consists of 4 subscores, which are stool frequency, rectal bleeding, findings on endoscopy and physician's global assessment. Each subscore graded 0 to 3 with the higher score indicating more severe disease activity. The partial Mayo score does not incorporate the endoscopy score and the partial Mayo score ranges from 0 to 9. | Baseline, Weeks 2, 4 and 8 | 
| Change From Baseline in Total Mayo Score at Week 8 (Induction Period) | The Mayo Score is a tool designed to measure disease activity for ulcerative colitis. The Mayo scoring system ranges from 0 to 12 points and consists of 4 subscores, which are stool frequency, rectal bleeding, findings on endoscopy and physician's global assessment. Each subscore graded 0 to 3 with the higher score indicating more severe disease activity. | Baseline, Week 8 | 
| Inflammatory Bowel Disease Questionnaire (IBDQ) Domain Score and Total Score at Weeks 4 and 8 (Induction Period) | IBDQ is a psychometrically validated patient reported outcome (PRO) instrument for measuring the disease specific quality of life in participants with inflammatory bowel disease (IBD). The IBDQ is comprised of 32 items, which are grouped into 4 dimensions: 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. The total IBDQ score ranges from 32 to 224. For the total score and each domain, a higher score indicates better quality of life. | Week 4 and Week 8 | 
| Change From Baseline in IBDQ Total Score at Weeks 4 and 8 (Induction Period) | IBDQ is a psychometrically validated PRO instrument for measuring the disease specific quality of life in participants with IBD. The IBDQ is comprised of 32 items, which are grouped into 4 dimensions: 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. The total IBDQ score ranges from 32 to 224. For the total score and each domain, a higher score indicates better quality of life. Baseline value is defined as the last non-missing measurement collected prior to or on Day 1. | Baseline, Weeks 4 and 8 | 
| Percentage of Participants With IBDQ Total Score Greater Than or Equal to 170 at Weeks 4 and 8 (Induction Period) | IBDQ is a psychometrically validated PRO instrument for measuring the disease specific quality of life in participants with IBD. The IBDQ is comprised of 32 items, which are grouped into 4 dimensions: 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. The total IBDQ score ranges from 32 to 224. For the total score and each domain, a higher score indicates better quality of life. | Week 4 and Week 8 | 
| Percentage of Participants With Greater Than or Equal to 16 Points Increase in IBDQ Total Score From Baseline at Weeks 4 and 8 (Induction Period) | IBDQ is a psychometrically validated PRO instrument for measuring the disease specific quality of life in participants with IBD. The IBDQ is comprised of 32 items, which are grouped into 4 dimensions: 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. The total IBDQ score ranges from 32 to 224. For the total score and each domain, a higher score indicates better quality of life. | Baseline, Week 4 and 8 | 
| Percentage of Participants With Improvement in IBDQ Bowel Symptom Domain at Weeks 4 and 8 (Induction Period) | IBDQ is a psychometrically validated PRO instrument for measuring the disease specific quality of life in participants with IBD. The IBDQ is comprised of 32 items, which are grouped into 4 dimensions: 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. The total IBDQ score ranges from 32 to 224. For the total score and each domain, a higher score indicates better quality of life. The improvement in IBDQ bowel symptom domain was defined as an increase of ≥1.2 points from baseline in average score among bowel symptoms domain (items 1, 5, 9, 13, 17, 20, 22, 24, 26, 29). | Week 4 and Week 8 | 
| Change From Baseline in Short Form 36 Version 2 (SF-36v2) Acute Mental Component Summary (MCS) Score and Physical Component Summary (PCS) Score at Weeks 4 and 8 (Induction Period) | The SF-36 version 2 (Acute version) is a 36-item generic health status measure. It measures 8 general health concepts or domains: Physical Functioning (PF), Role-Physical (RP), Bodily Pain (BP), General Health (GH), Vitality (VT), Social Functioning (SF), Role-Emotional (RE), and Mental Health (MH). These 8 domains can also be summarized as physical and mental component scores. The summary component scores, Physical Component Summary (PCS) and Mental Component Summary (MCS), are based on a normalized sum of the 8 scale scores PF, RP, BP, GH, VT, SF, RE, and MH . All domains and summary components are scored such that a higher score indicates a higher functioning or health level. The minimum and maximum scores of the PCS Score are 6.1 and 79.7, respectively. The minimum and maximum scores of the MCS Score are -3.8 and 78.7, respectively. | Week 4 and Week 8 | 
| Change From Baseline in Euro Quality of Life Questionnaire 5 Dimensions 3 Levels (EQ-5D 3L) Utility Score and EQ-5D Visual Analog Scale (VAS) at Weeks 4 and 8 (Induction Period) | For EQ-5D 3L, participant rated questionnaire to assess generic health status in two parts: single utility score and visual analog scale. For utility score, participants rated their current health state on 5 dimensions: mobility, self-care, usual activities, pain and discomfort, and anxiety and depression with each dimension having three levels of function: 1 indicates no problem; 2 indicates some problem; 3 indicates extreme problem. Scoring formula developed by EuroQol Group assigns a utility value for each domain in the profile. Score was transformed and results in a total score range of 0.05 to 1.00; higher scores indicating a better health state. The EQ-5D VAS records the respondent's self rated health on a scale from 0 (worst imaginable health state) to 100 (best imaginable health state). | Week 4 and Week 8 | 
| Total Mayo Score at Week 32 (Chronic Period) | The Mayo Score is a tool designed to measure disease activity for ulcerative colitis. The Mayo scoring system ranges from 0 to 12 points and consists of 4 subscores, which are stool frequency, rectal bleeding, findings on endoscopy and physician's global assessment. Each subscore graded 0 to 3 with the higher score indicating more severe disease activity. | Week 32 | 
| Percentage of Participants Achieving Remission Based on Total Mayo Score at Week 32 (Chronic Period) | The Mayo Score is a tool designed to measure disease activity for ulcerative colitis. The Mayo scoring system ranges from 0 to 12 points and consists of 4 subscores, which are stool frequency, rectal bleeding, findings on endoscopy and physician's global assessment. Each subscore graded 0 to 3 with the higher score indicating more severe disease activity. Clinical remission was defined as total Mayo score of 2 points or lower, with no individual subscore exceeding 1 point and a rectal bleeding subscore of 0. | Week 32 | 
| Percentage of Participants Achieving Improvement in Endoscopic Appearance Based on Mayo Score at Week 32 (Chronic Period) | The Mayo Score is a tool designed to measure disease activity for ulcerative colitis. The Mayo scoring system ranges from 0 to 12 points and consists of 4 subscores, which are stool frequency, rectal bleeding, findings on endoscopy and physician's global assessment. Each subscore graded 0 to 3 with the higher score indicating more severe disease activity. Improvement in endoscopic appearance was defined at Mayo endoscopic subscore of ≤1. | Week 32 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Mayo score