Study To Evaluate The Efficacy And Safety Of Oral PF-06651600 And PF-06700841 In Subjects With Moderate To Severe Crohn's Disease

SES CD50 was defined as 50% improvement from baseline in SES-CD. Baseline was defined as last measurement prior to first dosing on Day 1. Following bowel segments were used for calculating SES-CD scores: Ileum, right colon(C), transverse C, left C and rectum. Each segment assessed for four domains: presence of ulcers, ulcerated surface, affected surface and presence of narrowing, each scored on a scale of 0 to 3, higher scores indicated more severe condition. Presence of ulcers score: 0=none, 1=small ulcer: (0.1-0.5 centimeter[cm]), 2=Large ulcer(0.5-2 cm), 3=very large ulcer(>2 cm); ulcerated surface score: 0=none, 1=<10%, 2=10-30% and 3=>30%; affected surface score: 0=unaffected segment, 1=<50%, 2=50-75% and 3=>75%; presence of narrowing score: 0=none,1=single, can be passed, 2=multiple, can be passed and 3=cannot be passed. Total SES CD score was determined by sum of each domain score for all 5 bowel segments and ranged from 0 to 60, higher score indicating more severe disease.

Pre-specified criteria for lab abnormalities included- hematology: hemoglobin(Hb), erythrocytes (ery),hematocrit:<0.8*lower limit of normal(LLN);reticulocytes: <0.5*LLN, >1.5*upper limit of normal(ULN); ery mean corpuscular(EMC) volume: <0.9*ULN, >1.11*ULN;EMC Hb: <0.9*LLN; platelets:>1.75*ULN; leukocytes(10^9/L): <0.6*LLN,>1.5*ULN;lymphocyte,neutrophil(10^9/L):<0.8*LLN,>1.2*ULN;basophil,eosinophil,monocyte(10^9/L):>1.2*ULN;activated partial thromboplastin time (sec): >1.1*ULN. Chemistry: bilirubin(mg/dL),aspartate aminotransferase(AT),alanine AT(units per litre)>3.0*ULN; protein, albumin(g/dL):<0.8*LLN; creatinine, triglycerides (mg/dL):>1.3*ULN; urate(mg/dL):>1.2*ULN, potassium (mEq/L):<0.9*LLN; calcium (mg/dL): <0.9*LLN,>1.1*ULN. Urinalysis: pH>8;urine,glucose,protein(mg/dl); ketones, nitrite, urine Hb(scalar):>=1. Number of participants with any lab abnormality meeting pre-specified criteria are reported.

Vital signs including blood pressure (diastolic blood pressure [DBP], systolic blood pressure [SBP], and pulse rate [PR]) were measured in a supine position using automated devices. DBP included value < 50 (millimeter of mercury [mmHg]), change >=20 (mmHg) increase and change >=20 (mmHg) decrease; SBP: value < 90 (mmHg), change >= 30 (mmHg) increase and change >= 30 (mmHg) decrease; PR: value > 120 (beats per minute [bpm]).

Single twelve lead ECGs were obtained using an automated ECG machine after participant had rested quietly for at least 10 minutes in a supine position. QTc prolongations were defined as a QTc >=480 milli second (msec) or an absolute change in QTc greater than (>) 60 msec. Clinically significant ECG findings were determined by the investigator.

An adverse event (AE) was any untoward medical occurrence in a study participant administered a study intervention; the event need not necessarily have a causal relationship with the treatment or usage. An AE was considered TEAE to a given treatment if the event started during the effective duration of treatment regardless of whether a similar event of equal or greater severity existed in the baseline period.

A serious adverse event (SAE) was any untoward medical occurrence at any dose that: resulted in death; was life-threatening (immediate risk of death); required inpatient hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity (substantial disruption of the ability to conduct normal life functions) or resulted in congenital anomaly/birth defect or was considered an important medical event. An SAE was considered as TESAE if the event started during the effective duration of treatment regardless of whether a similar event of equal or greater severity existed in the baseline period.

An AE was any untoward medical occurrence in a study participant administered a study intervention; the event need not necessarily have a causal relationship with the treatment or usage. Discontinuations from study due to TEAEs were defined as participants with an AE record indicating the AE caused permanent discontinuation from the study but action taken with study treatment was not drug withdrawn. Permanent discontinuations from any study intervention due to TEAEs were defined as participants with an AE record indicating that action taken with study treatment was drug withdrawn. In this outcome measure number of participants with discontinuation from study due to AEs and permanent discontinuation from study intervention due to AEs are reported.

Pre-specified criteria for lab abnormalities included- hematology: hemoglobin, erythrocytes, hematocrit:<0.8*LLN; reticulocytes: <0.5*LLN, >1.5*ULN; EMC volume: <0.9*ULN, >1.11*ULN;EMC Hb: <0.9*LLN; platelets:>1.75*ULN; leukocytes(10^9/L): <0.6*LLN, >1.5*ULN; lymphocyte, neutrophil(10^9/L):<0.8*LLN, >1.2*ULN; basophil, eosinophil, monocyte(10^9/L):>1.2*ULN; activated partial thromboplastin time (sec): >1.1*ULN. Chemistry: bilirubin(mg/dL),aspartate aminotransferase(AT),alanine AT(units per litre)>3.0*ULN; protein, albumin(g/dL):<0.8*LLN; creatinine, triglycerides (mg/dL):>1.3*ULN; urate(mg/dL):>1.2*ULN, potassium (mEq/L):<0.9*LLN; calcium (mg/dL): <0.9*LLN,>1.1*ULN. Urinalysis: pH>8; urine, glucose, protein(mg/dl); ketones, nitrite, urine Hb(scalar):>=1. Number of participants with any lab abnormality meeting pre-specified criteria are reported.

Vital signs including blood pressure (diastolic blood pressure [DBP], systolic blood pressure [SBP], and pulse rate [PR]) were measured in a supine position using automated devices. DBP included value < 50 (mmHg), change >=20 (mmHg) increase and change >=20 (mmHg) decrease; SBP: value < 90 (mmHg), change >= 30 (mmHg) increase and PR: value > 120 (bpm).

Single twelve lead ECGs were obtained using an automated ECG machine after participant had rested quietly for at least 10 minutes in a supine position. QTc prolongations were defined as a QTc greater than or equal to (>=)480 milli second (msec) or an absolute change in QTc greater than (>)60 msec. Clinically significant ECG findings were determined by the investigator.

An AE was any untoward medical occurrence in a study participant administered a study intervention; the event need not necessarily have a causal relationship with the treatment or usage. An AE was considered TEAE to a given treatment if the event started during the effective duration of treatment regardless of whether a similar event of equal or greater severity existed in the baseline period.

A SAE was any untoward medical occurrence at any dose that: resulted in death; was life-threatening (immediate risk of death); required inpatient hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity (substantial disruption of the ability to conduct normal life functions) or resulted in congenital anomaly/birth defect or was considered an important medical event. An SAE was considered as TESAE if the event started during the effective duration of treatment regardless of whether a similar event of equal or greater severity existed in the baseline period.

An AE was any untoward medical occurrence in a study participant administered a study intervention; the event need not necessarily have a causal relationship with the treatment or usage. Discontinuations from study due to TEAEs were defined as participants with an AE record indicating the AE caused permanent discontinuation from the study but action taken with study treatment was not drug withdrawn. Permanent discontinuations from any study intervention due to TEAEs were defined as participants with an AE record indicating that action taken with study treatment was drug withdrawn. In this outcome measure number of participants with discontinuation from study due to AEs and permanent discontinuation from study intervention due to AEs are reported.

Participants were monitored for development of any infection (viral, bacterial and fungal). Serious infections were treated infections that required parenteral antimicrobial therapy and were present with positive pre-treatment culture and required hospitalization for treatment/met other criteria that required the infection to be classified as SAE. An SAE was any untoward medical occurrence at any dose that: resulted in death; is life-threatening; requires inpatient hospitalization/prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity/results in congenital anomaly/birth defect. Treated infections were infections that required antimicrobial therapy by any route of administration/required any surgical intervention (e.g., incision and drainage).

CMEI was defined as reduction of >=3 points from baseline in SES-CD score as assessed by centrally read SES-CD score. Baseline: last measurement prior to first dosing on Day1. Following bowel segments were used for calculating SES-CD scores: Ileum, right C, transverse C, left C and rectum. Each segment assessed for 4 domains: presence of ulcers, ulcerated surface, affected surface and presence of narrowing, each scored on scale of 0-3, higher scores indicated more severe condition. Presence of ulcers score: 0=none,1=small ulcer: (0.1-0.5cm),2=Large ulcer(0.5-2cm),3=very large ulcer(>2cm); ulcerated surface score: 0=none,1=<10%,2=10-30% and 3=>30%; affected surface score: 0=unaffected segment, 1=<50%, 2=50-75% and 3=>75%; presence of narrowing score: 0=none,1=single, can be passed, 2=multiple, can be passed and 3=cannot be passed. Total SES CD score was determined by sum of each domain score for all 5 bowel segments and ranged from 0 to 60, higher score indicating more severe disease.

Mean change from baseline in SES-CD score at Week 12 analyzed using analysis of covariance(ANCOVA)model with treatment,baseline disease activity/extent as factors, baseline SES CD score as covariate. Baseline=last measurement prior to first dosing on Day 1. Following bowel segments used for calculating SES-CD scores: Ileum,right C,transverse C,left C,rectum. Each segment assessed for four domains:presence of ulcers, ulcerated surface, affected surface,presence of narrowing, each score on a scale of 0-3,higher scores=more severe condition. Presence of ulcers score:0=none,1=small ulcer:(0.1-0.5cm),2=large ulcer(0.5-2cm),3=very large ulcer(>2 cm);ulcerated surface score:0=none,1=<10%,2=10-30%,3=>30%;affected surface score:0=unaffected segment,1=<50%, 2=50-75%,3=>75%;presence of narrowing score:0=none,1=single,can be passed,2=multiple can be passed,3=cannot be passed. Total SES CD score=sum of each domain score for all 5 bowel segments,range from 0 to 60,higher score =more severe disease.

SES CD25 was defined as >=25% improvement from baseline in SES CD. Baseline was defined as the last measurement prior to first dosing on Day 1. Following bowel segments were used for calculating SES-CD scores: Ileum, right C, transverse C, left C and rectum. Each segment assessed for four domains: presence of ulcers, ulcerated surface, affected surface and presence of narrowing, each scored on a scale of 0 to 3, higher scores indicated more severe condition. Presence of ulcers score: 0=none, 1=small ulcer: (0.1-0.5 centimeter[cm]), 2=Large ulcer(0.5-2 cm), 3=very large ulcer(>2 cm); ulcerated surface score: 0=none, 1=<10%, 2=10-30% and 3=>30%; affected surface score: 0=unaffected segment, 1=<50%, 2=50-75% and 3=>75%; presence of narrowing score: 0=none,1=single, can be passed, 2=multiple, can be passed and 3=cannot be passed. Total SES CD score was determined by sum of each domain score for all 5 bowel segments and ranged from 0 to 60, higher score indicating more severe disease.

Endoscopic remission was defined as SES-CD score of <= 2. Following bowel segments were used for calculating SES-CD scores: Ileum, right colon(C), transverse C, left C and rectum. Each segment assessed for four domains: presence of ulcers, ulcerated surface, affected surface and presence of narrowing, each scored on a scale of 0 to 3, higher scores indicated more severe condition. Presence of ulcers score: 0=none, 1=small ulcer: (0.1-0.5 centimeter[cm]), 2=Large ulcer(0.5-2 cm), 3=very large ulcer(>2 cm); ulcerated surface score: 0=none, 1=<10%, 2=10-30% and 3=>30%; affected surface score: 0=unaffected segment, 1=<50%, 2=50-75% and 3=>75%; presence of narrowing score: 0=none,1=single, can be passed, 2=multiple, can be passed and 3=cannot be passed. Total SES CD score was determined by sum of each domain score for all 5 bowel segments and ranged from 0 to 60, higher score indicating more severe disease.

Mucosal healing was defined as complete absence of ulcers.

CMEI was defined as reduction of >=3 points from baseline as assessed by centrally read SES CD score. Baseline: last measurement prior to first dosing on Day 1 of Week 12. Following bowel segments were used for calculating SES-CD scores: Ileum, right C, transverse C, left C and rectum. Each segment assessed for four domains: presence of ulcers, ulcerated surface, affected surface and presence of narrowing, each scored on scale of 0-3, higher scores indicated more severe condition. Presence of ulcers score: 0=none,1=small ulcer: (0.1-0.5 cm),2=Large ulcer(0.5-2 cm),3=very large ulcer(>2 cm); ulcerated surface score: 0=none,1=<10%, 2=10-30% and 3=>30%; affected surface score: 0=unaffected segment, 1=<50%, 2=50-75% and 3=>75%; presence of narrowing score: 0=none,1=single, can be passed, 2=multiple, can be passed and 3=cannot be passed. Total SES CD score was determined by sum of each domain score for all 5 bowel segments and ranged from 0-60, higher score indicating more severe disease.

SES CD50 and SES CD25: 50% and 25% improvement from baseline, respectively. Baseline: last measurement prior to first dosing on Day 1 of Week 12. Following bowel segments were used for calculating SES-CD scores: Ileum, right C, transverse C, left C and rectum. Each segment assessed for four domains: presence of ulcers, ulcerated surface, affected surface and presence of narrowing, each scored on a scale of 0 to 3, higher scores indicated more severe condition. Presence of ulcers score: 0=none, 1=small ulcer: (0.1-0.5 cm), 2=Large ulcer(0.5-2 cm), 3=very large ulcer(>2 cm); ulcerated surface score: 0=none, 1=<10%, 2=10-30% and 3=>30%; affected surface score: 0=unaffected segment, 1=<50%, 2=50-75% and 3=>75%; presence of narrowing score: 0=none,1=single, can be passed, 2=multiple, can be passed and 3=cannot be passed. Total SES CD score was determined by sum of each domain score for all 5 bowel segments and ranged from 0 to 60, higher score indicating more severe disease.