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Clinical Trial Results:
A Phase 2a, Double-Blind, Randomized, Placebo-Controlled, Parallel Group Study to Evaluate the Efficacy and Safety of Oral PF-06651600 and PF-06700841 as Induction and Open Label Extension Treatment in Subjects With Moderate to Severe Crohn’s Disease

Summary
EudraCT number	2017-003359-43
Trial protocol	LT DE SK AT PL HU ES CZ BE HR IT
Global end of trial date	19 Oct 2023

Results information
Results version number	v1(current)
This version publication date	23 Oct 2024
First version publication date	23 Oct 2024
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

Top of page

Sponsor protocol code

B7981007

ISRCTN number

-

US NCT number

NCT03395184

WHO universal trial number (UTN)

-

Other trial identifiers

PIZZICATO: Other Study ID

Sponsor organisation name

Pfizer Inc.

Sponsor organisation address

235 E 42nd Street, New York, United States, NY 10017

Public contact

Pfizer ClinicalTrials.gov Call Center, Pfizer Inc., 001 8007181021, ClinicalTrials.gov_Inquiries@pfizer.com

Scientific contact

Pfizer ClinicalTrials.gov Call Center, Pfizer Inc., 001 8007181021, ClinicalTrials.gov_Inquiries@pfizer.com

Is trial part of an agreed paediatric investigation plan (PIP)

No

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

No

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

No

Analysis stage

Final

Date of interim/final analysis

06 Apr 2024

Is this the analysis of the primary completion data?

No

Global end of trial reached?

Yes

Global end of trial date

19 Oct 2023

Was the trial ended prematurely?

No

Main objective of the trial

Induction Period: To evaluate the efficacy of PF-06651600 (ritlecitinib) and PF-06700841 (brepocitinib) compared to placebo at Week 12 in participants with moderate to severe Crohn’s disease (CD). Open label extension (OLE) period: To assess the safety and tolerability of PF-06651600 and PF-06700841 therapy during open label extension period for subjects with moderate to severe CD.

Protection of trial subjects

The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Council for Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. All the local regulatory requirements pertinent to safety of trials subjects were followed.

Background therapy

-

Evidence for comparator

-

Actual start date of recruitment

02 Feb 2018

Long term follow-up planned

No

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Australia: 5

Country: Number of subjects enrolled

Bosnia and Herzegovina: 1

Country: Number of subjects enrolled

Canada: 4

Country: Number of subjects enrolled

Czechia: 6

Country: Number of subjects enrolled

Germany: 16

Country: Number of subjects enrolled

Georgia: 3

Country: Number of subjects enrolled

Hungary: 2

Country: Number of subjects enrolled

Italy: 15

Country: Number of subjects enrolled

Belgium: 9

Country: Number of subjects enrolled

Saudi Arabia: 1

Country: Number of subjects enrolled

Spain: 9

Country: Number of subjects enrolled

Lebanon: 7

Country: Number of subjects enrolled

Austria: 2

Country: Number of subjects enrolled

Korea, Republic of: 15

Country: Number of subjects enrolled

Poland: 39

Country: Number of subjects enrolled

Serbia: 4

Country: Number of subjects enrolled

South Africa: 2

Country: Number of subjects enrolled

Tunisia: 1

Country: Number of subjects enrolled

Türkiye: 6

Country: Number of subjects enrolled

Russian Federation: 24

Country: Number of subjects enrolled

Slovakia: 8

Country: Number of subjects enrolled

Switzerland: 4

Country: Number of subjects enrolled

Ukraine: 9

Country: Number of subjects enrolled

United Arab Emirates: 1

Country: Number of subjects enrolled

United States: 51

Worldwide total number of subjects

244

EEA total number of subjects

106

Number of subjects enrolled per age group

In utero

0

Preterm newborn - gestational age < 37 wk

0

Newborns (0-27 days)

0

Infants and toddlers (28 days-23 months)

0

Children (2-11 years)

0

Adolescents (12-17 years)

0

Adults (18-64 years)

240

From 65 to 84 years

4

85 years and over

0

Subject disposition

Top of page

Recruitment details

The study consisted of a 12-weeks induction period and a 52-weeks open label extension (OLE) period. The participants who completed induction period, entered the 52-week OLE period.

Screening details

A total of 645 participants were screened across 26 countries of which 401 were screen failures and 244 participants were randomized in the study.

Period 1 title

Induction Period (Up to 12 weeks)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator

Are arms mutually exclusive

Yes

Induction Period: Placebo QD

Arm description

Participants received placebo matched to either PF-06651600 (ritlecitinib) or PF-06700841 (brepocitinib) once daily (QD) orally for 12 weeks in induction period.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Single dose of placebo QD orally for 12 weeks.

Induction period: Ritlecitinib 200 mg/50 mg QD

Arm description

Participants received PF-06651600 (ritlecitinib) 200 milligrams (mg) once daily orally for 8 weeks followed by ritlecitinib 50 mg QD orally for 4 weeks in induction period.

Arm type

Experimental

Investigational medicinal product name

Ritlecitinib

Investigational medicinal product code

PF-06651600

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Single dose of PF-06651600 (ritlecitinib) 200 mg QD orally for 8 weeks followed by ritlecitinib 50 mg QD orally for 4 weeks administered as 50 mg tablets.

Induction period: Brepocitinib 60 mg QD

Arm description

Participants received PF-06700841 (brepocitinib) 60 mg QD orally for 12 weeks in induction period.

Arm type

Experimental

Investigational medicinal product name

Brepocitinib

Investigational medicinal product code

PF-06700841

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Single dose of PF-06700841 (brepocitinib) 60 mg QD orally for 12 weeks administered as 25 mg and 5 mg tablets.

Number of subjects in period 1	Induction Period: Placebo QD	Induction period: Ritlecitinib 200 mg/50 mg QD	Induction period: Brepocitinib 60 mg QD
Started	79	93	72
Completed	68	84	65
Not completed	11	9	7
Consent withdrawn by subject	2	2	-
Adverse events	6	4	4
No longer met eligibility criteria	-	2	1
Unspecified	1	-	-
Lost to follow-up	-	1	-
Lack of efficacy	2	-	2

Period 2 title

OLE Period (Up to 52 weeks)

Is this the baseline period?

No

Allocation method

Non-randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

OLE Period: Placebo QD -> Ritlecitinib 50 mg QD

Arm description

Participants who received placebo matched to ritlecitinib during the induction period were administered ritlecitinib 50 mg QD orally for 52 weeks in OLE period.

Arm type

Experimental

Investigational medicinal product name

Ritlecitinib

Investigational medicinal product code

PF-06651600

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Single dose of PF-06651600 (ritlecitinib) 50 mg QD orally for 52 weeks

OLE Period: Ritlecitinib 200 mg/50mgQD->Ritlecitinib 50mgQD

Arm description

Participants who received ritlecitinib 200 mg /50 mg QD in the induction period continued to receive ritlecitinib 50 mg QD for 52 weeks in OLE period.

Arm type

Experimental

Investigational medicinal product name

Ritlecitinib

Investigational medicinal product code

PF-06651600

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Single dose of PF-06651600 (ritlecitinib) 50 mg QD orally for 52 weeks administered as 50 mg tablets.

OLE Period: Placebo QD -> Brepocitinib 30 mg QD

Arm description

Participants who received placebo matched to brepocitinib in the induction period were administered brepocitinib 30 mg QD orally for 52 weeks in OLE period.

Arm type

Experimental

Investigational medicinal product name

Brepocitinib

Investigational medicinal product code

PF-06700841

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Single dose of PF-06700841 (brepocitinib) 30 mg QD orally for 52 weeks administered as 25 mg and 5 mg tablets.

OLE Period: Brepocitinib 60 mg QD -> Brepocitinib 30 mg QD

Arm description

Participants who received brepocitinib 60 mg QD in the induction period were administered brepocitinib 30 mg QD for 52 weeks in OLE period.

Arm type

Experimental

Investigational medicinal product name

Brepocitinib

Investigational medicinal product code

PF-06700841

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Single dose of PF-06700841 (brepocitinib) 30 mg QD orally for 12 weeks administered as 25 mg and 5 mg tablets.

Number of subjects in period 2 ^[1]	OLE Period: Placebo QD -> Ritlecitinib 50 mg QD	OLE Period: Ritlecitinib 200 mg/50mgQD->Ritlecitinib 50mgQD	OLE Period: Placebo QD -> Brepocitinib 30 mg QD	OLE Period: Brepocitinib 60 mg QD -> Brepocitinib 30 mg QD
Started	36	84	32	64
Completed	20	45	21	34
Not completed	16	39	11	30
Consent withdrawn by subject	3	11	3	8
Adverse events	7	13	4	15
No longer met eligibility criteria	1	-	1	-
Unspecified	-	2	-	2
Lost to follow-up	-	2	-	-
Lack of efficacy	5	11	3	5

Notes
[1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
Justification: Not all participants chose to participate in the extension phase

Baseline characteristics

Top of page

Reporting group title

Induction Period: Placebo QD

Reporting group description

Participants received placebo matched to either PF-06651600 (ritlecitinib) or PF-06700841 (brepocitinib) once daily (QD) orally for 12 weeks in induction period.

Reporting group title

Induction period: Ritlecitinib 200 mg/50 mg QD

Reporting group description

Participants received PF-06651600 (ritlecitinib) 200 milligrams (mg) once daily orally for 8 weeks followed by ritlecitinib 50 mg QD orally for 4 weeks in induction period.

Reporting group title

Induction period: Brepocitinib 60 mg QD

Reporting group description

Participants received PF-06700841 (brepocitinib) 60 mg QD orally for 12 weeks in induction period.

Reporting group values	Induction Period: Placebo QD	Induction period: Ritlecitinib 200 mg/50 mg QD	Induction period: Brepocitinib 60 mg QD	Total
Number of subjects	79	93	72	244
Age categorical
Units: Subjects
In utero	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0
Newborns (0-27 days)	0	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0	0
Children (2-11 years)	0	0	0	0
Adolescents (12-17 years)	0	0	0	0
Adults (18-64 years)	77	92	71	240
From 65-84 years	2	1	1	4
85 years and over	0	0	0	0
Age Continuous
Units: Years
arithmetic mean (standard deviation)	36.1 ( 13.03 )	34.6 ( 10.64 )	36.5 ( 12.70 )	-
Sex: Female, Male
Units: Participants
Female	37	41	29	107
Male	42	52	43	137
Race
Units: Subjects
White	71	84	61	216
Black or African American	0	0	2	2
Asian	5	6	7	18
Multiracial	1	1	1	3
Not reported	2	2	1	5
Ethinicity
Units: Subjects
Hispanic or Latino	2	1	1	4
Not Hispanic or Latino	75	91	69	235
Not reported	2	1	2	5

End points

Top of page

Reporting group title

Induction Period: Placebo QD

Reporting group description

Participants received placebo matched to either PF-06651600 (ritlecitinib) or PF-06700841 (brepocitinib) once daily (QD) orally for 12 weeks in induction period.

Reporting group title

Induction period: Ritlecitinib 200 mg/50 mg QD

Reporting group description

Participants received PF-06651600 (ritlecitinib) 200 milligrams (mg) once daily orally for 8 weeks followed by ritlecitinib 50 mg QD orally for 4 weeks in induction period.

Reporting group title

Induction period: Brepocitinib 60 mg QD

Reporting group description

Participants received PF-06700841 (brepocitinib) 60 mg QD orally for 12 weeks in induction period.

Reporting group title

OLE Period: Placebo QD -> Ritlecitinib 50 mg QD

Reporting group description

Participants who received placebo matched to ritlecitinib during the induction period were administered ritlecitinib 50 mg QD orally for 52 weeks in OLE period.

Reporting group title

OLE Period: Ritlecitinib 200 mg/50mgQD->Ritlecitinib 50mgQD

Reporting group description

Participants who received ritlecitinib 200 mg /50 mg QD in the induction period continued to receive ritlecitinib 50 mg QD for 52 weeks in OLE period.

Reporting group title

OLE Period: Placebo QD -> Brepocitinib 30 mg QD

Reporting group description

Participants who received placebo matched to brepocitinib in the induction period were administered brepocitinib 30 mg QD orally for 52 weeks in OLE period.

Reporting group title

OLE Period: Brepocitinib 60 mg QD -> Brepocitinib 30 mg QD

Reporting group description

Participants who received brepocitinib 60 mg QD in the induction period were administered brepocitinib 30 mg QD for 52 weeks in OLE period.

Primary: Percentage of Participants Achieving Greater Than or Equal to (>=) 50 Percent (%) Reduction in Simple Endoscopic Score for Crohn’s Disease (SES CD50) at Week 12: Induction Period

Top of page

End point title

Percentage of Participants Achieving Greater Than or Equal to (>=) 50 Percent (%) Reduction in Simple Endoscopic Score for Crohn’s Disease (SES CD50) at Week 12: Induction Period

End point description

SES CD50: 50% improvement from baseline(B) in SES-CD. B: last measurement prior to first dosing on Day1. Following bowel segments(S) were used: Ileum, right colon(C),transverse C, left C & rectum. Each S assessed for 4 domains: presence of ulcers(U), Ulcerated surface,affected surface & presence of narrowing,each scored on scale; 0-3. Presence of U score: 0=none,1=small U:(0.1-0.5cm),2=Large U(0.5-2cm),3=very large U(>2cm); Uted surface score:0=none,1=<10%,2=10-30%&3=>30%; affected surface score: 0=unaffected S,1=<50%,2=50-75%&3=>75%;presence of narrowing score:0=none,1=single,can be passed(CNB), 2=multiple,CNB&3=cannot be passed.Total SES CD score determined by sum of each domain score for all 5 bowel S, ranged;0-60,higher score=more severe disease. FAS=all randomized participants who received at least one dose of randomized investigational drug. Participants who received placebo in induction period were analyzed as single reporting group. N=participants evaluable for this endpoint.

End point type

Primary

End point timeframe

Week 12

End point values	Induction Period: Placebo QD	Induction period: Ritlecitinib 200 mg/50 mg QD	Induction period: Brepocitinib 60 mg QD
Number of subjects analysed	78	92	71
Units: Percentage of participants
number (confidence interval 90%)	12.8 (7.1 to 19.9)	27.2 (19.6 to 35.7)	33.8 (25.1 to 43.1)

Placebo QD versus Brepocitinib 60 mg QD

Statistical analysis description

Analysis: Cochran Mantel Hansel (CMH) with test treatment & baseline disease activity/extent as factors, & baseline SES-CD score as covariate.

Comparison groups

Induction Period: Placebo QD v Induction period: Brepocitinib 60 mg QD

Number of subjects included in analysis

149

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0012

Method

Min risk weight method(Mehrotra&Railkar)

Parameter type

Percentage risk difference

Point estimate

21.4

Confidence interval

level

90%

sides

2-sided

lower limit

10

upper limit

32.9

Placebo QD versus Ritlecitinib 200 mg/50 mg QD

Statistical analysis description

Analysis: Cochran Mantel Hansel (CMH) with test treatment & baseline disease activity/extent as factors, & baseline SES-CD score as covariate.

Comparison groups

Induction Period: Placebo QD v Induction period: Ritlecitinib 200 mg/50 mg QD

Number of subjects included in analysis

170

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0119

Method

Min risk weight method(Mehrotra-Railkar)

Parameter type

Percentage risk difference

Point estimate

14.3

Confidence interval

level

90%

sides

2-sided

lower limit

4

upper limit

24.5

Primary: Number of Participants With Laboratory Test Abnormalities During OLE Period

Top of page

End point title

Number of Participants With Laboratory Test Abnormalities During OLE Period ^[1]

End point description

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. 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. Safety analysis set(SAS)=participants who received at least one dose of the investigational drug. N=participants evaluable for this endpoint.

End point type

Primary

End point timeframe

From start of study intervention in OLE period up to 4 weeks after last dose of study intervention (up to 56 weeks)

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analysis was planned for this endpoint

End point values	OLE Period: Placebo QD -> Ritlecitinib 50 mg QD	OLE Period: Ritlecitinib 200 mg/50mgQD->Ritlecitinib 50mgQD	OLE Period: Placebo QD -> Brepocitinib 30 mg QD	OLE Period: Brepocitinib 60 mg QD -> Brepocitinib 30 mg QD
Number of subjects analysed	36	83	32	63
Units: Participants	33	76	26	56

No statistical analyses for this end point

Primary: Number of Participants According to Categorization of Vital Signs During OLE Period

Top of page

End point title

Number of Participants According to Categorization of Vital Signs During OLE Period ^[2]

End point description

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]). SAS included all those participants who received at least one dose of the investigational drug (ritlecitinib, brepocitinib, or placebo). Here, Number of Participants Analyzed signifies participants evaluable for this endpoint.

End point type

Primary

End point timeframe

From start of study intervention in OLE period up to 4 weeks after last dose of study intervention (up to 56 weeks)

Notes
[2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analysis was planned for this endpoint

End point values	OLE Period: Placebo QD -> Ritlecitinib 50 mg QD	OLE Period: Ritlecitinib 200 mg/50mgQD->Ritlecitinib 50mgQD	OLE Period: Placebo QD -> Brepocitinib 30 mg QD	OLE Period: Brepocitinib 60 mg QD -> Brepocitinib 30 mg QD
Number of subjects analysed	36	83	32	63
Units: Participants
DBP; value < 50 (mmHg)	0	2	0	1
DBP; change >=20 (mmHg) increase	4	6	2	6
DBP; change >=20 (mmHg) decrease	1	4	3	8
PR; value > 120 (bpm)	0	1	0	0
SBP; value < 90 (mmHg)	0	2	0	1
SBP; change >= 30 (mmHg) increase	1	2	0	5
SBP; change >= 30 (mmHg) decrease	3	0	3	2

No statistical analyses for this end point

Primary: Number of Participants With Abnormal Clinically Significant Electrocardiogram Findings During OLE Period

Top of page

End point title

Number of Participants With Abnormal Clinically Significant Electrocardiogram Findings During OLE Period ^[3]

End point description

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. SAS included all those participants who received at least one dose of the investigational drug (ritlecitinib, brepocitinib, or placebo). Here, Number of Participants Analyzed signifies participants evaluable for this endpoint.

End point type

Primary

End point timeframe

From start of study intervention in OLE period up to 4 weeks after last dose of study intervention (up to 56 weeks)

Notes
[3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analysis was planned for this endpoint

End point values	OLE Period: Placebo QD -> Ritlecitinib 50 mg QD	OLE Period: Ritlecitinib 200 mg/50mgQD->Ritlecitinib 50mgQD	OLE Period: Placebo QD -> Brepocitinib 30 mg QD	OLE Period: Brepocitinib 60 mg QD -> Brepocitinib 30 mg QD
Number of subjects analysed	23	50	21	40
Units: Participants	0	0	0	1

No statistical analyses for this end point

Primary: Number of Participants With Treatment Emergent Adverse Events (TEAEs) During OLE Period

Top of page

End point title

Number of Participants With Treatment Emergent Adverse Events (TEAEs) During OLE Period ^[4]

End point description

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. SAS included all those participants who received at least one dose of the investigational drug (ritlecitinib, brepocitinib, or placebo).

End point type

Primary

End point timeframe

From start of study intervention in OLE period up to 4 weeks after last dose of study intervention (up to 56 weeks)

Notes
[4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analysis was planned for this endpoint

End point values	OLE Period: Placebo QD -> Ritlecitinib 50 mg QD	OLE Period: Ritlecitinib 200 mg/50mgQD->Ritlecitinib 50mgQD	OLE Period: Placebo QD -> Brepocitinib 30 mg QD	OLE Period: Brepocitinib 60 mg QD -> Brepocitinib 30 mg QD
Number of subjects analysed	36	84	32	64
Units: Participants	32	58	25	54

No statistical analyses for this end point

Primary: Number of Participants With Treatment Emergent Serious Adverse Events (TESAE) During OLE Period

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End point title

Number of Participants With Treatment Emergent Serious Adverse Events (TESAE) During OLE Period ^[5]

End point description

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. SAS included all those participants who received at least one dose of the investigational drug (ritlecitinib, brepocitinib, or placebo).

End point type

Primary

End point timeframe

From start of study intervention in OLE period up to 4 weeks after last dose of study intervention (up to 56 weeks)

Notes
[5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analysis was planned for this endpoint

End point values	OLE Period: Placebo QD -> Ritlecitinib 50 mg QD	OLE Period: Ritlecitinib 200 mg/50mgQD->Ritlecitinib 50mgQD	OLE Period: Placebo QD -> Brepocitinib 30 mg QD	OLE Period: Brepocitinib 60 mg QD -> Brepocitinib 30 mg QD
Number of subjects analysed	36	84	32	64
Units: Participants	6	10	5	16

No statistical analyses for this end point

Primary: Number of Participants With Discontinuations due to Adverse Events During OLE Period

Top of page

End point title

Number of Participants With Discontinuations due to Adverse Events During OLE Period ^[6]

End point description

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 endpoint number of participants with discontinuation from study due to AEs and permanent discontinuation from study intervention due to AEs are reported. SAS included all those participants who received at least one dose of the investigational drug (ritlecitinib, brepocitinib, or placebo).

End point type

Primary

End point timeframe

From start of study intervention in OLE period up to 4 weeks after last dose of study intervention (up to 56 weeks)

Notes
[6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analysis was planned for this endpoint

End point values	OLE Period: Placebo QD -> Ritlecitinib 50 mg QD	OLE Period: Ritlecitinib 200 mg/50mgQD->Ritlecitinib 50mgQD	OLE Period: Placebo QD -> Brepocitinib 30 mg QD	OLE Period: Brepocitinib 60 mg QD -> Brepocitinib 30 mg QD
Number of subjects analysed	36	84	32	64
Units: Participants
Discontinuation from study due to TEAEs	0	1	0	0
PD from any study intervention due to TEAEs	7	13	4	15

No statistical analyses for this end point

Secondary: Number of Participants With Laboratory Test Abnormalities During Induction Period

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End point title

Number of Participants With Laboratory Test Abnormalities During Induction Period

End point description

Pre-specified criteria for lab abnormalities included- hematology: hemoglobin(Hb), erythrocytes(ery), hematocrit:<0.8*LLN; reticulocytes: <0.5*LLN, >1.5*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. 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. SAS was used. Participants who received placebo in induction period were analyzed as a single reporting group. N=participants evaluable for this endpoint.

End point type

Secondary

End point timeframe

From start of study intervention on Day 1 up to Week 12

End point values	Induction Period: Placebo QD	Induction period: Ritlecitinib 200 mg/50 mg QD	Induction period: Brepocitinib 60 mg QD
Number of subjects analysed	78	92	72
Units: Participants	67	72	61

No statistical analyses for this end point

Secondary: Number of Participants According to Categorization of Vital Signs During Induction Period

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End point title

Number of Participants According to Categorization of Vital Signs During Induction Period

End point description

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). SAS included all those participants who received at least one dose of the investigational drug (ritlecitinib, brepocitinib, or placebo). Participants who received placebo in induction period were analyzed as a single reporting group. Here, n= number of participants evaluable for specific rows.

End point type

Secondary

End point timeframe

From start of study intervention on Day 1 up to Week 12

End point values	Induction Period: Placebo QD	Induction period: Ritlecitinib 200 mg/50 mg QD	Induction period: Brepocitinib 60 mg QD
Number of subjects analysed	79	93	72
Units: Participants
DBP; value < 50 (mmHg) (n=79,93,72)	1	0	0
DBP; change >=20 (mmHg) increase (n=78,92,72)	4	2	4
DBP; change >=20 (mmHg) decrease (n=78,92,72)	4	2	4
Pulse rate; value > 120 (bpm) (n=79,93,72)	4	1	0
SBP; value < 90 (mmHg) (n=79,93,72)	0	3	0
SBP; change >= 30 (mmHg) increase (n=78,92,72)	3	2	7
SBP; change >= 30 (mmHg) decrease (n=78,92,72)	0	0	0

No statistical analyses for this end point

Secondary: Number of Participants With Abnormal Clinically Significant Electrocardiogram Findings During Induction Period

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End point title

Number of Participants With Abnormal Clinically Significant Electrocardiogram Findings During Induction Period

End point description

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. SAS included all those participants who received at least one dose of the investigational drug (ritlecitinib, brepocitinib, or placebo). Participants who received placebo in induction period were analyzed as a single reporting group. Here Number of Participants Analyzed signifies number of participants evaluable for this endpoint.

End point type

Secondary

End point timeframe

From start of study intervention on Day 1 up to Week 12

End point values	Induction Period: Placebo QD	Induction period: Ritlecitinib 200 mg/50 mg QD	Induction period: Brepocitinib 60 mg QD
Number of subjects analysed	68	83	63
Units: Participants	1	0	0

No statistical analyses for this end point

Secondary: Number of Participants With Treatment Emergent Adverse Events (TEAEs) During Induction Period

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End point title

Number of Participants With Treatment Emergent Adverse Events (TEAEs) During Induction Period

End point description

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. SAS included all those participants who received at least one dose of the investigational drug (ritlecitinib, brepocitinib, or placebo). Participants who received placebo in induction period were analyzed as a single reporting group.

End point type

Secondary

End point timeframe

From start of study intervention on Day 1 up to Week 12

End point values	Induction Period: Placebo QD	Induction period: Ritlecitinib 200 mg/50 mg QD	Induction period: Brepocitinib 60 mg QD
Number of subjects analysed	79	93	72
Units: Participants	51	46	49

No statistical analyses for this end point

Secondary: Number of Participants With Treatment Emergent Serious Adverse Events (TESAE) During Induction Period

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End point title

Number of Participants With Treatment Emergent Serious Adverse Events (TESAE) During Induction Period

End point description

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. SAS included all those participants who received at least one dose of the investigational drug (ritlecitinib, brepocitinib, or placebo). Participants who received placebo in induction period were analyzed as a single reporting group.

End point type

Secondary

End point timeframe

From start of study intervention on Day 1 up to Week 12

End point values	Induction Period: Placebo QD	Induction period: Ritlecitinib 200 mg/50 mg QD	Induction period: Brepocitinib 60 mg QD
Number of subjects analysed	79	93	72
Units: Participants	6	4	4

No statistical analyses for this end point

Secondary: Number of Participants Discontinuation due to Adverse Events During Induction Period

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End point title

Number of Participants Discontinuation due to Adverse Events During Induction Period

End point description

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 endpoint number of participants with discontinuation from study due to AEs and permanent discontinuation from study intervention due to AEs are reported. SAS included all those participants who received at least one dose of the investigational drug (ritlecitinib, brepocitinib, or placebo). Participants who received placebo in induction period were analyzed as a single reporting group.

End point type

Secondary

End point timeframe

From start of study intervention on Day 1 up to Week 12

End point values	Induction Period: Placebo QD	Induction period: Ritlecitinib 200 mg/50 mg QD	Induction period: Brepocitinib 60 mg QD
Number of subjects analysed	79	93	72
Units: Participants
Discontinuations from study due to TEAEs	0	1	0
PD from any study intervention due to TEAEs	6	4	4

No statistical analyses for this end point

Secondary: Number of Participants With Serious Infections During Induction Period

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End point title

Number of Participants With Serious Infections During Induction Period

End point description

Participants were monitored for development of any infection (viral, bacterial & 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 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). SAS was used for analysis. Participants who received placebo in induction period were analyzed as a single reporting group.

End point type

Secondary

End point timeframe

From start of study intervention on Day 1 up to Week 12

End point values	Induction Period: Placebo QD	Induction period: Ritlecitinib 200 mg/50 mg QD	Induction period: Brepocitinib 60 mg QD
Number of subjects analysed	79	93	72
Units: Participants	0	1	2

No statistical analyses for this end point

Secondary: Percentage of Participants who Achieved Clinically Meaningful Endoscopic Improvement (CMEI) (Reduction of >=3 Points From Baseline in SES-CD Score) at Week 12: Induction Period

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End point title

Percentage of Participants who Achieved Clinically Meaningful Endoscopic Improvement (CMEI) (Reduction of >=3 Points From Baseline in SES-CD Score) at Week 12: Induction Period

End point description

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(U), ulcerated surface, affected surface & presence of narrowing, each scored on scale:0-3, higher scores=more severe condition. Presence of U score: 0=none,1=small U: (0.1-0.5cm),2=Large U(0.5-2cm),3=very large U(>2cm); 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 was determined by sum of each domain score for all 5 bowel segments & ranged: 0-60, higher score=more severe disease. FAS. N=participants evaluable for this endpoint.

End point type

Secondary

End point timeframe

Week 12

End point values	Induction Period: Placebo QD	Induction period: Ritlecitinib 200 mg/50 mg QD	Induction period: Brepocitinib 60 mg QD
Number of subjects analysed	78	92	71
Units: Percentage of participants
number (confidence interval 90%)	29.5 (21.7 to 38.9)	42.4 (34.2 to 51.5)	57.7 (47.6 to 67.2)

Placebo QD versus Brepocitinib 60 mg QD

Statistical analysis description

Analysis: Cochran Mantel Hansel (CMH) with test treatment & baseline disease activity/extent as factors, & baseline SES-CD score as covariate.

Comparison groups

Induction Period: Placebo QD v Induction period: Brepocitinib 60 mg QD

Number of subjects included in analysis

149

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0001

Method

Min risk weight method(Mehrotra&Railkar)

Parameter type

Percentage risk difference

Point estimate

29.7

Confidence interval

level

90%

sides

2-sided

lower limit

17.2

upper limit

42.2

Placebo QD versus Ritlecitinib 200 mg/50 mg QD

Statistical analysis description

Analysis: Cochran Mantel Hansel (CMH) with test treatment & baseline disease activity/extent as factors, & baseline SES-CD score as covariate.

Comparison groups

Induction Period: Placebo QD v Induction period: Ritlecitinib 200 mg/50 mg QD

Number of subjects included in analysis

170

Analysis specification

Pre-specified

Analysis type

P-value

= 0.039

Method

Min risk weight method(Mehrotra&Railkar)

Parameter type

Percentage risk difference

Point estimate

13.3

Confidence interval

level

90%

sides

2-sided

lower limit

1

upper limit

25.7

Secondary: Mean Change From Baseline in SES-CD Score at Week 12: Induction Period

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End point title

Mean Change From Baseline in SES-CD Score at Week 12: Induction Period

End point description

Mean change from baseline in SES-CD score: 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 4 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 U score:0=none,1=small U:(0.1-0.5cm),2=large U(0.5-2cm),3=very large U(>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,CNB,2=multiple CNB,3=cannot be passed. Total SES CD score=sum of each domain score for all 5 bowel segments,range: 0-60, higher score =more severe disease. FAS. N= participants evaluable for this endpoint.

End point type

Secondary

End point timeframe

Baseline and Week 12

End point values	Induction Period: Placebo QD	Induction period: Ritlecitinib 200 mg/50 mg QD	Induction period: Brepocitinib 60 mg QD
Number of subjects analysed	68	82	63
Units: Units on a scale
least squares mean (confidence interval 90%)	-0.1 (-1.32 to 1.12)	-3.1 (-4.22 to -2.02)	-5.0 (-6.36 to -3.72)

Placebo QD versus Brepocitinib 60 mg QD

Statistical analysis description

Analysis: ANCOVA model with treatment and baseline disease activity/extent as factors, and baseline SES CD score as a covariate.

Comparison groups

Induction Period: Placebo QD v Induction period: Brepocitinib 60 mg QD

Number of subjects included in analysis

131

Analysis specification

Pre-specified

Analysis type

P-value

< 0.0001

Method

ANCOVA

Parameter type

LS mean difference

Point estimate

-4.9

Confidence interval

level

90%

sides

2-sided

lower limit

-6.62

upper limit

-3.26

Placebo QD versus Ritlecitinib 200 mg/50 mg QD

Statistical analysis description

Analysis: Analysis of covariance (ANCOVA) model with treatment and baseline disease activity/extent as factors, and baseline SES CD score as a covariate.

Comparison groups

Induction Period: Placebo QD v Induction period: Ritlecitinib 200 mg/50 mg QD

Number of subjects included in analysis

150

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0007

Method

ANCOVA

Parameter type

LS mean difference

Point estimate

-3

Confidence interval

level

90%

sides

2-sided

lower limit

-4.55

upper limit

-1.48

Secondary: Percentage of Participants Achieving >=25% Reduction in SES-CD from Baseline (SES-CD 25) at Week 12: Induction Period

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End point title

Percentage of Participants Achieving >=25% Reduction in SES-CD from Baseline (SES-CD 25) at Week 12: Induction Period

End point description

SES CD25 was defined as >=25% improvement from baseline in SES CD. 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 a scale of 0 to 3, higher scores=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. FAS. N=participants evaluable for this endpoint.

End point type

Secondary

End point timeframe

Week 12

End point values	Induction Period: Placebo QD	Induction period: Ritlecitinib 200 mg/50 mg QD	Induction period: Brepocitinib 60 mg QD
Number of subjects analysed	78	92	71
Units: Percentage of participants
number (confidence interval 90%)	25.6 (17.7 to 34.3)	39.1 (30.6 to 47.4)	56.3 (46.2 to 66.4)

Placebo QD versus Ritlecitinib 200 mg/50 mg QD

Statistical analysis description

Analysis: CMH with test treatment & baseline disease activity/extent as factors, & baseline SES-CD score as covariate.

Comparison groups

Induction Period: Placebo QD v Induction period: Ritlecitinib 200 mg/50 mg QD

Number of subjects included in analysis

170

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0279

Method

Min risk weight method(Mehrotra&Railkar)

Parameter type

Percentage risk difference

Point estimate

13.9

Confidence interval

level

90%

sides

2-sided

lower limit

2.1

upper limit

25.6

Placebo QD versus Brepocitinib 60 mg QD

Statistical analysis description

Analysis: CMH with test treatment & baseline disease activity/extent as factors, & baseline SES-CD score as covariate.

Comparison groups

Induction Period: Placebo QD v Induction period: Brepocitinib 60 mg QD

Number of subjects included in analysis

149

Analysis specification

Pre-specified

Analysis type

P-value

< 0.0001

Method

Min risk weight method(Mehrotra&Railkar)

Parameter type

Percentage risk difference

Point estimate

31.5

Confidence interval

level

90%

sides

2-sided

lower limit

19.1

upper limit

43.9

Secondary: Percentage of Participants Achieving Endoscopic Remission at Week 12: Induction Period

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End point title

Percentage of Participants Achieving Endoscopic Remission at Week 12: Induction Period

End point description

Endoscopic remission was defined as SES-CD score of <= 2. 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. FAS. N=participants evaluable for this endpoint.

End point type

Secondary

End point timeframe

Week 12

End point values	Induction Period: Placebo QD	Induction period: Ritlecitinib 200 mg/50 mg QD	Induction period: Brepocitinib 60 mg QD
Number of subjects analysed	78	92	71
Units: Percentage of participants
number (confidence interval 90%)	5.1 (2.3 to 11.2)	7.6 (4.0 to 13.2)	12.7 (7.2 to 20.8)

Placebo QD versus Brepocitinib 60 mg QD

Statistical analysis description

Analysis: CMH with test treatment & baseline disease activity/extent as factors, & baseline SES-CD score as covariate.

Comparison groups

Induction Period: Placebo QD v Induction period: Brepocitinib 60 mg QD

Number of subjects included in analysis

149

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0449

Method

Min risk weight method(Mehrotra&Railkar)

Parameter type

Percentage risk difference

Point estimate

7.4

Confidence interval

level

90%

sides

2-sided

lower limit

-0.4

upper limit

15.2

Placebo QD versus Ritlecitinib 200 mg/50 mg QD

Statistical analysis description

Analysis: CMH with test treatment & baseline disease activity/extent as factors, & baseline SES-CD score as covariate.

Comparison groups

Induction Period: Placebo QD v Induction period: Ritlecitinib 200 mg/50 mg QD

Number of subjects included in analysis

170

Analysis specification

Pre-specified

Analysis type

P-value

= 0.2922

Method

Min risk weight method(Mehrotra&Railkar)

Parameter type

Percentage risk difference

Point estimate

2.5

Confidence interval

level

90%

sides

2-sided

lower limit

-4.3

upper limit

9.3

Secondary: Percentage of Participants Achieving Mucosal Healing at Week 12: Induction Period

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End point title

Percentage of Participants Achieving Mucosal Healing at Week 12: Induction Period

End point description

Mucosal healing was defined as complete absence of ulcers. FAS included all randomized participants who received at least one dose of the randomized investigational drug (ritlecitinib, brepocitinib, or placebo). Participants who received placebo in induction period were analyzed as a single reporting group. Here, Number of Participants Analyzed signifies participants evaluable for this endpoint.

End point type

Secondary

End point timeframe

Week 12

End point values	Induction Period: Placebo QD	Induction period: Ritlecitinib 200 mg/50 mg QD	Induction period: Brepocitinib 60 mg QD
Number of subjects analysed	78	92	71
Units: Percentage of participants
number (confidence interval 90%)	5.1 (2.3 to 11.2)	10.9 (6.1 to 17.7)	16.9 (10.1 to 25.8)

Placebo QD versus Brepocitinib 60 mg QD

Statistical analysis description

Analysis was performed using CMH with test treatment & baseline disease activity/extent as factors, and baseline SES CD score as a covariate.

Comparison groups

Induction Period: Placebo QD v Induction period: Brepocitinib 60 mg QD

Number of subjects included in analysis

149

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0111

Method

Percentage risk difference

Parameter type

Risk difference (RD)

Point estimate

11.8

Confidence interval

level

90%

sides

2-sided

lower limit

2.8

upper limit

20.9

Placebo QD versus Ritlecitinib 200 mg/50 mg QD

Statistical analysis description

Analysis was performed using CMH with test treatment & baseline disease activity/extent as factors, and baseline SES CD score as a covariate.

Comparison groups

Induction Period: Placebo QD v Induction period: Ritlecitinib 200 mg/50 mg QD

Number of subjects included in analysis

170

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0998

Method

Min risk weight method(Mehrotra&Railkar)

Parameter type

Percentage risk difference

Point estimate

5.8

Confidence interval

level

90%

sides

2-sided

lower limit

-1.6

upper limit

13.3

Secondary: Percentage of Participants Achieving CMEI at Week 64 Among Participants who Achieved CMEI response at Week 12 (Baseline of OLE Period): OLE Period

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End point title

Percentage of Participants Achieving CMEI at Week 64 Among Participants who Achieved CMEI response at Week 12 (Baseline of OLE Period): OLE Period

End point description

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 4 domains: presence of U, ulcerated surface, affected surface and presence of narrowing, each scored on scale of 0-3, higher scores=more severe condition. Presence of ulcers score: 0=none,1=small U: (0.1-0.5 cm),2=Large U(0.5-2 cm),3=very large U(>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, CNB, 2=multiple, CNB & 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 = more severe disease. FAS. N=participants evaluable for this endpoint.

End point type

Secondary

End point timeframe

Week 64 (Week 52 of OLE period)

End point values	OLE Period: Placebo QD -> Ritlecitinib 50 mg QD	OLE Period: Ritlecitinib 200 mg/50mgQD->Ritlecitinib 50mgQD	OLE Period: Placebo QD -> Brepocitinib 30 mg QD	OLE Period: Brepocitinib 60 mg QD -> Brepocitinib 30 mg QD
Number of subjects analysed	11	34	11	38
Units: Percentage of participants
number (confidence interval 90%)	27.3 (10.5 to 56.4)	44.1 (30.7 to 59.5)	54.5 (30.2 to 80.0)	42.1 (28.5 to 56.7)

No statistical analyses for this end point

Secondary: Percentage of Participants Achieving SES CD 25 and SES CD 50 at Week 64 Among Participants who Achieved SES CD 25 and SES CD 50 at Week 12 (Baseline of OLE Period): OLE Period

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End point title

Percentage of Participants Achieving SES CD 25 and SES CD 50 at Week 64 Among Participants who Achieved SES CD 25 and SES CD 50 at Week 12 (Baseline of OLE Period): OLE Period

End point description

SES CD50 and SES CD25: 50% & 25% improvement from baseline, respectively. Baseline: last measurement prior to first dosing on Day1 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 4 domains: presence of U, ulcerated surface, affected surface & presence of narrowing, each scored on scale of 0 to 3, higher scores=more severe condition. Presence of U score: 0=none, 1=small U: (0.1-0.5 cm), 2=Large U(0.5-2 cm), 3=very large U(>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% and 3=>75%; presence of narrowing score: 0=none,1=single, CNB, 2=multiple, CNB and 3=cannot be passed. Total SES CD score was determined by sum of each domain score for all 5 bowel segments & ranged, 0-60, higher score=more severe disease. FAS. N=participants evaluable for this endpoint & n= participants evaluable for specified rows.

End point type

Secondary

End point timeframe

Week 64 (Week 52 of OLE period)

End point values	OLE Period: Placebo QD -> Ritlecitinib 50 mg QD	OLE Period: Ritlecitinib 200 mg/50mgQD->Ritlecitinib 50mgQD	OLE Period: Placebo QD -> Brepocitinib 30 mg QD	OLE Period: Brepocitinib 60 mg QD -> Brepocitinib 30 mg QD
Number of subjects analysed	8	31	11	38
Units: Percentage of participants
number (confidence interval 90%)
SES-CD 25 (n=8,31,11,38)	25.0 (6.9 to 58.2)	41.9 (26.9 to 57.9)	54.5 (30.2 to 80.0)	42.1 (28.5 to 56.7)
SES-CD 50 (n=4,22,6,22)	25.0 (2.6 to 68.0)	36.4 (19.6 to 55.6)	50.0 (20.1 to 79.9)	36.4 (19.6 to 55.6)

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Induction Period(P): From start of study intervention on Day1 upto Week12(for maximum duration:12weeks); OLE P: From start of study intervention in OLE period (Week12) upto 4weeks after last dose of study intervention on Week64(for max. duration:56weeks)

Adverse event reporting additional description

Same event may appear as both non-SAE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and non-serious in another participants, or one participant may have experienced both serious and non-serious event during the study.

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

26.1

Reporting group title

Induction Period: Placebo QD

Reporting group description

Participants received placebo matched to either PF-06651600 (ritlecitinib) or PF-06700841 (brepocitinib) once daily (QD) orally for 12 weeks in induction period.

Reporting group title

Induction period: Ritlecitinib 200 mg/50 mg QD

Reporting group description

Participants received PF-06651600 (ritlecitinib) 200 milligrams (mg) once daily orally for 8 weeks followed by ritlecitinib 50 mg QD orally for 4 weeks in induction period.

Reporting group title

Induction period: Brepocitinib 60 mg QD

Reporting group description

Participants received PF-06700841 (brepocitinib) 60 mg QD orally for 12 weeks in induction period.

Reporting group title

OLE Period: Brepocitinib 60 mg QD -> Brepocitinib 30 mg QD

Reporting group description

Participants who received brepocitinib 60 mg QD in the induction period were administered brepocitinib 30 mg QD for 52 weeks in OLE period.

Reporting group title

OLE Period:Ritlecitinib 200 mg/50 mg QD->Ritlecitinib 50 mgQD

Reporting group description

Participants who received ritlecitinib 200 mg /50 mg QD in the induction period were administered ritlecitinib 50 mg QD for 52 weeks in OLE period.

Reporting group title

OLE Period: Placebo QD -> Brepocitinib 30 mg QD

Reporting group description

Participants who received placebo matched to brepocitinib in the induction period were administered brepocitinib 30 mg QD orally for 52 weeks in OLE period.

Reporting group title

OLE Period: Placebo QD -> Ritlecitinib 50 mg QD

Reporting group description

Participants who received placebo matched to ritlecitinib during the induction phase were administered ritlecitinib 50 mg QD orally for 52 weeks in OLE period.

Serious adverse events	Induction Period: Placebo QD	Induction period: Ritlecitinib 200 mg/50 mg QD	Induction period: Brepocitinib 60 mg QD	OLE Period: Brepocitinib 60 mg QD -> Brepocitinib 30 mg QD	OLE Period:Ritlecitinib 200 mg/50 mg QD->Ritlecitinib 50 mgQD	OLE Period: Placebo QD -> Brepocitinib 30 mg QD	OLE Period: Placebo QD -> Ritlecitinib 50 mg QD
Total subjects affected by serious adverse events
subjects affected / exposed	6 / 79 (7.59%)	4 / 93 (4.30%)	4 / 72 (5.56%)	16 / 64 (25.00%)	10 / 84 (11.90%)	5 / 32 (15.63%)	6 / 36 (16.67%)
number of deaths (all causes)	0	0	0	0	0	0	0
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Cervix carcinoma
subjects affected / exposed	0 / 79 (0.00%)	0 / 93 (0.00%)	0 / 72 (0.00%)	0 / 64 (0.00%)	0 / 84 (0.00%)	1 / 32 (3.13%)	0 / 36 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Parathyroid tumour benign
subjects affected / exposed	0 / 79 (0.00%)	0 / 93 (0.00%)	0 / 72 (0.00%)	1 / 64 (1.56%)	0 / 84 (0.00%)	0 / 32 (0.00%)	0 / 36 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Thyroid adenoma
subjects affected / exposed	0 / 79 (0.00%)	0 / 93 (0.00%)	0 / 72 (0.00%)	1 / 64 (1.56%)	0 / 84 (0.00%)	0 / 32 (0.00%)	0 / 36 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Humerus fracture
subjects affected / exposed	0 / 79 (0.00%)	0 / 93 (0.00%)	0 / 72 (0.00%)	0 / 64 (0.00%)	0 / 84 (0.00%)	1 / 32 (3.13%)	0 / 36 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Hypertension
subjects affected / exposed	0 / 79 (0.00%)	0 / 93 (0.00%)	1 / 72 (1.39%)	0 / 64 (0.00%)	0 / 84 (0.00%)	0 / 32 (0.00%)	0 / 36 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Acute myocardial infarction
subjects affected / exposed	0 / 79 (0.00%)	0 / 93 (0.00%)	0 / 72 (0.00%)	1 / 64 (1.56%)	0 / 84 (0.00%)	0 / 32 (0.00%)	0 / 36 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Lymphopenia
subjects affected / exposed	0 / 79 (0.00%)	0 / 93 (0.00%)	0 / 72 (0.00%)	0 / 64 (0.00%)	1 / 84 (1.19%)	0 / 32 (0.00%)	0 / 36 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Anaemia
subjects affected / exposed	1 / 79 (1.27%)	0 / 93 (0.00%)	0 / 72 (0.00%)	0 / 64 (0.00%)	0 / 84 (0.00%)	0 / 32 (0.00%)	1 / 36 (2.78%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Pyrexia
subjects affected / exposed	0 / 79 (0.00%)	1 / 93 (1.08%)	0 / 72 (0.00%)	0 / 64 (0.00%)	0 / 84 (0.00%)	0 / 32 (0.00%)	0 / 36 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	0 / 79 (0.00%)	0 / 93 (0.00%)	0 / 72 (0.00%)	1 / 64 (1.56%)	0 / 84 (0.00%)	0 / 32 (0.00%)	1 / 36 (2.78%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	0 / 79 (0.00%)	0 / 93 (0.00%)	0 / 72 (0.00%)	0 / 64 (0.00%)	0 / 84 (0.00%)	0 / 32 (0.00%)	1 / 36 (2.78%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Crohn's disease
subjects affected / exposed	5 / 79 (6.33%)	2 / 93 (2.15%)	0 / 72 (0.00%)	7 / 64 (10.94%)	5 / 84 (5.95%)	3 / 32 (9.38%)	3 / 36 (8.33%)
occurrences causally related to treatment / all	0 / 5	0 / 2	0 / 0	0 / 7	0 / 6	0 / 3	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Constipation
subjects affected / exposed	0 / 79 (0.00%)	0 / 93 (0.00%)	0 / 72 (0.00%)	1 / 64 (1.56%)	0 / 84 (0.00%)	0 / 32 (0.00%)	0 / 36 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ileus
subjects affected / exposed	0 / 79 (0.00%)	0 / 93 (0.00%)	0 / 72 (0.00%)	1 / 64 (1.56%)	1 / 84 (1.19%)	0 / 32 (0.00%)	0 / 36 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nausea
subjects affected / exposed	0 / 79 (0.00%)	0 / 93 (0.00%)	0 / 72 (0.00%)	0 / 64 (0.00%)	1 / 84 (1.19%)	0 / 32 (0.00%)	0 / 36 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ileus paralytic
subjects affected / exposed	0 / 79 (0.00%)	0 / 93 (0.00%)	0 / 72 (0.00%)	0 / 64 (0.00%)	1 / 84 (1.19%)	0 / 32 (0.00%)	0 / 36 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Rectal ulcer
subjects affected / exposed	0 / 79 (0.00%)	1 / 93 (1.08%)	0 / 72 (0.00%)	0 / 64 (0.00%)	0 / 84 (0.00%)	0 / 32 (0.00%)	0 / 36 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Small intestinal obstruction
subjects affected / exposed	0 / 79 (0.00%)	0 / 93 (0.00%)	0 / 72 (0.00%)	1 / 64 (1.56%)	1 / 84 (1.19%)	0 / 32 (0.00%)	0 / 36 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	0 / 79 (0.00%)	0 / 93 (0.00%)	0 / 72 (0.00%)	0 / 64 (0.00%)	1 / 84 (1.19%)	0 / 32 (0.00%)	0 / 36 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Subileus
subjects affected / exposed	0 / 79 (0.00%)	0 / 93 (0.00%)	0 / 72 (0.00%)	1 / 64 (1.56%)	0 / 84 (0.00%)	0 / 32 (0.00%)	0 / 36 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Reproductive system and breast disorders
Female genital tract fistula
subjects affected / exposed	0 / 79 (0.00%)	0 / 93 (0.00%)	0 / 72 (0.00%)	0 / 64 (0.00%)	1 / 84 (1.19%)	0 / 32 (0.00%)	0 / 36 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Musculoskeletal chest pain
subjects affected / exposed	0 / 79 (0.00%)	0 / 93 (0.00%)	1 / 72 (1.39%)	0 / 64 (0.00%)	0 / 84 (0.00%)	0 / 32 (0.00%)	0 / 36 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Abdominal abscess
subjects affected / exposed	0 / 79 (0.00%)	0 / 93 (0.00%)	0 / 72 (0.00%)	0 / 64 (0.00%)	1 / 84 (1.19%)	0 / 32 (0.00%)	0 / 36 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastritis viral
subjects affected / exposed	0 / 79 (0.00%)	0 / 93 (0.00%)	0 / 72 (0.00%)	1 / 64 (1.56%)	0 / 84 (0.00%)	0 / 32 (0.00%)	0 / 36 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cytomegalovirus infection
subjects affected / exposed	0 / 79 (0.00%)	1 / 93 (1.08%)	1 / 72 (1.39%)	0 / 64 (0.00%)	0 / 84 (0.00%)	0 / 32 (0.00%)	0 / 36 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cytomegalovirus colitis
subjects affected / exposed	0 / 79 (0.00%)	0 / 93 (0.00%)	1 / 72 (1.39%)	0 / 64 (0.00%)	0 / 84 (0.00%)	0 / 32 (0.00%)	0 / 36 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Clostridium difficile colitis
subjects affected / exposed	0 / 79 (0.00%)	0 / 93 (0.00%)	0 / 72 (0.00%)	0 / 64 (0.00%)	0 / 84 (0.00%)	0 / 32 (0.00%)	1 / 36 (2.78%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bartholin's abscess
subjects affected / exposed	0 / 79 (0.00%)	0 / 93 (0.00%)	0 / 72 (0.00%)	0 / 64 (0.00%)	1 / 84 (1.19%)	0 / 32 (0.00%)	0 / 36 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tonsillitis
subjects affected / exposed	0 / 79 (0.00%)	0 / 93 (0.00%)	0 / 72 (0.00%)	0 / 64 (0.00%)	1 / 84 (1.19%)	0 / 32 (0.00%)	0 / 36 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Kidney infection
subjects affected / exposed	0 / 79 (0.00%)	0 / 93 (0.00%)	0 / 72 (0.00%)	1 / 64 (1.56%)	0 / 84 (0.00%)	0 / 32 (0.00%)	0 / 36 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Mesenteric abscess
subjects affected / exposed	0 / 79 (0.00%)	0 / 93 (0.00%)	0 / 72 (0.00%)	0 / 64 (0.00%)	0 / 84 (0.00%)	0 / 32 (0.00%)	1 / 36 (2.78%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Induction Period: Placebo QD	Induction period: Ritlecitinib 200 mg/50 mg QD	Induction period: Brepocitinib 60 mg QD	OLE Period: Brepocitinib 60 mg QD -> Brepocitinib 30 mg QD	OLE Period:Ritlecitinib 200 mg/50 mg QD->Ritlecitinib 50 mgQD	OLE Period: Placebo QD -> Brepocitinib 30 mg QD	OLE Period: Placebo QD -> Ritlecitinib 50 mg QD
Total subjects affected by non serious adverse events
subjects affected / exposed	20 / 79 (25.32%)	20 / 93 (21.51%)	17 / 72 (23.61%)	31 / 64 (48.44%)	34 / 84 (40.48%)	19 / 32 (59.38%)	29 / 36 (80.56%)
Investigations
SARS-CoV-2 test positive
subjects affected / exposed	3 / 79 (3.80%)	6 / 93 (6.45%)	1 / 72 (1.39%)	8 / 64 (12.50%)	4 / 84 (4.76%)	4 / 32 (12.50%)	6 / 36 (16.67%)
occurrences all number	3	6	1	8	4	5	6
Blood creatinine increased
subjects affected / exposed	0 / 79 (0.00%)	0 / 93 (0.00%)	0 / 72 (0.00%)	0 / 64 (0.00%)	0 / 84 (0.00%)	2 / 32 (6.25%)	0 / 36 (0.00%)
occurrences all number	0	0	0	0	0	2	0
Vascular disorders
Hypertension
subjects affected / exposed	0 / 79 (0.00%)	0 / 93 (0.00%)	0 / 72 (0.00%)	1 / 64 (1.56%)	0 / 84 (0.00%)	0 / 32 (0.00%)	2 / 36 (5.56%)
occurrences all number	0	0	0	1	0	0	2
Nervous system disorders
Hypoaesthesia
subjects affected / exposed	0 / 79 (0.00%)	0 / 93 (0.00%)	0 / 72 (0.00%)	0 / 64 (0.00%)	0 / 84 (0.00%)	0 / 32 (0.00%)	2 / 36 (5.56%)
occurrences all number	0	0	0	0	0	0	2
Headache
subjects affected / exposed	4 / 79 (5.06%)	3 / 93 (3.23%)	5 / 72 (6.94%)	2 / 64 (3.13%)	1 / 84 (1.19%)	2 / 32 (6.25%)	1 / 36 (2.78%)
occurrences all number	4	5	5	2	6	2	1
Blood and lymphatic system disorders
Lymphopenia
subjects affected / exposed	1 / 79 (1.27%)	3 / 93 (3.23%)	4 / 72 (5.56%)	0 / 64 (0.00%)	0 / 84 (0.00%)	0 / 32 (0.00%)	0 / 36 (0.00%)
occurrences all number	1	5	7	0	0	0	0
Anaemia
subjects affected / exposed	0 / 79 (0.00%)	0 / 93 (0.00%)	0 / 72 (0.00%)	2 / 64 (3.13%)	0 / 84 (0.00%)	2 / 32 (6.25%)	3 / 36 (8.33%)
occurrences all number	0	0	0	2	0	2	3
General disorders and administration site conditions
Pyrexia
subjects affected / exposed	0 / 79 (0.00%)	0 / 93 (0.00%)	0 / 72 (0.00%)	3 / 64 (4.69%)	2 / 84 (2.38%)	1 / 32 (3.13%)	3 / 36 (8.33%)
occurrences all number	0	0	0	3	2	3	3
Peripheral swelling
subjects affected / exposed	0 / 79 (0.00%)	0 / 93 (0.00%)	0 / 72 (0.00%)	0 / 64 (0.00%)	0 / 84 (0.00%)	0 / 32 (0.00%)	2 / 36 (5.56%)
occurrences all number	0	0	0	0	0	0	2
Fatigue
subjects affected / exposed	0 / 79 (0.00%)	0 / 93 (0.00%)	0 / 72 (0.00%)	0 / 64 (0.00%)	2 / 84 (2.38%)	1 / 32 (3.13%)	3 / 36 (8.33%)
occurrences all number	0	0	0	0	2	1	4
Ear and labyrinth disorders
Tinnitus
subjects affected / exposed	0 / 79 (0.00%)	0 / 93 (0.00%)	0 / 72 (0.00%)	0 / 64 (0.00%)	1 / 84 (1.19%)	0 / 32 (0.00%)	3 / 36 (8.33%)
occurrences all number	0	0	0	0	1	0	3
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	1 / 79 (1.27%)	2 / 93 (2.15%)	4 / 72 (5.56%)	6 / 64 (9.38%)	5 / 84 (5.95%)	4 / 32 (12.50%)	4 / 36 (11.11%)
occurrences all number	1	2	4	6	6	4	4
Abdominal pain lower
subjects affected / exposed	0 / 79 (0.00%)	0 / 93 (0.00%)	0 / 72 (0.00%)	0 / 64 (0.00%)	0 / 84 (0.00%)	0 / 32 (0.00%)	2 / 36 (5.56%)
occurrences all number	0	0	0	0	0	0	2
Aphthous ulcer
subjects affected / exposed	0 / 79 (0.00%)	0 / 93 (0.00%)	0 / 72 (0.00%)	1 / 64 (1.56%)	0 / 84 (0.00%)	0 / 32 (0.00%)	2 / 36 (5.56%)
occurrences all number	0	0	0	1	0	0	2
Crohn's disease
subjects affected / exposed	4 / 79 (5.06%)	2 / 93 (2.15%)	2 / 72 (2.78%)	4 / 64 (6.25%)	9 / 84 (10.71%)	2 / 32 (6.25%)	4 / 36 (11.11%)
occurrences all number	4	2	2	4	11	2	4
Diarrhoea
subjects affected / exposed	0 / 79 (0.00%)	0 / 93 (0.00%)	0 / 72 (0.00%)	0 / 64 (0.00%)	3 / 84 (3.57%)	0 / 32 (0.00%)	2 / 36 (5.56%)
occurrences all number	0	0	0	0	3	0	2
Respiratory, thoracic and mediastinal disorders
Oropharyngeal pain
subjects affected / exposed	0 / 79 (0.00%)	0 / 93 (0.00%)	0 / 72 (0.00%)	0 / 64 (0.00%)	0 / 84 (0.00%)	0 / 32 (0.00%)	3 / 36 (8.33%)
occurrences all number	0	0	0	0	0	0	3
Cough
subjects affected / exposed	0 / 79 (0.00%)	0 / 93 (0.00%)	0 / 72 (0.00%)	2 / 64 (3.13%)	1 / 84 (1.19%)	0 / 32 (0.00%)	2 / 36 (5.56%)
occurrences all number	0	0	0	2	1	0	2
Skin and subcutaneous tissue disorders
Acne
subjects affected / exposed	0 / 79 (0.00%)	1 / 93 (1.08%)	4 / 72 (5.56%)	2 / 64 (3.13%)	1 / 84 (1.19%)	1 / 32 (3.13%)	4 / 36 (11.11%)
occurrences all number	0	1	4	3	1	1	4
Rash
subjects affected / exposed	0 / 79 (0.00%)	0 / 93 (0.00%)	0 / 72 (0.00%)	3 / 64 (4.69%)	0 / 84 (0.00%)	2 / 32 (6.25%)	1 / 36 (2.78%)
occurrences all number	0	0	0	4	0	2	1
Psychiatric disorders
Insomnia
subjects affected / exposed	0 / 79 (0.00%)	0 / 93 (0.00%)	0 / 72 (0.00%)	0 / 64 (0.00%)	0 / 84 (0.00%)	1 / 32 (3.13%)	4 / 36 (11.11%)
occurrences all number	0	0	0	0	0	1	4
Musculoskeletal and connective tissue disorders
Myalgia
subjects affected / exposed	0 / 79 (0.00%)	0 / 93 (0.00%)	0 / 72 (0.00%)	0 / 64 (0.00%)	0 / 84 (0.00%)	0 / 32 (0.00%)	3 / 36 (8.33%)
occurrences all number	0	0	0	0	0	0	3
Muscle spasms
subjects affected / exposed	0 / 79 (0.00%)	0 / 93 (0.00%)	0 / 72 (0.00%)	0 / 64 (0.00%)	2 / 84 (2.38%)	0 / 32 (0.00%)	2 / 36 (5.56%)
occurrences all number	0	0	0	0	2	0	2
Arthralgia
subjects affected / exposed	4 / 79 (5.06%)	3 / 93 (3.23%)	2 / 72 (2.78%)	4 / 64 (6.25%)	1 / 84 (1.19%)	1 / 32 (3.13%)	2 / 36 (5.56%)
occurrences all number	4	3	2	4	1	1	3
Infections and infestations
Influenza
subjects affected / exposed	0 / 79 (0.00%)	0 / 93 (0.00%)	0 / 72 (0.00%)	0 / 64 (0.00%)	2 / 84 (2.38%)	0 / 32 (0.00%)	3 / 36 (8.33%)
occurrences all number	0	0	0	0	2	0	3
Gastroenteritis
subjects affected / exposed	0 / 79 (0.00%)	0 / 93 (0.00%)	0 / 72 (0.00%)	1 / 64 (1.56%)	0 / 84 (0.00%)	0 / 32 (0.00%)	3 / 36 (8.33%)
occurrences all number	0	0	0	1	0	0	3
Folliculitis
subjects affected / exposed	0 / 79 (0.00%)	0 / 93 (0.00%)	0 / 72 (0.00%)	1 / 64 (1.56%)	0 / 84 (0.00%)	2 / 32 (6.25%)	0 / 36 (0.00%)
occurrences all number	0	0	0	1	0	2	0
Urinary tract infection
subjects affected / exposed	0 / 79 (0.00%)	0 / 93 (0.00%)	0 / 72 (0.00%)	0 / 64 (0.00%)	1 / 84 (1.19%)	1 / 32 (3.13%)	2 / 36 (5.56%)
occurrences all number	0	0	0	0	1	1	2
Upper respiratory tract infection
subjects affected / exposed	4 / 79 (5.06%)	2 / 93 (2.15%)	0 / 72 (0.00%)	2 / 64 (3.13%)	3 / 84 (3.57%)	2 / 32 (6.25%)	1 / 36 (2.78%)
occurrences all number	6	2	0	2	4	2	1
Respiratory tract infection
subjects affected / exposed	0 / 79 (0.00%)	0 / 93 (0.00%)	0 / 72 (0.00%)	0 / 64 (0.00%)	3 / 84 (3.57%)	0 / 32 (0.00%)	2 / 36 (5.56%)
occurrences all number	0	0	0	0	3	0	2

More information

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Were there any global substantial amendments to the protocol? Yes

27 Nov 2017

Amendment 1: (The OLE SOA was updated to add ECG monitoring at Weeks 32, 48 and 64. This update is to ensure subject safety during the study. The induction SOA is being revised to clarify that PGIS will be collected continuously for 12 weeks throughout the induction phase (including at Week 2). The induction SOA, footnote j, is being revised to clarify that fasting lipid profile will be assessed from Baseline visit. The induction and OLE SOAs are being updated to add: Review and report to the Sponsor of any incidental endoscopic findings reported by Robarts that are deemed clinically significant by the PI/sites.

15 Mar 2018

Amendment 2: To address the VHP (VoluntaryHarmonization Procedure) request, theprotocol summary, Section 2.2, andSection 9.5.2 are updated to add a secondaryobjective and endpoint to assess theproportion of patients who maintain response after the induction period. To address the VHP request, Section 4.1 isupdated to clarify that inclusion criterion number 5 should be met only after the usual clinical practice in each center has been fulfilled, which may involve administration of more than one line of previous treatment. To address the VHP request, Section 4.2 is updated to exclude subjects with heart failure (NYHA III, NYHA IV). To address the VHP request, Section 4.4.1 is updated to add that male subject must refrain from donating sperm during the study and for 90 days after the last dose of investigational product. To address the VHP request, Section 5.9.2 is updated to add that subjects requiring a second step up in corticosteroid usage will be required to discontinue the study.

24 Aug 2018

Amendment 3: Section 4.2, exclusion criteria 11 is being updated to clarify that subjects with adenomatous polyps finding at screening will be eligible if the polyps have been completely removed and subjects are free of polyps at baseline. Section 4.2, Exclusion criterion 14 and Section 7.1.6 Screening for Clostridium Difficile are revised to permit treatment and re-testing or re-screening of subjects and to allow subjects with appropriately resolved infection to enter the study. Section 4.2, Exclusion criterion 16 is revised to allow subjects adequately treated for latent and/or active tuberculosis infection to enter the study. Section 4.2, Exclusion criterion 33 is revised to correct that “ALT or AST ≥1.5 times > ULN” not “ALT and AST ≥1.5 times ULN “will be exclusionary. Section 4.4.1 and Exclusion criterion 27 are being updated to align with the Clinical Trials Facilitation Group (CTFG) European guidance of the Heads of Medicines Agencies (HMA) and TransCelerate initiative across Pharma. Section 5.9.3, is updated to clarify the timeframe in which the listed medications are not permitted for those for which the information is not already stated.

27 Jul 2021

Amendment 5: Sections Summary, 1, 1.3.2, 1.4.2, 1.5.3, 1.6, 1.6.2.2, 2.1, 3.1, 4.3, 5.4.1: updated to eliminate the PF-06700841 (brepocitinib) active and corresponding (brepocitinib) placebo arms.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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