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Clinical Trial Results:
A Phase 2, randomized, double-blind, placebo-controlled, multicenter proof-of-concept study evaluating efficacy and safety of rilzabrutinib in adult patients with moderate to severe atopic dermatitis who are inadequate responders or intolerant to topical corticosteroids

Summary
EudraCT number	2021-001704-15
Trial protocol	DE NL CZ
Global end of trial date	23 Jun 2023

Results information
Results version number	v1(current)
This version publication date	04 Jul 2024
First version publication date	04 Jul 2024
Other versions

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

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Trial information

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Sponsor protocol code

ACT17207

ISRCTN number

US NCT number

NCT05018806

WHO universal trial number (UTN)

U1111-1261-7565

Sponsor organisation name

Sanofi aventis recherche & développement

Sponsor organisation address

82 Avenue Raspail, Gentilly, France, 94250

Public contact

Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.com

Scientific contact

Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.com

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

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

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

Analysis stage

Final

Date of interim/final analysis

21 Jul 2023

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

23 Jun 2023

Was the trial ended prematurely?

Main objective of the trial

To assess the efficacy of rilzabrutinib in participants with atopic dermatitis (AD).

Protection of trial subjects

Participants were fully informed of all pertinent aspects of clinical trial as well as the possibility to discontinue at any time in language and terms appropriate for the participant and considering the local culture. During the course of the trail, participants were provided with individual participant cards indicating the nature of the trial the participant is participating, contact details and any information needed in the event of a medical emergency. Collected personal data and human biological samples were processed in compliance with the Sanofi-Aventis Group Personal Data Protection Charter ensuring that the Group abides by the laws governing personal data protection in force in all countries in which it operates.

Background therapy

Evidence for comparator

Actual start date of recruitment

09 Sep 2021

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Canada: 23

Country: Number of subjects enrolled

Chile: 25

Country: Number of subjects enrolled

Czechia: 33

Country: Number of subjects enrolled

Germany: 5

Country: Number of subjects enrolled

Netherlands: 1

Country: Number of subjects enrolled

Poland: 11

Country: Number of subjects enrolled

United States: 26

Worldwide total number of subjects

124

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

119

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

The study was conducted at 31 centers in 7 countries. 61 participants in twice a day(BID) cohort and 106 participants in three times a day(TID) cohort were screened from 09 September 2021 to 24 February 2023, of which 16 in BID cohort and 27 in TID cohort were screen failures. Screen failures were mainly due to not meeting the eligibility criteria.

Screening details

A total of 45 participants in BID cohort and 79 participants in TID cohort were randomized in a ratio of 3:2 to receive either rilzabrutinib or matching placebo on Day 1 in the BID and TID cohorts, respectively.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Carer

Are arms mutually exclusive

Yes

BID cohort: Placebo

Arm description

Participants received placebo matched to rilzabrutinib orally BID from Day 1 up to Week 16. Consecutive doses were ideally administered 12 hours apart (and not less than 8 hours apart).

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

Placebo matched to rilzabrutinib was available as tablets (modified-capsule shaped tablets/caplets) and was administered orally BID from Day 1 up to Week 16.

BID cohort: Rilzabrutinib 400 mg BID

Arm description

Participants received rilzabrutinib 400 milligrams (mg) orally BID from Day 1 up to Week 16. Consecutive doses were ideally administered 12 hours apart (and not less than 8 hours apart).

Arm type

Experimental

Investigational medicinal product name

Rilzabrutinib

Investigational medicinal product code

Other name

SAR444671, PRN1008

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Rilzabrutinib was supplied as 400 mg tablets (modified-capsule shaped tablets/caplets) and was administered orally BID from Day 1 up to Week 16.

TID cohort: Placebo

Arm description

Participants received placebo matched to rilzabrutinib orally TID from Day 1 up to Week 16. Consecutive doses were ideally administered at least 6 hours apart (and not less than 4 hours apart).

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

Placebo matched to rilzabrutinib was available as tablets (modified-capsule shaped tablets/caplets) and was administered orally TID from Day 1 up to Week 16.

TID cohort: Rilzabrutinib 400 mg TID

Arm description

Participants received rilzabrutinib 400 mg orally TID from Day 1 up to Week 16. Consecutive doses were ideally administered at least 6 hours apart (and not less than 4 hours apart).

Arm type

Experimental

Investigational medicinal product name

Rilzabrutinib

Investigational medicinal product code

Other name

SAR444671, PRN1008

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Rilzabrutinib was supplied as 400 mg tablets (modified-capsule shaped tablets/caplets) and was administered orally TID from Day 1 up to Week 16.

Number of subjects in period 1	BID cohort: Placebo	BID cohort: Rilzabrutinib 400 mg BID	TID cohort: Placebo	TID cohort: Rilzabrutinib 400 mg TID
Started	18	27	31	48
Completed	14	23	26	31
Not completed	4	4	5	17
Consent withdrawn by subject	3	3	3	10
Adverse event: Not related to COVID-19	1	1	2	7

Baseline characteristics

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Reporting group title

BID cohort: Placebo

Reporting group description

Participants received placebo matched to rilzabrutinib orally BID from Day 1 up to Week 16. Consecutive doses were ideally administered 12 hours apart (and not less than 8 hours apart).

Reporting group title

BID cohort: Rilzabrutinib 400 mg BID

Reporting group description

Participants received rilzabrutinib 400 milligrams (mg) orally BID from Day 1 up to Week 16. Consecutive doses were ideally administered 12 hours apart (and not less than 8 hours apart).

Reporting group title

TID cohort: Placebo

Reporting group description

Participants received placebo matched to rilzabrutinib orally TID from Day 1 up to Week 16. Consecutive doses were ideally administered at least 6 hours apart (and not less than 4 hours apart).

Reporting group title

TID cohort: Rilzabrutinib 400 mg TID

Reporting group description

Participants received rilzabrutinib 400 mg orally TID from Day 1 up to Week 16. Consecutive doses were ideally administered at least 6 hours apart (and not less than 4 hours apart).

Reporting group values	BID cohort: Placebo	BID cohort: Rilzabrutinib 400 mg BID	TID cohort: Placebo	TID cohort: Rilzabrutinib 400 mg TID	Total
Number of subjects	18	27	31	48	124
Age categorical
Units: Subjects
Adults (18-64 years)	18	25	29	47	119
From 65-84 years	0	2	2	1	5
Age Continuous
Units: Years
arithmetic mean (standard deviation)	33.9 ( 13.0 )	38.3 ( 16.1 )	33.1 ( 12.4 )	36.1 ( 14.1 )	-
Sex: Female, Male
Units: Participants
Female	10	15	15	31	71
Male	8	12	16	17	53
Race (NIH/OMB)
Units: Subjects
American Indian or Alaska Native	0	0	0	0	0
Asian	2	2	4	6	14
Native Hawaiian or Other Pacific Islander	0	0	0	0	0
Black or African American	0	1	2	4	7
White	16	23	25	38	102
More than one race	0	1	0	0	1
Unknown or Not Reported	0	0	0	0	0

End points

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Reporting group title

BID cohort: Placebo

Reporting group description

Participants received placebo matched to rilzabrutinib orally BID from Day 1 up to Week 16. Consecutive doses were ideally administered 12 hours apart (and not less than 8 hours apart).

Reporting group title

BID cohort: Rilzabrutinib 400 mg BID

Reporting group description

Participants received rilzabrutinib 400 milligrams (mg) orally BID from Day 1 up to Week 16. Consecutive doses were ideally administered 12 hours apart (and not less than 8 hours apart).

Reporting group title

TID cohort: Placebo

Reporting group description

Participants received placebo matched to rilzabrutinib orally TID from Day 1 up to Week 16. Consecutive doses were ideally administered at least 6 hours apart (and not less than 4 hours apart).

Reporting group title

TID cohort: Rilzabrutinib 400 mg TID

Reporting group description

Participants received rilzabrutinib 400 mg orally TID from Day 1 up to Week 16. Consecutive doses were ideally administered at least 6 hours apart (and not less than 4 hours apart).

Primary: Percent Change From Baseline to Week 16 in Eczema Area and Severity Index (EASI) Score

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End point title

Percent Change From Baseline to Week 16 in Eczema Area and Severity Index (EASI) Score

End point description

EASI index is validated investigator-administered scoring system to measure severity of clinical signs in atopic dermatitis(AD). Four AD disease characteristics(erythema, thickness[induration, papulation, edema],scratching[excoriation],and lichenification) were each assessed for severity by investigator or designee on scale of "0"(absent) through "3(severe).In addition, area of AD involvement were assessed as percentage by body area of head,trunk,upper limbs,and lower limbs,and converted to score of 0 to 6. 0: 0% of body surface area(BSA) involvement with AD;1:1-9%;2: 10-29%;2:30-49%;4: 50-69%;5: 70-89% and 6: 90-100%.Total score=0(minimum) to 72(maximum);higher scores=greater severity of AD.Baseline=Day 1 assessment value. Intent-to-treat(ITT) population:all randomized participants analyzed according to intervention group allocated by randomization regardless of whether intervention was received or not.Only those participants with data collected at specified timepoints are reported.

End point type

Primary

End point timeframe

Baseline (Day 1) to Week 16

End point values	BID cohort: Placebo	BID cohort: Rilzabrutinib 400 mg BID	TID cohort: Placebo	TID cohort: Rilzabrutinib 400 mg TID
Number of subjects analysed	18	24	29	37
Units: Percent change
least squares mean (standard error)	-47.33 ( 9.77 )	-53.57 ( 8.25 )	-43.33 ( 6.99 )	-47.21 ( 6.26 )

BID cohort:Placebo versus Rilzabrutinib 400 mg BID

Statistical analysis description

Analysis was performed by using an analysis of covariance (ANCOVA) model with the baseline EASI score, intervention group, randomization stratification of screening Immunoglobulin E (IgE) levels (< or ≥300 units international per milliliter [UI/mL]) as covariates.

Comparison groups

BID cohort: Placebo v BID cohort: Rilzabrutinib 400 mg BID

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.6246

Method

ANCOVA

Parameter type

Least Square Mean Difference

Point estimate

-6.25

Confidence interval

level

95%

sides

2-sided

lower limit

-31.26

upper limit

18.77

TID cohort:Placebo versus Rilzabrutinib 400 mg TID

Statistical analysis description

Analysis was performed by using an ANCOVA model with the baseline EASI score, intervention group, randomization stratification of screening IgE levels (< or ≥300UI/mL) as covariates.

Comparison groups

TID cohort: Placebo v TID cohort: Rilzabrutinib 400 mg TID

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.674

Method

ANCOVA

Parameter type

Least Square Mean Difference

Point estimate

-3.88

Confidence interval

level

95%

sides

2-sided

lower limit

-21.97

upper limit

14.21

Secondary: Percentage of Participants With Investigator's Global Assessment (IGA) of 0 or 1 At Week 16

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End point title

Percentage of Participants With Investigator's Global Assessment (IGA) of 0 or 1 At Week 16

End point description

IGA is a static 5-point measure of disease severity based on an overall assessment of the skin lesions on a 5-point scale (0 = clear, 1 = almost clear, 2 = mild disease, 3 = moderate disease, 4 = severe disease). Higher score indicated higher severity. ITT population included all randomized participants analyzed according to the intervention group allocated by randomization regardless of whether the intervention was received or not.

End point type

Secondary

End point timeframe

Week 16

End point values	BID cohort: Placebo	BID cohort: Rilzabrutinib 400 mg BID	TID cohort: Placebo	TID cohort: Rilzabrutinib 400 mg TID
Number of subjects analysed	18	27	31	48
Units: Percentage of participants
number (not applicable)	22.2	7.4	12.9	14.6

No statistical analyses for this end point

Secondary: Percentage of Participants Achieving EASI-75 (Reduction of EASI Score By ≥75% From Baseline) At Week 16

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End point title

Percentage of Participants Achieving EASI-75 (Reduction of EASI Score By ≥75% From Baseline) At Week 16

End point description

The EASI index is validated investigator-administered scoring system used to measure severity of clinical signs in AD. Four AD disease characteristics (erythema, thickness [induration, papulation, edema], scratching [excoriation], and lichenification) were each assessed for severity by investigator or designee on scale of "0" (absent) through "3" (severe).In addition, area of AD involvement were assessed as percentage by body area of head, trunk, upper limbs, and lower limbs, and converted to score of 0 to 6. 0: 0% of BSA involvement with AD; 1: 1-9%; 2: 10-29%; 2: 30-49%; 4: 50-69%; 5: 70-89% and 6: 90-100%. Total score=0 (minimum) to 72 (maximum); higher scores indicated greater severity of AD. Participants who achieved EASI-75 were defined as participants with reduction of EASI score by ≥75% from baseline. ITT population included all randomized participants analyzed according to intervention group allocated by randomization regardless of whether intervention was received or not.

End point type

Secondary

End point timeframe

Baseline (Day 1) and at Week 16

End point values	BID cohort: Placebo	BID cohort: Rilzabrutinib 400 mg BID	TID cohort: Placebo	TID cohort: Rilzabrutinib 400 mg TID
Number of subjects analysed	18	27	31	48
Units: Percentage of participants
number (not applicable)	27.8	29.6	29.0	18.8

No statistical analyses for this end point

Secondary: Percentage Of Participants With Reduction of Weekly Average of Daily Peak Pruritus Numerical Rating Scale (PP-NRS) of ≥4 Points From Baseline at Week 16

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End point title

Percentage Of Participants With Reduction of Weekly Average of Daily Peak Pruritus Numerical Rating Scale (PP-NRS) of ≥4 Points From Baseline at Week 16

End point description

The PP-NRS is a simple assessment tool that participants used to report the intensity of their pruritus (itch) during a daily recall period. Participants were asked to rate their worst itch on a 0 (no itch) to 10 (worst itch imaginable) NRS by answering the following question: For itch intensity, "On a scale of 0 to 10, with 0 being 'no itch' and 10 being the 'worst itch imaginable', how would you rate your itch at the worst moment during the previous 24 hours?". The total score on the scale ranged from 0 (no itch) to 10 (worst itch imaginable). Higher scores indicated worse symptoms. A minimum of 4 daily scores out of the 7 days is required to calculate the baseline average score. ITT population included all randomized participants analyzed according to the intervention group allocated by randomization regardless of whether the intervention was received or not.

End point type

Secondary

End point timeframe

Baseline (Day 1) and at Week 16

End point values	BID cohort: Placebo	BID cohort: Rilzabrutinib 400 mg BID	TID cohort: Placebo	TID cohort: Rilzabrutinib 400 mg TID
Number of subjects analysed	18	27	31	48
Units: Percentage of participants
number (not applicable)	11.1	18.5	12.9	20.8

No statistical analyses for this end point

Secondary: Number of Participants With Weekly Average of Daily PP-NRS Reduction ≥4 From Baseline During The 16-Week Treatment Period

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End point title

Number of Participants With Weekly Average of Daily PP-NRS Reduction ≥4 From Baseline During The 16-Week Treatment Period

End point description

The PP-NRS is a simple assessment tool that participants used to report the intensity of their pruritus (itch) during a daily recall period. Participants were asked to rate their worst itch on a 0 (no itch) to 10 (worst itch imaginable) NRS by answering the following question: For itch intensity, "On a scale of 0 to 10, with 0 being 'no itch' and 10 being the 'worst itch imaginable', howwould you rate your itch at the worst moment during the previous 24 hours?". The total score on the scale ranged from 0 (no itch) to 10 (worst itch imaginable). Higher scores indicated worse symptoms. A minimum of 4 daily scores out of the 7 days is required to calculate the baseline average score. ITT population included all randomized participants analyzed according to the intervention group allocated by randomization regardless of whether the intervention was received or not.

End point type

Secondary

End point timeframe

Baseline (Day 1) and Week 16

End point values	BID cohort: Placebo	BID cohort: Rilzabrutinib 400 mg BID	TID cohort: Placebo	TID cohort: Rilzabrutinib 400 mg TID
Number of subjects analysed	18	27	31	48
Units: Participants	2	7	4	13

No statistical analyses for this end point

Secondary: Absolute Change From Baseline to Week 16 in EASI Score

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End point title

Absolute Change From Baseline to Week 16 in EASI Score

End point description

EASI index is validated investigator-administered scoring system used to measure severity of clinical signs in AD. Four AD disease characteristics (erythema, thickness [induration, papulation, edema], scratching [excoriation], and lichenification) were each assessed for severity by investigator or designee on scale of "0" (absent) through "3" (severe).In addition, area of AD involvement were assessed as a percentage by body area of head, trunk, upper limbs, and lower limbs, and converted to score of 0 to 6. 0: 0% of BSA involvement with AD; 1: 1-9%; 2: 10-29%; 2: 30-49%; 4: 50-69%; 5: 70-89% and 6: 90-100%. Total score=0 (minimum) to 72 (maximum); higher scores indicated greater severity of AD. Baseline=Day 1 assessment value. ITT population included all randomized participants analyzed according to intervention group allocated by randomization regardless of whether intervention was received or not. Only those participants with data collected at specified timepoints are reported.

End point type

Secondary

End point timeframe

Baseline (Day 1) to Week 16

End point values	BID cohort: Placebo	BID cohort: Rilzabrutinib 400 mg BID	TID cohort: Placebo	TID cohort: Rilzabrutinib 400 mg TID
Number of subjects analysed	18	24	29	37
Units: Scores on a scale
least squares mean (standard error)	-12.83 ( 2.31 )	-14.00 ( 1.94 )	-10.37 ( 2.48 )	-11.34 ( 2.20 )

No statistical analyses for this end point

Secondary: Percentage of Participants Achieving EASI-50/90 (Reduction of EASI Score by ≥50% or ≥90% From Baseline) at Week 16

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End point title

Percentage of Participants Achieving EASI-50/90 (Reduction of EASI Score by ≥50% or ≥90% From Baseline) at Week 16

End point description

EASI index is validated investigator-administered scoring system used to measure severity of clinical signs in AD. Four AD disease characteristics(erythema, thickness[induration, papulation, edema],scratching[excoriation], and lichenification)were each assessed for severity by investigator or designee on scale of "0" (absent) through "3" (severe).In addition, area of AD involvement were assessed as percentage by body area of head, trunk, upper limbs, and lower limbs, and converted to a score of 0 to 6.0: 0% of BSA involvement with AD;1: 1-9%;2: 10-29%;2: 30-49%;4: 50-69%;5: 70-89% and6: 90-100%. Total score=0 (minimum) to 72 (maximum);higher scores=greater severity of AD. Participants who achieved EASI-50/90 were defined as participants with reduction of EASI score by ≥50% or ≥90% from baseline respectively. ITT population included all randomized participants analyzed according to intervention group allocated by randomization regardless of whether intervention was received or not.

End point type

Secondary

End point timeframe

Baseline (Day 1) and at Week 16

End point values	BID cohort: Placebo	BID cohort: Rilzabrutinib 400 mg BID	TID cohort: Placebo	TID cohort: Rilzabrutinib 400 mg TID
Number of subjects analysed	18	27	31	48
Units: Percentage of participants
number (not applicable)
EASI-50	55.6	44.4	38.7	29.2
EASI-90	16.7	11.1	12.9	8.3

No statistical analyses for this end point

Secondary: Change From Baseline to Week 16 in Percent BSA of AD

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End point title

Change From Baseline to Week 16 in Percent BSA of AD

End point description

BSA affected by AD were assessed for each section of the body (the possible highest score for each region was: head and neck [10%], trunk including genitalia [30%], upper limbs [20%], lower limbs [40%]) and were reported as a percentage of all major body sections combined. Total score ranges from 0% to 100%. The higher score indicates a worse value and a lower score indicates a better value. Baseline was defined as the Day 1 assessment value. ITT population included all randomized participants analyzed according to the intervention group allocated by randomization regardless of whether the intervention was received or not. Only those participants with data collected at specified timepoints are reported.

End point type

Secondary

End point timeframe

Baseline (Day 1) to Week 16

End point values	BID cohort: Placebo	BID cohort: Rilzabrutinib 400 mg BID	TID cohort: Placebo	TID cohort: Rilzabrutinib 400 mg TID
Number of subjects analysed	14	20	29	37
Units: Percent of body surface area
least squares mean (standard error)	-10.45 ( 4.37 )	-15.30 ( 3.61 )	-7.35 ( 3.38 )	-11.80 ( 3.08 )

No statistical analyses for this end point

Secondary: Absolute Change From Baseline to Week 16 in Weekly Average of Daily PP-NRS

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End point title

Absolute Change From Baseline to Week 16 in Weekly Average of Daily PP-NRS

End point description

The PP-NRS is a simple assessment tool that participants used to report the intensity of their pruritus (itch) during a daily recall period. Participants were asked to rate their worst itch on a 0 (no itch) to 10 (worst itch imaginable) NRS by answering the following question: For itch intensity, "On a scale of 0 to 10, with 0 being 'no itch' and 10 being the 'worst itch imaginable', how would you rate your itch at the worst moment during the previous 24 hours?". The total score on the scale ranged from 0 (no itch) to 10 (worst itch imaginable). Higher scores indicated worse symptoms. A minimum of 4 daily scores out of the 7 days is required to calculate the baseline average score. Baseline was defined as the Day 1 assessment value. ITT population=all randomized participants analyzed according to intervention group allocated by randomization regardless of whether intervention was received or not. Only those participants with data collected at specified timepoints are reported.

End point type

Secondary

End point timeframe

Baseline (Day 1) to Week 16

End point values	BID cohort: Placebo	BID cohort: Rilzabrutinib 400 mg BID	TID cohort: Placebo	TID cohort: Rilzabrutinib 400 mg TID
Number of subjects analysed	16	23	26	36
Units: Scores on a scale
least squares mean (standard error)	-1.60 ( 0.66 )	-3.11 ( 0.52 )	-0.83 ( 0.51 )	-2.07 ( 0.43 )

No statistical analyses for this end point

Secondary: Percent Change From Baseline to Week 16 in Weekly Average of Daily PP-NRS

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End point title

Percent Change From Baseline to Week 16 in Weekly Average of Daily PP-NRS

End point description

The PP-NRS is a simple assessment tool that participants used to report the intensity of their pruritus (itch) during a daily recall period. Participants were asked to rate their worst itch on a 0 (no itch) to 10 (worst itch imaginable) NRS by answering the following question: For itch intensity, "On a scale of 0 to 10, with 0 being 'no itch' and 10 being the 'worst itch imaginable', how would you rate your itch at the worst moment during the previous 24 hours?". The total score on the scale ranged from 0 (no itch) to 10 (worst itch imaginable). Higher scores indicated worse symptoms. A minimum of 4 daily scores out of the 7 days is required to calculate the baseline average score. Baseline was defined as the Day 1 assessment value. ITT population=all randomized participants analyzed according to intervention group allocated by randomization regardless of whether intervention was received or not. Only those participants with data collected at specified timepoints are reported

End point type

Secondary

End point timeframe

Baseline (Day 1) to Week 16

End point values	BID cohort: Placebo	BID cohort: Rilzabrutinib 400 mg BID	TID cohort: Placebo	TID cohort: Rilzabrutinib 400 mg TID
Number of subjects analysed	16	23	26	36
Units: Percent change
least squares mean (standard error)	-21.55 ( 8.37 )	-43.53 ( 6.80 )	-10.36 ( 7.19 )	-30.13 ( 6.08 )

No statistical analyses for this end point

Secondary: Percentage of Participants Achieving IGABSA-50/75/90 (Reduction of IGABSA by ≥50% or 75% or 90% From Baseline) At Week 16

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End point title

Percentage of Participants Achieving IGA*BSA-50/75/90 (Reduction of IGA*BSA by ≥50% or 75% or 90% From Baseline) At Week 16

End point description

IGA is a static 5-point measure of disease severity based on an overall assessment of the skin lesions on a 5-point scale (0 = clear, 1 = almost clear, 2 = mild disease, 3 = moderate disease, 4 = severe disease). Higher score indicated higher severity. Participants who achieved IGA*BSA-50-75-90 were defined as participants with reduction of IGA*BSA by ≥50% or 75% or 90% from baseline. ITT population included all randomized participants analyzed according to the intervention group allocated by randomization regardless of whether the intervention was received or not.

End point type

Secondary

End point timeframe

Baseline (Day 1) and at Week 16

End point values	BID cohort: Placebo	BID cohort: Rilzabrutinib 400 mg BID	TID cohort: Placebo	TID cohort: Rilzabrutinib 400 mg TID
Number of subjects analysed	18	27	31	48
Units: Percentage of participants
number (not applicable)
IGA*BSA-50	38.9	40.7	38.7	29.2
IGA*BSA-75	22.2	25.9	22.6	18.8
IGA*BSA-90	5.6	18.5	9.7	10.4

No statistical analyses for this end point

Secondary: Number Of Participants With Treatment-Emergent Adverse Events (TEAEs), Treatment-Emergent Serious Adverse Events (TESAEs), Adverse Events of Special Interest (AESIs) and Study intervention Discontinuation

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End point title

Number Of Participants With Treatment-Emergent Adverse Events (TEAEs), Treatment-Emergent Serious Adverse Events (TESAEs), Adverse Events of Special Interest (AESIs) and Study intervention Discontinuation

End point description

An AE was any untoward medical occurrence in a participant or clinical study participant, temporally associated with use of study intervention, whether or not considered related to study intervention. TEAEs were defined as AEs that developed, worsened or became serious during treatment-emergent period. SAE was any AE that at any dose: resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect, was a medically important event. An AESI was an AE (serious or nonserious) of scientific and medical concern specific to Sponsor’s product or program, for which ongoing monitoring and immediate notification by investigator to Sponsor was required. Safety population included all randomized participants who took at least 1 dose of study intervention. Participants were analyzed according to the intervention they actually received.

End point type

Secondary

End point timeframe

Baseline (Day 1) to 16 weeks

End point values	BID cohort: Placebo	BID cohort: Rilzabrutinib 400 mg BID	TID cohort: Placebo	TID cohort: Rilzabrutinib 400 mg TID
Number of subjects analysed	18	27	31	48
Units: Participants
TEAEs	10	15	19	38
TESAEs	0	0	1	1
AESI	3	0	2	0
TEAE leading to study intervention discontinuation	0	2	2	9

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

TEAEs were collected from Baseline (Day 1) to 16 weeks. All-cause mortality (Deaths) was collected throughout the study, approximately 97 weeks.

Adverse event reporting additional description

Analysis was performed on safety population.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

26.0

Reporting group title

BID cohort: Placebo

Reporting group description

Participants received placebo matched to rilzabrutinib orally BID from Day 1 up to Week 16. Consecutive doses were ideally administered 12 hours apart (and not less than 8 hours apart).

Reporting group title

BID cohort: Rilzabrutinib 400 mg BID

Reporting group description

Participants received rilzabrutinib 400 mg orally BID from Day 1 up to Week 16. Consecutive doses were ideally administered 12 hours apart (and not less than 8 hours apart).

Reporting group title

TID cohort: Placebo

Reporting group description

Participants received placebo matched to rilzabrutinib orally TID from Day 1 up to Week 16. Consecutive doses were ideally administered at least 6 hours apart (and not less than 4 hours apart).

Reporting group title

TID cohort: Rilzabrutinib 400 mg TID

Reporting group description

Participants received rilzabrutinib 400 mg orally TID from Day 1 up to Week 16. Consecutive doses were ideally administered at least 6 hours apart (and not less than 4 hours apart).

Serious adverse events	BID cohort: Placebo	BID cohort: Rilzabrutinib 400 mg BID	TID cohort: Placebo	TID cohort: Rilzabrutinib 400 mg TID
Total subjects affected by serious adverse events
subjects affected / exposed	0 / 18 (0.00%)	0 / 27 (0.00%)	1 / 31 (3.23%)	1 / 48 (2.08%)
number of deaths (all causes)	0	0	0	0
number of deaths resulting from adverse events	0	0	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Cutaneous T-Cell Lymphoma
subjects affected / exposed	0 / 18 (0.00%)	0 / 27 (0.00%)	0 / 31 (0.00%)	1 / 48 (2.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Abscess Limb
subjects affected / exposed	0 / 18 (0.00%)	0 / 27 (0.00%)	1 / 31 (3.23%)	0 / 48 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 0%

Non-serious adverse events	BID cohort: Placebo	BID cohort: Rilzabrutinib 400 mg BID	TID cohort: Placebo	TID cohort: Rilzabrutinib 400 mg TID
Total subjects affected by non serious adverse events
subjects affected / exposed	10 / 18 (55.56%)	15 / 27 (55.56%)	19 / 31 (61.29%)	38 / 48 (79.17%)
Vascular disorders
Hot Flush
subjects affected / exposed	0 / 18 (0.00%)	1 / 27 (3.70%)	0 / 31 (0.00%)	0 / 48 (0.00%)
occurrences all number	0	1	0	0
General disorders and administration site conditions
Fatigue
subjects affected / exposed	0 / 18 (0.00%)	1 / 27 (3.70%)	1 / 31 (3.23%)	1 / 48 (2.08%)
occurrences all number	0	1	1	1
Influenza Like Illness
subjects affected / exposed	0 / 18 (0.00%)	0 / 27 (0.00%)	1 / 31 (3.23%)	0 / 48 (0.00%)
occurrences all number	0	0	1	0
Oedema
subjects affected / exposed	0 / 18 (0.00%)	0 / 27 (0.00%)	1 / 31 (3.23%)	0 / 48 (0.00%)
occurrences all number	0	0	1	0
Pyrexia
subjects affected / exposed	0 / 18 (0.00%)	0 / 27 (0.00%)	0 / 31 (0.00%)	1 / 48 (2.08%)
occurrences all number	0	0	0	1
Reproductive system and breast disorders
Menstruation Delayed
subjects affected / exposed	0 / 18 (0.00%)	0 / 27 (0.00%)	0 / 31 (0.00%)	1 / 48 (2.08%)
occurrences all number	0	0	0	1
Respiratory, thoracic and mediastinal disorders
Oropharyngeal Pain
subjects affected / exposed	1 / 18 (5.56%)	0 / 27 (0.00%)	1 / 31 (3.23%)	1 / 48 (2.08%)
occurrences all number	1	0	1	1
Epistaxis
subjects affected / exposed	0 / 18 (0.00%)	1 / 27 (3.70%)	0 / 31 (0.00%)	0 / 48 (0.00%)
occurrences all number	0	1	0	0
Dyspnoea
subjects affected / exposed	0 / 18 (0.00%)	2 / 27 (7.41%)	0 / 31 (0.00%)	0 / 48 (0.00%)
occurrences all number	0	2	0	0
Rhinorrhoea
subjects affected / exposed	0 / 18 (0.00%)	0 / 27 (0.00%)	1 / 31 (3.23%)	0 / 48 (0.00%)
occurrences all number	0	0	1	0
Cough
subjects affected / exposed	0 / 18 (0.00%)	0 / 27 (0.00%)	1 / 31 (3.23%)	0 / 48 (0.00%)
occurrences all number	0	0	1	0
Psychiatric disorders
Stress
subjects affected / exposed	0 / 18 (0.00%)	0 / 27 (0.00%)	0 / 31 (0.00%)	1 / 48 (2.08%)
occurrences all number	0	0	0	1
Insomnia
subjects affected / exposed	0 / 18 (0.00%)	1 / 27 (3.70%)	0 / 31 (0.00%)	0 / 48 (0.00%)
occurrences all number	0	1	0	0
Anxiety
subjects affected / exposed	0 / 18 (0.00%)	1 / 27 (3.70%)	0 / 31 (0.00%)	0 / 48 (0.00%)
occurrences all number	0	1	0	0
Investigations
Aspartate Aminotransferase Increased
subjects affected / exposed	1 / 18 (5.56%)	0 / 27 (0.00%)	0 / 31 (0.00%)	1 / 48 (2.08%)
occurrences all number	1	0	0	1
Alanine Aminotransferase Increased
subjects affected / exposed	1 / 18 (5.56%)	0 / 27 (0.00%)	0 / 31 (0.00%)	1 / 48 (2.08%)
occurrences all number	1	0	0	1
Blood Creatine Phosphokinase Increased
subjects affected / exposed	0 / 18 (0.00%)	1 / 27 (3.70%)	2 / 31 (6.45%)	1 / 48 (2.08%)
occurrences all number	0	1	2	1
Activated Partial Thromboplastin Time Prolonged
subjects affected / exposed	0 / 18 (0.00%)	1 / 27 (3.70%)	1 / 31 (3.23%)	2 / 48 (4.17%)
occurrences all number	0	1	1	2
Weight Decreased
subjects affected / exposed	0 / 18 (0.00%)	1 / 27 (3.70%)	0 / 31 (0.00%)	1 / 48 (2.08%)
occurrences all number	0	1	0	1
Transaminases Increased
subjects affected / exposed	0 / 18 (0.00%)	1 / 27 (3.70%)	0 / 31 (0.00%)	1 / 48 (2.08%)
occurrences all number	0	1	0	1
Body Temperature Increased
subjects affected / exposed	0 / 18 (0.00%)	1 / 27 (3.70%)	0 / 31 (0.00%)	0 / 48 (0.00%)
occurrences all number	0	1	0	0
Blood Pressure Increased
subjects affected / exposed	0 / 18 (0.00%)	0 / 27 (0.00%)	0 / 31 (0.00%)	1 / 48 (2.08%)
occurrences all number	0	0	0	1
Injury, poisoning and procedural complications
Eyelid Injury
subjects affected / exposed	0 / 18 (0.00%)	0 / 27 (0.00%)	1 / 31 (3.23%)	0 / 48 (0.00%)
occurrences all number	0	0	1	0
Ligament Sprain
subjects affected / exposed	0 / 18 (0.00%)	0 / 27 (0.00%)	0 / 31 (0.00%)	1 / 48 (2.08%)
occurrences all number	0	0	0	1
Limb Crushing Injury
subjects affected / exposed	0 / 18 (0.00%)	1 / 27 (3.70%)	0 / 31 (0.00%)	0 / 48 (0.00%)
occurrences all number	0	1	0	0
Stab Wound
subjects affected / exposed	0 / 18 (0.00%)	0 / 27 (0.00%)	0 / 31 (0.00%)	1 / 48 (2.08%)
occurrences all number	0	0	0	1
Cardiac disorders
Coronary Artery Stenosis
subjects affected / exposed	0 / 18 (0.00%)	1 / 27 (3.70%)	0 / 31 (0.00%)	1 / 48 (2.08%)
occurrences all number	0	1	0	1
Coronary Artery Disease
subjects affected / exposed	0 / 18 (0.00%)	0 / 27 (0.00%)	0 / 31 (0.00%)	1 / 48 (2.08%)
occurrences all number	0	0	0	1
Supraventricular Tachycardia
subjects affected / exposed	0 / 18 (0.00%)	0 / 27 (0.00%)	0 / 31 (0.00%)	1 / 48 (2.08%)
occurrences all number	0	0	0	1
Nervous system disorders
Hyperaesthesia
subjects affected / exposed	0 / 18 (0.00%)	0 / 27 (0.00%)	0 / 31 (0.00%)	1 / 48 (2.08%)
occurrences all number	0	0	0	1
Headache
subjects affected / exposed	1 / 18 (5.56%)	2 / 27 (7.41%)	1 / 31 (3.23%)	0 / 48 (0.00%)
occurrences all number	1	2	1	0
Dysaesthesia
subjects affected / exposed	0 / 18 (0.00%)	1 / 27 (3.70%)	0 / 31 (0.00%)	0 / 48 (0.00%)
occurrences all number	0	2	0	0
Tremor
subjects affected / exposed	0 / 18 (0.00%)	1 / 27 (3.70%)	0 / 31 (0.00%)	0 / 48 (0.00%)
occurrences all number	0	1	0	0
Blood and lymphatic system disorders
Spontaneous Haematoma
subjects affected / exposed	0 / 18 (0.00%)	1 / 27 (3.70%)	0 / 31 (0.00%)	0 / 48 (0.00%)
occurrences all number	0	1	0	0
Lymphopenia
subjects affected / exposed	0 / 18 (0.00%)	0 / 27 (0.00%)	1 / 31 (3.23%)	0 / 48 (0.00%)
occurrences all number	0	0	1	0
Deficiency Anaemia
subjects affected / exposed	0 / 18 (0.00%)	0 / 27 (0.00%)	0 / 31 (0.00%)	1 / 48 (2.08%)
occurrences all number	0	0	0	1
Anaemia
subjects affected / exposed	0 / 18 (0.00%)	0 / 27 (0.00%)	0 / 31 (0.00%)	1 / 48 (2.08%)
occurrences all number	0	0	0	1
Eye disorders
Swelling Of Eyelid
subjects affected / exposed	0 / 18 (0.00%)	0 / 27 (0.00%)	1 / 31 (3.23%)	0 / 48 (0.00%)
occurrences all number	0	0	1	0
Conjunctivitis Allergic
subjects affected / exposed	1 / 18 (5.56%)	0 / 27 (0.00%)	0 / 31 (0.00%)	0 / 48 (0.00%)
occurrences all number	1	0	0	0
Cataract
subjects affected / exposed	0 / 18 (0.00%)	1 / 27 (3.70%)	0 / 31 (0.00%)	0 / 48 (0.00%)
occurrences all number	0	1	0	0
Blepharitis
subjects affected / exposed	0 / 18 (0.00%)	0 / 27 (0.00%)	0 / 31 (0.00%)	1 / 48 (2.08%)
occurrences all number	0	0	0	1
Gastrointestinal disorders
Abdominal Pain
subjects affected / exposed	0 / 18 (0.00%)	0 / 27 (0.00%)	0 / 31 (0.00%)	3 / 48 (6.25%)
occurrences all number	0	0	0	3
Abdominal Distension
subjects affected / exposed	0 / 18 (0.00%)	0 / 27 (0.00%)	0 / 31 (0.00%)	1 / 48 (2.08%)
occurrences all number	0	0	0	1
Abdominal Discomfort
subjects affected / exposed	0 / 18 (0.00%)	0 / 27 (0.00%)	0 / 31 (0.00%)	1 / 48 (2.08%)
occurrences all number	0	0	0	1
Abdominal Pain Lower
subjects affected / exposed	0 / 18 (0.00%)	1 / 27 (3.70%)	0 / 31 (0.00%)	0 / 48 (0.00%)
occurrences all number	0	1	0	0
Constipation
subjects affected / exposed	0 / 18 (0.00%)	0 / 27 (0.00%)	0 / 31 (0.00%)	1 / 48 (2.08%)
occurrences all number	0	0	0	1
Diarrhoea
subjects affected / exposed	0 / 18 (0.00%)	4 / 27 (14.81%)	0 / 31 (0.00%)	10 / 48 (20.83%)
occurrences all number	0	7	0	10
Dyspepsia
subjects affected / exposed	0 / 18 (0.00%)	0 / 27 (0.00%)	0 / 31 (0.00%)	1 / 48 (2.08%)
occurrences all number	0	0	0	1
Flatulence
subjects affected / exposed	0 / 18 (0.00%)	0 / 27 (0.00%)	0 / 31 (0.00%)	1 / 48 (2.08%)
occurrences all number	0	0	0	1
Frequent Bowel Movements
subjects affected / exposed	0 / 18 (0.00%)	0 / 27 (0.00%)	0 / 31 (0.00%)	1 / 48 (2.08%)
occurrences all number	0	0	0	1
Vomiting
subjects affected / exposed	0 / 18 (0.00%)	0 / 27 (0.00%)	1 / 31 (3.23%)	0 / 48 (0.00%)
occurrences all number	0	0	1	0
Nausea
subjects affected / exposed	0 / 18 (0.00%)	8 / 27 (29.63%)	1 / 31 (3.23%)	15 / 48 (31.25%)
occurrences all number	0	8	1	16
Haemorrhoidal Haemorrhage
subjects affected / exposed	0 / 18 (0.00%)	0 / 27 (0.00%)	1 / 31 (3.23%)	0 / 48 (0.00%)
occurrences all number	0	0	1	0
Gastrooesophageal Reflux Disease
subjects affected / exposed	0 / 18 (0.00%)	0 / 27 (0.00%)	0 / 31 (0.00%)	1 / 48 (2.08%)
occurrences all number	0	0	0	1
Abdominal Pain Upper
subjects affected / exposed	0 / 18 (0.00%)	1 / 27 (3.70%)	0 / 31 (0.00%)	0 / 48 (0.00%)
occurrences all number	0	1	0	0
Skin and subcutaneous tissue disorders
Chronic Spontaneous Urticaria
subjects affected / exposed	0 / 18 (0.00%)	1 / 27 (3.70%)	0 / 31 (0.00%)	0 / 48 (0.00%)
occurrences all number	0	1	0	0
Alopecia
subjects affected / exposed	0 / 18 (0.00%)	1 / 27 (3.70%)	0 / 31 (0.00%)	0 / 48 (0.00%)
occurrences all number	0	1	0	0
Acne
subjects affected / exposed	1 / 18 (5.56%)	0 / 27 (0.00%)	3 / 31 (9.68%)	0 / 48 (0.00%)
occurrences all number	1	0	3	0
Dermatitis Atopic
subjects affected / exposed	3 / 18 (16.67%)	4 / 27 (14.81%)	9 / 31 (29.03%)	15 / 48 (31.25%)
occurrences all number	3	7	13	15
Hand Dermatitis
subjects affected / exposed	0 / 18 (0.00%)	0 / 27 (0.00%)	1 / 31 (3.23%)	0 / 48 (0.00%)
occurrences all number	0	0	1	0
Hyperhidrosis
subjects affected / exposed	0 / 18 (0.00%)	0 / 27 (0.00%)	0 / 31 (0.00%)	1 / 48 (2.08%)
occurrences all number	0	0	0	1
Livedo Reticularis
subjects affected / exposed	0 / 18 (0.00%)	0 / 27 (0.00%)	0 / 31 (0.00%)	1 / 48 (2.08%)
occurrences all number	0	0	0	1
Sensitive Skin
subjects affected / exposed	0 / 18 (0.00%)	1 / 27 (3.70%)	0 / 31 (0.00%)	0 / 48 (0.00%)
occurrences all number	0	1	0	0
Renal and urinary disorders
Nephrolithiasis
subjects affected / exposed	0 / 18 (0.00%)	0 / 27 (0.00%)	1 / 31 (3.23%)	0 / 48 (0.00%)
occurrences all number	0	0	1	0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	0 / 18 (0.00%)	0 / 27 (0.00%)	0 / 31 (0.00%)	4 / 48 (8.33%)
occurrences all number	0	0	0	4
Arthropathy
subjects affected / exposed	0 / 18 (0.00%)	1 / 27 (3.70%)	0 / 31 (0.00%)	0 / 48 (0.00%)
occurrences all number	0	1	0	0
Back Pain
subjects affected / exposed	0 / 18 (0.00%)	0 / 27 (0.00%)	0 / 31 (0.00%)	1 / 48 (2.08%)
occurrences all number	0	0	0	1
Bursitis
subjects affected / exposed	0 / 18 (0.00%)	1 / 27 (3.70%)	0 / 31 (0.00%)	0 / 48 (0.00%)
occurrences all number	0	1	0	0
Myalgia
subjects affected / exposed	1 / 18 (5.56%)	0 / 27 (0.00%)	0 / 31 (0.00%)	0 / 48 (0.00%)
occurrences all number	1	0	0	0
Infections and infestations
Acute Sinusitis
subjects affected / exposed	0 / 18 (0.00%)	0 / 27 (0.00%)	1 / 31 (3.23%)	0 / 48 (0.00%)
occurrences all number	0	0	1	0
Covid-19
subjects affected / exposed	2 / 18 (11.11%)	0 / 27 (0.00%)	2 / 31 (6.45%)	0 / 48 (0.00%)
occurrences all number	2	0	2	0
Eczema Impetiginous
subjects affected / exposed	0 / 18 (0.00%)	0 / 27 (0.00%)	1 / 31 (3.23%)	0 / 48 (0.00%)
occurrences all number	0	0	1	0
Pustule
subjects affected / exposed	0 / 18 (0.00%)	0 / 27 (0.00%)	0 / 31 (0.00%)	1 / 48 (2.08%)
occurrences all number	0	0	0	1
Conjunctivitis
subjects affected / exposed	0 / 18 (0.00%)	0 / 27 (0.00%)	0 / 31 (0.00%)	1 / 48 (2.08%)
occurrences all number	0	0	0	1
Cellulitis
subjects affected / exposed	0 / 18 (0.00%)	0 / 27 (0.00%)	0 / 31 (0.00%)	1 / 48 (2.08%)
occurrences all number	0	0	0	1
Eczema Infected
subjects affected / exposed	0 / 18 (0.00%)	0 / 27 (0.00%)	0 / 31 (0.00%)	1 / 48 (2.08%)
occurrences all number	0	0	0	1
Folliculitis
subjects affected / exposed	0 / 18 (0.00%)	0 / 27 (0.00%)	1 / 31 (3.23%)	0 / 48 (0.00%)
occurrences all number	0	0	1	0
Gastroenteritis
subjects affected / exposed	0 / 18 (0.00%)	0 / 27 (0.00%)	1 / 31 (3.23%)	0 / 48 (0.00%)
occurrences all number	0	0	1	0
Gastroenteritis Viral
subjects affected / exposed	1 / 18 (5.56%)	0 / 27 (0.00%)	0 / 31 (0.00%)	0 / 48 (0.00%)
occurrences all number	1	0	0	0
Gastrointestinal Viral Infection
subjects affected / exposed	0 / 18 (0.00%)	1 / 27 (3.70%)	0 / 31 (0.00%)	0 / 48 (0.00%)
occurrences all number	0	1	0	0
Impetigo
subjects affected / exposed	0 / 18 (0.00%)	0 / 27 (0.00%)	0 / 31 (0.00%)	1 / 48 (2.08%)
occurrences all number	0	0	0	1
Influenza
subjects affected / exposed	0 / 18 (0.00%)	0 / 27 (0.00%)	1 / 31 (3.23%)	0 / 48 (0.00%)
occurrences all number	0	0	1	0
Laryngitis
subjects affected / exposed	0 / 18 (0.00%)	0 / 27 (0.00%)	1 / 31 (3.23%)	0 / 48 (0.00%)
occurrences all number	0	0	1	0
Nasopharyngitis
subjects affected / exposed	0 / 18 (0.00%)	2 / 27 (7.41%)	2 / 31 (6.45%)	3 / 48 (6.25%)
occurrences all number	0	2	2	3
Oral Herpes
subjects affected / exposed	0 / 18 (0.00%)	0 / 27 (0.00%)	1 / 31 (3.23%)	0 / 48 (0.00%)
occurrences all number	0	0	1	0
Pulpitis Dental
subjects affected / exposed	0 / 18 (0.00%)	0 / 27 (0.00%)	1 / 31 (3.23%)	0 / 48 (0.00%)
occurrences all number	0	0	1	0
Cystitis
subjects affected / exposed	0 / 18 (0.00%)	0 / 27 (0.00%)	0 / 31 (0.00%)	1 / 48 (2.08%)
occurrences all number	0	0	0	1
Skin Bacterial Infection
subjects affected / exposed	1 / 18 (5.56%)	0 / 27 (0.00%)	0 / 31 (0.00%)	0 / 48 (0.00%)
occurrences all number	1	0	0	0
Sinusitis
subjects affected / exposed	0 / 18 (0.00%)	1 / 27 (3.70%)	0 / 31 (0.00%)	0 / 48 (0.00%)
occurrences all number	0	1	0	0
Rhinolaryngitis
subjects affected / exposed	0 / 18 (0.00%)	0 / 27 (0.00%)	0 / 31 (0.00%)	1 / 48 (2.08%)
occurrences all number	0	0	0	1
Rash Pustular
subjects affected / exposed	0 / 18 (0.00%)	0 / 27 (0.00%)	0 / 31 (0.00%)	1 / 48 (2.08%)
occurrences all number	0	0	0	1
Staphylococcal Skin Infection
subjects affected / exposed	0 / 18 (0.00%)	1 / 27 (3.70%)	0 / 31 (0.00%)	0 / 48 (0.00%)
occurrences all number	0	1	0	0
Vulvovaginal Candidiasis
subjects affected / exposed	0 / 18 (0.00%)	0 / 27 (0.00%)	0 / 31 (0.00%)	1 / 48 (2.08%)
occurrences all number	0	0	0	1
Viral Upper Respiratory Tract Infection
subjects affected / exposed	0 / 18 (0.00%)	0 / 27 (0.00%)	0 / 31 (0.00%)	2 / 48 (4.17%)
occurrences all number	0	0	0	2
Urinary Tract Infection Bacterial
subjects affected / exposed	0 / 18 (0.00%)	0 / 27 (0.00%)	0 / 31 (0.00%)	2 / 48 (4.17%)
occurrences all number	0	0	0	2
Upper Respiratory Tract Infection Bacterial
subjects affected / exposed	0 / 18 (0.00%)	0 / 27 (0.00%)	1 / 31 (3.23%)	0 / 48 (0.00%)
occurrences all number	0	0	1	0
Upper Respiratory Tract Infection
subjects affected / exposed	0 / 18 (0.00%)	0 / 27 (0.00%)	1 / 31 (3.23%)	0 / 48 (0.00%)
occurrences all number	0	0	1	0
Tinea Pedis
subjects affected / exposed	0 / 18 (0.00%)	0 / 27 (0.00%)	0 / 31 (0.00%)	1 / 48 (2.08%)
occurrences all number	0	0	0	1
Systemic Viral Infection
subjects affected / exposed	0 / 18 (0.00%)	0 / 27 (0.00%)	1 / 31 (3.23%)	0 / 48 (0.00%)
occurrences all number	0	0	1	0
Metabolism and nutrition disorders
Decreased Appetite
subjects affected / exposed	0 / 18 (0.00%)	1 / 27 (3.70%)	0 / 31 (0.00%)	0 / 48 (0.00%)
occurrences all number	0	1	0	0
Food Aversion
subjects affected / exposed	0 / 18 (0.00%)	0 / 27 (0.00%)	0 / 31 (0.00%)	1 / 48 (2.08%)
occurrences all number	0	0	0	1
Hypercholesterolaemia
subjects affected / exposed	0 / 18 (0.00%)	1 / 27 (3.70%)	0 / 31 (0.00%)	0 / 48 (0.00%)
occurrences all number	0	1	0	0

More information

Top of page

Were there any global substantial amendments to the protocol? Yes

08 Jul 2021

To incorporate feedback from health authorities as well as other clarifications and corrections deemed necessary by the Sponsor. Correction and clarification were done in the schedule of activities and inclusion criteria. Consistency was provided in Pregnancy section. In addition, other minor editorial changes (e.g., grammatical and minor typographical error corrections) were implemented throughout the protocol.

03 Jan 2022

The main reason was to evaluate the efficacy and safety of two dose regimen of rilzabrutinib, the current dose regimen of 400 mg BID and an additional higher regimen of 400 mg TID in two staggered double-blind cohorts for a total number of 120 participants split as follows: The total number of participants in the BID cohort was reduced from 70 to 50 (n=30 rilzabrutinib / 20 matching placebo); The total number of participants in the TID cohort is 70 (n=42 rilzabrutinib / 28 matching placebo). Bruton’s tyrosine kinase (BTK) appeared as an attractive drug target in AD by inhibiting the dysregulated signaling and activation of the pathogenic cells B-cells, mast cells and basophils implicated in skin inflammation suggesting the presence of both Type 1 and Type 2 inflammation as per the Gell and Coombs classification (Type 1 being an immediate hypersensitivity mediated by IgE and Type 2b being mediated by IgG autoantibody). The basophil histamine release assay (BHRA) had been used in assessing endotypes of chronic spontaneous urticaria. Those with BHRA- results were classified as Type 1 (immediate hypersensitivity mediated by IgE) while those with BHRA+ results were classified as Type 2b (mediated by IgG autoantibody). This endotype classification system had been demonstrated to contribute to clinical responses to BTK inhibitors. BHRA had not been studied extensively in AD. Thus, determining the BHRA status at baseline and end of study would provide epidemiology of BHRA classification in AD and assess if a given endotype had a better response to BTK inhibitor or not. In addition, clarifications and corrections had been made based on feedback from study sites. In addition, other minor editorial changes were implemented throughout the protocol. Administrative changes in the cover page were done. Clarification was provided in schedule of activities, study intervention(s) and concomitant therapy, eligibility criteria. Template language update was made.

24 Aug 2022

Inclusion and exclusion criteria were updated. In addition, clarifications and corrections deemed necessary by Sponsor were implemented. Administrative change to comply with Sanofi standard format was added. Clarification and accuracy in synopsis, schema, overall design, population for analysis, schedule of activities, study intervention compliance, concomitant therapy was provided. Updated information with the current investigator brochure. Changes were made for clarification in Clinical Safety laboratory assessments, AESI and exploratory endpoint.

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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Clinical trials

Clinical Trial Results: A Phase 2, randomized, double-blind, placebo-controlled, multicenter proof-of-concept study evaluating efficacy and safety of rilzabrutinib in adult patients with moderate to severe atopic dermatitis who are inadequate responders or intolerant to topical corticosteroids

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Percent Change From Baseline to Week 16 in Eczema Area and Severity Index (EASI) Score

Primary: Percent Change From Baseline to Week 16 in Eczema Area and Severity Index (EASI) Score

Secondary: Percentage of Participants With Investigator's Global Assessment (IGA) of 0 or 1 At Week 16

Secondary: Percentage of Participants With Investigator's Global Assessment (IGA) of 0 or 1 At Week 16

Secondary: Percentage of Participants Achieving EASI-75 (Reduction of EASI Score By ≥75% From Baseline) At Week 16

Secondary: Percentage of Participants Achieving EASI-75 (Reduction of EASI Score By ≥75% From Baseline) At Week 16

Secondary: Percentage Of Participants With Reduction of Weekly Average of Daily Peak Pruritus Numerical Rating Scale (PP-NRS) of ≥4 Points From Baseline at Week 16

Secondary: Percentage Of Participants With Reduction of Weekly Average of Daily Peak Pruritus Numerical Rating Scale (PP-NRS) of ≥4 Points From Baseline at Week 16

Secondary: Number of Participants With Weekly Average of Daily PP-NRS Reduction ≥4 From Baseline During The 16-Week Treatment Period

Secondary: Number of Participants With Weekly Average of Daily PP-NRS Reduction ≥4 From Baseline During The 16-Week Treatment Period

Secondary: Absolute Change From Baseline to Week 16 in EASI Score

Secondary: Absolute Change From Baseline to Week 16 in EASI Score

Secondary: Percentage of Participants Achieving EASI-50/90 (Reduction of EASI Score by ≥50% or ≥90% From Baseline) at Week 16

Secondary: Percentage of Participants Achieving EASI-50/90 (Reduction of EASI Score by ≥50% or ≥90% From Baseline) at Week 16

Secondary: Change From Baseline to Week 16 in Percent BSA of AD

Secondary: Change From Baseline to Week 16 in Percent BSA of AD

Secondary: Absolute Change From Baseline to Week 16 in Weekly Average of Daily PP-NRS

Secondary: Absolute Change From Baseline to Week 16 in Weekly Average of Daily PP-NRS

Secondary: Percent Change From Baseline to Week 16 in Weekly Average of Daily PP-NRS

Secondary: Percent Change From Baseline to Week 16 in Weekly Average of Daily PP-NRS

Secondary: Percentage of Participants Achieving IGA*BSA-50/75/90 (Reduction of IGA*BSA by ≥50% or 75% or 90% From Baseline) At Week 16

Secondary: Percentage of Participants Achieving IGA*BSA-50/75/90 (Reduction of IGA*BSA by ≥50% or 75% or 90% From Baseline) At Week 16

Secondary: Number Of Participants With Treatment-Emergent Adverse Events (TEAEs), Treatment-Emergent Serious Adverse Events (TESAEs), Adverse Events of Special Interest (AESIs) and Study intervention Discontinuation

Secondary: Number Of Participants With Treatment-Emergent Adverse Events (TEAEs), Treatment-Emergent Serious Adverse Events (TESAEs), Adverse Events of Special Interest (AESIs) and Study intervention Discontinuation

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A Phase 2, randomized, double-blind, placebo-controlled, multicenter proof-of-concept study evaluating efficacy and safety of rilzabrutinib in adult patients with moderate to severe atopic dermatitis who are inadequate responders or intolerant to topical corticosteroids

Secondary: Percentage of Participants Achieving IGABSA-50/75/90 (Reduction of IGABSA by ≥50% or 75% or 90% From Baseline) At Week 16

Secondary: Percentage of Participants Achieving IGABSA-50/75/90 (Reduction of IGABSA by ≥50% or 75% or 90% From Baseline) At Week 16