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Clinical Trial Results:
A Phase 2b Dose-finding Study for SAR442168, a Bruton's Tyrosine Kinase Inhibitor, in Participants With Relapsing Multiple Sclerosis

Summary
EudraCT number	2018-003927-12
Trial protocol	SE ES NL SK EE
Global end of trial date	02 Jan 2020

Results information
Results version number	v1(current)
This version publication date	31 Dec 2020
First version publication date	31 Dec 2020
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

DRI15928

ISRCTN number

US NCT number

NCT03889639

WHO universal trial number (UTN)

U1111-1220-0572

Sponsor organisation name

Sanofi aventis recherche & développement

Sponsor organisation address

1 avenue Pierre Brossolette, Chilly-Mazarin, France, 91380

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

16 Jan 2020

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

02 Jan 2020

Was the trial ended prematurely?

Main objective of the trial

To determine the dose-response relationship for SAR442168 to reduce the number of new active brain lesions.

Protection of trial subjects

Subjects were fully informed of all pertinent aspects of the clinical trial as well as the possibility to discontinue at any time in language and terms appropriate for the subject and considering the local culture. During the course of the trial, subjects were provided with individual subject cards indicating the nature of the trial the subject 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

29 Mar 2019

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Czech Republic: 31

Country: Number of subjects enrolled

Canada: 5

Country: Number of subjects enrolled

Spain: 7

Country: Number of subjects enrolled

Estonia: 8

Country: Number of subjects enrolled

France: 2

Country: Number of subjects enrolled

Netherlands: 1

Country: Number of subjects enrolled

Russian Federation: 28

Country: Number of subjects enrolled

Slovakia: 1

Country: Number of subjects enrolled

Ukraine: 26

Country: Number of subjects enrolled

United States: 21

Worldwide total number of subjects

130

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)

130

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

The study was conducted at 44 active centers in 10 countries. A total of 168 subjects were screened from 29-March-2019 to 29-August-2019, of which 38 subjects were screen failures. Screen failures were mainly due to selection criteria not met.

Screening details

A total of 130 subjects were randomised and treated in this study. Subjects were centrally assigned to 1 of 8 arms (4 dose groups at an equal ratio to start with SAR442168 [all considered as Cohort 1] or placebo [all considered as Cohort 2]).

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

Are arms mutually exclusive

Yes

Cohort 1: SAR442168 5 mg Then Placebo

Arm description

Subjects received SAR442168 5 milligrams (mg), orally once daily for first 12 weeks then crossed over to matching placebo orally once daily for 4 weeks during the 16 weeks treatment period. To maintain the blinding, each subject was given a total of 4 tablets daily, either of SAR442168 or SAR442168 and placebo, to achieve the specified daily dose of SAR442168.

Arm type

Experimental

Investigational medicinal product name

SAR442168

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Subjects received SAR442168 5 mg once daily, with or without food.

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Subjects received placebo matching to SAR442168 (up to 4 tablets) once daily, with or without food.

Cohort 1: SAR442168 15 mg Then Placebo

Arm description

Subjects received SAR442168 15 mg, orally once daily for first 12 weeks then crossed over to matching placebo orally once daily for 4 weeks during the 16 weeks treatment period. To maintain the blinding, each subject was given a total of 4 tablets daily, either of SAR442168 or SAR442168 and placebo, to achieve the specified daily dose of SAR442168.

Arm type

Experimental

Investigational medicinal product name

SAR442168

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Subjects received SAR442168 15 mg once daily, with or without food.

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Subjects received placebo matching to SAR442168 (up to 4 tablets) once daily, with or without food.

Cohort 1: SAR442168 30 mg Then Placebo

Arm description

Subjects received SAR442168 30 mg, orally once daily for first 12 weeks then crossed over to matching placebo orally once daily for 4 weeks during the 16 weeks treatment period. To maintain the blinding, each subject was given a total of 4 tablets daily, either of SAR442168 or SAR442168 and placebo, to achieve the specified daily dose of SAR442168.

Arm type

Experimental

Investigational medicinal product name

SAR442168

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Subjects received SAR442168 30 mg once daily, with or without food.

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Subjects received placebo matching to SAR442168 (up to 4 tablets) once daily, with or without food.

Cohort 1: SAR442168 60 mg Then Placebo

Arm description

Subjects received SAR442168 60 mg, orally once daily for first 12 weeks then crossed over to matching placebo orally once daily for 4 weeks during the 16 weeks treatment period. To maintain the blinding, each subject was given a total of 4 tablets daily, either of SAR442168 or SAR442168 and placebo, to achieve the specified daily dose of SAR442168.

Arm type

Experimental

Investigational medicinal product name

SAR442168

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Subjects received SAR442168 60 mg once daily, with or without food.

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Subjects received placebo matching to SAR442168 (up to 4 tablets) once daily, with or without food.

Cohort 2: Placebo Then SAR442168 5 mg

Arm description

Subjects received placebo matching to SAR442168 tablets, orally once daily for first 4 weeks then crossed over to SAR442168 5 mg orally once daily for 12 weeks during the 16 weeks treatment period. To maintain the blinding, each subject was given a total of 4 tablets daily, either of SAR442168 or SAR442168 and placebo, to achieve the specified daily dose of SAR442168.

Arm type

Experimental

Investigational medicinal product name

SAR442168

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Subjects received SAR442168 5 mg once daily, with or without food.

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Subjects received placebo matching to SAR442168 (up to 4 tablets) once daily, with or without food.

Cohort 2: Placebo Then SAR442168 15 mg

Arm description

Subjects received placebo matching to SAR442168 tablets, orally once daily for first 4 weeks then crossed over to SAR442168 15 mg orally once daily for 12 weeks during the 16 weeks treatment period. To maintain the blinding, each subject was given a total of 4 tablets daily, either of SAR442168 or SAR442168 and placebo, to achieve the specified daily dose of SAR442168.

Arm type

Experimental

Investigational medicinal product name

SAR442168

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Subjects received SAR442168 15 mg once daily, with or without food.

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Subjects received placebo matching to SAR442168 (up to 4 tablets) once daily, with or without food.

Cohort 2: Placebo Then SAR442168 30 mg

Arm description

Subjects received placebo matching to SAR442168 tablets, orally once daily for first 4 weeks then crossed over to SAR442168 30 mg orally once daily for 12 weeks during the 16 weeks treatment period. To maintain the blinding, each subject was given a total of 4 tablets daily, either of SAR442168 or SAR442168 and placebo, to achieve the specified daily dose of SAR442168.

Arm type

Experimental

Investigational medicinal product name

SAR442168

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Subjects received SAR442168 30 mg once daily, with or without food.

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Subjects received placebo matching to SAR442168 (up to 4 tablets) once daily, with or without food.

Cohort 2: Placebo Then SAR442168 60 mg

Arm description

Subjects received placebo matching to SAR442168 tablets, orally once daily for first 4 weeks then crossed over to SAR442168 60 mg orally once daily for 12 weeks during the 16 weeks treatment period. To maintain the blinding, each subject was given a total of 4 tablets daily, either of SAR442168 or SAR442168 and placebo, to achieve the specified daily dose of SAR442168.

Arm type

Experimental

Investigational medicinal product name

SAR442168

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Subjects received SAR442168 60 mg once daily, with or without food.

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Subjects received placebo matching to SAR442168 (up to 4 tablets) once daily, with or without food.

Number of subjects in period 1	Cohort 1: SAR442168 5 mg Then Placebo	Cohort 1: SAR442168 15 mg Then Placebo	Cohort 1: SAR442168 30 mg Then Placebo	Cohort 1: SAR442168 60 mg Then Placebo	Cohort 2: Placebo Then SAR442168 5 mg	Cohort 2: Placebo Then SAR442168 15 mg	Cohort 2: Placebo Then SAR442168 30 mg	Cohort 2: Placebo Then SAR442168 60 mg
Started	16	16	16	16	17	16	17	16
Completed	16	16	16	16	17	16	17	15
Not completed	0	0	0	0	0	0	0	1
Withdrawal by subject	-	-	-	-	-	-	-	1

Baseline characteristics

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Reporting group title

Cohort 1: SAR442168 5 mg Then Placebo

Reporting group description

Reporting group title

Cohort 1: SAR442168 15 mg Then Placebo

Reporting group description

Reporting group title

Cohort 1: SAR442168 30 mg Then Placebo

Reporting group description

Reporting group title

Cohort 1: SAR442168 60 mg Then Placebo

Reporting group description

Reporting group title

Cohort 2: Placebo Then SAR442168 5 mg

Reporting group description

Reporting group title

Cohort 2: Placebo Then SAR442168 15 mg

Reporting group description

Reporting group title

Cohort 2: Placebo Then SAR442168 30 mg

Reporting group description

Reporting group title

Cohort 2: Placebo Then SAR442168 60 mg

Reporting group description

Reporting group values	Cohort 1: SAR442168 5 mg Then Placebo	Cohort 1: SAR442168 15 mg Then Placebo	Cohort 1: SAR442168 30 mg Then Placebo	Cohort 1: SAR442168 60 mg Then Placebo	Cohort 2: Placebo Then SAR442168 5 mg	Cohort 2: Placebo Then SAR442168 15 mg	Cohort 2: Placebo Then SAR442168 30 mg	Cohort 2: Placebo Then SAR442168 60 mg	Total
Number of subjects	16	16	16	16	17	16	17	16	130
Age categorical
Units: Subjects
Age continuous
Units: years
arithmetic mean (standard deviation)	37.4 ± 11.1	35.1 ± 7.9	40.8 ± 8.7	38.1 ± 9.1	34.8 ± 8.6	36.7 ± 10.7	37.5 ± 11.6	36.1 ± 8.7	-
Gender categorical
Units: Subjects
Female	9	10	11	15	16	11	10	9	91
Male	7	6	5	1	1	5	7	7	39
Race
Units: Subjects
White	15	15	13	15	17	14	16	14	119
Black or African American	1	0	2	1	0	1	0	1	6
Asian	0	0	0	0	0	0	0	1	1
Multiple	0	0	0	0	0	1	0	0	1
Not Reported	0	1	1	0	0	0	1	0	3

End points

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Reporting group title

Cohort 1: SAR442168 5 mg Then Placebo

Reporting group description

Reporting group title

Cohort 1: SAR442168 15 mg Then Placebo

Reporting group description

Reporting group title

Cohort 1: SAR442168 30 mg Then Placebo

Reporting group description

Reporting group title

Cohort 1: SAR442168 60 mg Then Placebo

Reporting group description

Reporting group title

Cohort 2: Placebo Then SAR442168 5 mg

Reporting group description

Reporting group title

Cohort 2: Placebo Then SAR442168 15 mg

Reporting group description

Reporting group title

Cohort 2: Placebo Then SAR442168 30 mg

Reporting group description

Reporting group title

Cohort 2: Placebo Then SAR442168 60 mg

Reporting group description

Subject analysis set title

Cohort 2: Pooled Placebo

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

All subjects who received placebo matching to SAR442168 orally once daily for first 4 weeks during the 16 weeks treatment period.

Subject analysis set title

Cohorts 1 and 2: SAR442168 5 mg

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

All subjects who received SAR442168 5 mg orally once daily for 12 weeks (either in Cohort 1 or 2) during the 16 weeks treatment period.

Subject analysis set title

Cohorts 1 and 2: SAR442168 15 mg

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

All subjects who received SAR442168 15 mg orally once daily for 12 weeks (either in Cohort 1 or 2) during the 16 weeks treatment period.

Subject analysis set title

Cohorts 1 and 2: SAR442168 30 mg

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

All subjects who received SAR442168 30 mg orally once daily for 12 weeks (either in Cohort 1 or 2) during the 16 weeks treatment period.

Subject analysis set title

Cohorts 1 and 2: SAR442168 60 mg

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

All subjects who received SAR442168 60 mg orally once daily for 12 weeks (either in Cohort 1 or 2) during the 16 weeks treatment period.

Subject analysis set title

Cohort 1: SAR442168 5 mg

Subject analysis set type

Safety analysis

Subject analysis set description

All subjects who received SAR442168 5 mg orally once daily in Cohort 1.

Subject analysis set title

Cohort 1: SAR442168 15 mg

Subject analysis set type

Safety analysis

Subject analysis set description

Subjects who received SAR442168 15 mg orally once daily in Cohort 1.

Subject analysis set title

Cohort 1: SAR442168 30 mg

Subject analysis set type

Safety analysis

Subject analysis set description

Subjects who received SAR442168 30 mg orally once daily in Cohort 1.

Subject analysis set title

Cohort 1: SAR442168 60 mg

Subject analysis set type

Safety analysis

Subject analysis set description

Subjects who received SAR442168 60 mg orally once daily in Cohort 1.

Primary: Brain Magnetic Resonance Imaging (MRI) Assessment: Number of New Gadolinium (Gd) Enhancing T1-hyperintense Lesions

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End point title

Brain Magnetic Resonance Imaging (MRI) Assessment: Number of New Gadolinium (Gd) Enhancing T1-hyperintense Lesions

End point description

Number of new Gd-enhancing T1-hyperintense lesions was detected by brain MRI at the end of 12 weeks of SAR442168 treatment (i.e., at Week 12 for Cohort 1 subjects and Week 16 for Cohort 2 subjects). Analysis was performed on modified intent-to-treat (mITT) population that included all randomly assigned subjects exposed to the study drug, analysed according to the treatment assigned by randomisation. Data was planned to be collected and analysed on pooled population of subjects at each dose level of SAR442168 (either in Cohort 1 and 2) and pooled population of subjects receiving Placebo in Cohort 2 and was not planned to collected during placebo administration in Cohort 1 (Weeks 12 to 16). Here, “number of subjects analysed” signifies number of subjects evaluable for this endpoint.

End point type

Primary

End point timeframe

After 12 weeks of SAR442168 treatment for SAR442168 reporting arms (i.e., at Week 12 for Cohort 1 subjects, at Week 16 for Cohort 2 subjects) and at Week 4 for Cohort 2 placebo

End point values	Cohort 2: Pooled Placebo	Cohorts 1 and 2: SAR442168 5 mg	Cohorts 1 and 2: SAR442168 15 mg	Cohorts 1 and 2: SAR442168 30 mg	Cohorts 1 and 2: SAR442168 60 mg
Number of subjects analysed	59	31	31	33	31
Units: lesions
arithmetic mean (standard deviation)	1.03 ± 2.50	1.39 ± 3.20	0.77 ± 1.48	0.76 ± 3.31	0.13 ± 0.43

SAR442168 5 mg/Placebo

Statistical analysis description

Relative reduction in lesions in SAR442168 5 mg (Cohorts 1 and 2) when compared with placebo (Cohort 2) with 95 percentage (%) confidence interval (CI) were reported. Analysis was performed using a negative binomial regression model adjusted for baseline gadolinium-enhancing T1-hyperintense lesion activity (presence/absence).

Comparison groups

Cohorts 1 and 2: SAR442168 5 mg v Cohort 2: Pooled Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1673 ^[1]

Method

Negative binomial regression model

Parameter type

Relative reduction in lesions

Point estimate

-56.16

Confidence interval

level

95%

sides

2-sided

lower limit

-193.99

upper limit

17.05

Notes
[1] - Threshold for significance for p value was 0.05.

SAR442168 15 mg/Placebo

Statistical analysis description

Relative reduction in lesions in SAR442168 15 mg (Cohorts 1 and 2) when compared with placebo (Cohort 2) with 95% CI were reported. Analysis was performed using a negative binomial regression model adjusted for baseline gadolinium-enhancing T1-hyperintense lesion activity (presence/absence).

Comparison groups

Cohorts 1 and 2: SAR442168 15 mg v Cohort 2: Pooled Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.354 ^[2]

Method

Negative binomial regression model

Parameter type

Relative reduction in lesions

Point estimate

-62.8

Confidence interval

level

95%

sides

2-sided

lower limit

-356.24

upper limit

41.91

Notes
[2] - Threshold for significance for p value was 0.05.

SAR442168 30 mg/Placebo

Statistical analysis description

Relative reduction in lesions in SAR442168 30 mg (Cohorts 1 and 2) when compared with placebo (Cohort 2) with 95% CI were reported. Analysis was performed using a negative binomial regression model adjusted for baseline gadolinium-enhancing T1-hyperintense lesion activity (presence/absence).

Comparison groups

Cohorts 1 and 2: SAR442168 30 mg v Cohort 2: Pooled Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.7674 ^[3]

Method

Negative binomial regression model

Parameter type

Relative reduction in lesions

Point estimate

13.49

Confidence interval

level

95%

sides

2-sided

lower limit

-126.05

upper limit

66.89

Notes
[3] - Threshold for significance for p value was 0.05.

SAR442168 60 mg/Placebo

Statistical analysis description

Relative reduction in lesions in SAR442168 60 mg (Cohorts 1 and 2) when compared with placebo (Cohort 2) with 95% CI were reported. Analysis was performed using a negative binomial regression model adjusted for baseline gadolinium-enhancing T1-hyperintense lesion activity (presence/absence).

Comparison groups

Cohorts 1 and 2: SAR442168 60 mg v Cohort 2: Pooled Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0178 ^[4]

Method

Negative binomial regression model

Parameter type

Relative reduction in lesions

Point estimate

85.02

Confidence interval

level

95%

sides

2-sided

lower limit

28.02

upper limit

96.88

Notes
[4] - Threshold for significance for p value was 0.05.

Secondary: Number of New or Enlarging T2 Lesions

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End point title

Number of New or Enlarging T2 Lesions

End point description

Number of new and enlarging T2 lesions was detected by brain MRI at the end of 12 weeks of SAR442168 treatment (i.e. at Week 12 for Cohort 1 subjects and Week 16 for Cohort 2 subjects). Analysis was performed on mITT population. Data was planned to be collected and analysed on pooled population of subjects at each dose level of SAR442168 (either in Cohort 1 and 2) and pooled population of subjects receiving Placebo in Cohort 2 and was not planned to collected during placebo administration in Cohort 1 (Week 12 to 16). Here, “number of subjects analysed” signifies number of subjects evaluable for this endpoint.

End point type

Secondary

End point timeframe

After 12 weeks of SAR442168 treatment for SAR442168 reporting arms (i.e. at Week 12 for Cohort 1 subjects, at Week 16 for Cohort 2 subjects), and at Week 4 for Cohort 2 placebo

End point values	Cohort 2: Pooled Placebo	Cohorts 1 and 2: SAR442168 5 mg	Cohorts 1 and 2: SAR442168 15 mg	Cohorts 1 and 2: SAR442168 30 mg	Cohorts 1 and 2: SAR442168 60 mg
Number of subjects analysed	59	31	31	33	31
Units: lesions
arithmetic mean (standard deviation)	2.12 ± 5.16	1.90 ± 3.97	1.32 ± 1.83	1.30 ± 4.90	0.23 ± 0.62

SAR442168 5 mg/Placebo

Statistical analysis description

Relative reduction in lesions in SAR442168 5 mg (Cohorts 1 and 2) when compared with placebo (Cohort 2) with 95% CI were reported. Analysis was performed using a negative binomial regression model without adjusting for baseline T2 lesion activity as all subjects had at least one T2 lesion at baseline.

Comparison groups

Cohorts 1 and 2: SAR442168 5 mg v Cohort 2: Pooled Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.7736 ^[5]

Method

Negative binomial regression model

Parameter type

Relative reduction in lesions

Point estimate

10.17

Confidence interval

level

95%

sides

2-sided

lower limit

-86.49

upper limit

56.73

Notes
[5] - Threshold for significance for p value was 0.05.

SAR442168 15 mg/Placebo

Statistical analysis description

Relative reduction in lesions in SAR442168 15 mg (Cohorts 1 and 2) when compared with placebo (Cohort 2) with 95% CI were reported. Analysis was performed using a negative binomial regression model without adjusting for baseline T2 lesion activity as all subjects had at least one T2 lesion at baseline.

Comparison groups

Cohorts 1 and 2: SAR442168 15 mg v Cohort 2: Pooled Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.248 ^[6]

Method

Negative binomial regression model

Parameter type

Relative reduction in lesions

Point estimate

37.07

Confidence interval

level

95%

sides

2-sided

lower limit

-38.08

upper limit

71.32

Notes
[6] - Threshold for significance for p value was 0.05.

SAR442168 30 mg/Placebo

Statistical analysis description

Relative reduction in lesions in SAR442168 30 mg (Cohort 1 and 2) when compared with placebo (Cohort 2) with 95% CI were reported. Analysis was performed using a negative binomial regression model without adjusting for baseline T2 lesion activity as all subjects had at least one T2 lesion at baseline.

Comparison groups

Cohorts 1 and 2: SAR442168 30 mg v Cohort 2: Pooled Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3081 ^[7]

Method

Negative binomial regression model

Parameter type

Relative reduction in lesions

Point estimate

38.5

Confidence interval

level

95%

sides

2-sided

lower limit

-56.61

upper limit

75.85

Notes
[7] - Threshold for significance for p value was 0.05.

SAR442168 60 mg/Placebo

Statistical analysis description

Relative reduction in lesions in SAR442168 60 mg (Cohorts 1 and 2) when compared with placebo (Cohort 2) with 95% CI were reported. Analysis was performed using a negative binomial regression model without adjusting for baseline T2 lesion activity as all subjects had at least one T2 lesion at baseline.

Comparison groups

Cohorts 1 and 2: SAR442168 60 mg v Cohort 2: Pooled Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0001 ^[8]

Method

Negative binomial regression model

Parameter type

Relative reduction in lesions

Point estimate

89.34

Confidence interval

level

95%

sides

2-sided

lower limit

68.39

upper limit

96.41

Notes
[8] - Threshold for significance for p value was 0.05.

Secondary: Total Number of Gd-enhancing T1-hyperintense Lesions

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End point title

Total Number of Gd-enhancing T1-hyperintense Lesions

End point description

Total number of Gd-enhancing T1-hyperintense lesions was detected by brain MRI at the end of 12 weeks of SAR442168 treatment (i.e., at Week 12 for Cohort 1 subjects and Week 16 for Cohort 2 subjects). Analysis was performed on mITT population. Data was planned to be collected and analysed on pooled population of subjects at each dose level of SAR442168 (either in Cohort 1 and 2) and pooled population of subjects receiving Placebo in Cohort 2 and was not planned to collected during placebo administration in Cohort 1 (Weeks 12 to 16) . Here, “number of subjects analysed” signifies number of subjects evaluable for this endpoint.

End point type

Secondary

End point timeframe

After 12 weeks of SAR442168 treatment for SAR442168 reporting arms (i.e. at Week 12 for Cohort 1 subjects, at Week 16 for Cohort 2 subjects), and at Week 4 for Cohort 2 placebo

End point values	Cohort 2: Pooled Placebo	Cohorts 1 and 2: SAR442168 5 mg	Cohorts 1 and 2: SAR442168 15 mg	Cohorts 1 and 2: SAR442168 30 mg	Cohorts 1 and 2: SAR442168 60 mg
Number of subjects analysed	59	31	31	33	31
Units: lesions
arithmetic mean (standard deviation)	1.36 ± 3.52	1.77 ± 4.10	0.87 ± 1.59	1.18 ± 4.87	0.29 ± 0.86

SAR442168 5 mg/Placebo

Statistical analysis description

Relative reduction in lesions in SAR442168 5 mg (Cohorts 1 and 2) when compared with placebo (Cohort 2) with 95% CI were reported. Analysis was performed using a negative binomial regression model adjusted for baseline gadolinium-enhancing T1-hyperintense lesion activity (presence/absence).

Comparison groups

Cohorts 1 and 2: SAR442168 5 mg v Cohort 2: Pooled Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1525 ^[9]

Method

Negative binomial regression model

Parameter type

Relative reduction in lesions

Point estimate

-62.16

Confidence interval

level

95%

sides

2-sided

lower limit

-214.44

upper limit

16.38

Notes
[9] - Threshold for significance for p value was 0.05.

SAR442168 15 mg/Placebo

Statistical analysis description

Comparison groups

Cohorts 1 and 2: SAR442168 15 mg v Cohort 2: Pooled Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.4606 ^[10]

Method

Negative binomial regression model

Parameter type

Relative reduction in lesions

Point estimate

-47.38

Confidence interval

level

95%

sides

2-sided

lower limit

-312.91

upper limit

47.4

Notes
[10] - Threshold for significance for p value was 0.05.

SAR442168 30 mg/Placebo

Statistical analysis description

Comparison groups

Cohorts 1 and 2: SAR442168 30 mg v Cohort 2: Pooled Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.949 ^[11]

Method

Negative binomial regression model

Parameter type

Relative reduction in lesions

Point estimate

2.9

Confidence interval

level

95%

sides

2-sided

lower limit

-138.96

upper limit

60.54

Notes
[11] - Threshold for significance for p value was 0.05.

SAR442168 60 mg/Placebo

Statistical analysis description

Comparison groups

Cohorts 1 and 2: SAR442168 60 mg v Cohort 2: Pooled Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.2324 ^[12]

Method

Negative binomial regression model

Parameter type

Relative reduction in lesions

Point estimate

65.05

Confidence interval

level

95%

sides

2-sided

lower limit

-96.21

upper limit

93.77

Notes
[12] - Threshold for significance for p value was 0.05.

Secondary: Number of Subjects With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs): Weeks 1-4 Period

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End point title

Number of Subjects With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs): Weeks 1-4 Period

End point description

Adverse event (AE):any unfavorable and unintended sign, symptom, or disease temporally associated with use of study drug. Serious AE (SAE):any untoward medical occurrence that, at any dose resulted in death, life-threatening, inpatient hospitalisation or prolongation of existing hospitalisation, disability/incapacity, congenital anomaly/birth defect, or medical event. TEAEs:AEs that developed, worsened, or became serious during on-treatment period(for this endpoint- “Weeks 1 to 4 period”: time from 1st administration of study drug to Week4). Cohorts 1 and 2 received SAR442168 and placebo for 1st 4weeks, respectively. Safety population:all subjects from randomised population who had received at least 1 dose or part of dose of study drug. Data was planned to be collected and analysed on subjects at each dose level of SAR442168 in Cohort 1 and pooled population of subjects receiving Placebo in Cohort2 and not planned to be collected during Cohort1 Placebo administration (Weeks 12 to 16).

End point type

Secondary

End point timeframe

From Baseline up to Week 4

End point values	Cohort 2: Pooled Placebo	Cohort 1: SAR442168 5 mg	Cohort 1: SAR442168 15 mg	Cohort 1: SAR442168 30 mg	Cohort 1: SAR442168 60 mg
Number of subjects analysed	66	16	16	16	16
Units: subjects
TEAE	23	5	3	2	5
TESAE	0	0	0	0	0

No statistical analyses for this end point

Secondary: Number of Subjects With Treatment-emergent Adverse Events and Treatment-emergent Serious Adverse Events: SAR442168 Treatment Period

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End point title

Number of Subjects With Treatment-emergent Adverse Events and Treatment-emergent Serious Adverse Events: SAR442168 Treatment Period

End point description

AE: any unfavorable and unintended sign (including abnormal laboratory finding), symptom, or disease temporally associated with use of study drug. SAE: any untoward medical occurrence that, at any dose resulted in death, was life-threatening, required inpatient hospitalisation or prolongation of existing hospitalisation, persistent disability/incapacity, congenital anomaly/birth defect, or medical event. TEAEs: AEs that developed, worsened, or became serious during on-treatment period (for this endpoint defined as “SAR442168 treatment period” which was considered as Weeks 1 to 12 for Cohort 1 and Weeks 4 to 16 for Cohort 2). Data was planned to be collected and analysed on pooled subjects at each dose level of SAR442168 (either in Cohort 1 or 2), and was not planned to be collected during placebo administration in either Cohort 1 or 2. Analysis was performed on safety population. Here, “number of subjects analysed” signifies number of subjects evaluable for this treatment period.

End point type

Secondary

End point timeframe

Weeks 1 to 12 for Cohort 1 subjects and Weeks 4 to 16 for Cohort 2 subjects

End point values	Cohorts 1 and 2: SAR442168 5 mg	Cohorts 1 and 2: SAR442168 15 mg	Cohorts 1 and 2: SAR442168 30 mg	Cohorts 1 and 2: SAR442168 60 mg
Number of subjects analysed	33	32	33	32
Units: subjects
TEAE	19	17	18	16
TESAE	0	0	0	1

No statistical analyses for this end point

Secondary: Number of Subjects With Individual Clinically Relevant Abnormalities in Laboratory Tests (Haematology, Chemistry, Urinalysis), Vital Signs, and Electrocardiograms (ECG)

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End point title

Number of Subjects With Individual Clinically Relevant Abnormalities in Laboratory Tests (Haematology, Chemistry, Urinalysis), Vital Signs, and Electrocardiograms (ECG)

End point description

Individual clinically relevant abnormalities: Potentially clinically significant abnormalities (PCSA) considered as SAEs or TEAEs leading to study treatment discontinuation or study discontinuation during the on-treatment period (time from first study drug administration until Week 16), considering all evaluations performed during the on-treatment period that included unscheduled or repeated evaluations. Analysis was performed on safety population. Data was planned to be collected and analysed on pooled population of subjects at each dose level of SAR442168 (either in Cohort 1 or 2), and pooled population of subjects receiving Placebo in Cohort 2 and was not planned to be collected during placebo administration in Cohort 1 (Weeks 12 to 16).

End point type

Secondary

End point timeframe

Baseline up to Week 12 for Cohort 1 subjects; Baseline up to Week 4 for Cohort 2 Placebo and from Week 4 to 16 for Cohort 2 SAR442168 receiving subjects

End point values	Cohort 2: Pooled Placebo	Cohorts 1 and 2: SAR442168 5 mg	Cohorts 1 and 2: SAR442168 15 mg	Cohorts 1 and 2: SAR442168 30 mg	Cohorts 1 and 2: SAR442168 60 mg
Number of subjects analysed	66	33	32	33	32
Units: subjects
Haematology	0	0	0	0	0
Chemistry	0	0	0	0	0
Urinalysis	0	0	0	0	0
Vital Signs	0	0	0	0	0
ECGs	0	0	0	0	0

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

All AEs were collected from the signature of the informed consent form until the end of the study (Week 16) regardless of seriousness or relationship to study drug.

Adverse event reporting additional description

Reported AEs and deaths are TEAEs that developed, worsened, or became serious during the treatment- emergent period (time from the first dose of study treatment up to 30 days after last dose of study.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

22.1

Reporting group title

Cohort 1: SAR442168 5 mg Then Placebo

Reporting group description

Subjects received SAR442168 5 mg, orally once daily for first 12 weeks then crossed over to matching placebo orally once daily for 4 weeks during the 16 weeks treatment period. To maintain the blinding, eachsubject was given a total of 4 tablets daily, either of SAR442168 or SAR442168 and placebo, to achieve the specified daily dose of SAR442168.

Reporting group title

Cohort 1: SAR442168 15 mg Then Placebo

Reporting group description

Reporting group title

Cohort 1: SAR442168 30 mg Then Placebo

Reporting group description

Reporting group title

Cohort 1: SAR442168 60 mg Then Placebo

Reporting group description

Reporting group title

Cohort 2: Placebo Then SAR442168 5 mg

Reporting group description

Reporting group title

Cohort 2: Placebo then SAR442168 15 mg

Reporting group description

Reporting group title

Cohort 2: Placebo Then SAR442168 30 mg

Reporting group description

Subjects received placebo matching to SAR442168 tablets, orally once daily for first 4 weeks then crossed over to SAR442168 30 mg orally once daily for 12 weeks during the 16 weeks treatment period. To maintain the blinding, each subject was given a total of 4 tablets daily, either of SAR442168 or SAR442168 andplacebo, to achieve the specified daily dose of SAR442168.

Reporting group title

Cohort 2: Placebo Then SAR442168 60 mg

Reporting group description

Subjects received placebo matching to SAR442168 tablets, orally once daily for first 4 weeks then crossed over to SAR442168 60 mg orally once daily for 12 weeks during the 16 weeks treatment period. To maintain the blinding, each subject was given a total of 4 tablets daily, either of SAR442168 or SAR442168 andplacebo, to achieve the specified daily dose of SAR442168.

Serious adverse events	Cohort 1: SAR442168 5 mg Then Placebo	Cohort 1: SAR442168 15 mg Then Placebo	Cohort 1: SAR442168 30 mg Then Placebo	Cohort 1: SAR442168 60 mg Then Placebo	Cohort 2: Placebo Then SAR442168 5 mg	Cohort 2: Placebo then SAR442168 15 mg	Cohort 2: Placebo Then SAR442168 30 mg	Cohort 2: Placebo Then SAR442168 60 mg
Total subjects affected by serious adverse events
subjects affected / exposed	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 16 (0.00%)	1 / 16 (6.25%)	0 / 17 (0.00%)	0 / 16 (0.00%)	0 / 17 (0.00%)	0 / 16 (0.00%)
number of deaths (all causes)	0	0	0	0	0	0	0	0
number of deaths resulting from adverse events
Nervous system disorders
Multiple Sclerosis Relapse
subjects affected / exposed	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 16 (0.00%)	1 / 16 (6.25%)	0 / 17 (0.00%)	0 / 16 (0.00%)	0 / 17 (0.00%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0

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

Non-serious adverse events	Cohort 1: SAR442168 5 mg Then Placebo	Cohort 1: SAR442168 15 mg Then Placebo	Cohort 1: SAR442168 30 mg Then Placebo	Cohort 1: SAR442168 60 mg Then Placebo	Cohort 2: Placebo Then SAR442168 5 mg	Cohort 2: Placebo then SAR442168 15 mg	Cohort 2: Placebo Then SAR442168 30 mg	Cohort 2: Placebo Then SAR442168 60 mg
Total subjects affected by non serious adverse events
subjects affected / exposed	11 / 16 (68.75%)	8 / 16 (50.00%)	8 / 16 (50.00%)	6 / 16 (37.50%)	13 / 17 (76.47%)	12 / 16 (75.00%)	11 / 17 (64.71%)	11 / 16 (68.75%)
Vascular disorders
Hot Flush
subjects affected / exposed	1 / 16 (6.25%)	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 17 (0.00%)	0 / 16 (0.00%)	0 / 17 (0.00%)	0 / 16 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0
General disorders and administration site conditions
Chronic Fatigue Syndrome
subjects affected / exposed	0 / 16 (0.00%)	0 / 16 (0.00%)	1 / 16 (6.25%)	0 / 16 (0.00%)	0 / 17 (0.00%)	0 / 16 (0.00%)	0 / 17 (0.00%)	0 / 16 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
Fatigue
subjects affected / exposed	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 16 (0.00%)	1 / 16 (6.25%)	1 / 17 (5.88%)	0 / 16 (0.00%)	0 / 17 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	0	0	1	1	0	0	1
Injection Site Erythema
subjects affected / exposed	0 / 16 (0.00%)	0 / 16 (0.00%)	1 / 16 (6.25%)	0 / 16 (0.00%)	0 / 17 (0.00%)	0 / 16 (0.00%)	0 / 17 (0.00%)	0 / 16 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
Oedema Peripheral
subjects affected / exposed	1 / 16 (6.25%)	0 / 16 (0.00%)	0 / 16 (0.00%)	2 / 16 (12.50%)	1 / 17 (5.88%)	0 / 16 (0.00%)	0 / 17 (0.00%)	0 / 16 (0.00%)
occurrences all number	1	0	0	2	1	0	0	0
Pain
subjects affected / exposed	0 / 16 (0.00%)	0 / 16 (0.00%)	1 / 16 (6.25%)	0 / 16 (0.00%)	0 / 17 (0.00%)	0 / 16 (0.00%)	0 / 17 (0.00%)	0 / 16 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
Pyrexia
subjects affected / exposed	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 17 (0.00%)	1 / 16 (6.25%)	0 / 17 (0.00%)	0 / 16 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Immune system disorders
Allergy To Animal
subjects affected / exposed	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 17 (0.00%)	0 / 16 (0.00%)	0 / 17 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	0	0	0	0	0	0	1
Reproductive system and breast disorders
Cervix Inflammation
subjects affected / exposed	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 16 (0.00%)	1 / 17 (5.88%)	0 / 16 (0.00%)	0 / 17 (0.00%)	0 / 16 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0
Dysmenorrhoea
subjects affected / exposed	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 16 (0.00%)	1 / 17 (5.88%)	0 / 16 (0.00%)	0 / 17 (0.00%)	0 / 16 (0.00%)
occurrences all number	0	0	0	0	2	0	0	0
Premenstrual Headache
subjects affected / exposed	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 16 (0.00%)	1 / 16 (6.25%)	0 / 17 (0.00%)	0 / 16 (0.00%)	0 / 17 (0.00%)	0 / 16 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0
Uterine Polyp
subjects affected / exposed	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 17 (0.00%)	0 / 16 (0.00%)	0 / 17 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	0	0	0	0	0	0	1
Respiratory, thoracic and mediastinal disorders
Nasal Congestion
subjects affected / exposed	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 17 (0.00%)	0 / 16 (0.00%)	1 / 17 (5.88%)	0 / 16 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0
Oropharyngeal Pain
subjects affected / exposed	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 16 (0.00%)	1 / 17 (5.88%)	0 / 16 (0.00%)	1 / 17 (5.88%)	1 / 16 (6.25%)
occurrences all number	0	0	0	0	1	0	1	1
Sinus Pain
subjects affected / exposed	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 16 (0.00%)	1 / 16 (6.25%)	0 / 17 (0.00%)	0 / 16 (0.00%)	0 / 17 (0.00%)	0 / 16 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0
Upper Respiratory Tract Inflammation
subjects affected / exposed	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 17 (0.00%)	0 / 16 (0.00%)	1 / 17 (5.88%)	0 / 16 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0
Psychiatric disorders
Anxiety
subjects affected / exposed	0 / 16 (0.00%)	1 / 16 (6.25%)	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 17 (0.00%)	1 / 16 (6.25%)	0 / 17 (0.00%)	0 / 16 (0.00%)
occurrences all number	0	1	0	0	0	1	0	0
Depression
subjects affected / exposed	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 16 (0.00%)	1 / 17 (5.88%)	0 / 16 (0.00%)	0 / 17 (0.00%)	0 / 16 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0
Grief Reaction
subjects affected / exposed	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 17 (0.00%)	1 / 16 (6.25%)	0 / 17 (0.00%)	0 / 16 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Insomnia
subjects affected / exposed	0 / 16 (0.00%)	1 / 16 (6.25%)	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 17 (0.00%)	0 / 16 (0.00%)	0 / 17 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1	0	0	0	0	0	1
Irritability
subjects affected / exposed	1 / 16 (6.25%)	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 17 (0.00%)	0 / 16 (0.00%)	0 / 17 (0.00%)	0 / 16 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0
Investigations
Alanine Aminotransferase Increased
subjects affected / exposed	1 / 16 (6.25%)	0 / 16 (0.00%)	1 / 16 (6.25%)	0 / 16 (0.00%)	0 / 17 (0.00%)	0 / 16 (0.00%)	0 / 17 (0.00%)	1 / 16 (6.25%)
occurrences all number	1	0	1	0	0	0	0	1
Aspartate Aminotransferase Increased
subjects affected / exposed	0 / 16 (0.00%)	0 / 16 (0.00%)	1 / 16 (6.25%)	0 / 16 (0.00%)	0 / 17 (0.00%)	0 / 16 (0.00%)	0 / 17 (0.00%)	0 / 16 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
Blood Glucose Increased
subjects affected / exposed	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 17 (0.00%)	1 / 16 (6.25%)	0 / 17 (0.00%)	0 / 16 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Blood Immunoglobulin M Decreased
subjects affected / exposed	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 17 (0.00%)	0 / 16 (0.00%)	0 / 17 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	0	0	0	0	0	0	1
Glomerular Filtration Rate Decreased
subjects affected / exposed	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 17 (0.00%)	0 / 16 (0.00%)	0 / 17 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	0	0	0	0	0	0	2
Red Blood Cell Count Decreased
subjects affected / exposed	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 17 (0.00%)	0 / 16 (0.00%)	0 / 17 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	0	0	0	0	0	0	1
Reticulocyte Count Decreased
subjects affected / exposed	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 17 (0.00%)	0 / 16 (0.00%)	0 / 17 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	0	0	0	0	0	0	1
Weight Increased
subjects affected / exposed	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 17 (0.00%)	1 / 16 (6.25%)	0 / 17 (0.00%)	0 / 16 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Injury, poisoning and procedural complications
Accidental Overdose
subjects affected / exposed	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 17 (0.00%)	0 / 16 (0.00%)	0 / 17 (0.00%)	3 / 16 (18.75%)
occurrences all number	0	0	0	0	0	0	0	4
Animal Bite
subjects affected / exposed	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 17 (0.00%)	1 / 16 (6.25%)	0 / 17 (0.00%)	0 / 16 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Arthropod Sting
subjects affected / exposed	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 17 (0.00%)	1 / 16 (6.25%)	0 / 17 (0.00%)	0 / 16 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Rib Fracture
subjects affected / exposed	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 17 (0.00%)	0 / 16 (0.00%)	1 / 17 (5.88%)	0 / 16 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0
Congenital, familial and genetic disorders
Cystic Lymphangioma
subjects affected / exposed	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 16 (0.00%)	1 / 17 (5.88%)	0 / 16 (0.00%)	0 / 17 (0.00%)	0 / 16 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0
Cardiac disorders
Atrioventricular Block First Degree
subjects affected / exposed	1 / 16 (6.25%)	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 17 (0.00%)	0 / 16 (0.00%)	0 / 17 (0.00%)	0 / 16 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0
Sinus Bradycardia
subjects affected / exposed	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 16 (0.00%)	1 / 17 (5.88%)	0 / 16 (0.00%)	0 / 17 (0.00%)	0 / 16 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0
Supraventricular Extrasystoles
subjects affected / exposed	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 17 (0.00%)	0 / 16 (0.00%)	0 / 17 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	0	0	0	0	0	0	1
Nervous system disorders
Headache
subjects affected / exposed	1 / 16 (6.25%)	1 / 16 (6.25%)	0 / 16 (0.00%)	2 / 16 (12.50%)	2 / 17 (11.76%)	4 / 16 (25.00%)	1 / 17 (5.88%)	2 / 16 (12.50%)
occurrences all number	3	1	0	2	2	4	1	5
Hypersomnia
subjects affected / exposed	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 17 (0.00%)	1 / 16 (6.25%)	0 / 17 (0.00%)	0 / 16 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Hypoaesthesia
subjects affected / exposed	1 / 16 (6.25%)	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 17 (0.00%)	0 / 16 (0.00%)	0 / 17 (0.00%)	0 / 16 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0
Migraine
subjects affected / exposed	1 / 16 (6.25%)	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 17 (0.00%)	1 / 16 (6.25%)	0 / 17 (0.00%)	0 / 16 (0.00%)
occurrences all number	1	0	0	0	0	1	0	0
Migraine Without Aura
subjects affected / exposed	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 16 (0.00%)	1 / 16 (6.25%)	0 / 17 (0.00%)	1 / 16 (6.25%)	0 / 17 (0.00%)	0 / 16 (0.00%)
occurrences all number	0	0	0	2	0	1	0	0
Muscle Spasticity
subjects affected / exposed	0 / 16 (0.00%)	0 / 16 (0.00%)	1 / 16 (6.25%)	0 / 16 (0.00%)	0 / 17 (0.00%)	0 / 16 (0.00%)	0 / 17 (0.00%)	2 / 16 (12.50%)
occurrences all number	0	0	1	0	0	0	0	2
Paraesthesia
subjects affected / exposed	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 17 (0.00%)	0 / 16 (0.00%)	0 / 17 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	0	0	0	0	0	0	1
Restless Legs Syndrome
subjects affected / exposed	1 / 16 (6.25%)	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 17 (0.00%)	0 / 16 (0.00%)	0 / 17 (0.00%)	0 / 16 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0
Syncope
subjects affected / exposed	1 / 16 (6.25%)	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 17 (0.00%)	0 / 16 (0.00%)	0 / 17 (0.00%)	0 / 16 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0
Tension Headache
subjects affected / exposed	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 16 (0.00%)	1 / 17 (5.88%)	0 / 16 (0.00%)	1 / 17 (5.88%)	0 / 16 (0.00%)
occurrences all number	0	0	0	0	1	0	1	0
Blood and lymphatic system disorders
Lymphadenopathy
subjects affected / exposed	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 17 (0.00%)	0 / 16 (0.00%)	0 / 17 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	0	0	0	0	0	0	1
Eye disorders
Dry Eye
subjects affected / exposed	1 / 16 (6.25%)	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 17 (0.00%)	0 / 16 (0.00%)	0 / 17 (0.00%)	0 / 16 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0
Eye Pain
subjects affected / exposed	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 17 (0.00%)	0 / 16 (0.00%)	0 / 17 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	0	0	0	0	0	0	1
Gastrointestinal disorders
Chronic Gastritis
subjects affected / exposed	1 / 16 (6.25%)	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 17 (0.00%)	0 / 16 (0.00%)	0 / 17 (0.00%)	0 / 16 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0
Constipation
subjects affected / exposed	1 / 16 (6.25%)	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 17 (0.00%)	0 / 16 (0.00%)	1 / 17 (5.88%)	0 / 16 (0.00%)
occurrences all number	1	0	0	0	0	0	1	0
Dental Caries
subjects affected / exposed	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 17 (0.00%)	1 / 16 (6.25%)	0 / 17 (0.00%)	0 / 16 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Diarrhoea
subjects affected / exposed	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 16 (0.00%)	1 / 17 (5.88%)	0 / 16 (0.00%)	0 / 17 (0.00%)	0 / 16 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0
Gastrooesophageal Reflux Disease
subjects affected / exposed	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 17 (0.00%)	0 / 16 (0.00%)	0 / 17 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	0	0	0	0	0	0	1
Nausea
subjects affected / exposed	1 / 16 (6.25%)	0 / 16 (0.00%)	1 / 16 (6.25%)	0 / 16 (0.00%)	1 / 17 (5.88%)	0 / 16 (0.00%)	0 / 17 (0.00%)	0 / 16 (0.00%)
occurrences all number	1	0	1	0	1	0	0	0
Stomatitis
subjects affected / exposed	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 17 (0.00%)	0 / 16 (0.00%)	1 / 17 (5.88%)	0 / 16 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0
Vomiting
subjects affected / exposed	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 17 (0.00%)	2 / 16 (12.50%)	0 / 17 (0.00%)	0 / 16 (0.00%)
occurrences all number	0	0	0	0	0	3	0	0
Skin and subcutaneous tissue disorders
Acne
subjects affected / exposed	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 17 (0.00%)	0 / 16 (0.00%)	1 / 17 (5.88%)	0 / 16 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0
Alopecia
subjects affected / exposed	1 / 16 (6.25%)	1 / 16 (6.25%)	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 17 (0.00%)	0 / 16 (0.00%)	0 / 17 (0.00%)	1 / 16 (6.25%)
occurrences all number	1	1	0	0	0	0	0	1
Petechiae
subjects affected / exposed	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 17 (0.00%)	0 / 16 (0.00%)	1 / 17 (5.88%)	0 / 16 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0
Rash
subjects affected / exposed	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 17 (0.00%)	0 / 16 (0.00%)	0 / 17 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	0	0	0	0	0	0	1
Urticaria
subjects affected / exposed	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 17 (0.00%)	0 / 16 (0.00%)	0 / 17 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	0	0	0	0	0	0	1
Renal and urinary disorders
Calculus Urinary
subjects affected / exposed	0 / 16 (0.00%)	0 / 16 (0.00%)	1 / 16 (6.25%)	0 / 16 (0.00%)	0 / 17 (0.00%)	0 / 16 (0.00%)	0 / 17 (0.00%)	0 / 16 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
Haematuria
subjects affected / exposed	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 16 (0.00%)	1 / 16 (6.25%)	0 / 17 (0.00%)	0 / 16 (0.00%)	1 / 17 (5.88%)	0 / 16 (0.00%)
occurrences all number	0	0	0	1	0	0	1	0
Renal Colic
subjects affected / exposed	0 / 16 (0.00%)	0 / 16 (0.00%)	1 / 16 (6.25%)	0 / 16 (0.00%)	0 / 17 (0.00%)	0 / 16 (0.00%)	0 / 17 (0.00%)	0 / 16 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
Urinary Incontinence
subjects affected / exposed	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 16 (0.00%)	1 / 17 (5.88%)	0 / 16 (0.00%)	0 / 17 (0.00%)	0 / 16 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0
Urinary Tract Inflammation
subjects affected / exposed	0 / 16 (0.00%)	1 / 16 (6.25%)	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 17 (0.00%)	0 / 16 (0.00%)	0 / 17 (0.00%)	0 / 16 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	0 / 16 (0.00%)	0 / 16 (0.00%)	1 / 16 (6.25%)	0 / 16 (0.00%)	1 / 17 (5.88%)	0 / 16 (0.00%)	0 / 17 (0.00%)	0 / 16 (0.00%)
occurrences all number	0	0	1	0	1	0	0	0
Back Pain
subjects affected / exposed	0 / 16 (0.00%)	0 / 16 (0.00%)	1 / 16 (6.25%)	0 / 16 (0.00%)	1 / 17 (5.88%)	1 / 16 (6.25%)	1 / 17 (5.88%)	0 / 16 (0.00%)
occurrences all number	0	0	1	0	1	1	1	0
Bursitis
subjects affected / exposed	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 16 (0.00%)	1 / 16 (6.25%)	0 / 17 (0.00%)	0 / 16 (0.00%)	0 / 17 (0.00%)	0 / 16 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0
Intervertebral Disc Degeneration
subjects affected / exposed	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 17 (0.00%)	1 / 16 (6.25%)	0 / 17 (0.00%)	0 / 16 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Muscle Spasms
subjects affected / exposed	0 / 16 (0.00%)	0 / 16 (0.00%)	1 / 16 (6.25%)	0 / 16 (0.00%)	0 / 17 (0.00%)	0 / 16 (0.00%)	0 / 17 (0.00%)	0 / 16 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
Muscle Twitching
subjects affected / exposed	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 17 (0.00%)	0 / 16 (0.00%)	0 / 17 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	0	0	0	0	0	0	1
Pain In Extremity
subjects affected / exposed	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 17 (0.00%)	0 / 16 (0.00%)	0 / 17 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	0	0	0	0	0	0	1
Infections and infestations
Bronchitis
subjects affected / exposed	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 17 (0.00%)	0 / 16 (0.00%)	1 / 17 (5.88%)	0 / 16 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0
Gastroenteritis
subjects affected / exposed	1 / 16 (6.25%)	0 / 16 (0.00%)	0 / 16 (0.00%)	1 / 16 (6.25%)	0 / 17 (0.00%)	0 / 16 (0.00%)	1 / 17 (5.88%)	1 / 16 (6.25%)
occurrences all number	1	0	0	1	0	0	1	1
Herpes Zoster
subjects affected / exposed	0 / 16 (0.00%)	0 / 16 (0.00%)	1 / 16 (6.25%)	0 / 16 (0.00%)	0 / 17 (0.00%)	0 / 16 (0.00%)	0 / 17 (0.00%)	0 / 16 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
Influenza
subjects affected / exposed	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 16 (0.00%)	1 / 17 (5.88%)	1 / 16 (6.25%)	0 / 17 (0.00%)	0 / 16 (0.00%)
occurrences all number	0	0	0	0	1	1	0	0
Nasopharyngitis
subjects affected / exposed	0 / 16 (0.00%)	0 / 16 (0.00%)	1 / 16 (6.25%)	0 / 16 (0.00%)	1 / 17 (5.88%)	1 / 16 (6.25%)	0 / 17 (0.00%)	3 / 16 (18.75%)
occurrences all number	0	0	1	0	1	1	0	3
Oral Herpes
subjects affected / exposed	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 17 (0.00%)	0 / 16 (0.00%)	1 / 17 (5.88%)	0 / 16 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0
Pharyngitis
subjects affected / exposed	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 17 (0.00%)	0 / 16 (0.00%)	0 / 17 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	0	0	0	0	0	0	1
Respiratory Tract Infection
subjects affected / exposed	0 / 16 (0.00%)	1 / 16 (6.25%)	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 17 (0.00%)	0 / 16 (0.00%)	1 / 17 (5.88%)	1 / 16 (6.25%)
occurrences all number	0	1	0	0	0	0	1	1
Respiratory Tract Infection Viral
subjects affected / exposed	0 / 16 (0.00%)	1 / 16 (6.25%)	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 17 (0.00%)	0 / 16 (0.00%)	0 / 17 (0.00%)	0 / 16 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0
Rhinitis
subjects affected / exposed	0 / 16 (0.00%)	1 / 16 (6.25%)	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 17 (0.00%)	1 / 16 (6.25%)	0 / 17 (0.00%)	0 / 16 (0.00%)
occurrences all number	0	1	0	0	0	1	0	0
Sinusitis
subjects affected / exposed	0 / 16 (0.00%)	1 / 16 (6.25%)	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 17 (0.00%)	0 / 16 (0.00%)	0 / 17 (0.00%)	0 / 16 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0
Tonsillitis
subjects affected / exposed	1 / 16 (6.25%)	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 17 (0.00%)	1 / 16 (6.25%)	0 / 17 (0.00%)	1 / 16 (6.25%)
occurrences all number	1	0	0	0	0	1	0	1
Upper Respiratory Tract Infection
subjects affected / exposed	1 / 16 (6.25%)	1 / 16 (6.25%)	1 / 16 (6.25%)	0 / 16 (0.00%)	1 / 17 (5.88%)	1 / 16 (6.25%)	0 / 17 (0.00%)	1 / 16 (6.25%)
occurrences all number	1	1	1	0	1	1	0	2
Urinary Tract Infection
subjects affected / exposed	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 16 (0.00%)	1 / 17 (5.88%)	1 / 16 (6.25%)	2 / 17 (11.76%)	0 / 16 (0.00%)
occurrences all number	0	0	0	0	1	1	2	0
Viral Upper Respiratory Tract Infection
subjects affected / exposed	1 / 16 (6.25%)	0 / 16 (0.00%)	1 / 16 (6.25%)	0 / 16 (0.00%)	0 / 17 (0.00%)	0 / 16 (0.00%)	0 / 17 (0.00%)	0 / 16 (0.00%)
occurrences all number	1	0	1	0	0	0	0	0
Vulvovaginal Candidiasis
subjects affected / exposed	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 16 (0.00%)	0 / 16 (0.00%)	1 / 17 (5.88%)	0 / 16 (0.00%)	0 / 17 (0.00%)	0 / 16 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0

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Were there any global substantial amendments to the protocol? Yes

13 Feb 2019

1. Addition of Weeks 2 and 6 hematology tests in response to the request by Health Canada. 2. Modification of the inclusion criteria to extend the time (i.e., up to 2 months after the last study dose) that a female subject had to use a double contraception method including a highly effective method of birth control, in response to the request by Health Canada. 3. Increase of maximum amount of blood collected per subject over the duration of the study from 60 to 70 millilitres (mL), and from 105 to 115 mL for subjects in the biomarker sub-study. 4. Addition of creatine phosphokinase to protocol-required safety laboratory assessments in response to the request by the United States Food and Drug Administration (FDA).

09 Apr 2019

1. Addition of clinical site visit (for hematology) in the schedule of activities at Weeks 2 and 6, and physical examination at Week 4. 2. Addition of “OR” in the inclusion criterion to clarify that subject had to have at least 1 documented relapse within the previous year OR greater than or equal to (>=) 2 documented relapses within the previous 2 years OR >=1 active Gd-enhancing brain lesion on an MRI scan in the past 6 months and prior to screening. 3. Update of exclusion criterion to delete “if more than 81 milligram (mg)/day” as aspirin use was prohibited in the study. 4. Addition of short course of non-acetylsalicylic acid nonsteroidal anti-inflammatory drug (NSAIDs) to permitted co-medications to specify that only short courses of NSAIDs could be used; also prolonged use might increase the risk of bleeding. 5. Addition of text regarding use of avoidance of use of proton pump inhibitors and timing of concomitant use of antacids and H2-receptor antagonists. 6. Addition of the sentence: “Female subjects of childbearing potential were eligible to participate if they agreed to use double methods of contraception, including 1 highly effective method consistently and correctly.

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 2b Dose-finding Study for SAR442168, a Bruton's Tyrosine Kinase Inhibitor, in Participants With Relapsing Multiple Sclerosis

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Brain Magnetic Resonance Imaging (MRI) Assessment: Number of New Gadolinium (Gd) Enhancing T1-hyperintense Lesions

Primary: Brain Magnetic Resonance Imaging (MRI) Assessment: Number of New Gadolinium (Gd) Enhancing T1-hyperintense Lesions

Secondary: Number of New or Enlarging T2 Lesions

Secondary: Number of New or Enlarging T2 Lesions

Secondary: Total Number of Gd-enhancing T1-hyperintense Lesions

Secondary: Total Number of Gd-enhancing T1-hyperintense Lesions

Secondary: Number of Subjects With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs): Weeks 1-4 Period

Secondary: Number of Subjects With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs): Weeks 1-4 Period

Secondary: Number of Subjects With Treatment-emergent Adverse Events and Treatment-emergent Serious Adverse Events: SAR442168 Treatment Period

Secondary: Number of Subjects With Treatment-emergent Adverse Events and Treatment-emergent Serious Adverse Events: SAR442168 Treatment Period

Secondary: Number of Subjects With Individual Clinically Relevant Abnormalities in Laboratory Tests (Haematology, Chemistry, Urinalysis), Vital Signs, and Electrocardiograms (ECG)

Secondary: Number of Subjects With Individual Clinically Relevant Abnormalities in Laboratory Tests (Haematology, Chemistry, Urinalysis), Vital Signs, and Electrocardiograms (ECG)

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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Clinical trials

Clinical Trial Results: A Phase 2b Dose-finding Study for SAR442168, a Bruton's Tyrosine Kinase Inhibitor, in Participants With Relapsing Multiple Sclerosis

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Brain Magnetic Resonance Imaging (MRI) Assessment: Number of New Gadolinium (Gd) Enhancing T1-hyperintense Lesions

Primary: Brain Magnetic Resonance Imaging (MRI) Assessment: Number of New Gadolinium (Gd) Enhancing T1-hyperintense Lesions

Secondary: Number of New or Enlarging T2 Lesions

Secondary: Number of New or Enlarging T2 Lesions

Secondary: Total Number of Gd-enhancing T1-hyperintense Lesions

Secondary: Total Number of Gd-enhancing T1-hyperintense Lesions

Secondary: Number of Subjects With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs): Weeks 1-4 Period

Secondary: Number of Subjects With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs): Weeks 1-4 Period

Secondary: Number of Subjects With Treatment-emergent Adverse Events and Treatment-emergent Serious Adverse Events: SAR442168 Treatment Period

Secondary: Number of Subjects With Treatment-emergent Adverse Events and Treatment-emergent Serious Adverse Events: SAR442168 Treatment Period

Secondary: Number of Subjects With Individual Clinically Relevant Abnormalities in Laboratory Tests (Haematology, Chemistry, Urinalysis), Vital Signs, and Electrocardiograms (ECG)

Secondary: Number of Subjects With Individual Clinically Relevant Abnormalities in Laboratory Tests (Haematology, Chemistry, Urinalysis), Vital Signs, and Electrocardiograms (ECG)

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A Phase 2b Dose-finding Study for SAR442168, a Bruton's Tyrosine Kinase Inhibitor, in Participants With Relapsing Multiple Sclerosis