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Clinical Trial Results:
A Phase II, Randomized, Double-blind, Placebo-controlled Dose-ranging Study to Evaluate the Safety and Efficacy of M2951 in Subjects with SLE

Summary
EudraCT number	2016-002950-19
Trial protocol	BG PL DE RO
Global end of trial date	23 Mar 2020

Results information
Results version number	v1(current)
This version publication date	01 Apr 2021
First version publication date	01 Apr 2021
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

MS200527-0018

ISRCTN number

US NCT number

NCT02975336

WHO universal trial number (UTN)

Sponsor organisation name

Merck KGaA, Darmstadt, Germany

Sponsor organisation address

Frankfurter Strasse 250, Darmstadt, Germany, 64293

Public contact

Communication Centre, Merck KGaA, Darmstadt, Germany, +49 6151725200, service@merckgroup.com

Scientific contact

Communication Center, Merck KGaA, Darmstadt, Germany, +49 6151725200, service@merckgroup.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

23 Mar 2020

Is this the analysis of the primary completion data?

Yes

Primary completion date

27 Nov 2019

Global end of trial reached?

Yes

Global end of trial date

23 Mar 2020

Was the trial ended prematurely?

Main objective of the trial

The main purpose of this study was to evaluate the efficacy and dose response of evobrutinib compared with placebo in reducing disease activity in adult subjects with active, autoantibody-positive Systemic Lupus Erythematosus (SLE) who received Standard of Care therapy based on systemic lupus erythematosus responder index (SRI-4) response at Week 52 in all subjects, or on SRI-6 response at Week 52 in the high disease activity (HDA) subgroup, defined as Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) greater than or equal to (>=)10.

Protection of trial subjects

Subject protection was ensured by following high medical and ethical standards in accordance with the principles laid down in the Declaration of Helsinki, and that are consistent with Good Clinical Practice and applicable regulations.

Background therapy

Evidence for comparator

Actual start date of recruitment

04 Jan 2017

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Argentina: 27

Country: Number of subjects enrolled

Colombia: 41

Country: Number of subjects enrolled

Mauritius: 18

Country: Number of subjects enrolled

Peru: 43

Country: Number of subjects enrolled

South Africa: 23

Country: Number of subjects enrolled

United States: 89

Country: Number of subjects enrolled

Japan: 20

Country: Number of subjects enrolled

Bulgaria: 48

Country: Number of subjects enrolled

Chile: 22

Country: Number of subjects enrolled

Korea, Republic of: 7

Country: Number of subjects enrolled

Malaysia: 3

Country: Number of subjects enrolled

Mexico: 42

Country: Number of subjects enrolled

Philippines: 26

Country: Number of subjects enrolled

Poland: 29

Country: Number of subjects enrolled

Russian Federation: 15

Country: Number of subjects enrolled

Taiwan: 6

Country: Number of subjects enrolled

Romania: 1

Country: Number of subjects enrolled

Italy: 9

Worldwide total number of subjects

469

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)

458

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Primary and Secondary endpoints were planned to be analyze only for Double-Blind Placebo-controlled period.

Screening details

A total of 1053 subjects with SLE were screened. Out of which, 469 subjects were randomized in ratio of 1:1:1:1 to 1 of 4 treatment groups: Placebo; M2951 25mg QD, M2951 75 mg QD and M2951 50 mg BID. 283 out of 348 subjects that completed Double-Blind Placebo-Controlled (DBPC) period, entered the Long-Term Extension (LTE) period of study.

Period 1 title

DBPC ( 52 weeks)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator

Are arms mutually exclusive

Yes

DBPC: Placebo

Arm description

Subjects received placebo matched to M2951 orally for 52 weeks.

Arm type

Placebo

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 matched to M2951 orally for 52 weeks.

DBPC: M2951 25 mg QD

Arm description

Subjects received 25 milligrams (mg) of M2951 orally once daily (QD) for 52 weeks.

Arm type

Experimental

Investigational medicinal product name

Evobrutinib

Investigational medicinal product code

M2951

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Subjects received 25 mg of M2951 orally QD for 52 weeks.

DBPC: M2951 75 mg QD

Arm description

Subjects received 75 mg of M2951 orally QD for 52 weeks.

Arm type

Experimental

Investigational medicinal product name

Evobrutinib

Investigational medicinal product code

M2951

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Subjects received 75 mg of M2951 orally QD for 52 weeks.

DBPC: M2951 50 mg BID

Arm description

Subjects received 50 mg of M2951 orally twice daily (BID) for 52 weeks.

Arm type

Experimental

Investigational medicinal product name

Evobrutinib

Investigational medicinal product code

M2951

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Subjects received 50 mg of M2951 orally BID for 52 weeks.

Number of subjects in period 1	DBPC: Placebo	DBPC: M2951 25 mg QD	DBPC: M2951 75 mg QD	DBPC: M2951 50 mg BID
Started	117	118	117	117
Completed	85	89	90	84
Not completed	32	29	27	33
Consent withdrawn by subject	1	-	1	3
Premature termination of the study	5	6	6	4
Adverse event, non-fatal	16	17	13	18
Lost to follow-up	2	1	2	4
Lack of efficacy	4	4	2	3
Protocol deviation	4	1	3	1

Period 2 title

LTE (104 weeks)

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

LTE: Placebo/ M2951 50 mg BID

Arm description

Subjects who received Placebo in DBPC period were switched to receive 50 mg M2951 orally BID in LTE period for 104 weeks.

Arm type

Experimental

Investigational medicinal product name

Evobrutinib

Investigational medicinal product code

M2951

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Subjects who received Placebo in DBPC period were switched to receive 50 mg M2951 orally BID in LTE period for 104 weeks.

LTE: M2951 25 mg QD/ M2951 50 mg BID

Arm description

Subjects who received 25 mg of M2951 orally QD in DBPC period were switched to receive 50 mg M2951 orally BID in LTE period for 104 weeks.

Arm type

Experimental

Investigational medicinal product name

Evobrutinib

Investigational medicinal product code

M2951

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Subjects who received 25 mg of M2951 orally QD in DBPC period were switched to receive 50 mg M2951 orally BID in LTE period for 104 weeks.

LTE: M2951 75 mg QD/ M2951 50 mg BID

Arm description

Subjects who received 75 mg of M2951 orally QD in DBPC period were switched to receive 50 mg M2951 orally BID in LTE period for 104 weeks.

Arm type

Experimental

Investigational medicinal product name

Evobrutinib

Investigational medicinal product code

M2951

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Subjects who received 75 mg of M2951 orally QD in DBPC period were switched to receive 50 mg M2951 orally BID in LTE period for 104 weeks.

LTE: M2951 50 mg BID/ M2951 50 mg BID

Arm description

Subjects who received 50 mg of M2951 orally BID in DBPC period continued to receive same dose of M2951 orally BID in LTE period for 104 weeks.

Arm type

Experimental

Investigational medicinal product name

Evobrutinib

Investigational medicinal product code

M2951

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Subjects who received 50 mg of M2951 orally BID in DBPC period continued to receive same dose of M2951 orally BID in LTE period for 104 weeks.

Number of subjects in period 2 ^[1]	LTE: Placebo/ M2951 50 mg BID	LTE: M2951 25 mg QD/ M2951 50 mg BID	LTE: M2951 75 mg QD/ M2951 50 mg BID	LTE: M2951 50 mg BID/ M2951 50 mg BID
Started	62	69	80	72
Completed	0	0	0	0
Not completed	62	69	80	72
Adverse event, non-fatal	7	4	2	-
Lost to follow-up	-	1	-	-
unspecified	55	63	76	72
Lack of efficacy	-	1	2	-

Notes
[1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
Justification: Only 283 subjects from Double-Blind Placebo-Controlled continued in the Long-Term Extension Period.

Baseline characteristics

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Reporting group title

DBPC: Placebo

Reporting group description

Subjects received placebo matched to M2951 orally for 52 weeks.

Reporting group title

DBPC: M2951 25 mg QD

Reporting group description

Subjects received 25 milligrams (mg) of M2951 orally once daily (QD) for 52 weeks.

Reporting group title

DBPC: M2951 75 mg QD

Reporting group description

Subjects received 75 mg of M2951 orally QD for 52 weeks.

Reporting group title

DBPC: M2951 50 mg BID

Reporting group description

Subjects received 50 mg of M2951 orally twice daily (BID) for 52 weeks.

Reporting group values	DBPC: Placebo	DBPC: M2951 25 mg QD	DBPC: M2951 75 mg QD	DBPC: M2951 50 mg BID	Total
Number of subjects	117	118	117	117	469
Age categorical
Units: Subjects
Age Continuous
Units: Years
arithmetic mean (standard deviation)	40.2 ( 12.49 )	38.8 ( 12.45 )	41.5 ( 12.52 )	42.2 ( 11.78 )	-
Sex: Female, Male
Units: Subjects
Female	110	112	111	112	445
Male	7	6	6	5	24
Race (NIH/OMB)
Units: Subjects
American Indian or Alaska Native	0	0	0	0	0
Asian	23	17	21	13	74
Native Hawaiian or Other Pacific Islander	0	0	0	0	0
Black or African American	10	12	11	12	45
White	66	73	68	83	290
More than one race	0	0	0	0	0
Unknown or Not Reported	18	16	17	9	60
Ethnicity (NIH/OMB)
Units: Subjects
Hispanic or Latino	45	51	47	42	185
Not Hispanic or Latino	72	67	70	75	284
Unknown or Not Reported	0	0	0	0	0

End points

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Reporting group title

DBPC: Placebo

Reporting group description

Subjects received placebo matched to M2951 orally for 52 weeks.

Reporting group title

DBPC: M2951 25 mg QD

Reporting group description

Subjects received 25 milligrams (mg) of M2951 orally once daily (QD) for 52 weeks.

Reporting group title

DBPC: M2951 75 mg QD

Reporting group description

Subjects received 75 mg of M2951 orally QD for 52 weeks.

Reporting group title

DBPC: M2951 50 mg BID

Reporting group description

Subjects received 50 mg of M2951 orally twice daily (BID) for 52 weeks.

Reporting group title

LTE: Placebo/ M2951 50 mg BID

Reporting group description

Subjects who received Placebo in DBPC period were switched to receive 50 mg M2951 orally BID in LTE period for 104 weeks.

Reporting group title

LTE: M2951 25 mg QD/ M2951 50 mg BID

Reporting group description

Subjects who received 25 mg of M2951 orally QD in DBPC period were switched to receive 50 mg M2951 orally BID in LTE period for 104 weeks.

Reporting group title

LTE: M2951 75 mg QD/ M2951 50 mg BID

Reporting group description

Subjects who received 75 mg of M2951 orally QD in DBPC period were switched to receive 50 mg M2951 orally BID in LTE period for 104 weeks.

Reporting group title

LTE: M2951 50 mg BID/ M2951 50 mg BID

Reporting group description

Subjects who received 50 mg of M2951 orally BID in DBPC period continued to receive same dose of M2951 orally BID in LTE period for 104 weeks.

Primary: DBPC: Number of Subjects With Response Based on Systemic Lupus Erythematosus Responder Index 4 (SRI-4) at Week 52

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End point title

DBPC: Number of Subjects With Response Based on Systemic Lupus Erythematosus Responder Index 4 (SRI-4) at Week 52

End point description

SRI-4 response was defined as >= 4-point reduction in SLEDAI-2K total score, no new British Isles Lupus Assessment Group (BILAG) A and no more than 1 new BILAG B domain score, no worsening (less than 10 percent increase) from baseline in Physician's Global Assessment of Disease Activity (PGA) and no treatment failure. SLEDAI-2K assessment consists of 24 items with total score of 0(no symptoms) to 105 (presence of all defined symptoms) with higher scores representing increased disease activity. BILAG Index: assessing clinical signs, symptoms, or laboratory parameters related to SLE divided into 9 organ systems. For each organ system A=severe disease, B=moderate disease, C=mild stable disease, D=inactive, but previously active, E=inactive and never affected. The PGA assess disease activity on a visual analogue scale =from 0(very well) to 100(very poor). The mITT analysis population was used.

End point type

Primary

End point timeframe

Week 52

End point values	DBPC: Placebo	DBPC: M2951 25 mg QD	DBPC: M2951 75 mg QD	DBPC: M2951 50 mg BID
Number of subjects analysed	114	115	116	114
Units: Subjects	52	64	60	55

Placebo and M2951 25mg QD

Comparison groups

DBPC: Placebo v DBPC: M2951 25 mg QD

Number of subjects included in analysis

229

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.5462

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

1.55

Confidence interval

level

95%

sides

2-sided

lower limit

0.91

upper limit

2.64

Placebo and M2951 75 mg QD

Comparison groups

DBPC: Placebo v DBPC: M2951 75 mg QD

Number of subjects included in analysis

230

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.5462

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

1.29

Confidence interval

level

95%

sides

2-sided

lower limit

0.76

upper limit

2.18

Placebo and M2951 50 mg BID

Comparison groups

DBPC: Placebo v DBPC: M2951 50 mg BID

Number of subjects included in analysis

228

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.5462

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

1.13

Confidence interval

level

95%

sides

2-sided

lower limit

0.67

upper limit

1.93

Primary: DBPC: Number of Subjects With Response Based on Systemic Lupus Erythematosus Responder Index 6 (SRI-6) at Week 52

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End point title

DBPC: Number of Subjects With Response Based on Systemic Lupus Erythematosus Responder Index 6 (SRI-6) at Week 52

End point description

SRI-6 response was defined as >= 6-point reduction in SLEDAI-2K total score, no new BILAG A and no more than 1 new BILAG B domain score and no worsening (less than 10 percent increase) from baseline in PGA of disease activity and treatment failure. SLEDAI-2K assessment consists of 24 items with total score of 0 (no symptoms) to 105 (presence of all defined symptoms) with higher scores representing increased disease activity. BILAG Index: assessing clinical signs, symptoms, or laboratory parameters related to SLE, divided into 9 organ systems. For each organ system :A=severe disease, B=moderate disease, C=mild stable disease, D=inactive, but previously active, E=inactive and never affected. The PGA assess disease activity on a visual analogue scale =from 0(very well) to 100(very poor). The mITT analysis set was used. Here, "Number of subjects analyzed" signifies High Disease Activity (HDA) subgroup who were evaluable for this endpoint.

End point type

Primary

End point timeframe

Week 52

End point values	DBPC: Placebo	DBPC: M2951 25 mg QD	DBPC: M2951 75 mg QD	DBPC: M2951 50 mg BID
Number of subjects analysed	56	54	65	55
Units: Subjects	22	27	30	24

Placebo and M2951 25 mg QD

Comparison groups

DBPC: Placebo v DBPC: M2951 25 mg QD

Number of subjects included in analysis

110

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.5462

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

1.5

Confidence interval

level

95%

sides

2-sided

lower limit

0.69

upper limit

3.24

Placebo and M2951 75 mg QD

Comparison groups

DBPC: Placebo v DBPC: M2951 75 mg QD

Number of subjects included in analysis

121

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.5462

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

1.42

Confidence interval

level

95%

sides

2-sided

lower limit

0.68

upper limit

2.97

Placebo and M2951 50 mg BID

Comparison groups

DBPC: Placebo v DBPC: M2951 50 mg BID

Number of subjects included in analysis

111

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.5462

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

1.27

Confidence interval

level

95%

sides

2-sided

lower limit

0.59

upper limit

2.75

Primary: DBPC: Number of Subjects With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs According to National Cancer Institute-Common Terminology Criteria for Adverse Events Version 4.03 (NCI-CTCAE v4.03)

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End point title

DBPC: Number of Subjects With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs According to National Cancer Institute-Common Terminology Criteria for Adverse Events Version 4.03 (NCI-CTCAE v4.03) ^[1]

End point description

Adverse event (AE) was defined as any untoward medical occurrence in a subject, which does not necessarily have causal relationship with treatment. A serious AE was defined as an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged in subject hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. TEAEs: events between first dose of study drug that were absent before treatment/that worsened relative to pre-treatment state up to 56 weeks. TEAEs included both serious TEAEs and non-serious TEAEs. Number of subjects with TEAEs and serious TEAEs were reported. The safety analysis set included all subjects who received at least one dose of IMP (Evobrutinib or Placebo).

End point type

Primary

End point timeframe

Baseline up to Week 56

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

End point values	DBPC: Placebo	DBPC: M2951 25 mg QD	DBPC: M2951 75 mg QD	DBPC: M2951 50 mg BID
Number of subjects analysed	117	118	117	117
Units: Subjects
Any TEAEs	96	103	100	99
Any serious TEAE	10	13	11	9

No statistical analyses for this end point

Primary: DBPC: Number of Subjects With Treatment-Emergent Adverse Events (TEAEs) by Severity According to National Cancer Institute-Common Terminology Criteria for Adverse Events Version 4.03 (NCI-CTCAE v4.03)

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End point title

DBPC: Number of Subjects With Treatment-Emergent Adverse Events (TEAEs) by Severity According to National Cancer Institute-Common Terminology Criteria for Adverse Events Version 4.03 (NCI-CTCAE v4.03) ^[2]

End point description

Severity of TEAEs were graded using NCI-CTCAE v4.03 toxicity grades, as follows: Grade 1= Mild; Grade 2 = Moderate; Grade 3 = Severe; Grade 4 = Life-threatening and Grade 5 = Death. Number of subjects with TEAEs by severity were reported. The Safety analysis set included all subjects who received at least one dose of IMP (Evobrutinib or Placebo).

End point type

Primary

End point timeframe

Baseline up to Week 56

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

End point values	DBPC: Placebo	DBPC: M2951 25 mg QD	DBPC: M2951 75 mg QD	DBPC: M2951 50 mg BID
Number of subjects analysed	117	118	117	117
Units: Subjects
Grade 1	76	80	79	76
Grade 2	63	77	72	78
Grade 3	24	29	24	21
Grade 4	1	1	0	2
Grade 5	0	1	1	0

No statistical analyses for this end point

Primary: DBPC: Number of Subjects With Clinically Significant Change From Baseline in Vital Signs

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End point title

DBPC: Number of Subjects With Clinically Significant Change From Baseline in Vital Signs ^[3]

End point description

Vital signs included body temperature, systolic and diastolic blood pressure, pulse rate, respiratory rate, weight and height. Clinical significance was determined by the investigator. The number of subjects with clinically significant changes from baseline in vital signs were reported. The safety analysis set included all subjects who received at least one dose of IMP (Evobrutinib or Placebo).

End point type

Primary

End point timeframe

Baseline up to Week 56

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

End point values	DBPC: Placebo	DBPC: M2951 25 mg QD	DBPC: M2951 75 mg QD	DBPC: M2951 50 mg BID
Number of subjects analysed	117	118	117	117
Units: Subjects	0	0	0	0

No statistical analyses for this end point

Primary: DBPC: Number of Subjects With Clinically Significant Changes From Baseline in 12-Lead Electrocardiogram (ECG) Findings

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End point title

DBPC: Number of Subjects With Clinically Significant Changes From Baseline in 12-Lead Electrocardiogram (ECG) Findings ^[4]

End point description

12-lead ECG recordings included rhythm, heart rate (as measured by RR interval), PR interval, QRS duration, and QT interval. The corrected QT interval (QTcF) was calculated using Fridericia’s formula. 12-lead ECG recordings were obtained after the subjects have rested for at least 10 minutes in semisupine position. Clinical significance was determined by the investigator. The number of subjects with clinically significant changes from baseline in 12-lead ECG findings were reported. The safety analysis set included all subjects who received at least one dose of IMP (Evobrutinib or Placebo).

End point type

Primary

End point timeframe

Baseline up to Week 56

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

End point values	DBPC: Placebo	DBPC: M2951 25 mg QD	DBPC: M2951 75 mg QD	DBPC: M2951 50 mg BID
Number of subjects analysed	117	118	117	117
Units: Subjects	0	0	0	0

No statistical analyses for this end point

Primary: DBPC: Number of Subjects With Clinically Significant Changes From Baseline in Laboratory Parameters

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End point title

DBPC: Number of Subjects With Clinically Significant Changes From Baseline in Laboratory Parameters ^[5]

End point description

Laboratory investigation included hematology, biochemistry, urinalysis and coagulation. Clinical significance was determined by the investigator. The number of subjects with clinically significant changes from baseline in laboratory parameters were reported. The safety analysis set included all subjects who received at least one dose of IMP (Evobrutinib or Placebo).

End point type

Primary

End point timeframe

Baseline up to Week 56

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

End point values	DBPC: Placebo	DBPC: M2951 25 mg QD	DBPC: M2951 75 mg QD	DBPC: M2951 50 mg BID
Number of subjects analysed	117	118	117	117
Units: Subjects	0	0	0	0

No statistical analyses for this end point

Primary: DBPC: Mean Absolute Value of Serum Immunoglobulin (Ig) Levels (IgG, IgA, IgM) at Week 2

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End point title

DBPC: Mean Absolute Value of Serum Immunoglobulin (Ig) Levels (IgG, IgA, IgM) at Week 2 ^[6]

End point description

Mean absolute value of serum levels of IgG, IgA, IgM were assessed at Week 2. The Safety analysis set included all subjects who received at least one dose of IMP (Evobrutinib or Placebo). Here, "number of subjects analyzed" signifies those subjects who were evaluable for this endpoint.

End point type

Primary

End point timeframe

Week 2

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

End point values	DBPC: Placebo	DBPC: M2951 25 mg QD	DBPC: M2951 75 mg QD	DBPC: M2951 50 mg BID
Number of subjects analysed	114	116	115	113
Units: gram per liter (g/L)
arithmetic mean (standard deviation)
IgG	14.56 ( 5.367 )	13.75 ( 4.652 )	14.37 ( 5.536 )	12.81 ( 3.847 )
IgA	2.62 ( 1.207 )	2.75 ( 1.374 )	2.78 ( 1.328 )	2.66 ( 1.137 )
IgM	1.12 ( 0.662 )	1.22 ( 0.890 )	1.09 ( 0.697 )	1.18 ( 0.776 )

No statistical analyses for this end point

Primary: DBPC: Mean Absolute Value of Serum Immunoglobulin (Ig) Levels (IgG, IgA, IgM) at Week 4

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End point title

DBPC: Mean Absolute Value of Serum Immunoglobulin (Ig) Levels (IgG, IgA, IgM) at Week 4 ^[7]

End point description

Mean absolute value of serum levels of IgG, IgA, IgM were assessed at Week 4. The Safety analysis set included all subjects who received at least one dose of IMP (Evobrutinib or Placebo). Here, "number of subjects analyzed" signifies those subjects who were evaluable for this endpoint.

End point type

Primary

End point timeframe

Week 4

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

End point values	DBPC: Placebo	DBPC: M2951 25 mg QD	DBPC: M2951 75 mg QD	DBPC: M2951 50 mg BID
Number of subjects analysed	114	114	114	115
Units: gram per liter (g/L)
arithmetic mean (standard deviation)
IgG	14.92 ( 5.497 )	13.60 ( 4.590 )	14.21 ( 4.828 )	12.73 ( 3.771 )
IgA	2.71 ( 1.284 )	2.73 ( 1.349 )	2.82 ( 1.293 )	2.64 ( 1.109 )
IgM	1.12 ( 0.699 )	1.18 ( 0.824 )	1.06 ( 0.676 )	1.16 ( 0.745 )

No statistical analyses for this end point

Primary: DBPC: Mean Absolute Value of Serum Immunoglobulin (Ig) Levels (IgG, IgA, IgM) at Week 12

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End point title

DBPC: Mean Absolute Value of Serum Immunoglobulin (Ig) Levels (IgG, IgA, IgM) at Week 12 ^[8]

End point description

Mean absolute value of serum levels of IgG, IgA, IgM were assessed at Week 12. The Safety analysis set included all subjects who received at least one dose of IMP (Evobrutinib or Placebo). Here, "number of subjects analyzed" signifies those subjects who were evaluable for this endpoint.

End point type

Primary

End point timeframe

Week 12

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

End point values	DBPC: Placebo	DBPC: M2951 25 mg QD	DBPC: M2951 75 mg QD	DBPC: M2951 50 mg BID
Number of subjects analysed	110	106	110	105
Units: gram per liter (g/L)
arithmetic mean (standard deviation)
IgG:	14.91 ( 5.312 )	12.92 ( 4.332 )	13.64 ( 4.035 )	12.38 ( 3.520 )
IgA	2.72 ( 1.321 )	2.73 ( 1.340 )	2.88 ( 1.363 )	2.68 ( 1.021 )
IgM	1.11 ( 0.683 )	1.05 ( 0.700 )	0.95 ( 0.610 )	1.02 ( 0.695 )

No statistical analyses for this end point

Primary: DBPC: Mean Absolute Value of Serum Immunoglobulin (Ig) Levels (IgG, IgA, IgM) at Week 24

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End point title

DBPC: Mean Absolute Value of Serum Immunoglobulin (Ig) Levels (IgG, IgA, IgM) at Week 24 ^[9]

End point description

Mean absolute value of serum levels of IgG, IgA, IgM were assessed at Week 24. The Safety analysis set included all subjects who received at least one dose of IMP (Evobrutinib or Placebo). Here, "number of subjects analyzed" signifies those subjects who were evaluable for this endpoint.

End point type

Primary

End point timeframe

Week 24

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

End point values	DBPC: Placebo	DBPC: M2951 25 mg QD	DBPC: M2951 75 mg QD	DBPC: M2951 50 mg BID
Number of subjects analysed	96	97	101	96
Units: gram per liter (g/L)
arithmetic mean (standard deviation)
IgG	15.01 ( 5.190 )	13.75 ( 4.783 )	13.79 ( 4.165 )	12.86 ( 3.725 )
IgA	2.79 ( 1.430 )	2.89 ( 1.460 )	2.98 ( 1.391 )	2.78 ( 1.091 )
IgM	1.07 ( 0.609 )	1.01 ( 0.686 )	0.89 ( 0.583 )	0.98 ( 0.656 )

No statistical analyses for this end point

Primary: DBPC: Mean Absolute Value of Serum Immunoglobulin (Ig) Levels (IgG, IgA, IgM) at Week 36

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End point title

DBPC: Mean Absolute Value of Serum Immunoglobulin (Ig) Levels (IgG, IgA, IgM) at Week 36 ^[10]

End point description

Mean absolute value of serum levels of IgG, IgA, IgM were assessed at Week 36. The Safety analysis set included all subjects who received at least one dose of IMP (Evobrutinib or Placebo). Here, "number of subjects analyzed" signifies those subjects who were evaluable for this endpoint.

End point type

Primary

End point timeframe

Week 36

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

End point values	DBPC: Placebo	DBPC: M2951 25 mg QD	DBPC: M2951 75 mg QD	DBPC: M2951 50 mg BID
Number of subjects analysed	92	91	97	86
Units: gram per liter (g/L)
arithmetic mean (standard deviation)
IgG	14.81 ( 5.217 )	13.54 ( 4.242 )	13.67 ( 3.934 )	12.65 ( 3.480 )
IgA	2.72 ( 1.378 )	2.89 ( 1.418 )	3.01 ( 1.420 )	2.86 ( 1.073 )
IgM	1.06 ( 0.630 )	1.01 ( 0.669 )	0.85 ( 0.541 )	0.95 ( 0.656 )

No statistical analyses for this end point

Primary: DBPC: Mean Absolute Value of Serum Immunoglobulin (Ig) Levels (IgG, IgA, IgM) at Week 52

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End point title

DBPC: Mean Absolute Value of Serum Immunoglobulin (Ig) Levels (IgG, IgA, IgM) at Week 52 ^[11]

End point description

Mean absolute value of serum levels of IgG, IgA, IgM were assessed at Week 52. The Safety analysis set included all subjects who received at least one dose of IMP (Evobrutinib or Placebo). Here, "number of subjects analyzed" signifies those subjects who were evaluable for this endpoint and "n" signifies those subjects who were evaluable for the specified category.

End point type

Primary

End point timeframe

Week 52

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

End point values	DBPC: Placebo	DBPC: M2951 25 mg QD	DBPC: M2951 75 mg QD	DBPC: M2951 50 mg BID
Number of subjects analysed	78	83	85	76
Units: gram per liter (g/L)
arithmetic mean (standard deviation)
IgG: n= 78, 83, 85, 76	15.21 ( 5.105 )	13.90 ( 4.087 )	14.32 ( 4.542 )	13.01 ( 3.723 )
IgA: n= 78, 83, 85, 76	2.82 ( 1.438 )	2.95 ( 1.596 )	3.17 ( 1.596 )	2.95 ( 1.159 )
IgM: n= 78, 83, 84, 76	1.08 ( 0.624 )	0.94 ( 0.645 )	0.82 ( 0.487 )	0.96 ( 0.670 )

No statistical analyses for this end point

Primary: DBPC: Mean Absolute Value of Serum Immunoglobulin (Ig) Levels (IgG, IgA, IgM) at Week 56

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End point title

DBPC: Mean Absolute Value of Serum Immunoglobulin (Ig) Levels (IgG, IgA, IgM) at Week 56 ^[12]

End point description

Mean absolute value of serum levels of IgG, IgA, IgM were assessed at Week 56. The Safety analysis set included all subjects who received at least one dose of IMP (Evobrutinib or Placebo). Here, "number of subjects analyzed" signifies those subjects who were evaluable for this endpoint.

End point type

Primary

End point timeframe

Week 56

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

End point values	DBPC: Placebo	DBPC: M2951 25 mg QD	DBPC: M2951 75 mg QD	DBPC: M2951 50 mg BID
Number of subjects analysed	37	36	31	33
Units: gram per liter (g/L)
arithmetic mean (standard deviation)
IgG	14.82 ( 5.504 )	14.25 ( 4.435 )	14.25 ( 4.626 )	13.12 ( 4.507 )
IgA	2.95 ( 1.549 )	3.01 ( 1.459 )	2.89 ( 1.655 )	3.03 ( 1.164 )
IgM	1.11 ( 0.642 )	1.01 ( 0.601 )	0.95 ( 0.624 )	1.31 ( 0.869 )

No statistical analyses for this end point

Primary: DBPC: Mean Absolute Total B Cell Count at Week 4

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End point title

DBPC: Mean Absolute Total B Cell Count at Week 4 ^[13]

End point description

Mean total B cell count were assessed. Flow cytometry analysis of lymphocyte populations using four-color fluorescence activated cell sorting was performed for the analysis of B cell counts. The Safety analysis set included all subjects who received at least one dose of IMP (Evobrutinib or Placebo). Here, "number of subjects analyzed" signifies those subjects who were evaluable for this endpoint.

End point type

Primary

End point timeframe

Week 4

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

End point values	DBPC: Placebo	DBPC: M2951 25 mg QD	DBPC: M2951 75 mg QD	DBPC: M2951 50 mg BID
Number of subjects analysed	98	99	99	99
Units: Cells per microliter
arithmetic mean (standard deviation)	150 ( 126.9 )	236 ( 197.4 )	296 ( 243.8 )	229 ( 232.9 )

No statistical analyses for this end point

Primary: DBPC: Mean Absolute Total B Cell Count at Week 24

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End point title

DBPC: Mean Absolute Total B Cell Count at Week 24 ^[14]

End point description

Mean absolute total B cell count were assessed. Flow cytometry analysis of lymphocyte populations using four-color fluorescence activated cell sorting was performed for the analysis of B cell counts. The Safety analysis set included all subjects who received at least one dose of IMP (Evobrutinib or Placebo). Here, "number of subjects analyzed" signifies those subjects who were evaluable for this endpoint.

End point type

Primary

End point timeframe

Week 24

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

End point values	DBPC: Placebo	DBPC: M2951 25 mg QD	DBPC: M2951 75 mg QD	DBPC: M2951 50 mg BID
Number of subjects analysed	89	90	87	88
Units: Cells per microliter
arithmetic mean (standard deviation)	161 ( 125.8 )	184 ( 152.6 )	204 ( 158.3 )	151 ( 129.2 )

No statistical analyses for this end point

Primary: DBPC: Mean Absolute Total B Cell Count at Week 52

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End point title

DBPC: Mean Absolute Total B Cell Count at Week 52 ^[15]

End point description

End point type

Primary

End point timeframe

Week 52

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

End point values	DBPC: Placebo	DBPC: M2951 25 mg QD	DBPC: M2951 75 mg QD	DBPC: M2951 50 mg BID
Number of subjects analysed	68	66	76	66
Units: Cells per microliter
arithmetic mean (standard deviation)	169 ( 121.9 )	167 ( 168.7 )	180 ( 170.7 )	119 ( 84.1 )

No statistical analyses for this end point

Primary: DBPC: Mean Absolute Total B Cell Count at Week 56

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End point title

DBPC: Mean Absolute Total B Cell Count at Week 56 ^[16]

End point description

End point type

Primary

End point timeframe

Week 56

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

End point values	DBPC: Placebo	DBPC: M2951 25 mg QD	DBPC: M2951 75 mg QD	DBPC: M2951 50 mg BID
Number of subjects analysed	35	30	27	30
Units: Cells per microliter
arithmetic mean (standard deviation)	164 ( 113.3 )	129 ( 100.0 )	156 ( 127.1 )	104 ( 71.9 )

No statistical analyses for this end point

Primary: DBPC: Change From Baseline in Serum Immunoglobulin (Ig) Levels (IgG, IgA, IgM) at Week 2

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End point title

DBPC: Change From Baseline in Serum Immunoglobulin (Ig) Levels (IgG, IgA, IgM) at Week 2 ^[17]

End point description

Change from baseline in the serum levels of IgG, IgA, IgM were assessed. The Safety analysis set included all subjects who received at least one dose of IMP (Evobrutinib or Placebo). Here, "number of subjects analyzed" signifies those subjects who were evaluable for this endpoint.

End point type

Primary

End point timeframe

Baseline and Week 2

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

End point values	DBPC: Placebo	DBPC: M2951 25 mg QD	DBPC: M2951 75 mg QD	DBPC: M2951 50 mg BID
Number of subjects analysed	114	116	115	113
Units: gram per liter (g/L)
arithmetic mean (standard deviation)
IgG	-0.51 ( 1.726 )	-0.06 ( 1.361 )	-0.15 ( 1.772 )	-0.40 ( 1.025 )
IgA	-0.11 ( 0.435 )	-0.04 ( 0.431 )	-0.01 ( 0.381 )	-0.03 ( 0.268 )
IgM	0.00 ( 0.197 )	-0.05 ( 0.194 )	-0.04 ( 0.155 )	-0.07 ( 0.116 )

No statistical analyses for this end point

Primary: DBPC: Change From Baseline in Serum Immunoglobulin (Ig) Levels (IgG, IgA, IgM) at Week 4

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End point title

DBPC: Change From Baseline in Serum Immunoglobulin (Ig) Levels (IgG, IgA, IgM) at Week 4 ^[18]

End point description

End point type

Primary

End point timeframe

Baseline and Week 4

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

End point values	DBPC: Placebo	DBPC: M2951 25 mg QD	DBPC: M2951 75 mg QD	DBPC: M2951 50 mg BID
Number of subjects analysed	114	114	114	115
Units: gram per liter (g/L)
arithmetic mean (standard deviation)
IgG	-0.26 ( 1.760 )	-0.16 ( 1.463 )	-0.24 ( 1.657 )	-0.45 ( 1.150 )
IgA	-0.01 ( 0.205 )	-0.04 ( 0.334 )	0.03 ( 0.447 )	-0.03 ( 0.301 )
IgM	0.01 ( 0.195 )	-0.09 ( 0.175 )	-0.07 ( 0.192 )	-0.08 ( 0.159 )

No statistical analyses for this end point

Primary: DBPC: Change From Baseline in Serum Immunoglobulin (Ig) Levels (IgG, IgA, IgM) at Week 12

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End point title

DBPC: Change From Baseline in Serum Immunoglobulin (Ig) Levels (IgG, IgA, IgM) at Week 12 ^[19]

End point description

End point type

Primary

End point timeframe

Baseline and Week 12

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

End point values	DBPC: Placebo	DBPC: M2951 25 mg QD	DBPC: M2951 75 mg QD	DBPC: M2951 50 mg BID
Number of subjects analysed	110	106	110	105
Units: gram per liter (g/L)
arithmetic mean (standard deviation)
IgG	-0.36 ( 2.073 )	-0.62 ( 1.827 )	-0.72 ( 2.552 )	-0.93 ( 1.640 )
IgA	0.00 ( 0.325 )	-0.02 ( 0.360 )	0.06 ( 0.518 )	-0.03 ( 0.340 )
IgM	-0.01 ( 0.194 )	-0.20 ( 0.301 )	-0.18 ( 0.277 )	-0.20 ( 0.250 )

No statistical analyses for this end point

Primary: DBPC: Change From Baseline in Serum Immunoglobulin (Ig) Levels (IgG, IgA, IgM) at Week 24

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End point title

DBPC: Change From Baseline in Serum Immunoglobulin (Ig) Levels (IgG, IgA, IgM) at Week 24 ^[20]

End point description

End point type

Primary

End point timeframe

Baseline and Week 24

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

End point values	DBPC: Placebo	DBPC: M2951 25 mg QD	DBPC: M2951 75 mg QD	DBPC: M2951 50 mg BID
Number of subjects analysed	96	97	101	96
Units: gram per liter (g/L)
arithmetic mean (standard deviation)
IgG	-0.21 ( 2.318 )	0.11 ( 2.234 )	-0.46 ( 2.912 )	-0.57 ( 2.363 )
IgA	0.06 ( 0.332 )	0.14 ( 0.390 )	0.19 ( 0.565 )	0.04 ( 0.563 )
IgM	-0.01 ( 0.264 )	-0.23 ( 0.369 )	-0.23 ( 0.321 )	-0.25 ( 0.346 )

No statistical analyses for this end point

Primary: DBPC: Change From Baseline in Serum Immunoglobulin (Ig) Levels (IgG, IgA, IgM) at Week 36

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End point title

DBPC: Change From Baseline in Serum Immunoglobulin (Ig) Levels (IgG, IgA, IgM) at Week 36 ^[21]

End point description

End point type

Primary

End point timeframe

Baseline and Week 36

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

End point values	DBPC: Placebo	DBPC: M2951 25 mg QD	DBPC: M2951 75 mg QD	DBPC: M2951 50 mg BID
Number of subjects analysed	92	91	97	86
Units: gram per liter (g/L)
arithmetic mean (standard deviation)
IgG	-0.15 ( 2.130 )	0.02 ( 2.487 )	-0.43 ( 2.572 )	-0.69 ( 2.189 )
IgA	-0.02 ( 0.361 )	0.22 ( 0.453 )	0.24 ( 0.583 )	0.08 ( 0.459 )
IgM	-0.04 ( 0.255 )	-0.25 ( 0.416 )	-0.25 ( 0.284 )	-0.28 ( 0.392 )

No statistical analyses for this end point

Primary: DBPC: Change From Baseline in Serum Immunoglobulin (Ig) Levels (IgG, IgA, IgM) at Week 52

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End point title

DBPC: Change From Baseline in Serum Immunoglobulin (Ig) Levels (IgG, IgA, IgM) at Week 52 ^[22]

End point description

End point type

Primary

End point timeframe

Baseline and Week 52

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

End point values	DBPC: Placebo	DBPC: M2951 25 mg QD	DBPC: M2951 75 mg QD	DBPC: M2951 50 mg BID
Number of subjects analysed	78	83	85	76
Units: gram per liter (g/L)
arithmetic mean (standard deviation)
IgG: n= 78, 83, 85, 76	0.41 ( 2.898 )	0.29 ( 2.361 )	0.35 ( 2.688 )	-0.31 ( 2.344 )
IgA: n= 78, 83, 85, 76	0.19 ( 0.420 )	0.32 ( 0.492 )	0.39 ( 0.767 )	0.18 ( 0.469 )
IgM: n= 78, 83, 84, 76	-0.02 ( 0.235 )	-0.25 ( 0.303 )	-0.21 ( 0.318 )	-0.33 ( 0.456 )

No statistical analyses for this end point

Primary: DBPC: Change From Baseline in Serum Immunoglobulin (Ig) Levels (IgG, IgA, IgM) at Week 56

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End point title

DBPC: Change From Baseline in Serum Immunoglobulin (Ig) Levels (IgG, IgA, IgM) at Week 56 ^[23]

End point description

End point type

Primary

End point timeframe

Baseline and Week 56

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

End point values	DBPC: Placebo	DBPC: M2951 25 mg QD	DBPC: M2951 75 mg QD	DBPC: M2951 50 mg BID
Number of subjects analysed	37	36	31	33
Units: gram per liter (g/L)
arithmetic mean (standard deviation)
IgG	0.74 ( 2.907 )	1.06 ( 2.607 )	0.74 ( 1.987 )	-0.40 ( 2.823 )
IgA	0.23 ( 0.468 )	0.48 ( 0.600 )	0.35 ( 0.488 )	0.26 ( 0.498 )
IgM	0.01 ( 0.266 )	-0.15 ( 0.219 )	-0.11 ( 0.225 )	-0.21 ( 0.488 )

No statistical analyses for this end point

Primary: DBPC: Change From Baseline in Total B Cell Count at Week 4

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End point title

DBPC: Change From Baseline in Total B Cell Count at Week 4 ^[24]

End point description

Change from baseline in Total B cell count were assessed. Flow cytometry analysis of lymphocyte populations using four-color fluorescence-activated cell sorting was performed for the analysis of B cell counts. The Safety analysis set included all subjects who received at least one dose of IMP (Evobrutinib or Placebo). Here, "number of subjects analyzed" signifies those subjects who were evaluable for this endpoint.

End point type

Primary

End point timeframe

Baseline and Week 4

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

End point values	DBPC: Placebo	DBPC: M2951 25 mg QD	DBPC: M2951 75 mg QD	DBPC: M2951 50 mg BID
Number of subjects analysed	90	88	88	91
Units: Cells per microliter
arithmetic mean (standard deviation)	-5 ( 93.7 )	65 ( 146.6 )	87 ( 146.2 )	67 ( 109.1 )

No statistical analyses for this end point

Primary: DBPC: Change From Baseline in Total B Cell Count at Week 24

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End point title

DBPC: Change From Baseline in Total B Cell Count at Week 24 ^[25]

End point description

End point type

Primary

End point timeframe

Baseline and Week 24

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

End point values	DBPC: Placebo	DBPC: M2951 25 mg QD	DBPC: M2951 75 mg QD	DBPC: M2951 50 mg BID
Number of subjects analysed	80	82	73	81
Units: Cells per microliter
arithmetic mean (standard deviation)	2 ( 98.1 )	5 ( 112.0 )	3 ( 103.2 )	-7 ( 134.7 )

No statistical analyses for this end point

Primary: DBPC: Change From Baseline in Total B Cell Count at Week 52

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End point title

DBPC: Change From Baseline in Total B Cell Count at Week 52 ^[26]

End point description

End point type

Primary

End point timeframe

Baseline and Week 52

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

End point values	DBPC: Placebo	DBPC: M2951 25 mg QD	DBPC: M2951 75 mg QD	DBPC: M2951 50 mg BID
Number of subjects analysed	57	60	63	60
Units: Cells per microliter
arithmetic mean (standard deviation)	-14 ( 103.0 )	-19 ( 133.3 )	-14 ( 147.5 )	-52 ( 215.7 )

No statistical analyses for this end point

Primary: DBPC: Change From Baseline in Total B Cell Count at Week 56

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End point title

DBPC: Change From Baseline in Total B Cell Count at Week 56 ^[27]

End point description

End point type

Primary

End point timeframe

Baseline and Week 56

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

End point values	DBPC: Placebo	DBPC: M2951 25 mg QD	DBPC: M2951 75 mg QD	DBPC: M2951 50 mg BID
Number of subjects analysed	30	27	24	24
Units: Cells per microliter
arithmetic mean (standard deviation)	7 ( 96.2 )	-70 ( 138.2 )	-75 ( 192.1 )	-48 ( 85.8 )

No statistical analyses for this end point

Secondary: DBPC: Time to First Severe British Isles Lupus Assessment Group (BILAG) A Flare

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End point title

DBPC: Time to First Severe British Isles Lupus Assessment Group (BILAG) A Flare

End point description

BILAG Index:assessing clinical signs,symptoms,laboratory parameters related to SLE,divided into 9 organ systems.For each organ system based on alphabetic score:A=severe disease,B=moderate disease,C=mild stable disease,D=inactive,but previously active,E=inactive&never affected.BILAG evaluated by scoring each of a list of signs and symptoms as:improving (1)same (2)worse (3)new (4)not present(0)not done(ND).Total BILAG score is sum of scores of 9 domains where A=12,B=8,C=1,D=0,E=0.Total score ranges from 0 to 108 with a higher score indicating > lupus activity.Time to first severe flare, where a severe flare is defined as at least 1BILAG A(Severe disease activity)score in any organ system due to items that are new or worse,compared to BILAG evaluation at previous visit,during 52-Week Treatment.The mITT analysis set was used &"number of subjects analyzed"=subjects who were evaluable for this endpoint.'999' indicated that median was not reached as number of subjects with events were low.

End point type

Secondary

End point timeframe

Baseline up to Week 56

End point values	DBPC: Placebo	DBPC: M2951 25 mg QD	DBPC: M2951 75 mg QD	DBPC: M2951 50 mg BID
Number of subjects analysed	14	16	11	12
Units: Days
median (full range (min-max))	99 (29.0 to 337.0)	99 (29.0 to 367.0)	99 (29.0 to 225.0)	99 (28.0 to 162.0)

Placebo and M2951 25 mg QD

Comparison groups

DBPC: Placebo v DBPC: M2951 25 mg QD

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.7034

Method

Cox proportional hazards model

Parameter type

Hazard ratio (HR)

Point estimate

1.17

Confidence interval

level

95%

sides

2-sided

lower limit

0.57

upper limit

2.4

Placebo and M2951 50 mg BID

Comparison groups

DBPC: Placebo v DBPC: M2951 50 mg BID

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.5462

Method

Cox proportional hazards model

Parameter type

Hazard ratio (HR)

Point estimate

0.9

Confidence interval

level

95%

sides

2-sided

lower limit

0.42

upper limit

1.97

Placebo and M2951 75 mg QD

Comparison groups

DBPC: Placebo v DBPC: M2951 75 mg QD

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.5462

Method

Cox proportional hazards model

Parameter type

Hazard ratio (HR)

Point estimate

0.69

Confidence interval

level

95%

sides

2-sided

lower limit

0.31

upper limit

1.52

Secondary: DBPC: Number of Subjects With Response Based on Systemic Lupus Erythematosus Responder Index 4 (SRI-4) at Week 52 in Serologically Active Subgroup

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End point title

DBPC: Number of Subjects With Response Based on Systemic Lupus Erythematosus Responder Index 4 (SRI-4) at Week 52 in Serologically Active Subgroup

End point description

SRI-4 response was defined as >= 4-point reduction in SLEDAI-2K total score, no new BILAG A and no more than 1 new BILAG B domain score, no worsening (<10 percent (%)increase) from baseline in PGA and no treatment failure.SLEDAI-2K assessment consists of 24 items with total score of 0(no symptoms) to 105 (presence of all defined symptoms) with higher scores representing increased disease activity.BILAG Index: assessing clinical signs, symptoms, or laboratory parameters related to SLE, divided into 9 organ systems.For each organ system A=severe disease, B=moderate disease, C=mild stable disease, D=inactive, but previously active, E=inactive and never affected. PGA assess disease activity on a visual analogue scale =from 0(very well) to 100(very poor).The mITT analysis set was used and "number of subjects analyzed" signifies those subjects with positive anti-double-stranded deoxyribonucleic acid (antidsDNA) and/or low complement levels at screening (Serologically active subgroup).

End point type

Secondary

End point timeframe

Week 52

End point values	DBPC: Placebo	DBPC: M2951 25 mg QD	DBPC: M2951 75 mg QD	DBPC: M2951 50 mg BID
Number of subjects analysed	59	65	60	63
Units: Subjects	28	38	29	34

Placebo and M2951 25 mg QD

Comparison groups

DBPC: Placebo v DBPC: M2951 25 mg QD

Number of subjects included in analysis

124

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.5462

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

1.52

Confidence interval

level

95%

sides

2-sided

lower limit

0.74

upper limit

3.15

Placebo and M2951 75 mg QD

Comparison groups

DBPC: Placebo v DBPC: M2951 75 mg QD

Number of subjects included in analysis

119

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.5462

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

1.03

Confidence interval

level

95%

sides

2-sided

lower limit

0.49

upper limit

2.13

Placebo and M2951 50 mg BID

Comparison groups

DBPC: Placebo v DBPC: M2951 50 mg BID

Number of subjects included in analysis

122

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.5462

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

1.35

Confidence interval

level

95%

sides

2-sided

lower limit

0.65

upper limit

2.81

Secondary: DBPC: Number of Subjects With Response Based on Systemic Lupus Erythematosus Responder Index 6 (SRI-6) at Week 52 in Serologically Active Subgroup

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End point title

DBPC: Number of Subjects With Response Based on Systemic Lupus Erythematosus Responder Index 6 (SRI-6) at Week 52 in Serologically Active Subgroup

End point description

SRI-6 response was defined as >= 6-point reduction in SLEDAI-2K total score, no new BILAG A and no more than 1 new BILAG B domain score and no worsening (<10 % increase) from baseline in PGA of Disease Activity and treatment failure. SLEDAI-2K assessment consists of 24 items with total score of 0 (no symptoms) to 105 (presence of all defined symptoms) with higher scores representing increased disease activity. BILAG Index: assessing clinical signs, symptoms, or laboratory parameters related to SLE, divided into 9 organ systems. For each organ system :A=severe disease, B=moderate disease, C=mild stable disease, D=inactive, but previously active, E=inactive and never affected. The PGA assess disease activity on a visual analogue scale = from 0(very well) to 100(very poor). The mITT analysis set was used and "number of subjects analyzed" signifies those subjects with positive antidsDNA and/or low complement levels at screening (Serologically active subgroup).

End point type

Secondary

End point timeframe

Week 52

End point values	DBPC: Placebo	DBPC: M2951 25 mg QD	DBPC: M2951 75 mg QD	DBPC: M2951 50 mg BID
Number of subjects analysed	59	65	60	63
Units: Subjects	17	25	23	23

Placebo and M2951 25 mg QD

Comparison groups

DBPC: Placebo v DBPC: M2951 25 mg QD

Number of subjects included in analysis

124

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.2434

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

1.6

Confidence interval

level

95%

sides

2-sided

lower limit

0.73

upper limit

3.54

Placebo and M2951 75 mg QD

Comparison groups

DBPC: Placebo v DBPC: M2951 75 mg QD

Number of subjects included in analysis

119

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.2389

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

1.62

Confidence interval

level

95%

sides

2-sided

lower limit

0.73

upper limit

3.63

Placebo and M2951 50 mg BID

Comparison groups

DBPC: Placebo v DBPC: M2951 50 mg BID

Number of subjects included in analysis

122

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1952

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

1.71

Confidence interval

level

95%

sides

2-sided

lower limit

0.76

upper limit

3.85

Secondary: DBPC: Time to First British Isles Lupus Assessment Group (BILAG) A or 2B Moderate to Severe Flare

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End point title

DBPC: Time to First British Isles Lupus Assessment Group (BILAG) A or 2B Moderate to Severe Flare

End point description

BILAG Index:assessing clinical signs,symptoms,laboratory parameters related to SLE,divided into 9 organ systems.For each organ system based on alphabetic score:A=severe disease,B=moderate disease,C=mild stable disease,D=inactive,but previously active,E=inactive&never affected.BILAG evaluated by scoring each of a list of signs and symptoms as:improving (1)same (2)worse (3)new (4)not present(0)not done(ND).Total BILAG score is sum of scores of 9 domains where A=12,B=8,C=1,D=0,E=0.Total score ranges from 0 to 108 with a higher score indicating > lupus activity.Time to first severe flare, where a severe flare is defined as at least 1BILAG A(Severe disease activity)score in any organ system due to items that are new or worse,compared to BILAG evaluation at previous visit,during 52-Week Treatment.The mITT analysis set was used &"number of subjects analyzed"=subjects who were evaluable for this endpoint.'99' signifies data not available as number of the subjects with events were low.

End point type

Secondary

End point timeframe

Baseline up to Week 56

End point values	DBPC: Placebo	DBPC: M2951 25 mg QD	DBPC: M2951 75 mg QD	DBPC: M2951 50 mg BID
Number of subjects analysed	18	27	19	19
Units: Days
median (full range (min-max))	99 (29.0 to 337.0)	99 (27.0 to 365.0)	99 (29.0 to 308.0)	99 (28.0 to 334.0)

Placebo and M2951 25mg QD

Comparison groups

DBPC: Placebo v DBPC: M2951 25 mg QD

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0987

Method

Cox proportional hazards model

Parameter type

Hazard ratio (HR)

Point estimate

1.59

Confidence interval

level

95%

sides

2-sided

lower limit

0.87

upper limit

2.89

Placebo and M2951 75 mg QD

Comparison groups

DBPC: Placebo v DBPC: M2951 75 mg QD

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.9201

Method

Cox proportional hazards model

Parameter type

Hazard ratio (HR)

Point estimate

0.97

Confidence interval

level

95%

sides

2-sided

lower limit

0.51

upper limit

1.85

Placebo and M2951 50 mg BID

Comparison groups

DBPC: Placebo v DBPC: M2951 50 mg BID

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.5645

Method

Cox proportional hazards model

Parameter type

Hazard ratio (HR)

Point estimate

1.15

Confidence interval

level

95%

sides

2-sided

lower limit

0.6

upper limit

2.2

Secondary: DBPC: Number of Subjects With British Isles Lupus Assessment Group (BILAG) 2004 Flare-Free Status During the 52-Week Treatment Period

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End point title

DBPC: Number of Subjects With British Isles Lupus Assessment Group (BILAG) 2004 Flare-Free Status During the 52-Week Treatment Period

End point description

A subject has a flare-free status if no flare has been reported during the 52-week treatment period. Subjects who discontinued treatment prior to Week 52, without having a flare are counted as not being flare free at Week 52. A flare was defined as either 1 or more new BILAG-2004 A (severe disease activity) or 2 or more new BILAG-2004 B (moderate disease activity) items compared to the previous visit. BILAG Index: assessing clinical signs, symptoms, or laboratory parameters related to SLE, divided into 9 organ systems. For each organ system based on alphabetic score: A=severe disease, B=moderate disease, C=mild stable disease, D=inactive, but previously active, E=inactive and never affected. The mITT analysis set was used.

End point type

Secondary

End point timeframe

up to Week 52

End point values	DBPC: Placebo	DBPC: M2951 25 mg QD	DBPC: M2951 75 mg QD	DBPC: M2951 50 mg BID
Number of subjects analysed	114	115	116	114
Units: Subjects	41	35	37	33

Placebo and M2951 25 mg QD

Comparison groups

DBPC: Placebo v DBPC: M2951 25 mg QD

Number of subjects included in analysis

229

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3743

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

0.77

Confidence interval

level

95%

sides

2-sided

lower limit

0.44

upper limit

1.37

Placebo and M2951 75 mg QD

Comparison groups

DBPC: Placebo v DBPC: M2951 75 mg QD

Number of subjects included in analysis

230

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.6445

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

0.88

Confidence interval

level

95%

sides

2-sided

lower limit

0.5

upper limit

1.54

Placebo and M2951 50 mg BID

Comparison groups

DBPC: Placebo v DBPC: M2951 50 mg BID

Number of subjects included in analysis

228

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.2634

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

0.72

Confidence interval

level

95%

sides

2-sided

lower limit

0.41

upper limit

1.28

Secondary: DBPC: Annualized Flare Rate

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End point title

DBPC: Annualized Flare Rate

End point description

A flare was defined as either 1 or more new BILAG-2004 A (severe disease activity) or 2 or more new BILAG-2004 B (moderate disease activity) items compared to the previous visit. The occurrence of a new flare was checked for each available visit versus the previous available visit up to Week 52. If no new flares occurred, the number of flares was set to 0. Otherwise all flares were counted leading to the maximum number of flares of 13. The annualized flare rate was calculated as the number of flares divided by the flare exposure time in days multiplied with 365.25 (1 year). The flare exposure time is the time up to Week 52 (date of BILAG-2004 assessment at Week 52) or up to the date of last available BILAG 2004 assessment. The mITT analysis set was used.

End point type

Secondary

End point timeframe

Baseline up to Week 52

End point values	DBPC: Placebo	DBPC: M2951 25 mg QD	DBPC: M2951 75 mg QD	DBPC: M2951 50 mg BID
Number of subjects analysed	114	115	116	114
Units: Annualized flare rate ratio
number (confidence interval 95%)	0.15 (0.06 to 0.39)	0.23 (0.09 to 0.59)	0.13 (0.05 to 0.33)	0.19 (0.07 to 0.51)

Placebo and M2951 25 mg QD

Comparison groups

DBPC: Placebo v DBPC: M2951 25 mg QD

Number of subjects included in analysis

229

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.2989 ^[28]

Method

Negative binomial regression

Parameter type

Rate Ratio

Point estimate

1.59

Confidence interval

level

95%

sides

2-sided

lower limit

0.66

upper limit

3.81

Notes
[28] - Nominal p-value

Placebo and M2951 75 mg QD

Comparison groups

DBPC: Placebo v DBPC: M2951 75 mg QD

Number of subjects included in analysis

230

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.7325 ^[29]

Method

Negative binomial regression

Parameter type

Rate Ratio

Point estimate

0.85

Confidence interval

level

95%

sides

2-sided

lower limit

0.33

upper limit

2.19

Notes
[29] - Nominal p-value

Placebo and M2951 50 mg BID

Comparison groups

DBPC: Placebo v DBPC: M2951 50 mg BID

Number of subjects included in analysis

228

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.591 ^[30]

Method

Negative binomial regression

Parameter type

Rate Ratio

Point estimate

1.29

Confidence interval

level

95%

sides

2-sided

lower limit

0.51

upper limit

3.22

Notes
[30] - Nominal p-value

Secondary: DBPC: Number of Subjects With Low Disease Activity Status, Defined by Systemic Lupus Erythematosus Disease Activity Index-2000 (SLEDAI-2K) Score of less than or equal (<= ) 2 at Week 52

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End point title

DBPC: Number of Subjects With Low Disease Activity Status, Defined by Systemic Lupus Erythematosus Disease Activity Index-2000 (SLEDAI-2K) Score of less than or equal (<= ) 2 at Week 52

End point description

Low disease activity is defined as SLEDAI-2K score <=2. SLEDAI-2K is an activity index that measures disease activity and records feature of active lupus as present or not present. SLEDAI-2K uses a weighted checklist to assign a numerical score based on the presence or absence of 24 symptoms at the time of assessment or during the previous 30 days. Each symptom present is assigned between 1 and 8 points based on its usual clinical importance, yielding a total score that ranges from 0 points (no symptoms) to 105 points (presence of all defined symptoms). The mITT analysis set was used.

End point type

Secondary

End point timeframe

Week 52

End point values	DBPC: Placebo	DBPC: M2951 25 mg QD	DBPC: M2951 75 mg QD	DBPC: M2951 50 mg BID
Number of subjects analysed	114	115	116	114
Units: Subjects	26	32	39	28

Placebo and M2951 25 mg QD

Comparison groups

DBPC: Placebo v DBPC: M2951 25 mg QD

Number of subjects included in analysis

229

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3635

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

1.33

Confidence interval

level

95%

sides

2-sided

lower limit

0.72

upper limit

2.47

Placebo and M2951 75 mg QD

Comparison groups

DBPC: Placebo v DBPC: M2951 75 mg QD

Number of subjects included in analysis

230

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0329

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

1.94

Confidence interval

level

95%

sides

2-sided

lower limit

1.06

upper limit

3.56

Placebo and M2951 50 mg BID

Comparison groups

DBPC: Placebo v DBPC: M2951 50 mg BID

Number of subjects included in analysis

228

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.7619

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

1.1

Confidence interval

level

95%

sides

2-sided

lower limit

0.59

upper limit

2.07

Secondary: DBPC: Number of Subjects With Low Disease Activity Status, Defined by Clinical Systemic Lupus Erythematosus Disease Activity Index-2000 (SLEDAI-2K) Score of less than or equal (<= ) 2 at Week 52

Top of page

End point title

DBPC: Number of Subjects With Low Disease Activity Status, Defined by Clinical Systemic Lupus Erythematosus Disease Activity Index-2000 (SLEDAI-2K) Score of less than or equal (<= ) 2 at Week 52

End point description

End point type

Secondary

End point timeframe

Week 52

End point values	DBPC: Placebo	DBPC: M2951 25 mg QD	DBPC: M2951 75 mg QD	DBPC: M2951 50 mg BID
Number of subjects analysed	114	115	116	114
Units: Subjects	42	50	52	41

Placebo and M2951 25 mg QD

Comparison groups

DBPC: Placebo v DBPC: M2951 25 mg QD

Number of subjects included in analysis

229

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.2642

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

1.36

Confidence interval

level

95%

sides

2-sided

lower limit

0.79

upper limit

2.35

Placebo and M2951 75 mg QD

Comparison groups

DBPC: Placebo v DBPC: M2951 75 mg QD

Number of subjects included in analysis

230

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1489

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

1.49

Confidence interval

level

95%

sides

2-sided

lower limit

0.87

upper limit

2.57

Placebo and M2951 50 mg BID

Comparison groups

DBPC: Placebo v DBPC: M2951 50 mg BID

Number of subjects included in analysis

228

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.9285

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

0.97

Confidence interval

level

95%

sides

2-sided

lower limit

0.56

upper limit

1.7

Secondary: DBPC: Change From Baseline in Systemic Lupus Erythematosus Disease Activity Index-2000 (SLEDAI-2K) Score at Week 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48 and 52

Top of page

End point title

DBPC: Change From Baseline in Systemic Lupus Erythematosus Disease Activity Index-2000 (SLEDAI-2K) Score at Week 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48 and 52

End point description

SLEDAI-2K is an activity index that measures disease activity and records feature of active lupus as present or not present. SLEDAI-2K uses a weighted checklist to assign a numerical score based on the presence or absence of 24 symptoms at the time of assessment or during the previous 30 days. Each symptom present is assigned between 1 and 8 points based on its usual clinical importance, yielding a total score that ranges from 0 points (no symptoms) to 105 points (presence of all defined symptoms). The mITT analysis set was used. Here, "Number of subjects analyzed" signifies subjects who were evaluable for this endpoint and "n" signifies those subjects who were evaluable for specified category at given time point.

End point type

Secondary

End point timeframe

Baseline, Week 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48 and 52

End point values	DBPC: Placebo	DBPC: M2951 25 mg QD	DBPC: M2951 75 mg QD	DBPC: M2951 50 mg BID
Number of subjects analysed	111	115	115	113
Units: Units on a Scale
arithmetic mean (standard deviation)
Week 4: n= 111, 115, 115, 113	-1 ( 1.9 )	-1 ( 2.1 )	0 ( 1.9 )	-1 ( 2.2 )
Week 8: n= 111, 111, 112, 109	-2 ( 3.1 )	-2 ( 3.2 )	-2 ( 3.0 )	-2 ( 3.2 )
Week 12: n= 109, 106, 109, 104	-3 ( 3.8 )	-3 ( 3.3 )	-3 ( 3.2 )	-3 ( 3.4 )
Week 16: n= 104, 102, 107, 98	-4 ( 3.7 )	-3 ( 3.4 )	-3 ( 3.4 )	-3 ( 3.6 )
Week 20: n= 101, 99, 103, 96	-4 ( 4.1 )	-4 ( 3.8 )	-4 ( 3.4 )	-4 ( 3.4 )
Week 24: n= 98, 95, 101, 94	-4 ( 4.0 )	-4 ( 3.7 )	-4 ( 3.6 )	-3 ( 3.4 )
Week 28: n= 93, 94, 99, 89	-4 ( 3.9 )	-4 ( 3.6 )	-4 ( 3.5 )	-4 ( 3.5 )
Week 32: n= 92, 91, 97, 88	-4 ( 4.0 )	-4 ( 3.5 )	-4 ( 3.7 )	-4 ( 3.4 )
Week 36: n= 91, 90, 95, 113,	-4 ( 4.3 )	-5 ( 3.5 )	-5 ( 3.6 )	-4 ( 3.5 )
Week 40; n= 90, 90, 95, 87	-5 ( 4.1 )	-5 ( 3.6 )	-5 ( 3.8 )	-4 ( 3.3 )
Week 44: n= 89, 90, 92, 96	-4 ( 4.0 )	-5 ( 3.7 )	-5 ( 3.9 )	-4 ( 3.5 )
Week 48: n= 89, 90, 92, 85	-4 ( 4.1 )	-5 ( 3.7 )	-5 ( 3.8 )	-5 ( 3.3 )
Week 52: n= 85, 89, 91, 84	-5 ( 4.0 )	-5 ( 3.7 )	-5 ( 3.7 )	-5 ( 3.9 )

No statistical analyses for this end point

Secondary: DBPC: Change From Baseline in Cutaneous Lupus Erythematosus Disease Area and Severity Index Activity (CLASI-A) Score at Week 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48 and 52

Top of page

End point title

DBPC: Change From Baseline in Cutaneous Lupus Erythematosus Disease Area and Severity Index Activity (CLASI-A) Score at Week 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48 and 52

End point description

CLASI is an validated measurement instrument for lupus erythematosus developed for use in clinical studies that consists of separate scores for the activity of the disease (CLASI-A). The CLASI activity score is calculated on the basis of erythema, scale/hyperkeratosis, mucous membrane involvement, acute hair loss and non-scarring alopecia. The CLASI activity score ranges from 0-70, with higher scores indicating more severe skin disease. Severity categories based on the CLASI activity score are as follows: mild (0-9), moderate (10-20), and severe (21-70). The mITT analysis set was used. Here, "Number of subjects analyzed" signifies subjects who were evaluable for this endpoint and "n" signifies those subjects who were evaluable for specified category at given time point.

End point type

Secondary

End point timeframe

Baseline, Week 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48 and 52

End point values	DBPC: Placebo	DBPC: M2951 25 mg QD	DBPC: M2951 75 mg QD	DBPC: M2951 50 mg BID
Number of subjects analysed	111	113	115	113
Units: Units on a Scale
arithmetic mean (standard deviation)
Week 2: n=110, 113, 113, 109	-1 ( 1.9 )	-1 ( 1.6 )	0 ( 1.6 )	0 ( 1.2 )
Week 4: n= 111, 113, 115, 113	-1 ( 1.9 )	-1 ( 3.5 )	-1 ( 2.4 )	-1 ( 2.2 )
Week 8: n=110, 109, 110, 107	-2 ( 2.8 )	-1 ( 4.2 )	-1 ( 2.3 )	-1 ( 2.5 )
Week 12: n= 107, 104, 107, 101	-2 ( 2.8 )	-2 ( 3.3 )	-2 ( 3.2 )	-2 ( 2.7 )
Week 16: n= 104, 102, 107, 98	-2 ( 3.1 )	-2 ( 3.9 )	-2 ( 3.3 )	-2 ( 2.7 )
Week 20: n= 99, 96, 102, 95	-3 ( 3.6 )	-3 ( 4.4 )	-3 ( 3.4 )	-2 ( 2.9 )
Week 24: n= 97, 95, 100, 92	-3 ( 3.5 )	-3 ( 4.7 )	-3 ( 3.6 )	-2 ( 2.7 )
Week 28: 92, 91, 96, 89	-3 ( 3.7 )	-3 ( 4.6 )	-3 ( 3.4 )	-2 ( 2.7 )
Week 32: n= 91, 91, 96, 87	-3 ( 3.5 )	-3 ( 4.4 )	-3 ( 3.6 )	-3 ( 3.2 )
Week 36: n= 90, 89, 95, 86	-3 ( 3.5 )	-3 ( 4.6 )	-3 ( 3.4 )	-3 ( 3.6 )
Week 40: n= 90, 90, 92, 85	-3 ( 3.0 )	-3 ( 4.6 )	-3 ( 3.6 )	-3 ( 3.8 )
Week 44: n= 89, 90, 92, 85	-3 ( 3.2 )	-3 ( 4.5 )	-3 ( 3.7 )	-3 ( 3.8 )
Week 48: n= 88, 89, 91, 83	-3 ( 3.2 )	-3 ( 4.7 )	-3 ( 3.7 )	-3 ( 3.9 )
Week 52: n= 84, 86, 89, 84	-3 ( 3.6 )	-4 ( 4.8 )	-3 ( 3.7 )	-3 ( 4.0 )

No statistical analyses for this end point

Secondary: DBPC: Number of Subjects With Response Based on BILAG-Based Composite Lupus Assessment (BICLA) at Week 52

Top of page

End point title

DBPC: Number of Subjects With Response Based on BILAG-Based Composite Lupus Assessment (BICLA) at Week 52

End point description

BICLA response defined as subjects meeting following criteria: 1] At least one gradation of improvement in baseline BILAG scores in all body systems with moderate or severe disease activity at entry (example: all A (severe disease) scores falling to B (moderate), C (mild), or D (no activity) and all B scores falling to C or D; 2] No new BILAG A or more than one new BILAG B scores; 3] No worsening of total SLEDAI-2K score from baseline; 4] No significant deterioration (=<10%) in physician's global assessment and 5] No treatment failure (initiation of non-protocol treatment). The mITT analysis set was used. Here, "Number of subjects Analyzed" signifies those subjects who have at least 1 BILAG A or 2 BILAG B grades at Baseline (BICLA Subpopulation).

End point type

Secondary

End point timeframe

Week 52

End point values	DBPC: Placebo	DBPC: M2951 25 mg QD	DBPC: M2951 75 mg QD	DBPC: M2951 50 mg BID
Number of subjects analysed	76	73	76	70
Units: Subjects	30	29	33	24

Placebo and M2951 25 mg QD

Comparison groups

DBPC: Placebo v DBPC: M2951 25 mg QD

Number of subjects included in analysis

149

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.9061

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

0.96

Confidence interval

level

95%

sides

2-sided

lower limit

0.49

upper limit

1.88

Placebo and M2951 50 mg BID

Comparison groups

DBPC: Placebo v DBPC: M2951 50 mg BID

Number of subjects included in analysis

146

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.52

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

0.8

Confidence interval

level

95%

sides

2-sided

lower limit

0.4

upper limit

1.59

Placebo and M2951 75 mg QD

Comparison groups

DBPC: Placebo v DBPC: M2951 75 mg QD

Number of subjects included in analysis

152

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.6053

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

1.19

Confidence interval

level

95%

sides

2-sided

lower limit

0.61

upper limit

2.31

Secondary: DBPC: Change From Baseline in British Isles Lupus Assessment Group (BILAG)-2004 Score at Week 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48 and 52

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End point title

DBPC: Change From Baseline in British Isles Lupus Assessment Group (BILAG)-2004 Score at Week 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48 and 52

End point description

BILAG 2004 disease activity Index: assessing clinical signs, symptoms, or laboratory parameters related to SLE, divided into 9 organ systems. For each organ system based on alphabetic score: A=severe disease, B=moderate disease, C=mild stable disease, D=inactive, but previously active, E=inactive and never affected. BILAG evaluated by scoring each of a list of signs and symptoms as: improving (1); same (2); worse (3); new (4); not present (0); not done (ND). Total BILAG score is sum of scores of 9 domains where A=12, B=8, C=1, D=0, and E=0. Total score ranges from 0 to 108 with a higher score indicating greater lupus activity. The mITT analysis set was used. Here, "Number of subjects analyzed" signifies subjects who were evaluable for this endpoint and "n" signifies those subjects who were evaluable for specified category at given time points.

End point type

Secondary

End point timeframe

Baseline, Week 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48 and 52

End point values	DBPC: Placebo	DBPC: M2951 25 mg QD	DBPC: M2951 75 mg QD	DBPC: M2951 50 mg BID
Number of subjects analysed	110	111	109	109
Units: Units on a Scale
arithmetic mean (standard deviation)
Week 4: n= 108, 108, 108, 105	-4 ( 5.8 )	-4 ( 6.1 )	-3 ( 6.3 )	-4 ( 6.2 )
Week 8: n= 110, 111, 109, 109	-6 ( 6.0 )	-5 ( 7.0 )	-6 ( 6.3 )	-6 ( 6.1 )
Week 12: n= 109, 106, 107, 104	-7 ( 6.7 )	-7 ( 6.8 )	-6 ( 7.0 )	-6 ( 6.2 )
Week 16: n= 104, 102, 105, 98	-7 ( 6.9 )	-7 ( 7.6 )	-6 ( 6.8 )	-6 ( 5.9 )
Week 20: n= 101, 99, 102, 96	-7 ( 6.8 )	-7 ( 7.3 )	-7 ( 7.6 )	-6 ( 6.2 )
Week 24: n= 97, 95, 100, 94	-8 ( 6.9 )	-7 ( 6.5 )	-8 ( 7.7 )	-6 ( 6.3 )
Week 28: n= 93, 94, 98, 89	-8 ( 6.7 )	-8 ( 6.9 )	-8 ( 7.4 )	-7 ( 6.2 )
Week 32: n= 92, 91, 96, 89	-9 ( 6.7 )	-8 ( 7.3 )	-8 ( 7.9 )	-7 ( 6.0 )
Week 36: n= 91, 90, 95, 88	-8 ( 7.1 )	-8 ( 7.2 )	-8 ( 7.4 )	-7 ( 6.7 )
Week 40: n= 88, 90, 95, 87	-9 ( 6.8 )	-8 ( 6.7 )	-9 ( 7.7 )	-7 ( 6.6 )
Week 44: n= 88, 90, 92, 85	-9 ( 7.2 )	-9 ( 7.2 )	-9 ( 7.9 )	-7 ( 6.7 )
Week 48: n= 89, 90, 92, 85	-8 ( 7.1 )	-8 ( 7.2 )	-9 ( 7.6 )	-7 ( 6.5 )
Week 52: n=85, 89, 91, 84	-8 ( 7.0 )	-9 ( 6.8 )	-9 ( 7.8 )	-7 ( 6.7 )

No statistical analyses for this end point

Secondary: DBPC: Change From Baseline in Physician's Global Assessment (PGA) Score at Week 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48 and 52

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End point title

DBPC: Change From Baseline in Physician's Global Assessment (PGA) Score at Week 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48 and 52

End point description

The Physician's Global Assessment of Disease Activity was recorded using the 100 millimeter horizontal Visual Analog Scale (VAS). Physician rated subject's disease activity on a scale ranged from 0-100 millimeter (mm), where 0 indicated no disease activity and 100 represented maximum disease activity. The mITT analysis set was used. Here, "Number of subjects analyzed" signifies subjects who were evaluable for this endpoint and "n" signifies those subjects who were evaluable for specified category at given time point.

End point type

Secondary

End point timeframe

Baseline, Week 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48 and 52

End point values	DBPC: Placebo	DBPC: M2951 25 mg QD	DBPC: M2951 75 mg QD	DBPC: M2951 50 mg BID
Number of subjects analysed	111	115	115	113
Units: Millimeter
arithmetic mean (standard deviation)
Week 4: n= 111, 115, 115, 113	-8 ( 11.7 )	-8 ( 14.1 )	-9 ( 13.4 )	-9 ( 12.1 )
Week 8: n= 110, 109, 111, 107	-13 ( 16.2 )	-14 ( 16.5 )	-13 ( 15.5 )	-14 ( 15.9 )
Week 12: n= 107, 104, 107, 101	-18 ( 17.4 )	-18 ( 18.8 )	-19 ( 18.3 )	-18 ( 16.9 )
Week 16: n= 104, 102, 105, 98	-21 ( 17.6 )	-20 ( 19.7 )	-21 ( 18.7 )	-19 ( 18.0 )
Week 20: n= 99, 96, 102, 95	-23 ( 19.2 )	-21 ( 19.5 )	-24 ( 17.9 )	-20 ( 18.6 )
Week 24: n= 97, 95, 100, 92	-24 ( 17.8 )	-24 ( 20.0 )	-25 ( 19.2 )	-21 ( 18.0 )
Week 28: n= 92, 91, 96, 89	-26 ( 17.6 )	-26 ( 20.3 )	-26 ( 18.6 )	-24 ( 17.8 )
Week 32: n= 91, 91, 96, 87	-26 ( 17.8 )	-26 ( 20.8 )	-26 ( 19.0 )	-26 ( 17.5 )
Week 36: n= 90, 89, 95, 86	-26 ( 17.9 )	-26 ( 20.9 )	-29 ( 18.3 )	-26 ( 18.3 )
Week 40: n= 90, 90, 91, 85	-27 ( 16.9 )	-27 ( 19.1 )	-30 ( 19.7 )	-25 ( 18.1 )
Week 44: n= 89, 90, 92, 85	-28 ( 16.6 )	-28 ( 20.1 )	-30 ( 20.7 )	-26 ( 16.6 )
Week 48: n= 88, 89, 91, 83	-29 ( 16.5 )	-29 ( 19.5 )	-32 ( 18.8 )	-28 ( 18.3 )
Week 52: n= 84, 86, 89, 84	-29 ( 16.2 )	-31 ( 20.7 )	-33 ( 19.2 )	-27 ( 18.1 )

No statistical analyses for this end point

Secondary: DBPC: Change From Baseline in Study 36-Item Short Form Health Survey version 2 (SF-36v2) Physical Component Summary Score and Mental Component Summary Scores at Week 4, 8, 12, 16, 24, 32, 40 and 52

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End point title

DBPC: Change From Baseline in Study 36-Item Short Form Health Survey version 2 (SF-36v2) Physical Component Summary Score and Mental Component Summary Scores at Week 4, 8, 12, 16, 24, 32, 40 and 52

End point description

36-Item SF-36 was standardized survey evaluating 8 aspects of functional health and well-being. 8 subscales were relating to either physical or mental health. Physical component summary (PCS) was based primarily on physical functioning, role-physical, bodily pain, and general health scales and mental component summary (MCS) encompasses vitality, social functioning, role-emotional, and mental health scales. Score from mental health, role emotional, social functioning, and vitality domains were averaged to calculate MCS. Total score range for MCS was 0 - 100 (100 = highest level of mental functioning). Score from physical function, role physical, bodily pain, and general health domains were averaged to calculate PCS. Total score range for PCS was 0-100 (100 = highest level of physical functioning). QOL set was used. "Number of subjects analyzed" signifies those subjects who were evaluable for this endpoint and "n" signifies those subjects who were evaluable for the specified category.

End point type

Secondary

End point timeframe

Baseline, Week 4, 8, 12, 16, 24, 32, 40 and 52

End point values	DBPC: Placebo	DBPC: M2951 25 mg QD	DBPC: M2951 75 mg QD	DBPC: M2951 50 mg BID
Number of subjects analysed	110	114	112	113
Units: Units on a Scale
arithmetic mean (standard deviation)
PCS at Week 4 (n=110, 114, 112, 113)	1.2 ( 5.42 )	2.5 ( 7.40 )	3.5 ( 6.01 )	2.2 ( 5.86 )
PCS at Week 8 (n=107, 108, 109, 106)	1.8 ( 6.35 )	3.5 ( 7.69 )	3.0 ( 6.61 )	2.2 ( 6.63 )
PCS at Week 12 (n=106,102, 103, 101)	2.4 ( 6.44 )	3.7 ( 7.71 )	4.2 ( 6.68 )	3.0 ( 6.99 )
PCS at Week 16 (n=101,101, 105, 96)	3.3 ( 7.04 )	4.0 ( 7.56 )	4.4 ( 5.81 )	3.4 ( 6.77 )
PCS at Week 24 (n=96, 95,99, 95)	3.4 ( 7.08 )	4.6 ( 7.57 )	5.4 ( 7.63 )	2.8 ( 7.15 )
PCS at Week 32 (n=90, 91,93, 88)	3.5 ( 8.03 )	3.8 ( 7.36 )	5.4 ( 7.24 )	3.8 ( 6.89 )
PCS at Week 40 (n=88, 89,91, 86)	4.2 ( 7.11 )	4.6 ( 7.97 )	5.7 ( 7.76 )	4.1 ( 8.59 )
PCS at Week 52 (n=86, 84,87, 82)	3.7 ( 8.32 )	5.4 ( 7.05 )	6.5 ( 8.58 )	4.8 ( 7.76 )
MCS at Week 4 (n= 110, 114, 112, 113)	3.9 ( 9.38 )	1.7 ( 9.25 )	1.9 ( 7.92 )	2.4 ( 7.68 )
MCS at Week 8 (n= 107, 108, 109, 106)	2.5 ( 8.59 )	2.2 ( 8.81 )	1.6 ( 8.48 )	3.6 ( 9.04 )
MCS at Week 12 (n= 106,102,103, 101)	3.1 ( 10.07 )	3.1 ( 8.45 )	0.8 ( 10.39 )	2.9 ( 8.89 )
MCS at Week 16 (n= 101,101,105, 96)	3.6 ( 9.84 )	2.5 ( 8.39 )	2.8 ( 9.39 )	2.9 ( 9.13 )
MCS at Week 24 (n= 96,95,99, 95)	2.9 ( 9.75 )	2.4 ( 8.41 )	3.4 ( 9.68 )	2.7 ( 8.87 )
MCS at Week 32 (n= 90,91,93, 88)	3.5 ( 8.55 )	1.8 ( 9.51 )	2.8 ( 9.71 )	4.3 ( 9.03 )
MCS at Week 40 (n= 88, 89, 91, 86)	4.5 ( 8.81 )	1.5 ( 10.55 )	3.2 ( 9.81 )	4.0 ( 9.85 )
MCS at Week 52 (n= 86, 84, 87, 82)	3.8 ( 9.45 )	1.7 ( 9.91 )	3.9 ( 11.21 )	4.6 ( 9.80 )

No statistical analyses for this end point

Secondary: DBPC: Change From Baseline in European Quality of Life 5-dimensions (EQ-5D-5L) Health Outcome Questionnaire at Week 4, 8, 12, 16, 24, 32, 40 and 52

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End point title

DBPC: Change From Baseline in European Quality of Life 5-dimensions (EQ-5D-5L) Health Outcome Questionnaire at Week 4, 8, 12, 16, 24, 32, 40 and 52

End point description

The EQ-5D-5L questionnaire is a generic measure of health status that provides a simple descriptive profile and a single index value. The EQ-5D-5L profile defines health in terms of mobility, self-care, usual activities, pain or discomfort, and anxiety or depression. Each dimension has five levels: 1: no problems, 2: slight problems, 3: moderate problems, 4: severe problems, and 5: extreme problems. Responses were used to generate a weighted summary index (EQ-5D index), which ranges from 0 (dead) to 1.00 (perfect health). A higher score indicates better health and positive changes from baseline indicate improvement of health. Quality of Life analysis set was used. Here, "Number of subjects analyzed" signifies subjects who were evaluable for this endpoint and "n" signifies those subjects who were evaluable for specified category at given time point.

End point type

Secondary

End point timeframe

Baseline, Week 4, 8, 12, 16, 24, 32, 40, and 52

End point values	DBPC: Placebo	DBPC: M2951 25 mg QD	DBPC: M2951 75 mg QD	DBPC: M2951 50 mg BID
Number of subjects analysed	110	114	112	113
Units: Units on a Scale
arithmetic mean (standard deviation)
Week 4: n= 110, 114, 112, 113	0.036 ( 0.1626 )	0.045 ( 0.1931 )	0.036 ( 0.1618 )	0.038 ( 0.1908 )
Week 8: n= 107, 108, 109, 106	0.034 ( 0.2164 )	0.064 ( 0.2505 )	0.046 ( 0.1842 )	0.061 ( 0.1603 )
Week 12: n= 106, 102, 103, 101	0.061 ( 0.2014 )	0.070 ( 0.2189 )	0.055 ( 0.1912 )	0.065 ( 0.1732 )
Week 16: n= 101, 101, 105, 96	0.083 ( 0.1818 )	0.072 ( 0.2252 )	0.067 ( 0.2287 )	0.056 ( 0.1738 )
Week 24: n= 96, 95, 99, 95	0.080 ( 0.1901 )	0.067 ( 0.2271 )	0.086 ( 0.2110 )	0.055 ( 0.1817 )
Week 32: n= 90, 91, 93, 88	0.083 ( 0.1758 )	0.067 ( 0.2262 )	0.075 ( 0.2009 )	0.071 ( 0.1941 )
Week 40: n= 88, 89, 91, 86	0.093 ( 0.1521 )	0.061 ( 0.1850 )	0.090 ( 0.1853 )	0.084 ( 0.2172 )
Week 52: n= 86, 84, 87, 82	0.096 ( 0.2092 )	0.078 ( 0.2197 )	0.102 ( 0.2224 )	0.096 ( 0.2051 )

No statistical analyses for this end point

Secondary: DBPC: Change From Baseline in European Quality of Life 5-dimensions (EQ-5D-5L) Visual Analog Scale (VAS) at Week 4, 8, 12, 16, 24, 32, 40 and 52

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End point title

DBPC: Change From Baseline in European Quality of Life 5-dimensions (EQ-5D-5L) Visual Analog Scale (VAS) at Week 4, 8, 12, 16, 24, 32, 40 and 52

End point description

The EQ-5D-5L questionnaire is a generic measure of health status that provides a simple descriptive profile and a single index value. The EQ-5D-5L profile defines health in terms of mobility, self-care, usual activities, pain or discomfort, and anxiety or depression. Each dimension has five levels: 1: no problems, 2: slight problems, 3: moderate problems, 4: severe problems, and 5: extreme problems. The responses were used to derive overall score using a visual analog scale (VAS) that ranged from 0 to 100 millimeter (mm), where 0 was the worst health you can imagine and 100 was the best health you can imagine. Quality of Life analysis set was used. Here, "Number of subjects analyzed" signifies subjects who were evaluable for this endpoint and "n" signifies those subjects who were evaluable for specified category at given time point.

End point type

Secondary

End point timeframe

Baseline, Week 4, 8, 12, 16, 24, 32, 40, and 52

End point values	DBPC: Placebo	DBPC: M2951 25 mg QD	DBPC: M2951 75 mg QD	DBPC: M2951 50 mg BID
Number of subjects analysed	110	114	112	113
Units: Millimeter
arithmetic mean (standard deviation)
Week 4: n= 110, 114, 112, 113	3 ( 16.8 )	2 ( 19.0 )	4 ( 17.6 )	4 ( 18.2 )
Week 8: n= 107, 108, 109, 106	3 ( 18.8 )	6 ( 20.0 )	4 ( 14.5 )	6 ( 16.5 )
Week 12: n= 106, 102, 103, 101	5 ( 19.7 )	6 ( 17.4 )	5 ( 17.2 )	4 ( 16.8 )
Week 16: n= 101, 101, 105, 96	7 ( 19.3 )	5 ( 18.1 )	6 ( 18.5 )	4 ( 15.5 )
Week 24: n= 96, 95, 99, 95	7 ( 18.7 )	5 ( 18.4 )	9 ( 20.4 )	4 ( 17.3 )
Week 32: n= 90, 91, 93, 88	8 ( 17.2 )	4 ( 21.1 )	7 ( 17.8 )	7 ( 16.6 )
Week 40: n= 88, 89, 91, 86	8 ( 18.1 )	6 ( 18.1 )	10 ( 19.5 )	8 ( 18.9 )
Week 52: n= 86, 84, 87, 82	8 ( 19.9 )	8 ( 18.6 )	10 ( 21.3 )	10 ( 18.9 )

No statistical analyses for this end point

Secondary: DBPC: Change From Baseline in Lupus Quality of Life (LupusQoL) Questionnaire Score at Week 4, 8, 12, 16, 24, 32, 40 and 52

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End point title

DBPC: Change From Baseline in Lupus Quality of Life (LupusQoL) Questionnaire Score at Week 4, 8, 12, 16, 24, 32, 40 and 52

End point description

The Lupus QoL assessment is a 34 item questionnaire across 8 domains that is designed to find out how SLE affects a subject's life. Domains include physical health (PH), pain, planning, intimate relationships (IR), burden to others (BTO), emotional health (EH), body image, and fatigue. Subjects indicate their responses on a 5-point Likert response format, where 4=never,3=occasionally,2= a good bit of the time,1=most of the time and 0=worst of the time. Summary scores can be calculated for all 8 domains. LupusQoL score for each domain was reported on a 0 to 100 scale, with greater values indicating better health related QoL. QOL analysis set was used. Here, "Number of subjects analyzed" signifies subjects who were evaluable for this endpoint and "n" signifies those subjects who were evaluable for specified category at given time point.

End point type

Secondary

End point timeframe

Baseline, Week 4, 8, 12, 16, 24, 32, 40, and 52

End point values	DBPC: Placebo	DBPC: M2951 25 mg QD	DBPC: M2951 75 mg QD	DBPC: M2951 50 mg BID
Number of subjects analysed	110	114	112	113
Units: Units on a scale
arithmetic mean (standard deviation)
PH Week 4: n=110,114,112,113	1.9 ( 12.58 )	4.7 ( 17.68 )	4.0 ( 14.04 )	3.5 ( 13.43 )
PH Week 8: n=107, 108, 109, 106	2.8 ( 15.20 )	6.3 ( 19.94 )	3.8 ( 17.64 )	4.6 ( 14.69 )
PH Week 12: n= 106, 102, 103, 101	4.8 ( 16.75 )	6.7 ( 19.78 )	5.6 ( 15.95 )	5.7 ( 14.94 )
PH Week 16: n= 101, 101, 105, 96	6.6 ( 17.45 )	6.1 ( 18.71 )	7.4 ( 17.61 )	6.2 ( 15.59 )
PH Week 24: n= 96, 95, 99, 95	6.9 ( 17.17 )	7.2 ( 18.59 )	8.4 ( 20.47 )	6.1 ( 13.63 )
PH Week 32: n= 90, 91, 93, 88	5.7 ( 16.82 )	6.7 ( 19.45 )	9.4 ( 17.21 )	7.0 ( 16.21 )
PH Week 40: n= 88, 89, 91, 86	7.6 ( 15.32 )	8.2 ( 17.38 )	9.6 ( 19.10 )	7.1 ( 17.98 )
PH Week 52: n= 86, 84, 87, 82	7.1 ( 20.39 )	9.0 ( 18.44 )	11.6 ( 19.88 )	7.9 ( 18.73 )
Pain Week 4: n= 110, 114, 112, 113	3.6 ( 16.30 )	6.7 ( 21.81 )	9.0 ( 20.90 )	5.7 ( 16.26 )
Pain Week 8: n=107, 108, 109, 106	4.8 ( 18.71 )	9.9 ( 24.65 )	7.3 ( 21.76 )	6.7 ( 18.31 )
Pain Week 12: n= 106, 102, 103, 101	7.5 ( 19.04 )	8.8 ( 24.00 )	9.8 ( 23.35 )	5.5 ( 14.73 )
Pain Week 16: n= 101, 101, 105, 96	9.4 ( 18.58 )	8.3 ( 25.60 )	10.5 ( 26.33 )	6.9 ( 15.47 )
Pain Week 24: n= 96, 95, 99, 95	9.4 ( 19.95 )	9.3 ( 24.31 )	13.0 ( 28.18 )	6.2 ( 17.02 )
Pain Week 32: n= 90, 91, 93, 88	6.7 ( 23.74 )	9.2 ( 24.60 )	12.8 ( 22.87 )	8.7 ( 17.18 )
Pain Week 40: n= 88, 89, 91, 86	11.0 ( 19.43 )	10.9 ( 23.68 )	15.3 ( 23.81 )	9.6 ( 20.51 )
Pain Week 52: n= 86, 84, 87, 82	10.2 ( 21.37 )	12.9 ( 22.64 )	14.9 ( 26.11 )	9.6 ( 19.99 )
Planning Week 4: n=110,114, 112, 113	4.8 ( 20.14 )	4.9 ( 19.64 )	5.4 ( 24.30 )	4.6 ( 18.73 )
Planning Week 8: n= 107, 108, 109, 106	5.5 ( 23.32 )	8.4 ( 23.25 )	5.8 ( 25.14 )	3.9 ( 22.98 )
Planning Week 12: n= 106,102,103,101	7.8 ( 23.58 )	5.8 ( 23.39 )	6.8 ( 25.74 )	5.1 ( 20.55 )
Planning Week 16: n=101,101,105,96	8.3 ( 21.65 )	5.3 ( 24.12 )	6.5 ( 28.00 )	6.3 ( 22.91 )
Planning Week 24: n= 96,95, 99, 95	7.9 ( 22.92 )	8.1 ( 23.55 )	11.5 ( 29.08 )	5.6 ( 21.79 )
Planning Week 32: n= 90,91,93,88	6.5 ( 24.82 )	7.6 ( 22.66 )	9.9 ( 25.90 )	6.9 ( 22.07 )
Planning Week 40: n= 88,89,91,86	9.0 ( 20.69 )	7.8 ( 23.19 )	11.6 ( 26.17 )	8.0 ( 23.52 )
Planning Week 52: n= 86,84,87,82	9.9 ( 22.38 )	7.0 ( 23.12 )	9.9 ( 28.29 )	10.5 ( 21.59 )
IR Week 4: n= 74,88,80,71	3.4 ( 26.11 )	1.6 ( 28.29 )	4.7 ( 24.06 )	3.2 ( 24.06 )
IR Week 8: n= 70,81,75,61	8.2 ( 30.31 )	4.2 ( 28.44 )	9.7 ( 29.10 )	3.7 ( 18.73 )
IR Week 12: n= 70,75,65,59	5.5 ( 27.31 )	4.7 ( 25.65 )	2.3 ( 30.37 )	6.4 ( 21.32 )
IR Week 16: n= 60,72,69,53	8.8 ( 26.77 )	1.6 ( 30.76 )	3.8 ( 32.46 )	4.2 ( 22.99 )
IR Week 24: n= 59,70,62,47	6.4 ( 30.12 )	2.1 ( 28.79 )	6.7 ( 30.76 )	5.3 ( 26.29 )
IR Week 32: n= 54,66,54,52	2.5 ( 28.77 )	1.3 ( 31.78 )	6.5 ( 29.41 )	1.4 ( 27.86 )
IR Week 40: n= 49,61,55,48	12.0 ( 27.59 )	6.6 ( 27.91 )	6.4 ( 32.53 )	7.8 ( 22.72 )
IR Week 52: n= 51,60,49,45	7.4 ( 26.48 )	4.4 ( 28.36 )	8.4 ( 29.58 )	8.9 ( 24.52 )
BTO Week 4: n= 110,114,112,113	5.8 ( 23.83 )	5.2 ( 22.84 )	6.8 ( 24.85 )	2.2 ( 24.24 )
BTO Week 8: n= 107,108,109,106	5.6 ( 22.42 )	9.3 ( 27.17 )	5.7 ( 25.80 )	8.0 ( 25.79 )
BTO Week 12: n= 106,102,103,101	8.6 ( 25.86 )	6.7 ( 28.00 )	7.4 ( 25.93 )	7.3 ( 24.74 )
BTO Week 16: n= 101,101,105,96	11.8 ( 26.17 )	8.1 ( 23.32 )	6.7 ( 25.80 )	7.4 ( 24.30 )
BTO Week 24: n= 96, 95, 99,95	10.3 ( 28.68 )	9.0 ( 24.12 )	11.8 ( 27.15 )	5.8 ( 26.21 )
BTO Week 32: n= 90,91,93,88	10.6 ( 29.42 )	6.8 ( 24.09 )	9.6 ( 27.14 )	8.4 ( 28.21 )
BTO Week 40: n= 88,89,91,86	16.1 ( 25.07 )	12.4 ( 21.91 )	12.4 ( 28.74 )	12.1 ( 25.78 )
BTO Week 52: n= 86,84,87,82	15.3 ( 26.96 )	10.7 ( 22.13 )	13.0 ( 30.04 )	10.5 ( 25.89 )
EH Week 4: n= 110,114,112,113	6.4 ( 15.37 )	4.7 ( 18.48 )	4.2 ( 18.45 )	1.8 ( 16.73 )
EH Week 8: n= 107,108,109,106	4.5 ( 15.15 )	7.0 ( 19.26 )	2.3 ( 19.51 )	5.3 ( 15.53 )
EH Week 12: n= 106,102,103,101	6.3 ( 17.23 )	7.6 ( 21.08 )	4.9 ( 20.99 )	4.7 ( 16.39 )
EH Week 16: n= 101,101,105,96	8.3 ( 15.86 )	7.5 ( 19.59 )	7.4 ( 18.56 )	6.2 ( 18.32 )
EH Week 24: n= 96,95,99,95	7.1 ( 17.31 )	5.6 ( 24.02 )	8.9 ( 20.97 )	4.3 ( 20.04 )
EH Week 32: n= 90,91,93,88	6.3 ( 17.07 )	4.3 ( 23.55 )	9.0 ( 22.66 )	6.0 ( 20.56 )
EH Week 40: n= 88,89,91,86	8.4 ( 16.08 )	8.3 ( 19.94 )	7.6 ( 21.52 )	6.7 ( 19.14 )
EH Week 52: n= 86,84,87,82	8.5 ( 17.43 )	6.4 ( 21.31 )	8.2 ( 22.77 )	7.6 ( 18.80 )
Body Image Week 4:n=96,97,92,93	3.1 ( 17.70 )	8.4 ( 24.41 )	2.5 ( 24.60 )	4.0 ( 18.79 )
Body Image Week 8:n=90,92,91,85	5.7 ( 18.37 )	7.5 ( 23.40 )	-1.3 ( 27.06 )	6.5 ( 17.30 )
Body Image Week 12:n=88,84,83,85	6.5 ( 18.57 )	7.1 ( 21.07 )	2.3 ( 26.86 )	6.6 ( 16.53 )
Body Image Week 16:n=84,82,85,81	6.7 ( 18.10 )	7.6 ( 23.11 )	-0.4 ( 25.31 )	5.7 ( 20.39 )
Body Image Week 24:n=75,79,75,77	6.7 ( 20.84 )	10.2 ( 20.47 )	5.8 ( 27.31 )	6.7 ( 21.80 )
Body Image Week 32:n=71,76,68,73	5.1 ( 20.08 )	8.1 ( 23.71 )	3.3 ( 24.99 )	5.8 ( 21.54 )
Body Image Week 40:n=71,76,66,72	7.7 ( 14.11 )	8.2 ( 23.99 )	4.6 ( 26.67 )	9.0 ( 18.31 )
Body Image Week 52:n=74,68,66,67	6.6 ( 16.92 )	9.8 ( 21.46 )	5.1 ( 27.30 )	7.8 ( 21.56 )
Fatigue Week 4:n=110,114,112,113	4.4 ( 16.71 )	4.3 ( 18.98 )	6.2 ( 19.91 )	3.9 ( 17.08 )
Fatigue Week 8:n=107,108,109,106	5.0 ( 19.22 )	7.1 ( 21.31 )	4.9 ( 20.61 )	4.5 ( 16.78 )
Fatigue Week 12:n= 106,102,103,101	6.7 ( 18.22 )	5.8 ( 21.30 )	7.3 ( 23.11 )	5.0 ( 16.08 )
Fatigue Week 16:n=101,101,105,96	7.7 ( 17.61 )	6.6 ( 21.39 )	7.1 ( 24.16 )	4.1 ( 15.81 )
Fatigue Week 24: n=96,95,99,95	7.5 ( 19.06 )	4.8 ( 23.34 )	9.0 ( 26.00 )	3.6 ( 14.20 )
Fatigue Week 32: n=90,91,93,88	7.0 ( 19.20 )	3.7 ( 22.71 )	8.5 ( 22.96 )	4.1 ( 17.24 )
Fatigue Week 40: n= 88,89,91,86	11.3 ( 20.03 )	6.1 ( 25.28 )	11.0 ( 25.18 )	5.3 ( 16.73 )
Fatigue Week 52: n= 86,84,87,82	8.9 ( 21.15 )	4.5 ( 24.78 )	11.2 ( 22.56 )	6.7 ( 17.89 )

No statistical analyses for this end point

Secondary: DBPC: Number of Subjects With Patient Global Impression of Change (PGIC) Scale Score of Any Improvement, no Change and Any Worsening

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End point title

DBPC: Number of Subjects With Patient Global Impression of Change (PGIC) Scale Score of Any Improvement, no Change and Any Worsening

End point description

The PGIC is a self-rated scale that asks the subject to describe the change in activity limitations, symptoms, emotions, and overall quality of life (QoL) related to the subjects painful condition on the following scale: 1 (very much improved), 2 (much improved), 3 (minimally improved), 4 (no change), 5 (minimally worse), 6 (much worse) and 7 (very much worse). Number of subjects in the PGIC categories of any improvement (that is PGIC scale score 1, 2 or 3), no change (that is PGIC scale score 4) and any worsening (that is PGIC scale score 5, 6 or 7) are reported. QOL analysis set was used. Here, "n" signifies those subjects who were evaluable for specified category at given time points.

End point type

Secondary

End point timeframe

Week 4, 8, 12, 16, 24, 32, 40, and 52

End point values	DBPC: Placebo	DBPC: M2951 25 mg QD	DBPC: M2951 75 mg QD	DBPC: M2951 50 mg BID
Number of subjects analysed	112	114	113	113
Units: Subjects
Week 4 Any Improvement: n= 112, 114, 113, 113	69	78	81	71
Week 8 Any Improvement: n= 110, 110, 110, 109	80	81	85	75
Week 12 Any Improvement: n= 108, 105,107,104	78	82	81	77
Week 16 Any Improvement: n= 104, 101,105,98	75	81	87	79
Week 24 Any Improvement: n= 98, 95, 101, 95	67	77	87	73
Week 32 Any Improvement: n= 91, 91, 95, 89	70	70	80	72
Week 40 Any Improvement: n= 89, 89, 93, 87	67	69	80	73
Week 52 Any Improvement: n= 88, 89, 90, 85	66	64	76	64
Week 4 No Change: n= 112, 114, 113, 113	33	27	23	34
Week 8 No Change: n= 110, 110, 110,109	22	18	19	28
Week 12 No Change: n= 108, 105, 107, 104	23	13	15	20
Week 16 No Change: n= 104, 101,105,98	23	13	16	15
Week 24 No Change: n= 98, 95, 101, 95	23	12	7	17
Week 32 No Change: n= 91, 91, 95, 89	16	15	8	13
Week 40 No Change: n= 89, 89, 93, 87	19	12	7	9
Week 52 No Change: n= 88, 89, 90, 85	14	18	6	13
Week 4 Any Worsening: n= 112, 114, 113, 113	8	9	8	8
Week 8 Any Worsening: n= 110, 110, 110, 109	5	9	5	3
Week 12 Any Worsening: n= 108, 105, 107, 104	5	7	7	4
Week 16 Any Worsening: n= 104, 101, 105, 98	3	7	2	2
Week 24 Any Worsening: n= 98, 95, 101, 95	6	6	5	5
Week 32 Any Worsening: n= 91, 91, 95, 89	4	6	5	3
Week 40 Any Worsening: n= 89, 89, 93, 87	2	8	4	4
Week 52 Any Worsening: n= 88, 89, 90, 85	6	1	5	4
Week 4 Missing: n=112, 114, 113, 113	2	0	1	0
Week 8 Missing: n= 110, 110, 110, 109	3	2	1	3
Week 12 Missing: n= 108, 105, 107, 104	2	3	4	3
Week 16 Missing: n= 104, 101, 105, 98	3	0	0	2
Week 24 Missing: n= 98, 95, 101, 95	2	0	2	0
Week 32 Missing: n= 91, 91, 95, 89	1	0	2	1
Week 40 Missing: n= 89, 89, 93, 87	1	0	2	1
Week 52 Missing: n= 88, 89, 90, 85	2	6	3	4

No statistical analyses for this end point

Secondary: DBPC: Change From Baseline in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) Score at Week 4, 8, 12, 16, 24, 32, 40 and 52

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End point title

DBPC: Change From Baseline in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) Score at Week 4, 8, 12, 16, 24, 32, 40 and 52

End point description

The FACIT-Fatigue score was calculated according to a 13-item questionnaire that assess self reported fatigue and its impact upon daily activities and function. It uses a 5-point Likert-type scale (0 = not at all; 1 = a little bit; 2 = somewhat; 3 = quite a bit; 4 = very much). The sum of all responses resulted in the FACIT-Fatigue score for a total possible score of 0 (worse possible score) to 52 (best score). A higher score reflected an improvement in the subjects's health status. Quality of Life analysis set was used. "Number of subjects analyzed" signifies subjects who were evaluable for this endpoint and "n" signifies those subjects who were evaluable for specified category at given time point.

End point type

Secondary

End point timeframe

Baseline, Week 4, 8, 12, 16, 24, 32, 40, and 52

End point values	DBPC: Placebo	DBPC: M2951 25 mg QD	DBPC: M2951 75 mg QD	DBPC: M2951 50 mg BID
Number of subjects analysed	110	114	112	113
Units: Units on a scale
arithmetic mean (standard deviation)
Week 4: n= 110, 114, 112, 113	3 ( 8.0 )	2 ( 7.8 )	4 ( 9.1 )	3 ( 7.7 )
Week 8: n= 107, 108, 109, 106	3 ( 8.7 )	3 ( 8.3 )	3 ( 9.1 )	5 ( 8.2 )
Week 12: n= 106, 102, 103, 101	3 ( 10.0 )	4 ( 9.7 )	3 ( 9.7 )	4 ( 8.1 )
Week 16: n= 101, 101, 105, 96	4 ( 9.8 )	3 ( 9.8 )	4 ( 10.2 )	3 ( 8.4 )
Week 24: n= 96, 95, 99, 95	3 ( 9.9 )	4 ( 8.5 )	5 ( 10.3 )	3 ( 7.5 )
Week 32: n= 90, 91, 93, 88	4 ( 9.6 )	4 ( 9.5 )	5 ( 9.7 )	4 ( 6.8 )
Week 40: n= 88, 89, 91, 86	4 ( 8.8 )	3 ( 8.6 )	6 ( 9.9 )	4 ( 8.5 )
Week 52: n= 86, 84, 87, 82	4 ( 9.9 )	4 ( 7.9 )	5 ( 9.7 )	5 ( 8.7 )

No statistical analyses for this end point

Secondary: DBPC: Number of Subjects With Change From Baseline in Prednisone Equivalent Corticosteroid (CS) dose by >=25% to a dose of <=7.5 Milligram per day (mg/day), With no BILAG A or 2B Flare in Disease Activity at Week 52

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End point title

DBPC: Number of Subjects With Change From Baseline in Prednisone Equivalent Corticosteroid (CS) dose by >=25% to a dose of <=7.5 Milligram per day (mg/day), With no BILAG A or 2B Flare in Disease Activity at Week 52

End point description

BILAG A or 2B flare is defined as at least 1 BILAG A grade or 2 BILAG B grade in any organ system due to items that are new or worse, compared to the BILAG evaluation at the previous visit, during the 52 week treatment period. BILAG Index: assessing clinical signs, symptoms, or laboratory parameters related to SLE, divided into 9 organ systems. For each organ system based on alphabetic score: A=severe disease, B=moderate disease, C=mild stable disease, D=inactive, but previously active, E=inactive and never affected. The mITT analysis set was used. Here, "number of subjects analyzed" signifies those subjects who were evaluable for this endpoint.

End point type

Secondary

End point timeframe

Baseline and Week 52

End point values	DBPC: Placebo	DBPC: M2951 25 mg QD	DBPC: M2951 75 mg QD	DBPC: M2951 50 mg BID
Number of subjects analysed	68	68	70	71
Units: Subjects	19	23	20	21

Placebo and M2951 25 mg QD

Comparison groups

DBPC: Placebo v DBPC: M2951 25 mg QD

Number of subjects included in analysis

136

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Rate difference

Point estimate

5.9

Confidence interval

level

95%

sides

2-sided

lower limit

-9.7

upper limit

21.2

Placebo and M2951 75 mg QD

Comparison groups

DBPC: Placebo v DBPC: M2951 75 mg QD

Number of subjects included in analysis

138

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Rate Difference

Point estimate

0.6

Confidence interval

level

95%

sides

2-sided

lower limit

-14.5

upper limit

15.6

Placebo and M2951 50 mg BID

Comparison groups

DBPC: Placebo v DBPC: M2951 50 mg BID

Number of subjects included in analysis

139

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Rate difference

Point estimate

1.6

Confidence interval

level

95%

sides

2-sided

lower limit

-13.5

upper limit

16.6

Secondary: DBPC: Change From Baseline to Week 52 in Prednisone Equivalent Corticosteroid (CS) Daily Dose at at Week 1, 2, 4, 6, 8, 10, 12, 14, 16, 20, 24, 28, 32, 36, 40, 44, 48 and 52

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End point title

DBPC: Change From Baseline to Week 52 in Prednisone Equivalent Corticosteroid (CS) Daily Dose at at Week 1, 2, 4, 6, 8, 10, 12, 14, 16, 20, 24, 28, 32, 36, 40, 44, 48 and 52

End point description

Change From Baseline in Prednisone-equivalent CS Daily Dose at Week 1, 2, 4, 6, 8, 10, 12, 14, 16, 20, 24, 28, 32, 36, 40, 44, 48 and 52 were reported. The mITT analysis set included all randomized subjects who had received at least one dose of IMP (Evobrutinib or placebo) and have at least one Baseline and one post Baseline disease assessment among the following: SFI, SLEDAI 2K, PGA, BILAG 2004, CLASI. Here, "Number of subjects analyzed" signifies subjects who were evaluable for this endpoint and "n" signifies those subjects who were evaluable for specified category at given time point.

End point type

Secondary

End point timeframe

Baseline, Week 1, 2, 4, 6, 8, 10, 12, 14, 16, 20, 24, 28, 32, 36, 40, 44, 48 and 52

End point values	DBPC: Placebo	DBPC: M2951 25 mg QD	DBPC: M2951 75 mg QD	DBPC: M2951 50 mg BID
Number of subjects analysed	113	113	116	114
Units: Milligram (mg)
arithmetic mean (standard deviation)
Week 1: n= 48, 58, 60, 52	0.21 ( 1.443 )	0.00 ( 0.000 )	0.00 ( 0.000 )	0.00 ( 0.000 )
Week 2: n= 113, 113, 116, 114	0.10 ( 1.206 )	-0.07 ( 0.524 )	0.00 ( 0.000 )	-0.13 ( 1.405 )
Week 4: n= 111, 113, 115, 111	0.01 ( 1.267 )	-0.45 ( 2.879 )	-0.04 ( 0.739 )	-0.15 ( 1.428 )
Week 6: n= 57, 47, 55, 55	-1.07 ( 3.563 )	-0.64 ( 3.275 )	-0.59 ( 2.095 )	-0.70 ( 3.484 )
Week 8: n= 108, 110, 110, 105	-0.57 ( 2.588 )	-1.24 ( 3.915 )	-1.09 ( 3.640 )	-1.02 ( 3.422 )
Week 10: n= 55, 49, 61, 55	-1.43 ( 3.985 )	-2.04 ( 5.146 )	-1.56 ( 4.137 )	-2.50 ( 4.971 )
Week 12: n= 107, 102, 107, 99	-1.26 ( 3.260 )	-1.85 ( 4.158 )	-1.73 ( 4.574 )	-1.97 ( 4.150 )
Week 14: n= 60, 51, 63, 57	-2.00 ( 4.569 )	-2.70 ( 5.428 )	-1.87 ( 4.489 )	-2.76 ( 5.125 )
Week 16: n= 102, 101, 104, 97	-1.67 ( 4.427 )	-2.70 ( 4.955 )	-2.47 ( 5.365 )	-2.40 ( 4.535 )
Week 20: n= 98, 94, 101, 94	-1.94 ( 4.054 )	-2.82 ( 4.905 )	-2.64 ( 5.489 )	-2.53 ( 4.727 )
Week 24: n= 93, 95, 99, 91	-1.99 ( 4.228 )	-2.64 ( 5.066 )	-2.61 ( 5.568 )	-2.34 ( 5.330 )
Week 28: n= 92, 91, 97, 89	-2.23 ( 4.439 )	-2.97 ( 4.981 )	-3.07 ( 6.068 )	-2.46 ( 5.371 )
Week 32: n= 92, 90, 95, 88	-2.45 ( 4.584 )	-3.13 ( 5.193 )	-3.18 ( 6.161 )	-2.44 ( 5.347 )
Week 36: n= 90, 90, 95, 87	-2.42 ( 4.835 )	-3.31 ( 5.327 )	-3.18 ( 6.136 )	-2.37 ( 5.445 )
Week 40: n= 90, 90, 92, 86	-2.08 ( 6.149 )	-3.21 ( 5.280 )	-3.24 ( 6.218 )	-2.67 ( 5.202 )
Week 44: n= 89, 90, 92, 85	-2.42 ( 4.833 )	-3.21 ( 5.280 )	-3.27 ( 6.254 )	-2.56 ( 5.121 )
Week 48: n= 86, 89, 91, 84	-2.38 ( 4.895 )	-3.22 ( 5.310 )	-3.37 ( 6.265 )	-2.62 ( 5.136 )
Week 52: n= 99, 100, 100, 96	-1.70 ( 5.470 )	-2.94 ( 5.534 )	-3.09 ( 5.981 )	-2.63 ( 5.673 )

No statistical analyses for this end point

Secondary: DBPC: Number of Subjects With Reduction From Baseline in Prednisone Equivalent Corticosteroid (CS) Daily Dose by > 0 to 25%, >25% to 50%, >50% to 100% or an Increase at Week 1, 2, 4, 6, 8, 10, 12, 14, 16, 20, 24, 28, 32, 36, 40, 44, 48 and 52

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End point title

DBPC: Number of Subjects With Reduction From Baseline in Prednisone Equivalent Corticosteroid (CS) Daily Dose by > 0 to 25%, >25% to 50%, >50% to 100% or an Increase at Week 1, 2, 4, 6, 8, 10, 12, 14, 16, 20, 24, 28, 32, 36, 40, 44, 48 and 52

End point description

Number of Subjects With Reduction From Baseline in Prednisone-equivalent Corticosteroid (CS) Daily Dose by > 0 to 25%, >25% to 50%, >50% to 100% or an Increase at Week 1, 2, 4, 6, 8, 10, 12, 14, 16, 20, 24, 28, 32, 36, 40, 44, 48 and 52 were reported. The mITT analysis set included all randomized subjects who had received at least one dose of IMP (Evobrutinib or placebo) and have at least one Baseline and one post Baseline disease assessment among the following: SFI, SLEDAI 2K, PGA, BILAG 2004, CLASI.

End point type

Secondary

End point timeframe

Baseline, Week 1, 2, 4, 6, 8, 10, 12, 14, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52

End point values	DBPC: Placebo	DBPC: M2951 25 mg QD	DBPC: M2951 75 mg QD	DBPC: M2951 50 mg BID
Number of subjects analysed	114	115	116	114
Units: Subjects
Reduction of dose by >0-25% Week 1	0	0	0	0
Reduction of dose by >0-25% Week 2	1	2	0	0
Reduction of dose by >0-25% Week 4	1	5	2	1
Reduction of dose by >0-25% Week 6	3	4	3	4
Reduction of dose by >0-25% Week 8	6	6	5	6
Reduction of dose by >0-25% Week 10	0	3	4	5
Reduction of dose by >0-25% Week 12	5	11	8	6
Reduction of dose by >0-25% Week 14	2	2	4	5
Reduction of dose by >0-25% Week 16	5	10	5	6
Reduction of dose by >0-25% Week 20	5	10	5	5
Reduction of dose by >0-25% Week 24	4	10	5	5
Reduction of dose by >0-25% Week 28	2	8	5	4
Reduction of dose by >0-25% Week 32	1	7	4	3
Reduction of dose by >0-25% Week 36	1	5	4	3
Reduction of dose by >0-25% Week 40	1	5	3	3
Reduction of dose by >0-25% Week 44	1	5	3	3
Reduction of dose by >0-25% Week 48	0	5	4	3
Reduction of dose by >0-25% Week 52	1	5	4	4
Reduction of dose by >25- 50% Week 1	0	0	0	0
Reduction of dose by >25- 50% Week 2	0	0	0	0
Reduction of dose by >25- 50% Week 4	1	2	1	0
Reduction of dose by >25- 50% Week 6	4	1	2	0
Reduction of dose by >25- 50% Week 8	5	9	6	5
Reduction of dose by >25- 50% Week 10	7	6	4	10
Reduction of dose by >25- 50% Week 12	14	9	10	15
Reduction of dose by >25- 50% Week 14	7	6	2	8
Reduction of dose by >25- 50% Week 16	16	12	9	16
Reduction of dose by >25- 50% Week 20	13	11	8	14
Reduction of dose by >25- 50% Week 24	12	9	8	13
Reduction of dose by >25- 50% Week 28	14	12	9	16
Reduction of dose by >25- 50% Week 32	15	11	8	16
Reduction of dose by >25- 50% Week 36	15	13	6	15
Reduction of dose by >25- 50% Week 40	15	15	6	16
Reduction of dose by >25- 50% Week 44	15	15	6	16
Reduction of dose by >25- 50% Week 48	15	14	6	17
Reduction of dose by >25- 50% Week 52	16	12	7	17
Reduction of dose by >50-100% Week 1	0	0	0	0
Reduction of dose by >50-100% Week 2	0	0	0	1
Reduction of dose by >50-100% Week 4	0	1	0	1
Reduction of dose by >50-100% Week 6	1	1	0	1
Reduction of dose by >50-100% Week 8	1	3	4	3
Reduction of dose by >50-100% Week 10	2	3	3	4
Reduction of dose by >50-100% Week 12	1	6	6	6
Reduction of dose by >50-100% Week 14	5	6	7	7
Reduction of dose by >50-100% Week 16	5	13	13	9
Reduction of dose by >50-100% Week 20	7	13	14	11
Reduction of dose by >50-100% Week 24	7	14	13	11
Reduction of dose by >50-100% Week 28	9	14	15	11
Reduction of dose by >50-100% Week 32	11	16	16	12
Reduction of dose by >50-100% Week 36	10	17	18	11
Reduction of dose by >50-100% Week 40	10	15	18	11
Reduction of dose by >50-100% Week 44	10	15	18	10
Reduction of dose by >50-100% Week 48	9	15	19	10
Reduction of dose by >50-100% Week 52	9	17	19	12
Increased from Baseline Week 1	1	0	0	0
Increased from Baseline Week 2	2	0	0	0
Increased from Baseline Week 4	2	1	1	0
Increased from Baseline Week 6	1	1	0	0
Increased from Baseline Week 8	2	1	1	0
Increased from Baseline Week 10	1	1	0	0
Increased from Baseline Week 12	1	1	1	0
Increased from Baseline Week 14	1	0	0	0
Increased from Baseline Week 16	1	1	1	0
Increased from Baseline Week 20	0	0	0	0
Increased from Baseline Week 24	0	0	0	0
Increased from Baseline Week 28	0	0	0	1
Increased from Baseline Week 32	0	0	0	1
Increased from Baseline Week 36	0	0	0	1
Increased from Baseline Week 40	1	0	0	1
Increased from Baseline Week 44	0	0	0	1
Increased from Baseline Week 48	0	0	0	1
Increased from Baseline Week 52	2	0	0	2

No statistical analyses for this end point

Secondary: DBPC: Cumulative Prednisone Equivalent Corticosteroid (CS) Dose at Week 52

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End point title

DBPC: Cumulative Prednisone Equivalent Corticosteroid (CS) Dose at Week 52

End point description

Cumulative Prednisone-equivalent Corticosteroid (CS) Dose was calculated at Week 52. The mITT analysis set included all randomized subjects who had received at least one dose of IMP (Evobrutinib or placebo) and have at least one Baseline and one post Baseline disease assessment among the following: SFI, SLEDAI 2K, PGA, BILAG 2004, CLASI.

End point type

Secondary

End point timeframe

Week 52

End point values	DBPC: Placebo	DBPC: M2951 25 mg QD	DBPC: M2951 75 mg QD	DBPC: M2951 50 mg BID
Number of subjects analysed	114	115	116	114
Units: Milligrams
arithmetic mean (standard deviation)	2267.66 ( 1507.652 )	2209.46 ( 1922.557 )	2137.70 ( 1618.688 )	2205.56 ( 1737.092 )

No statistical analyses for this end point

Secondary: DBPC: Number of Subjects With a Sustained Reduction of Oral Corticosteroids (OCS) Dose to 7.5 mg Prednisone Equivalent per day or Less With Response Based on Systemic Lupus Erythematosus Responder Index 4 (SRI-4) at Week 52

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End point title

DBPC: Number of Subjects With a Sustained Reduction of Oral Corticosteroids (OCS) Dose to 7.5 mg Prednisone Equivalent per day or Less With Response Based on Systemic Lupus Erythematosus Responder Index 4 (SRI-4) at Week 52

End point description

SRI-4 response was defined as >= 4-point reduction in SLEDAI-2K total score, no new BILAG A and no more than 1 new BILAG B domain score, no worsening (<10 % increase) from baseline in PGA of Disease Activity and no treatment failure. SLEDAI-2K assessment consists of 24 items with total score of 0(no symptoms) to 105 (presence of all defined symptoms) with higher scores representing increased disease activity. BILAG Index: assessing clinical signs, symptoms, or laboratory parameters related to SLE, divided into 9 organ systems. For each organ system A=severe disease, B=moderate disease, C=mild stable disease, D=inactive, but previously active, E=inactive and never affected. The PGA assess disease activity on a visual analogue scale =from 0(very well) to 100(very poor). The mITT analysis set was used. "Number of subjects analyzed" signifies subjects who maintained Sustained Reduction of OCS were evaluable for this endpoint.

End point type

Secondary

End point timeframe

Week 52

End point values	DBPC: Placebo	DBPC: M2951 25 mg QD	DBPC: M2951 75 mg QD	DBPC: M2951 50 mg BID
Number of subjects analysed	56	59	63	57
Units: Subjects	43	45	43	41

Placebo and M2951 25mg QD

Comparison groups

DBPC: Placebo v DBPC: M2951 25 mg QD

Number of subjects included in analysis

115

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.7728

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

1.14

Confidence interval

level

95%

sides

2-sided

lower limit

0.46

upper limit

2.82

Placebo and M2951 75 mg QD

Comparison groups

DBPC: Placebo v DBPC: M2951 75 mg QD

Number of subjects included in analysis

119

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3314

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

0.66

Confidence interval

level

95%

sides

2-sided

lower limit

0.28

upper limit

1.54

Placebo and M2951 50 mg BID

Comparison groups

DBPC: Placebo v DBPC: M2951 50 mg BID

Number of subjects included in analysis

113

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.7205

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

0.85

Confidence interval

level

95%

sides

2-sided

lower limit

0.36

upper limit

2.04

Secondary: DBPC: Number of Subjects With a Sustained Reduction of Oral Corticosteroids (OCS) Dose to 7.5 mg Prednisone Equivalent per day or Less With Response Based on Systemic Lupus Erythematosus Responder Index 6 (SRI-6) at Week 52

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End point title

End point description

SRI-6 response was defined as >= 6-point reduction in SLEDAI-2K total score, no new BILAG A and no more than 1 new BILAG B domain score and no worsening (<10% increase) from baseline in PGA of Disease Activity and treatment failure. SLEDAI-2K assessment consists of 24 items with total score of 0 (no symptoms) to 105 (presence of all defined symptoms) with higher scores representing increased disease activity. BILAG Index: assessing clinical signs, symptoms, or laboratory parameters related to SLE, divided into 9 organ systems. For each organ system :A=severe disease, B=moderate disease, C=mild stable disease, D=inactive, but previously active, E=inactive and never affected. The PGA assess disease activity on a visual analogue scale =from 0(very well) to 100(very poor). The mITT analysis set was used. "Number of subjects analyzed" signifies subjects who achieved SLEDAI-2K total score >= 10 at screening (HDA subjects) and evaluable for this endpoint.

End point type

Secondary

End point timeframe

Week 52

End point values	DBPC: Placebo	DBPC: M2951 25 mg QD	DBPC: M2951 75 mg QD	DBPC: M2951 50 mg BID
Number of subjects analysed	27	28	35	24
Units: Subjects	18	19	23	15

Placebo and M2951 25 mg QD

Comparison groups

DBPC: Placebo v DBPC: M2951 25 mg QD

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8364

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

1.13

Confidence interval

level

95%

sides

2-sided

lower limit

0.35

upper limit

3.71

Placebo and M2951 75 mg QD

Comparison groups

DBPC: Placebo v DBPC: M2951 75 mg QD

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8287

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

1.13

Confidence interval

level

95%

sides

2-sided

lower limit

0.37

upper limit

3.45

Placebo and M2951 50 mg BID

Comparison groups

DBPC: Placebo v DBPC: M2951 50 mg BID

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.7621

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

1.21

Confidence interval

level

95%

sides

2-sided

lower limit

0.35

upper limit

4.16

Secondary: DBPC: Number of Subjects With a Sustained Reduction of Oral Corticosteroids (OCS) Dose to 7.5 mg Prednisone Equivalent per day or Less With Response Based on SRI-4 at Week 52 in Serologically Active Subgroup

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End point title

DBPC: Number of Subjects With a Sustained Reduction of Oral Corticosteroids (OCS) Dose to 7.5 mg Prednisone Equivalent per day or Less With Response Based on SRI-4 at Week 52 in Serologically Active Subgroup

End point description

SRI-4 response was defined as >= 4-point reduction in SLEDAI-2K total score, no new BILAG A and no more than 1 new BILAG B domain score, no worsening (<10 % increase) from baseline in PGA of Disease Activity and no treatment failure. SLEDAI-2K assessment consists of 24 items with total score of 0(no symptoms) to 105 (presence of all defined symptoms) with higher scores representing increased disease activity. BILAG Index: assessing clinical signs, symptoms, or laboratory parameters related to SLE, divided into 9 organ systems. For each organ system A=severe disease, B=moderate disease, C=mild stable disease, D=inactive, but previously active, E=inactive and never affected. The PGA assess disease activity on a visual analogue scale = from very well(0)-very poor(100). The mITT analysis set was used. Here, "Number of subjects analyzed" signifies subjects with positive antidsDNA and/or low complement levels at screening (Serologically active subgroup) were evaluable for this endpoint.

End point type

Secondary

End point timeframe

Week 52

End point values	DBPC: Placebo	DBPC: M2951 25 mg QD	DBPC: M2951 75 mg QD	DBPC: M2951 50 mg BID
Number of subjects analysed	26	33	32	34
Units: Subjects	21	25	22	25

Placebo and M2951 25 mg QD

Comparison groups

DBPC: Placebo v DBPC: M2951 25 mg QD

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8464

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

0.88

Confidence interval

level

95%

sides

2-sided

lower limit

0.23

upper limit

3.31

Placebo and M2951 50 mg BID

Comparison groups

DBPC: Placebo v DBPC: M2951 50 mg BID

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.9988

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

0.27

upper limit

3.74

Placebo and M2951 75 mg QD

Comparison groups

DBPC: Placebo v DBPC: M2951 75 mg QD

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.417

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

0.59

Confidence interval

level

95%

sides

2-sided

lower limit

0.16

upper limit

2.12

Secondary: DBPC: Number of Subjects With Lupus Low Disease Activity State (LLDAS) at Week 52

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End point title

DBPC: Number of Subjects With Lupus Low Disease Activity State (LLDAS) at Week 52

End point description

Lupus low disease activity state will be measured as: SLEDAI-2K <= 4; No activity in any major organ systems (renal, central nervous system, cardiopulmonary, vasculitis, fever); No new features of disease activity compared with the previous assessment; Prednisone-equivalent <= 7.5 milligram per day; Unchanged background immunosuppressive therapy. The mITT analysis set included all randomized subjects who had received at least one dose of IMP (Evobrutinib or placebo) and have at least one Baseline and one post Baseline disease assessment among the following: SFI, SLEDAI 2K, PGA, BILAG 2004, CLASI.

End point type

Secondary

End point timeframe

Week 52

End point values	DBPC: Placebo	DBPC: M2951 25 mg QD	DBPC: M2951 75 mg QD	DBPC: M2951 50 mg BID
Number of subjects analysed	114	115	116	114
Units: Subjects	29	32	35	29

Placebo and M2951 25 mg QD

Comparison groups

DBPC: Placebo v DBPC: M2951 25 mg QD

Number of subjects included in analysis

229

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.697

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

1.13

Confidence interval

level

95%

sides

2-sided

lower limit

0.62

upper limit

2.04

Placebo and M2951 75 mg QD

Comparison groups

DBPC: Placebo v DBPC: M2951 75 mg QD

Number of subjects included in analysis

230

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3234

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

1.34

Confidence interval

level

95%

sides

2-sided

lower limit

0.75

upper limit

2.42

Placebo and M2951 50 mg BID

Comparison groups

DBPC: Placebo v DBPC: M2951 50 mg BID

Number of subjects included in analysis

228

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.9846

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

0.99

Confidence interval

level

95%

sides

2-sided

lower limit

0.54

upper limit

1.82

Adverse events

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Timeframe for reporting adverse events

Double-Blind Placebo-Controlled: Baseline up to Week 56 Open-Label Long-Term Extension Period: Up to Week 108

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

22.1/23.0

Reporting group title

M2951 25 mg QD

Reporting group description

Participants received 25 milligrams (mg) of M2951 orally once daily (QD) for 52 weeks.

Reporting group title

Placebo

Reporting group description

Participants received placebo matched to M2951 orally for 52 weeks.

Reporting group title

M2951 50 mg BID

Reporting group description

Participants received 50 mg of M2951 orally twice daily (BID) for 52 weeks.

Reporting group title

Placebo/ M2951 50 mg BID

Reporting group description

Subjects who completed Double-blind Placebo-controlled period and entered in long-term extension period, received 50 mg of M2951 orally twice daily (BID) for 104 weeks.

Reporting group title

M2951 25 mg QD/ M2951 50 mg BID

Reporting group description

Subjects who completed Double-blind M2951 25mg QD period and entered in long-term extension period, received 50 mg of M2951 orally twice daily (BID) for 104 weeks.

Reporting group title

M2951 75 mg QD

Reporting group description

Participants received 75 mg of M2951 orally QD for 52 weeks.

Reporting group title

M2951 50 mg BID/ M2951 50 mg BID

Reporting group description

Subjects who completed Double-blind M2951 50 mg BID period and entered in long-term extension period, continued to receive 50 mg of M2951 orally twice daily (BID) for 104 weeks.

Reporting group title

M2951 75 mg QD/ M2951 50 mg BID

Reporting group description

Subjects who completed Double-blind M2951 75 mg QD period and entered in long-term extension period, received 50 mg of M2951 orally twice daily (BID) for 104 weeks.

Serious adverse events	M2951 25 mg QD	Placebo	M2951 50 mg BID	Placebo/ M2951 50 mg BID	M2951 25 mg QD/ M2951 50 mg BID	M2951 75 mg QD	M2951 50 mg BID/ M2951 50 mg BID	M2951 75 mg QD/ M2951 50 mg BID
Total subjects affected by serious adverse events
subjects affected / exposed	13 / 118 (11.02%)	10 / 117 (8.55%)	9 / 117 (7.69%)	5 / 62 (8.06%)	5 / 69 (7.25%)	11 / 117 (9.40%)	7 / 72 (9.72%)	5 / 80 (6.25%)
number of deaths (all causes)	1	0	0	0	0	1	0	0
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Papillary thyroid cancer
subjects affected / exposed	0 / 118 (0.00%)	1 / 117 (0.85%)	0 / 117 (0.00%)	0 / 62 (0.00%)	0 / 69 (0.00%)	0 / 117 (0.00%)	0 / 72 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Basal cell carcinoma
subjects affected / exposed	0 / 118 (0.00%)	0 / 117 (0.00%)	0 / 117 (0.00%)	1 / 62 (1.61%)	0 / 69 (0.00%)	0 / 117 (0.00%)	0 / 72 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 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
Vascular disorders
Hypertension
subjects affected / exposed	0 / 118 (0.00%)	0 / 117 (0.00%)	0 / 117 (0.00%)	0 / 62 (0.00%)	0 / 69 (0.00%)	1 / 117 (0.85%)	0 / 72 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Malignant hypertension
subjects affected / exposed	1 / 118 (0.85%)	0 / 117 (0.00%)	0 / 117 (0.00%)	0 / 62 (0.00%)	0 / 69 (0.00%)	0 / 117 (0.00%)	0 / 72 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypotension
subjects affected / exposed	0 / 118 (0.00%)	0 / 117 (0.00%)	0 / 117 (0.00%)	0 / 62 (0.00%)	0 / 69 (0.00%)	0 / 117 (0.00%)	0 / 72 (0.00%)	1 / 80 (1.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypovolaemic shock
subjects affected / exposed	0 / 118 (0.00%)	0 / 117 (0.00%)	0 / 117 (0.00%)	0 / 62 (0.00%)	0 / 69 (0.00%)	0 / 117 (0.00%)	1 / 72 (1.39%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Non-cardiac chest pain
subjects affected / exposed	2 / 118 (1.69%)	0 / 117 (0.00%)	2 / 117 (1.71%)	0 / 62 (0.00%)	0 / 69 (0.00%)	0 / 117 (0.00%)	0 / 72 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Chest pain
subjects affected / exposed	1 / 118 (0.85%)	0 / 117 (0.00%)	0 / 117 (0.00%)	0 / 62 (0.00%)	0 / 69 (0.00%)	0 / 117 (0.00%)	0 / 72 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Reproductive system and breast disorders
Pelvic pain
subjects affected / exposed	0 / 118 (0.00%)	0 / 117 (0.00%)	0 / 117 (0.00%)	0 / 62 (0.00%)	0 / 69 (0.00%)	1 / 117 (0.85%)	0 / 72 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Uterine polyp
subjects affected / exposed	0 / 118 (0.00%)	1 / 117 (0.85%)	0 / 117 (0.00%)	0 / 62 (0.00%)	1 / 69 (1.45%)	0 / 117 (0.00%)	0 / 72 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metrorrhagia
subjects affected / exposed	0 / 118 (0.00%)	0 / 117 (0.00%)	0 / 117 (0.00%)	0 / 62 (0.00%)	1 / 69 (1.45%)	0 / 117 (0.00%)	0 / 72 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ovarian cyst
subjects affected / exposed	0 / 118 (0.00%)	0 / 117 (0.00%)	0 / 117 (0.00%)	0 / 62 (0.00%)	0 / 69 (0.00%)	0 / 117 (0.00%)	0 / 72 (0.00%)	1 / 80 (1.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Asthma
subjects affected / exposed	0 / 118 (0.00%)	0 / 117 (0.00%)	1 / 117 (0.85%)	0 / 62 (0.00%)	0 / 69 (0.00%)	0 / 117 (0.00%)	0 / 72 (0.00%)	1 / 80 (1.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Investigations
Liver function test increased
subjects affected / exposed	0 / 118 (0.00%)	0 / 117 (0.00%)	0 / 117 (0.00%)	0 / 62 (0.00%)	0 / 69 (0.00%)	1 / 117 (0.85%)	0 / 72 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Transaminases increased
subjects affected / exposed	0 / 118 (0.00%)	0 / 117 (0.00%)	1 / 117 (0.85%)	0 / 62 (0.00%)	0 / 69 (0.00%)	0 / 117 (0.00%)	0 / 72 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Platelet count decreased
subjects affected / exposed	0 / 118 (0.00%)	1 / 117 (0.85%)	0 / 117 (0.00%)	0 / 62 (0.00%)	0 / 69 (0.00%)	0 / 117 (0.00%)	0 / 72 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Ligament injury
subjects affected / exposed	0 / 118 (0.00%)	0 / 117 (0.00%)	1 / 117 (0.85%)	0 / 62 (0.00%)	0 / 69 (0.00%)	0 / 117 (0.00%)	0 / 72 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Post procedural complication
subjects affected / exposed	0 / 118 (0.00%)	0 / 117 (0.00%)	0 / 117 (0.00%)	0 / 62 (0.00%)	0 / 69 (0.00%)	0 / 117 (0.00%)	1 / 72 (1.39%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Post procedural haemorrhage
subjects affected / exposed	0 / 118 (0.00%)	0 / 117 (0.00%)	0 / 117 (0.00%)	0 / 62 (0.00%)	0 / 69 (0.00%)	0 / 117 (0.00%)	1 / 72 (1.39%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Wound
subjects affected / exposed	0 / 118 (0.00%)	0 / 117 (0.00%)	0 / 117 (0.00%)	0 / 62 (0.00%)	0 / 69 (0.00%)	0 / 117 (0.00%)	1 / 72 (1.39%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Pericarditis lupus
subjects affected / exposed	1 / 118 (0.85%)	0 / 117 (0.00%)	0 / 117 (0.00%)	0 / 62 (0.00%)	0 / 69 (0.00%)	0 / 117 (0.00%)	0 / 72 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Dizziness
subjects affected / exposed	0 / 118 (0.00%)	0 / 117 (0.00%)	0 / 117 (0.00%)	0 / 62 (0.00%)	0 / 69 (0.00%)	1 / 117 (0.85%)	0 / 72 (0.00%)	1 / 80 (1.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Headache
subjects affected / exposed	1 / 118 (0.85%)	2 / 117 (1.71%)	0 / 117 (0.00%)	0 / 62 (0.00%)	0 / 69 (0.00%)	0 / 117 (0.00%)	0 / 72 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Presyncope
subjects affected / exposed	1 / 118 (0.85%)	0 / 117 (0.00%)	0 / 117 (0.00%)	0 / 62 (0.00%)	0 / 69 (0.00%)	0 / 117 (0.00%)	0 / 72 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Syncope
subjects affected / exposed	0 / 118 (0.00%)	0 / 117 (0.00%)	0 / 117 (0.00%)	0 / 62 (0.00%)	0 / 69 (0.00%)	1 / 117 (0.85%)	0 / 72 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ischaemic stroke
subjects affected / exposed	0 / 118 (0.00%)	1 / 117 (0.85%)	0 / 117 (0.00%)	0 / 62 (0.00%)	0 / 69 (0.00%)	0 / 117 (0.00%)	0 / 72 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cerebral infarction
subjects affected / exposed	0 / 118 (0.00%)	0 / 117 (0.00%)	0 / 117 (0.00%)	1 / 62 (1.61%)	0 / 69 (0.00%)	0 / 117 (0.00%)	0 / 72 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 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
Cerebral venous sinus thrombosis
subjects affected / exposed	0 / 118 (0.00%)	0 / 117 (0.00%)	0 / 117 (0.00%)	1 / 62 (1.61%)	0 / 69 (0.00%)	0 / 117 (0.00%)	0 / 72 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 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
Blood and lymphatic system disorders
Bone marrow failure
subjects affected / exposed	0 / 118 (0.00%)	0 / 117 (0.00%)	0 / 117 (0.00%)	0 / 62 (0.00%)	0 / 69 (0.00%)	1 / 117 (0.85%)	0 / 72 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pancytopenia
subjects affected / exposed	0 / 118 (0.00%)	0 / 117 (0.00%)	1 / 117 (0.85%)	0 / 62 (0.00%)	0 / 69 (0.00%)	0 / 117 (0.00%)	0 / 72 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Anemia
subjects affected / exposed	0 / 118 (0.00%)	0 / 117 (0.00%)	0 / 117 (0.00%)	1 / 62 (1.61%)	0 / 69 (0.00%)	0 / 117 (0.00%)	0 / 72 (0.00%)	0 / 80 (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
Leukopenia
subjects affected / exposed	0 / 118 (0.00%)	0 / 117 (0.00%)	0 / 117 (0.00%)	0 / 62 (0.00%)	0 / 69 (0.00%)	0 / 117 (0.00%)	0 / 72 (0.00%)	1 / 80 (1.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lymphadenitis, unspecified, except mesenteric
subjects affected / exposed	0 / 118 (0.00%)	0 / 117 (0.00%)	0 / 117 (0.00%)	1 / 62 (1.61%)	0 / 69 (0.00%)	0 / 117 (0.00%)	0 / 72 (0.00%)	0 / 80 (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
Thrombocytopenia
subjects affected / exposed	0 / 118 (0.00%)	0 / 117 (0.00%)	0 / 117 (0.00%)	1 / 62 (1.61%)	0 / 69 (0.00%)	0 / 117 (0.00%)	0 / 72 (0.00%)	0 / 80 (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
Ear and labyrinth disorders
Vertigo
subjects affected / exposed	0 / 118 (0.00%)	1 / 117 (0.85%)	0 / 117 (0.00%)	0 / 62 (0.00%)	0 / 69 (0.00%)	1 / 117 (0.85%)	0 / 72 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Eye disorders
Cataract
subjects affected / exposed	0 / 118 (0.00%)	0 / 117 (0.00%)	0 / 117 (0.00%)	0 / 62 (0.00%)	0 / 69 (0.00%)	0 / 117 (0.00%)	1 / 72 (1.39%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	0 / 118 (0.00%)	0 / 117 (0.00%)	0 / 117 (0.00%)	0 / 62 (0.00%)	0 / 69 (0.00%)	1 / 117 (0.85%)	0 / 72 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ascites
subjects affected / exposed	0 / 118 (0.00%)	0 / 117 (0.00%)	1 / 117 (0.85%)	0 / 62 (0.00%)	0 / 69 (0.00%)	0 / 117 (0.00%)	0 / 72 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Colitis
subjects affected / exposed	1 / 118 (0.85%)	0 / 117 (0.00%)	0 / 117 (0.00%)	0 / 62 (0.00%)	0 / 69 (0.00%)	0 / 117 (0.00%)	0 / 72 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lupus enteritis
subjects affected / exposed	0 / 118 (0.00%)	0 / 117 (0.00%)	1 / 117 (0.85%)	0 / 62 (0.00%)	0 / 69 (0.00%)	0 / 117 (0.00%)	0 / 72 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pancreatitis
subjects affected / exposed	1 / 118 (0.85%)	0 / 117 (0.00%)	0 / 117 (0.00%)	0 / 62 (0.00%)	0 / 69 (0.00%)	0 / 117 (0.00%)	0 / 72 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dental cyst
subjects affected / exposed	0 / 118 (0.00%)	1 / 117 (0.85%)	0 / 117 (0.00%)	0 / 62 (0.00%)	0 / 69 (0.00%)	0 / 117 (0.00%)	0 / 72 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	0 / 118 (0.00%)	1 / 117 (0.85%)	0 / 117 (0.00%)	0 / 62 (0.00%)	0 / 69 (0.00%)	0 / 117 (0.00%)	0 / 72 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal adhesions
subjects affected / exposed	0 / 118 (0.00%)	0 / 117 (0.00%)	0 / 117 (0.00%)	0 / 62 (0.00%)	0 / 69 (0.00%)	0 / 117 (0.00%)	1 / 72 (1.39%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Cholelithiasis
subjects affected / exposed	0 / 118 (0.00%)	0 / 117 (0.00%)	1 / 117 (0.85%)	0 / 62 (0.00%)	0 / 69 (0.00%)	0 / 117 (0.00%)	1 / 72 (1.39%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatitis
subjects affected / exposed	1 / 118 (0.85%)	0 / 117 (0.00%)	0 / 117 (0.00%)	1 / 62 (1.61%)	0 / 69 (0.00%)	0 / 117 (0.00%)	0 / 72 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	1 / 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
Skin and subcutaneous tissue disorders
Cutaneous vasculitis
subjects affected / exposed	1 / 118 (0.85%)	0 / 117 (0.00%)	0 / 117 (0.00%)	0 / 62 (0.00%)	0 / 69 (0.00%)	0 / 117 (0.00%)	0 / 72 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dermatosis
subjects affected / exposed	1 / 118 (0.85%)	0 / 117 (0.00%)	0 / 117 (0.00%)	0 / 62 (0.00%)	0 / 69 (0.00%)	0 / 117 (0.00%)	0 / 72 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dermatitis contact
subjects affected / exposed	0 / 118 (0.00%)	0 / 117 (0.00%)	0 / 117 (0.00%)	0 / 62 (0.00%)	0 / 69 (0.00%)	0 / 117 (0.00%)	1 / 72 (1.39%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Urticaria
subjects affected / exposed	0 / 118 (0.00%)	0 / 117 (0.00%)	0 / 117 (0.00%)	0 / 62 (0.00%)	1 / 69 (1.45%)	0 / 117 (0.00%)	0 / 72 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	1 / 118 (0.85%)	0 / 117 (0.00%)	0 / 117 (0.00%)	0 / 62 (0.00%)	0 / 69 (0.00%)	0 / 117 (0.00%)	0 / 72 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lupus nephritis
subjects affected / exposed	0 / 118 (0.00%)	0 / 117 (0.00%)	0 / 117 (0.00%)	1 / 62 (1.61%)	1 / 69 (1.45%)	0 / 117 (0.00%)	0 / 72 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Urinary retention
subjects affected / exposed	0 / 118 (0.00%)	0 / 117 (0.00%)	0 / 117 (0.00%)	0 / 62 (0.00%)	0 / 69 (0.00%)	0 / 117 (0.00%)	0 / 72 (0.00%)	1 / 80 (1.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	1 / 118 (0.85%)	0 / 117 (0.00%)	0 / 117 (0.00%)	0 / 62 (0.00%)	0 / 69 (0.00%)	0 / 117 (0.00%)	0 / 72 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Back pain
subjects affected / exposed	0 / 118 (0.00%)	0 / 117 (0.00%)	0 / 117 (0.00%)	0 / 62 (0.00%)	0 / 69 (0.00%)	1 / 117 (0.85%)	0 / 72 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Intervertebral disc protrusion
subjects affected / exposed	0 / 118 (0.00%)	0 / 117 (0.00%)	0 / 117 (0.00%)	0 / 62 (0.00%)	0 / 69 (0.00%)	1 / 117 (0.85%)	0 / 72 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal chest pain
subjects affected / exposed	1 / 118 (0.85%)	0 / 117 (0.00%)	0 / 117 (0.00%)	0 / 62 (0.00%)	0 / 69 (0.00%)	0 / 117 (0.00%)	0 / 72 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Osteoarthritis
subjects affected / exposed	1 / 118 (0.85%)	0 / 117 (0.00%)	0 / 117 (0.00%)	0 / 62 (0.00%)	0 / 69 (0.00%)	0 / 117 (0.00%)	0 / 72 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Osteonecrosis
subjects affected / exposed	1 / 118 (0.85%)	0 / 117 (0.00%)	0 / 117 (0.00%)	0 / 62 (0.00%)	0 / 69 (0.00%)	0 / 117 (0.00%)	1 / 72 (1.39%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Systemic lupus erythematosus
subjects affected / exposed	0 / 118 (0.00%)	0 / 117 (0.00%)	1 / 117 (0.85%)	0 / 62 (0.00%)	0 / 69 (0.00%)	0 / 117 (0.00%)	0 / 72 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Osteonecrosis of jaw
subjects affected / exposed	0 / 118 (0.00%)	1 / 117 (0.85%)	0 / 117 (0.00%)	1 / 62 (1.61%)	0 / 69 (0.00%)	0 / 117 (0.00%)	0 / 72 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	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
SLE arthritis
subjects affected / exposed	0 / 118 (0.00%)	1 / 117 (0.85%)	0 / 117 (0.00%)	0 / 62 (0.00%)	0 / 69 (0.00%)	0 / 117 (0.00%)	0 / 72 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Otitis media
subjects affected / exposed	0 / 118 (0.00%)	0 / 117 (0.00%)	0 / 117 (0.00%)	0 / 62 (0.00%)	0 / 69 (0.00%)	2 / 117 (1.71%)	0 / 72 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 2	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
Campylobacter sepsis
subjects affected / exposed	1 / 118 (0.85%)	0 / 117 (0.00%)	0 / 117 (0.00%)	0 / 62 (0.00%)	0 / 69 (0.00%)	0 / 117 (0.00%)	0 / 72 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	0 / 118 (0.00%)	0 / 117 (0.00%)	1 / 117 (0.85%)	0 / 62 (0.00%)	0 / 69 (0.00%)	0 / 117 (0.00%)	0 / 72 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Clostridium difficile infection
subjects affected / exposed	1 / 118 (0.85%)	0 / 117 (0.00%)	0 / 117 (0.00%)	0 / 62 (0.00%)	0 / 69 (0.00%)	0 / 117 (0.00%)	0 / 72 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Diverticulitis
subjects affected / exposed	1 / 118 (0.85%)	0 / 117 (0.00%)	0 / 117 (0.00%)	0 / 62 (0.00%)	0 / 69 (0.00%)	0 / 117 (0.00%)	0 / 72 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	1 / 118 (0.85%)	0 / 117 (0.00%)	0 / 117 (0.00%)	0 / 62 (0.00%)	0 / 69 (0.00%)	0 / 117 (0.00%)	0 / 72 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Giardiasis
subjects affected / exposed	1 / 118 (0.85%)	0 / 117 (0.00%)	0 / 117 (0.00%)	0 / 62 (0.00%)	0 / 69 (0.00%)	0 / 117 (0.00%)	0 / 72 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	0 / 118 (0.00%)	0 / 117 (0.00%)	1 / 117 (0.85%)	0 / 62 (0.00%)	0 / 69 (0.00%)	0 / 117 (0.00%)	1 / 72 (1.39%)	1 / 80 (1.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pyelonephritis acute
subjects affected / exposed	1 / 118 (0.85%)	0 / 117 (0.00%)	0 / 117 (0.00%)	0 / 62 (0.00%)	0 / 69 (0.00%)	0 / 117 (0.00%)	0 / 72 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Soft tissue infection
subjects affected / exposed	1 / 118 (0.85%)	0 / 117 (0.00%)	0 / 117 (0.00%)	0 / 62 (0.00%)	0 / 69 (0.00%)	0 / 117 (0.00%)	0 / 72 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Upper respiratory tract infection
subjects affected / exposed	0 / 118 (0.00%)	0 / 117 (0.00%)	0 / 117 (0.00%)	0 / 62 (0.00%)	2 / 69 (2.90%)	1 / 117 (0.85%)	0 / 72 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Herpes zoster
subjects affected / exposed	0 / 118 (0.00%)	1 / 117 (0.85%)	0 / 117 (0.00%)	0 / 62 (0.00%)	0 / 69 (0.00%)	0 / 117 (0.00%)	0 / 72 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Osteomyelitis
subjects affected / exposed	0 / 118 (0.00%)	1 / 117 (0.85%)	0 / 117 (0.00%)	1 / 62 (1.61%)	0 / 69 (0.00%)	0 / 117 (0.00%)	0 / 72 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	1 / 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
Urinary tract infection, site not specified
subjects affected / exposed	0 / 118 (0.00%)	0 / 117 (0.00%)	0 / 117 (0.00%)	0 / 62 (0.00%)	2 / 69 (2.90%)	0 / 117 (0.00%)	0 / 72 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Appendicitis
subjects affected / exposed	0 / 118 (0.00%)	0 / 117 (0.00%)	0 / 117 (0.00%)	0 / 62 (0.00%)	0 / 69 (0.00%)	0 / 117 (0.00%)	1 / 72 (1.39%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bronchitis
subjects affected / exposed	0 / 118 (0.00%)	0 / 117 (0.00%)	0 / 117 (0.00%)	0 / 62 (0.00%)	0 / 69 (0.00%)	0 / 117 (0.00%)	0 / 72 (0.00%)	1 / 80 (1.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia mycoplasmal
subjects affected / exposed	0 / 118 (0.00%)	0 / 117 (0.00%)	0 / 117 (0.00%)	0 / 62 (0.00%)	0 / 69 (0.00%)	0 / 117 (0.00%)	1 / 72 (1.39%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Subperiosteal abscess
subjects affected / exposed	0 / 118 (0.00%)	0 / 117 (0.00%)	0 / 117 (0.00%)	1 / 62 (1.61%)	0 / 69 (0.00%)	0 / 117 (0.00%)	0 / 72 (0.00%)	0 / 80 (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
Metabolism and nutrition disorders
Hypoglycaemia
subjects affected / exposed	0 / 118 (0.00%)	0 / 117 (0.00%)	0 / 117 (0.00%)	0 / 62 (0.00%)	0 / 69 (0.00%)	1 / 117 (0.85%)	0 / 72 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	M2951 25 mg QD	Placebo	M2951 50 mg BID	Placebo/ M2951 50 mg BID	M2951 25 mg QD/ M2951 50 mg BID	M2951 75 mg QD	M2951 50 mg BID/ M2951 50 mg BID	M2951 75 mg QD/ M2951 50 mg BID
Total subjects affected by non serious adverse events
subjects affected / exposed	85 / 118 (72.03%)	76 / 117 (64.96%)	78 / 117 (66.67%)	22 / 62 (35.48%)	34 / 69 (49.28%)	75 / 117 (64.10%)	23 / 72 (31.94%)	35 / 80 (43.75%)
Investigations
Alanine aminotransferase increased
subjects affected / exposed	8 / 118 (6.78%)	3 / 117 (2.56%)	6 / 117 (5.13%)	5 / 62 (8.06%)	4 / 69 (5.80%)	6 / 117 (5.13%)	2 / 72 (2.78%)	1 / 80 (1.25%)
occurrences all number	8	3	6	5	4	6	2	1
Lipase increased
subjects affected / exposed	4 / 118 (3.39%)	2 / 117 (1.71%)	6 / 117 (5.13%)	0 / 62 (0.00%)	0 / 69 (0.00%)	6 / 117 (5.13%)	0 / 72 (0.00%)	0 / 80 (0.00%)
occurrences all number	4	2	6	0	0	6	0	0
Aspartate aminotransferase increased
subjects affected / exposed	8 / 118 (6.78%)	3 / 117 (2.56%)	4 / 117 (3.42%)	3 / 62 (4.84%)	4 / 69 (5.80%)	3 / 117 (2.56%)	2 / 72 (2.78%)	1 / 80 (1.25%)
occurrences all number	8	3	4	3	4	3	2	1
Gamma-glutamyltransferase increased
subjects affected / exposed	4 / 118 (3.39%)	6 / 117 (5.13%)	7 / 117 (5.98%)	3 / 62 (4.84%)	3 / 69 (4.35%)	4 / 117 (3.42%)	4 / 72 (5.56%)	1 / 80 (1.25%)
occurrences all number	4	6	7	3	3	4	4	1
Amylase increased
subjects affected / exposed	2 / 118 (1.69%)	5 / 117 (4.27%)	8 / 117 (6.84%)	0 / 62 (0.00%)	0 / 69 (0.00%)	4 / 117 (3.42%)	0 / 72 (0.00%)	0 / 80 (0.00%)
occurrences all number	2	5	8	0	0	4	0	0
Transaminases increased
subjects affected / exposed	3 / 118 (2.54%)	3 / 117 (2.56%)	6 / 117 (5.13%)	0 / 62 (0.00%)	0 / 69 (0.00%)	3 / 117 (2.56%)	0 / 72 (0.00%)	0 / 80 (0.00%)
occurrences all number	3	3	6	0	0	3	0	0
Vascular disorders
Hypertension
subjects affected / exposed	6 / 118 (5.08%)	0 / 117 (0.00%)	1 / 117 (0.85%)	0 / 62 (0.00%)	0 / 69 (0.00%)	4 / 117 (3.42%)	0 / 72 (0.00%)	0 / 80 (0.00%)
occurrences all number	6	0	1	0	0	4	0	0
Nervous system disorders
Headache
subjects affected / exposed	17 / 118 (14.41%)	20 / 117 (17.09%)	17 / 117 (14.53%)	1 / 62 (1.61%)	7 / 69 (10.14%)	19 / 117 (16.24%)	5 / 72 (6.94%)	2 / 80 (2.50%)
occurrences all number	17	20	17	1	7	19	5	2
Dizziness
subjects affected / exposed	5 / 118 (4.24%)	3 / 117 (2.56%)	6 / 117 (5.13%)	0 / 62 (0.00%)	0 / 69 (0.00%)	4 / 117 (3.42%)	0 / 72 (0.00%)	0 / 80 (0.00%)
occurrences all number	5	3	6	0	0	4	0	0
Blood and lymphatic system disorders
Lymphopenia
subjects affected / exposed	4 / 118 (3.39%)	9 / 117 (7.69%)	2 / 117 (1.71%)	0 / 62 (0.00%)	0 / 69 (0.00%)	6 / 117 (5.13%)	0 / 72 (0.00%)	0 / 80 (0.00%)
occurrences all number	4	9	2	0	0	6	0	0
Neutropenia
subjects affected / exposed	1 / 118 (0.85%)	4 / 117 (3.42%)	6 / 117 (5.13%)	0 / 62 (0.00%)	0 / 69 (0.00%)	2 / 117 (1.71%)	0 / 72 (0.00%)	0 / 80 (0.00%)
occurrences all number	1	4	6	0	0	2	0	0
General disorders and administration site conditions
Influenza like illness
subjects affected / exposed	7 / 118 (5.93%)	5 / 117 (4.27%)	7 / 117 (5.98%)	4 / 62 (6.45%)	0 / 69 (0.00%)	9 / 117 (7.69%)	0 / 72 (0.00%)	2 / 80 (2.50%)
occurrences all number	7	5	7	4	0	9	0	2
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	12 / 118 (10.17%)	11 / 117 (9.40%)	10 / 117 (8.55%)	3 / 62 (4.84%)	5 / 69 (7.25%)	17 / 117 (14.53%)	2 / 72 (2.78%)	7 / 80 (8.75%)
occurrences all number	12	11	10	3	5	17	2	7
Nausea
subjects affected / exposed	8 / 118 (6.78%)	7 / 117 (5.98%)	5 / 117 (4.27%)	0 / 62 (0.00%)	0 / 69 (0.00%)	9 / 117 (7.69%)	0 / 72 (0.00%)	0 / 80 (0.00%)
occurrences all number	8	7	5	0	0	9	0	0
Vomiting
subjects affected / exposed	9 / 118 (7.63%)	4 / 117 (3.42%)	3 / 117 (2.56%)	0 / 62 (0.00%)	0 / 69 (0.00%)	8 / 117 (6.84%)	0 / 72 (0.00%)	0 / 80 (0.00%)
occurrences all number	9	4	3	0	0	8	0	0
Abdominal pain upper
subjects affected / exposed	6 / 118 (5.08%)	5 / 117 (4.27%)	5 / 117 (4.27%)	0 / 62 (0.00%)	0 / 69 (0.00%)	8 / 117 (6.84%)	0 / 72 (0.00%)	0 / 80 (0.00%)
occurrences all number	6	5	5	0	0	8	0	0
Abdominal pain
subjects affected / exposed	7 / 118 (5.93%)	3 / 117 (2.56%)	5 / 117 (4.27%)	0 / 62 (0.00%)	0 / 69 (0.00%)	3 / 117 (2.56%)	0 / 72 (0.00%)	0 / 80 (0.00%)
occurrences all number	7	3	5	0	0	3	0	0
Gastritis
subjects affected / exposed	6 / 118 (5.08%)	3 / 117 (2.56%)	4 / 117 (3.42%)	0 / 62 (0.00%)	0 / 69 (0.00%)	3 / 117 (2.56%)	0 / 72 (0.00%)	0 / 80 (0.00%)
occurrences all number	6	3	4	0	0	3	0	0
Respiratory, thoracic and mediastinal disorders
Epistaxis
subjects affected / exposed	2 / 118 (1.69%)	6 / 117 (5.13%)	0 / 117 (0.00%)	0 / 62 (0.00%)	0 / 69 (0.00%)	1 / 117 (0.85%)	0 / 72 (0.00%)	0 / 80 (0.00%)
occurrences all number	2	6	0	0	0	1	0	0
Musculoskeletal and connective tissue disorders
Back Pain
subjects affected / exposed	4 / 118 (3.39%)	3 / 117 (2.56%)	9 / 117 (7.69%)	0 / 62 (0.00%)	0 / 69 (0.00%)	5 / 117 (4.27%)	0 / 72 (0.00%)	0 / 80 (0.00%)
occurrences all number	4	3	9	0	0	5	0	0
Infections and infestations
Urinary tract infection
subjects affected / exposed	21 / 118 (17.80%)	16 / 117 (13.68%)	21 / 117 (17.95%)	4 / 62 (6.45%)	7 / 69 (10.14%)	26 / 117 (22.22%)	6 / 72 (8.33%)	7 / 80 (8.75%)
occurrences all number	21	16	21	4	7	26	6	7
Nasopharyngitis
subjects affected / exposed	13 / 118 (11.02%)	8 / 117 (6.84%)	7 / 117 (5.98%)	5 / 62 (8.06%)	5 / 69 (7.25%)	15 / 117 (12.82%)	5 / 72 (6.94%)	7 / 80 (8.75%)
occurrences all number	13	8	7	5	5	15	5	7
Upper respiratory tract infection
subjects affected / exposed	15 / 118 (12.71%)	12 / 117 (10.26%)	8 / 117 (6.84%)	3 / 62 (4.84%)	6 / 69 (8.70%)	6 / 117 (5.13%)	0 / 72 (0.00%)	3 / 80 (3.75%)
occurrences all number	15	12	8	3	6	6	0	3
Pharyngitis
subjects affected / exposed	5 / 118 (4.24%)	8 / 117 (6.84%)	4 / 117 (3.42%)	0 / 62 (0.00%)	3 / 69 (4.35%)	4 / 117 (3.42%)	1 / 72 (1.39%)	6 / 80 (7.50%)
occurrences all number	5	8	4	0	3	4	1	6
Gastroenteritis
subjects affected / exposed	4 / 118 (3.39%)	6 / 117 (5.13%)	2 / 117 (1.71%)	0 / 62 (0.00%)	0 / 69 (0.00%)	2 / 117 (1.71%)	0 / 72 (0.00%)	0 / 80 (0.00%)
occurrences all number	4	6	2	0	0	2	0	0
Herpes zoster
subjects affected / exposed	2 / 118 (1.69%)	2 / 117 (1.71%)	0 / 117 (0.00%)	0 / 62 (0.00%)	0 / 69 (0.00%)	6 / 117 (5.13%)	0 / 72 (0.00%)	0 / 80 (0.00%)
occurrences all number	2	2	0	0	0	6	0	0
Bronchitis
subjects affected / exposed	0 / 118 (0.00%)	0 / 117 (0.00%)	0 / 117 (0.00%)	0 / 62 (0.00%)	4 / 69 (5.80%)	0 / 117 (0.00%)	3 / 72 (4.17%)	5 / 80 (6.25%)
occurrences all number	0	0	0	0	4	0	3	5

More information

Top of page

Were there any global substantial amendments to the protocol? Yes

14 Jul 2017

- Added of text describing the Study Steering Committee. - Provided updated safety and efficacy information from other clinical studies, and potential risks associated with the IMP - Provided additional safety data in the benefit-risk analysis - Added a Japanese cohort to the study - Added additional rescreening information - Modified inclusion criteria regarding contraceptive use in male subjects based on newly available data and provided clarifications regarding vaccination and background standard of care - Modified exclusion criteria to excluded JAK inhibitors and BTK inhibitors - Corrected Common Terminology Criteria for Adverse Events (CTCAE) laboratory parameters - Clarified that medical marijuana use is not excluded.

31 Aug 2017

- Study eligibility, and - Modified inclusion and exclusion criteria were added.

20 Nov 2017

Included all of the country specific changes in the global amended protocol, included a fasting requirement prior to dosing for all subjects in all countries, and added new safety information and additional visits for liver function test (LFT) monitoring.

05 Jan 2018

- Revisions of the criteria for withdrawal the IMP based on the outcome of an IDMC meeting; - Addition of visit window (±3) for the Visits 6, 10, and 14 and Correction of an inconsistency about the vital signs measurement position.

08 Feb 2018

-Provided additional rationale for dose selection, updated safety information from other clinical studies, and potential risks associated with the IMP. - Modified inclusion and exclusion criteria.

22 May 2018

- A Long term extension (LTE) period was added into the study, including 2 new schedule of activities (SoAs), and an additional study figure. - Stopping rules modified due to analysis of additional safety data. - Exclusion modified to permit low dose aspirin after medical review.

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 II, Randomized, Double-blind, Placebo-controlled Dose-ranging Study to Evaluate the Safety and Efficacy of M2951 in Subjects with SLE

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: DBPC: Number of Subjects With Response Based on Systemic Lupus Erythematosus Responder Index 4 (SRI-4) at Week 52

Primary: DBPC: Number of Subjects With Response Based on Systemic Lupus Erythematosus Responder Index 4 (SRI-4) at Week 52

Primary: DBPC: Number of Subjects With Response Based on Systemic Lupus Erythematosus Responder Index 6 (SRI-6) at Week 52

Primary: DBPC: Number of Subjects With Response Based on Systemic Lupus Erythematosus Responder Index 6 (SRI-6) at Week 52

Primary: DBPC: Number of Subjects With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs According to National Cancer Institute-Common Terminology Criteria for Adverse Events Version 4.03 (NCI-CTCAE v4.03)

Primary: DBPC: Number of Subjects With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs According to National Cancer Institute-Common Terminology Criteria for Adverse Events Version 4.03 (NCI-CTCAE v4.03)

Primary: DBPC: Number of Subjects With Treatment-Emergent Adverse Events (TEAEs) by Severity According to National Cancer Institute-Common Terminology Criteria for Adverse Events Version 4.03 (NCI-CTCAE v4.03)

Primary: DBPC: Number of Subjects With Treatment-Emergent Adverse Events (TEAEs) by Severity According to National Cancer Institute-Common Terminology Criteria for Adverse Events Version 4.03 (NCI-CTCAE v4.03)

Primary: DBPC: Number of Subjects With Clinically Significant Change From Baseline in Vital Signs

Primary: DBPC: Number of Subjects With Clinically Significant Change From Baseline in Vital Signs

Primary: DBPC: Number of Subjects With Clinically Significant Changes From Baseline in 12-Lead Electrocardiogram (ECG) Findings

Primary: DBPC: Number of Subjects With Clinically Significant Changes From Baseline in 12-Lead Electrocardiogram (ECG) Findings

Primary: DBPC: Number of Subjects With Clinically Significant Changes From Baseline in Laboratory Parameters

Primary: DBPC: Number of Subjects With Clinically Significant Changes From Baseline in Laboratory Parameters

Primary: DBPC: Mean Absolute Value of Serum Immunoglobulin (Ig) Levels (IgG, IgA, IgM) at Week 2

Primary: DBPC: Mean Absolute Value of Serum Immunoglobulin (Ig) Levels (IgG, IgA, IgM) at Week 2

Primary: DBPC: Mean Absolute Value of Serum Immunoglobulin (Ig) Levels (IgG, IgA, IgM) at Week 4

Primary: DBPC: Mean Absolute Value of Serum Immunoglobulin (Ig) Levels (IgG, IgA, IgM) at Week 4

Primary: DBPC: Mean Absolute Value of Serum Immunoglobulin (Ig) Levels (IgG, IgA, IgM) at Week 12

Primary: DBPC: Mean Absolute Value of Serum Immunoglobulin (Ig) Levels (IgG, IgA, IgM) at Week 12

Primary: DBPC: Mean Absolute Value of Serum Immunoglobulin (Ig) Levels (IgG, IgA, IgM) at Week 24

Primary: DBPC: Mean Absolute Value of Serum Immunoglobulin (Ig) Levels (IgG, IgA, IgM) at Week 24

Primary: DBPC: Mean Absolute Value of Serum Immunoglobulin (Ig) Levels (IgG, IgA, IgM) at Week 36

Primary: DBPC: Mean Absolute Value of Serum Immunoglobulin (Ig) Levels (IgG, IgA, IgM) at Week 36

Primary: DBPC: Mean Absolute Value of Serum Immunoglobulin (Ig) Levels (IgG, IgA, IgM) at Week 52

Primary: DBPC: Mean Absolute Value of Serum Immunoglobulin (Ig) Levels (IgG, IgA, IgM) at Week 52

Primary: DBPC: Mean Absolute Value of Serum Immunoglobulin (Ig) Levels (IgG, IgA, IgM) at Week 56

Primary: DBPC: Mean Absolute Value of Serum Immunoglobulin (Ig) Levels (IgG, IgA, IgM) at Week 56

Primary: DBPC: Mean Absolute Total B Cell Count at Week 4

Primary: DBPC: Mean Absolute Total B Cell Count at Week 4

Primary: DBPC: Mean Absolute Total B Cell Count at Week 24

Primary: DBPC: Mean Absolute Total B Cell Count at Week 24

Primary: DBPC: Mean Absolute Total B Cell Count at Week 52

Primary: DBPC: Mean Absolute Total B Cell Count at Week 52

Primary: DBPC: Mean Absolute Total B Cell Count at Week 56

Primary: DBPC: Mean Absolute Total B Cell Count at Week 56

Primary: DBPC: Change From Baseline in Serum Immunoglobulin (Ig) Levels (IgG, IgA, IgM) at Week 2

Primary: DBPC: Change From Baseline in Serum Immunoglobulin (Ig) Levels (IgG, IgA, IgM) at Week 2

Primary: DBPC: Change From Baseline in Serum Immunoglobulin (Ig) Levels (IgG, IgA, IgM) at Week 4

Primary: DBPC: Change From Baseline in Serum Immunoglobulin (Ig) Levels (IgG, IgA, IgM) at Week 4

Primary: DBPC: Change From Baseline in Serum Immunoglobulin (Ig) Levels (IgG, IgA, IgM) at Week 12

Primary: DBPC: Change From Baseline in Serum Immunoglobulin (Ig) Levels (IgG, IgA, IgM) at Week 12

Primary: DBPC: Change From Baseline in Serum Immunoglobulin (Ig) Levels (IgG, IgA, IgM) at Week 24

Primary: DBPC: Change From Baseline in Serum Immunoglobulin (Ig) Levels (IgG, IgA, IgM) at Week 24

Primary: DBPC: Change From Baseline in Serum Immunoglobulin (Ig) Levels (IgG, IgA, IgM) at Week 36

Primary: DBPC: Change From Baseline in Serum Immunoglobulin (Ig) Levels (IgG, IgA, IgM) at Week 36

Primary: DBPC: Change From Baseline in Serum Immunoglobulin (Ig) Levels (IgG, IgA, IgM) at Week 52

Primary: DBPC: Change From Baseline in Serum Immunoglobulin (Ig) Levels (IgG, IgA, IgM) at Week 52

Primary: DBPC: Change From Baseline in Serum Immunoglobulin (Ig) Levels (IgG, IgA, IgM) at Week 56

Primary: DBPC: Change From Baseline in Serum Immunoglobulin (Ig) Levels (IgG, IgA, IgM) at Week 56

Primary: DBPC: Change From Baseline in Total B Cell Count at Week 4

Primary: DBPC: Change From Baseline in Total B Cell Count at Week 4

Primary: DBPC: Change From Baseline in Total B Cell Count at Week 24

Primary: DBPC: Change From Baseline in Total B Cell Count at Week 24

Primary: DBPC: Change From Baseline in Total B Cell Count at Week 52

Primary: DBPC: Change From Baseline in Total B Cell Count at Week 52

Primary: DBPC: Change From Baseline in Total B Cell Count at Week 56

Primary: DBPC: Change From Baseline in Total B Cell Count at Week 56

Secondary: DBPC: Time to First Severe British Isles Lupus Assessment Group (BILAG) A Flare

Secondary: DBPC: Time to First Severe British Isles Lupus Assessment Group (BILAG) A Flare

Secondary: DBPC: Number of Subjects With Response Based on Systemic Lupus Erythematosus Responder Index 4 (SRI-4) at Week 52 in Serologically Active Subgroup

Secondary: DBPC: Number of Subjects With Response Based on Systemic Lupus Erythematosus Responder Index 4 (SRI-4) at Week 52 in Serologically Active Subgroup

Secondary: DBPC: Number of Subjects With Response Based on Systemic Lupus Erythematosus Responder Index 6 (SRI-6) at Week 52 in Serologically Active Subgroup

Secondary: DBPC: Number of Subjects With Response Based on Systemic Lupus Erythematosus Responder Index 6 (SRI-6) at Week 52 in Serologically Active Subgroup

Secondary: DBPC: Time to First British Isles Lupus Assessment Group (BILAG) A or 2B Moderate to Severe Flare

Secondary: DBPC: Time to First British Isles Lupus Assessment Group (BILAG) A or 2B Moderate to Severe Flare

Secondary: DBPC: Number of Subjects With British Isles Lupus Assessment Group (BILAG) 2004 Flare-Free Status During the 52-Week Treatment Period

Secondary: DBPC: Number of Subjects With British Isles Lupus Assessment Group (BILAG) 2004 Flare-Free Status During the 52-Week Treatment Period

Secondary: DBPC: Annualized Flare Rate

Secondary: DBPC: Annualized Flare Rate

Clinical Trial Results:
A Phase II, Randomized, Double-blind, Placebo-controlled Dose-ranging Study to Evaluate the Safety and Efficacy of M2951 in Subjects with SLE