Trial Outcomes & Findings for Safety and Efficacy Study of M2951 in Participants With Rheumatoid Arthritis (NCT NCT02784106)

Results Overview

ACR 20 response: greater than or equal to (\>=) 20 percent (%) improvement in both tender joint counts (based on a total of 68 joints) and swollen joint counts (based on a total of 66 joints) together with \>=20% improvement in at least 3 of the following: 1) participant's assessment of pain; 2) participant's global assessment of disease activity; 3) physician's global assessment of disease activity; 4) participant's assessment of physical function measured by Health Assessment Questionnaire-Disability Index (HAQ-DI); and 5) acute phase reactant as measured by high-sensitivity C-reactive protein (hsCRP). Proportion of ACR20 responders = Number of participants with ACR20 response divided by total participants.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

65 participants

Primary outcome timeframe

Day 84

Results posted on

2018-07-17

Participant Flow

The study consisted of a 12-week double-blind treatment period and a 26-week open-label extension period. Primary and secondary outcome measures were planned to be analyzed for double-blind treatment period only.

Participant milestones

Participant milestones
Measure	Placebo: Double-Blind Treatment Period Participants received placebo matched to M2951 twice daily up to Day 84 during the double-blind treatment period.	M2951: Double-Blind Treatment Period Participants received 50 milligrams (mg) M2951 orally twice daily up to Day 84 during the double-blind treatment period.	Placebo/M2951: Open-Label Extension Period Participants who received placebo matched to M2951 in double-blind treatment period, received 50 mg M2951 orally twice daily up to 26-weeks during the open-label extension period.	M2951/M2951: Open-Label Extension Period Participants who received M2951 in double-blind treatment period, received 50 mg M2951 orally twice daily up to 26-weeks during the open-label extension period.
Double-Blind Treatment Period (12 Weeks) STARTED	32	33	0	0
Double-Blind Treatment Period (12 Weeks) COMPLETED	24	27	0	0
Double-Blind Treatment Period (12 Weeks) NOT COMPLETED	8	6	0	0
Open-Label Extension Period (26 Weeks) STARTED	0	0	18	21
Open-Label Extension Period (26 Weeks) COMPLETED	0	0	15	19
Open-Label Extension Period (26 Weeks) NOT COMPLETED	0	0	3	2

Reasons for withdrawal

Reasons for withdrawal
Measure	Placebo: Double-Blind Treatment Period Participants received placebo matched to M2951 twice daily up to Day 84 during the double-blind treatment period.	M2951: Double-Blind Treatment Period Participants received 50 milligrams (mg) M2951 orally twice daily up to Day 84 during the double-blind treatment period.	Placebo/M2951: Open-Label Extension Period Participants who received placebo matched to M2951 in double-blind treatment period, received 50 mg M2951 orally twice daily up to 26-weeks during the open-label extension period.	M2951/M2951: Open-Label Extension Period Participants who received M2951 in double-blind treatment period, received 50 mg M2951 orally twice daily up to 26-weeks during the open-label extension period.
Double-Blind Treatment Period (12 Weeks) Adverse Event	3	5	0	0
Double-Blind Treatment Period (12 Weeks) Withdrawal by Subject	2	1	0	0
Double-Blind Treatment Period (12 Weeks) Other	2	0	0	0
Double-Blind Treatment Period (12 Weeks) Lack of Efficacy	1	0	0	0
Open-Label Extension Period (26 Weeks) Adverse Event	0	0	2	1
Open-Label Extension Period (26 Weeks) Lack of Efficacy	0	0	1	1

Baseline Characteristics

Safety and Efficacy Study of M2951 in Participants With Rheumatoid Arthritis

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Placebo: Double-Blind Treatment Period n=32 Participants Participants received placebo matched to M2951 twice daily up to Day 84 during the double-blind treatment period.	M2951: Double-Blind Treatment Period n=33 Participants Participants received 50 milligrams (mg) M2951 orally twice daily up to Day 84 during the double-blind treatment period.	Total n=65 Participants Total of all reporting groups
Age, Continuous	53.1 years STANDARD_DEVIATION 12.19 • n=5 Participants	53.8 years STANDARD_DEVIATION 10.73 • n=7 Participants	53.4 years STANDARD_DEVIATION 11.39 • n=5 Participants
Sex: Female, Male Female	25 Participants n=5 Participants	24 Participants n=7 Participants	49 Participants n=5 Participants
Sex: Female, Male Male	7 Participants n=5 Participants	9 Participants n=7 Participants	16 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	1 Participants n=5 Participants	1 Participants n=7 Participants	2 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	31 Participants n=5 Participants	32 Participants n=7 Participants	63 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants
Race (NIH/OMB) Black or African American	1 Participants n=5 Participants	1 Participants n=7 Participants	2 Participants n=5 Participants
Race (NIH/OMB) White	31 Participants n=5 Participants	31 Participants n=7 Participants	62 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants

PRIMARY outcome

Timeframe: Day 84

Population: The Modified Intent-to-Treat (mITT) Analysis Set included all participants who received at least 1 dose of M2951 or placebo and have at least 1 available ACR20 evaluation at a time point post-dose.

ACR 20 response: greater than or equal to (\>=) 20 percent (%) improvement in both tender joint counts (based on a total of 68 joints) and swollen joint counts (based on a total of 66 joints) together with \>=20% improvement in at least 3 of the following: 1) participant's assessment of pain; 2) participant's global assessment of disease activity; 3) physician's global assessment of disease activity; 4) participant's assessment of physical function measured by Health Assessment Questionnaire-Disability Index (HAQ-DI); and 5) acute phase reactant as measured by high-sensitivity C-reactive protein (hsCRP). Proportion of ACR20 responders = Number of participants with ACR20 response divided by total participants.

Outcome measures

Outcome measures
Measure	M2951: Double-Blind Treatment Period n=33 Participants Participants received 50 milligrams (mg) M2951 orally twice daily up to Day 84 during the double-blind treatment period.	Placebo: Double-Blind Treatment Period n=31 Participants Participants received placebo matched to M2951 twice daily up to Day 84 during the double-blind treatment period.
Proportion of Participants Who Achieved American College of Rheumatology-20 (ACR20) Response	0.52 proportion of participants	0.42 proportion of participants

SECONDARY outcome

Timeframe: Baseline, Day 28

Population: mITT analysis Set included all participants who received at least 1 dose of M2951 or placebo and have at least 1 available ACR20 evaluation at a time point post-dose.

Mean change in the hsCRP concentration from baseline at Day 28 was reported.

Outcome measures

Outcome measures
Measure	M2951: Double-Blind Treatment Period n=33 Participants Participants received 50 milligrams (mg) M2951 orally twice daily up to Day 84 during the double-blind treatment period.	Placebo: Double-Blind Treatment Period n=31 Participants Participants received placebo matched to M2951 twice daily up to Day 84 during the double-blind treatment period.
Mean Change From Baseline in High-Sensitivity C-Reactive Protein (hsCRP) at Day 28	-2.72 milligram/milliliter (mg/mL) Standard Error 1.93	-0.80 milligram/milliliter (mg/mL) Standard Error 2.00

SECONDARY outcome

Timeframe: Day 28, Day 56 and Day 84

Population: mITT analysis Set included all participants who received at least 1 dose of M2951 or placebo and have at least 1 available ACR20 evaluation at a time point post-dose.

ACR 50 response: \>=50% improvement in both tender joint counts (based on a total of 68 joints) and swollen joint counts (based on a total of 66 joints) together with \>=50% improvement in at least 3 of the following: 1) participant's assessment of pain; 2) participant's global assessment of disease activity; 3) physician's global assessment of disease activity; 4) participant's assessment of physical function measured by HAQ-DI; and 5) acute phase reactant as measured by hsCRP. Proportion of ACR50 responders = Number of participants with ACR50 response divided by total participants.

Outcome measures

Outcome measures
Measure	M2951: Double-Blind Treatment Period n=33 Participants Participants received 50 milligrams (mg) M2951 orally twice daily up to Day 84 during the double-blind treatment period.	Placebo: Double-Blind Treatment Period n=31 Participants Participants received placebo matched to M2951 twice daily up to Day 84 during the double-blind treatment period.
Proportion of Participants Achieving American College of Rheumatology-50 (ACR50) Response Day 28	0.06 proportion of participants	0.10 proportion of participants
Proportion of Participants Achieving American College of Rheumatology-50 (ACR50) Response Day 56	0.18 proportion of participants	0.23 proportion of participants
Proportion of Participants Achieving American College of Rheumatology-50 (ACR50) Response Day 84	0.21 proportion of participants	0.23 proportion of participants

SECONDARY outcome

Timeframe: Day 28, Day 56 and Day 84

Population: mITT analysis set included all participants who received at least 1 dose of M2951 or placebo and have at least 1 available ACR20 evaluation at a time point post-dose.

ACR 70 response: \>=70% improvement in both tender joint counts (based on a total of 68 joints) and swollen joint counts (based on a total of 66 joints) together with \>=70% improvement in at least 3 of the following: 1) participant's assessment of pain; 2) participant's global assessment of disease activity; 3) physician's global assessment of disease activity; 4) participant's assessment of physical function measured by HAQ-DI; and 5) acute phase reactant as measured by hsCRP. Proportion of ACR70 responders = Number of participants with ACR70 response divided by total participants.

Outcome measures

Outcome measures
Measure	M2951: Double-Blind Treatment Period n=33 Participants Participants received 50 milligrams (mg) M2951 orally twice daily up to Day 84 during the double-blind treatment period.	Placebo: Double-Blind Treatment Period n=31 Participants Participants received placebo matched to M2951 twice daily up to Day 84 during the double-blind treatment period.
Proportion of Participants Achieving American College of Rheumatology-70 (ACR70) Response Day 28	0.06 proportion of participants	0.00 proportion of participants
Proportion of Participants Achieving American College of Rheumatology-70 (ACR70) Response Day 56	0.06 proportion of participants	0.03 proportion of participants
Proportion of Participants Achieving American College of Rheumatology-70 (ACR70) Response Day 84	0.09 proportion of participants	0.13 proportion of participants

SECONDARY outcome

Timeframe: Baseline, Day 84

Population: mITT analysis Set included all participants who received at least 1 dose of M2951 or placebo and have at least 1 available ACR20 evaluation at a time point post-dose.

Mean change in the hsCRP concentration from baseline at Day 84 was reported.

Outcome measures

Outcome measures
Measure	M2951: Double-Blind Treatment Period n=33 Participants Participants received 50 milligrams (mg) M2951 orally twice daily up to Day 84 during the double-blind treatment period.	Placebo: Double-Blind Treatment Period n=31 Participants Participants received placebo matched to M2951 twice daily up to Day 84 during the double-blind treatment period.
Mean Change From Baseline in High-Sensitivity C-Reactive Protein (hsCRP) at Day 84	-3.54 mg/mL Standard Error 2.13	-2.14 mg/mL Standard Error 2.20

SECONDARY outcome

Timeframe: Baseline, Day 28 and Day 84

Population: mITT analysis Set included all participants who received at least 1 dose of M2951 or placebo and have at least 1 available ACR20 evaluation at a time point post-dose.

Disease Activity Score (DAS) based on a 28 joint count hsCRP consisted of composite numerical score of following variables: tender joint count (TJC28), swollen joint count (SJC28), hsCRP (mg/mL), and participant's global assessment of disease activity. DAS28-hsCRP was calculated using following formula: DAS28-hsCRP equals to (=) 0.56\*square root (sqrt) (TJC28) plus (+) 0.28\*sqrt (SJC28)+ 0.014\* participant's global assessment of disease activity + 0.36\*natural log(hsCRP+1) +0.96. Scores ranged 1.0-9.4, where lower scores indicated less disease activity.

Outcome measures

Outcome measures
Measure	M2951: Double-Blind Treatment Period n=33 Participants Participants received 50 milligrams (mg) M2951 orally twice daily up to Day 84 during the double-blind treatment period.	Placebo: Double-Blind Treatment Period n=31 Participants Participants received placebo matched to M2951 twice daily up to Day 84 during the double-blind treatment period.
Mean Change From Baseline in Disease Activity Score Based on a 28 Joint Count High-Sensitivity C-Reactive Protein (DAS28-hsCRP) at Day 28 and 84 Change at Day 28	-0.87 units on a scale Standard Error 0.13	-0.79 units on a scale Standard Error 0.14
Mean Change From Baseline in Disease Activity Score Based on a 28 Joint Count High-Sensitivity C-Reactive Protein (DAS28-hsCRP) at Day 28 and 84 Change at Day 84	-1.28 units on a scale Standard Error 0.19	-1.35 units on a scale Standard Error 0.20

SECONDARY outcome

Timeframe: Day 84

Population: mITT analysis Set included all participants who received at least 1 dose of M2951 or placebo and have at least 1 available ACR20 evaluation at a time point post-dose.

DAS28-hsCRP consisted of composite score of following variables: TJC28, SJC28, hsCRP (mg/mL), and participant's global assessment of disease activity. DAS28-hsCRP was calculated using following formula: DAS28-hsCRP =0.56\* sqrt(TJC28) + 0.28\*sqrt(SJC28)+ 0.014\* participant's global assessment of disease activity + 0.36\*natural log(hsCRP+1) +0.96. Scores ranged 1.0-9.4, where lower scores indicated less disease activity. Proportion of participants with DAS28-hsCRP value \<3.2 were reported.

Outcome measures

Outcome measures
Measure	M2951: Double-Blind Treatment Period n=33 Participants Participants received 50 milligrams (mg) M2951 orally twice daily up to Day 84 during the double-blind treatment period.	Placebo: Double-Blind Treatment Period n=31 Participants Participants received placebo matched to M2951 twice daily up to Day 84 during the double-blind treatment period.
Proportion of Participants With Disease Activity Score- High Sensitivity C-Reactive Protein (DAS28-hsCRP) Value Less Than (<) 3.2	0.21 proportion of participants	0.13 proportion of participants

SECONDARY outcome

Timeframe: Day 84

Population: mITT analysis Set included all participants who received at least 1 dose of M2951 or placebo and have at least 1 available ACR20 evaluation at a time point post-dose.

DAS28 consisted of composite score of following variables: TJC28, SJC28, hsCRP (mg/mL), and participant's global assessment of disease activity. DAS28-hsCRP was calculated using following formula: DAS28-hsCRP =0.56\* sqrt (TJC28) + 0.28\*sqrt (SJC28)+ 0.014\* participant's global assessment of disease activity + 0.36\*natural log(hsCRP+1) +0.96. Scores ranged 1.0-9.4, where lower scores indicated less disease activity. Proportion of participants with DAS28-hsCRP value \<2.6 were reported.

Outcome measures

Outcome measures
Measure	M2951: Double-Blind Treatment Period n=33 Participants Participants received 50 milligrams (mg) M2951 orally twice daily up to Day 84 during the double-blind treatment period.	Placebo: Double-Blind Treatment Period n=31 Participants Participants received placebo matched to M2951 twice daily up to Day 84 during the double-blind treatment period.
Proportion of Participants With Disease Activity Score- High Sensitivity C-Reactive Protein (DAS28-hsCRP) Value Less Than (<) 2.6	0.06 proportion of participants	0.10 proportion of participants

SECONDARY outcome

Timeframe: Baseline, Day 28 and Day 84

Population: mITT analysis set included all participants who received at least 1 dose of M2951 or placebo and have at least 1 available ACR20 evaluation at a time point post-dose. Here "Number Analyzed" signified those participants who were evaluable for this endpoint at the specified time point.

Erythrocyte sedimentation rate (ESR) is a type of blood test that measures how quickly erythrocytes (red blood cells) settle at the bottom of a test tube that contains a blood sample. Higher values indicate inflammation in the body.

Outcome measures

Outcome measures
Measure	M2951: Double-Blind Treatment Period n=33 Participants Participants received 50 milligrams (mg) M2951 orally twice daily up to Day 84 during the double-blind treatment period.	Placebo: Double-Blind Treatment Period n=31 Participants Participants received placebo matched to M2951 twice daily up to Day 84 during the double-blind treatment period.
Change From Baseline in Erythrocyte Sedimentation Rate (ESR) at Day 28 and 84 Change at Day 28	-7 millimeter/hour (mm/hour) Standard Deviation 22.1	-3 millimeter/hour (mm/hour) Standard Deviation 36.9
Change From Baseline in Erythrocyte Sedimentation Rate (ESR) at Day 28 and 84 Change at Day 84	-9 millimeter/hour (mm/hour) Standard Deviation 21.1	-3 millimeter/hour (mm/hour) Standard Deviation 21.0

SECONDARY outcome

Timeframe: Baseline, Day 28 and Day 84

Population: mITT analysis set included all participants who received at least 1 dose of M2951 or placebo and have at least 1 available ACR20 evaluation at a time point post-dose. Here "Number Analyzed" signified those participants who were evaluable for this endpoint at the specified time point.

Anti-cyclic citrullinated peptide (anti-CCP) is an antibody present in most rheumatoid arthritis participants.

Outcome measures

Outcome measures
Measure	M2951: Double-Blind Treatment Period n=33 Participants Participants received 50 milligrams (mg) M2951 orally twice daily up to Day 84 during the double-blind treatment period.	Placebo: Double-Blind Treatment Period n=31 Participants Participants received placebo matched to M2951 twice daily up to Day 84 during the double-blind treatment period.
Change From Baseline in Anti-cyclic Citrullinated Peptide (Anti-CCP) Antibody Levels at Day 28 and 84 Change at Day 28	-138 units/milliliter Standard Deviation 720.9	168 units/milliliter Standard Deviation 991.1
Change From Baseline in Anti-cyclic Citrullinated Peptide (Anti-CCP) Antibody Levels at Day 28 and 84 Change at Day 84	-396 units/milliliter Standard Deviation 736.8	301 units/milliliter Standard Deviation 1282.6

SECONDARY outcome

Timeframe: Baseline, Day 28 and Day 84

Population: mITT analysis set included all participants who received at least 1 dose of M2951 or placebo and have at least 1 available ACR20 evaluation at a time point post-dose. Here "Number Analyzed" signified those participants who were evaluable for this endpoint at the specified time point.

Rheumatoid Factor is an anti-body present in the blood.

Outcome measures

Outcome measures
Measure	M2951: Double-Blind Treatment Period n=33 Participants Participants received 50 milligrams (mg) M2951 orally twice daily up to Day 84 during the double-blind treatment period.	Placebo: Double-Blind Treatment Period n=31 Participants Participants received placebo matched to M2951 twice daily up to Day 84 during the double-blind treatment period.
Change From Baseline in Rheumatoid Factor (RF) at Day 28 and 84 Change at Day 28	-7 kiloUnit/Liter (kU/L) Standard Deviation 59.7	-30 kiloUnit/Liter (kU/L) Standard Deviation 124.2
Change From Baseline in Rheumatoid Factor (RF) at Day 28 and 84 Change at Day 84	-26 kiloUnit/Liter (kU/L) Standard Deviation 79.9	-34 kiloUnit/Liter (kU/L) Standard Deviation 132.1

SECONDARY outcome

Timeframe: Baseline, Day 84

Population: mITT analysis Set included all participants who received at least 1 dose of M2951 or placebo and have at least 1 available ACR20 evaluation at a time point post-dose. Here, "Overall Number of Participants Analyzed" signified those participants who were evaluable for this outcome measure.

The participant's overall assessment of disease activity was recorded using the 100 millimeter (mm) horizontal visual analog scale (VAS). The scale ranged from 0-100 mm, where 0 indicated no disease activity (symptom free and no arthritis symptoms) and 100 represented maximum disease activity (maximum arthritis disease activity).

Outcome measures

Outcome measures
Measure	M2951: Double-Blind Treatment Period n=26 Participants Participants received 50 milligrams (mg) M2951 orally twice daily up to Day 84 during the double-blind treatment period.	Placebo: Double-Blind Treatment Period n=25 Participants Participants received placebo matched to M2951 twice daily up to Day 84 during the double-blind treatment period.
Change From Baseline in Global Assessment of Disease Activity Based on Visual Analog Scale (VAS) Score at Day 84	-24 millimeter Standard Deviation 24.6	-21 millimeter Standard Deviation 23.5

SECONDARY outcome

Timeframe: Baseline, Day 84

Population: mITT analysis Set included all participants who received at least 1 dose of M2951 or placebo and have at least 1 available ACR20 evaluation at a time point post-dose. Here, "Overall Number of Participants Analyzed" signified those participants who were evaluable for this outcome measure.

The participants were asked to assess their level of pain by marking a vertical tick on a 100 mm horizontal VAS scale. The scale ranged from 0-100 mm, where 0 indicated no pain and 100 indicated worst possible pain.

Outcome measures

Outcome measures
Measure	M2951: Double-Blind Treatment Period n=26 Participants Participants received 50 milligrams (mg) M2951 orally twice daily up to Day 84 during the double-blind treatment period.	Placebo: Double-Blind Treatment Period n=25 Participants Participants received placebo matched to M2951 twice daily up to Day 84 during the double-blind treatment period.
Change From Baseline in Self-assessment of Pain Based on Visual Analog Scale (VAS) Score at Day 84	-22 millimeter Standard Deviation 22.0	-19 millimeter Standard Deviation 21.8

SECONDARY outcome

Timeframe: Baseline, Day 84

Population: mITT analysis Set included all participants who received at least 1 dose of M2951 or placebo and have at least 1 available ACR20 evaluation at a time point post-dose. Here, "Overall Number of Participants Analyzed" signified those participants who were evaluable for this outcome measure.

The HAQ-DI questionnaire assessed the participant's self-perception on the degree of difficulty \[0 (without any difficulty), 1 (with some difficulty), 2 (with much difficulty), and 3 (unable to do)\] when dressing and grooming, arising, eating, walking, hygiene, reaching, gripping, and performing other daily activities. Scores for each functional area were averaged to calculate HAQ-DI scores, which ranged from 0 (no disability) to 3 (worst disability). A decrease in HAQ-DI score indicated an improvement in the participant's condition.

Outcome measures

Outcome measures
Measure	M2951: Double-Blind Treatment Period n=26 Participants Participants received 50 milligrams (mg) M2951 orally twice daily up to Day 84 during the double-blind treatment period.	Placebo: Double-Blind Treatment Period n=25 Participants Participants received placebo matched to M2951 twice daily up to Day 84 during the double-blind treatment period.
Change From Baseline in Self-assessment of Disability Using Health Assessment Questionnaire - Disability Index (HAQ-DI) Score at Day 84	-0.3 units on a scale Standard Deviation 0.41	-0.3 units on a scale Standard Deviation 0.44

SECONDARY outcome

Timeframe: Baseline, Day 84

Population: mITT analysis set included all participants who received at least 1 dose of M2951 or placebo and have at least 1 available ACR20 evaluation at a time point post-dose. Here, "Overall Number of Participants Analyzed" signified those participants who were evaluable for this outcome measure.

The Physician's Global Assessment of Disease Activity was recorded using the 100 mm horizontal VAS. Physician rated participant's arthritis disease activity on a scale ranged from 0-100 mm, where 0 indicated no disease activity (no arthritis) and 100 represented maximum disease activity (maximum arthritis).

Outcome measures

Outcome measures
Measure	M2951: Double-Blind Treatment Period n=26 Participants Participants received 50 milligrams (mg) M2951 orally twice daily up to Day 84 during the double-blind treatment period.	Placebo: Double-Blind Treatment Period n=25 Participants Participants received placebo matched to M2951 twice daily up to Day 84 during the double-blind treatment period.
Change From Baseline in Physician's Global Assessment of Disease Activity Scale Based on Visual Analog Scale (VAS) Score at Day 84	-30 millimeter Standard Deviation 22.7	-33 millimeter Standard Deviation 20.3

SECONDARY outcome

Timeframe: Baseline up to 16 Weeks

Population: The Safety Analysis Set included all participants who received at least 1 dose of M2951 or placebo.

An Adverse event (AE) was defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of study drug, whether or not considered related to the study drug or worsening of pre-existing medical condition, whether or not related to study drug. A serious adverse event (SAE) was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. Treatment-emergent are events between first dose of study drug that were absent before treatment or that worsened relative to pre-treatment state. TEAEs included both Serious TEAEs and non-serious TEAEs.

Outcome measures

Outcome measures
Measure	M2951: Double-Blind Treatment Period n=33 Participants Participants received 50 milligrams (mg) M2951 orally twice daily up to Day 84 during the double-blind treatment period.	Placebo: Double-Blind Treatment Period n=32 Participants Participants received placebo matched to M2951 twice daily up to Day 84 during the double-blind treatment period.
Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) TEAEs	22 Participants	16 Participants
Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) SAEs	1 Participants	0 Participants

SECONDARY outcome

Timeframe: Baseline up to 16 Weeks

Population: The Safety Analysis Set included all participants who received at least 1 dose of M2951 or placebo.

Grade 3 and 4 TEAES as per National Cancer Institute Common Terminology Criteria for Adverse Experience version 4.03 (NCI-CTCAE v 4.03) were presented. Grade 3 refers to severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care and Activity of daily living (ADL).Grade 4 refers to Life-threatening consequences; where urgent intervention indicated.

Outcome measures

Outcome measures
Measure	M2951: Double-Blind Treatment Period n=33 Participants Participants received 50 milligrams (mg) M2951 orally twice daily up to Day 84 during the double-blind treatment period.	Placebo: Double-Blind Treatment Period n=32 Participants Participants received placebo matched to M2951 twice daily up to Day 84 during the double-blind treatment period.
Number of Participants With Treatment Emergent Adverse Events (TEAEs) by Severity NCI-CTCAE Severity grade >=3	3 Participants	2 Participants
Number of Participants With Treatment Emergent Adverse Events (TEAEs) by Severity NCI-CTCAE Severity grade >=4	1 Participants	0 Participants

SECONDARY outcome

Timeframe: Baseline up to 16 Weeks

Population: The Safety Analysis Set included all participants who received at least 1 dose of M2951 or placebo.

Clinically significant abnormalities for hematology, biochemistry or coagulation were graded with National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-CTCAE) v4.03 toxicity grades, where Grade 1 = mild, Grade 2 = moderate, Grade 3 = severe, Grade 4 = life threatening and Grade 5 = death. Participants with grade 3 or higher were reported.

Outcome measures

Outcome measures
Measure	M2951: Double-Blind Treatment Period n=33 Participants Participants received 50 milligrams (mg) M2951 orally twice daily up to Day 84 during the double-blind treatment period.	Placebo: Double-Blind Treatment Period n=32 Participants Participants received placebo matched to M2951 twice daily up to Day 84 during the double-blind treatment period.
Number of Participants With Grade 3 or Higher Clinically Significant Abnormality for Hematology, Biochemistry, Urinalysis or Coagulation Hematology	0 Participants	2 Participants
Number of Participants With Grade 3 or Higher Clinically Significant Abnormality for Hematology, Biochemistry, Urinalysis or Coagulation Biochemistry	2 Participants	4 Participants
Number of Participants With Grade 3 or Higher Clinically Significant Abnormality for Hematology, Biochemistry, Urinalysis or Coagulation Coagulation	0 Participants	0 Participants
Number of Participants With Grade 3 or Higher Clinically Significant Abnormality for Hematology, Biochemistry, Urinalysis or Coagulation Urinalysis	0 Participants	0 Participants

SECONDARY outcome

Timeframe: Baseline up to 16 Weeks

Population: The Safety Analysis Set included all participants who received at least 1 dose of M2951 or placebo.

Vital sign assessment included blood pressure, pulse rate, respiratory rate and temperature. Clinical significance was determined by the investigator.

Outcome measures

Outcome measures
Measure	M2951: Double-Blind Treatment Period n=33 Participants Participants received 50 milligrams (mg) M2951 orally twice daily up to Day 84 during the double-blind treatment period.	Placebo: Double-Blind Treatment Period n=32 Participants Participants received placebo matched to M2951 twice daily up to Day 84 during the double-blind treatment period.
Number of Participants With Clinically Significant Vital Signs Abnormalities	0 Participants	0 Participants

SECONDARY outcome

Timeframe: Baseline up to 16 Weeks

Population: The Safety Analysis Set included all participants who received at least 1 dose of M2951 or placebo.

The 12-lead ECG recordings were obtained after 10 minutes of rest in a semi-supine position. The ECG parameters obtained directly from the computerized 12-lead ECG recordings included rhythm, ventricular rate, PR interval, QRS duration, and QT interval. Clinical significance was determined by the investigator.

Outcome measures

Outcome measures
Measure	M2951: Double-Blind Treatment Period n=33 Participants Participants received 50 milligrams (mg) M2951 orally twice daily up to Day 84 during the double-blind treatment period.	Placebo: Double-Blind Treatment Period n=32 Participants Participants received placebo matched to M2951 twice daily up to Day 84 during the double-blind treatment period.
Number of Participants With Clinically Significant 12-lead Electrocardiogram (ECG) Findings	0 Participants	0 Participants

SECONDARY outcome

Timeframe: Pre-dose at Day 1; 0.25, 0.5, 1.0, 2.0, 4.0, 6.0 hours post-dose at Day 1 and Day 29

Population: The Pharmacokinetic (PK) Analysis Set included all participants who receive at least 1 dose of M2951 and have at least 1 quantifiable M2951 plasma concentration at a scheduled PK time point post-dose. Here "Number Analyzed" signified those participants who were evaluable for this endpoint at the specified time point.

Outcome measures

Outcome measures
Measure	M2951: Double-Blind Treatment Period Participants received 50 milligrams (mg) M2951 orally twice daily up to Day 84 during the double-blind treatment period.	Placebo: Double-Blind Treatment Period n=33 Participants Participants received placebo matched to M2951 twice daily up to Day 84 during the double-blind treatment period.
Plasma Concentration of M2951 Day 1: Pre-Dose:	—	0.00 nanogram per milliliter (ng/mL) Standard Deviation NA Statistical Analysis was not applicable as mean concentration of the drug is zero.
Plasma Concentration of M2951 Day 1: 0.25 hours post-dose	—	10.3 nanogram per milliliter (ng/mL) Standard Deviation 23.37
Plasma Concentration of M2951 Day 1: 0.5 hours post-dose	—	80.5 nanogram per milliliter (ng/mL) Standard Deviation 136.9
Plasma Concentration of M2951 Day 1: 1 hour post-dose	—	160 nanogram per milliliter (ng/mL) Standard Deviation 219.7
Plasma Concentration of M2951 Day 1: 2 hours post-dose	—	125 nanogram per milliliter (ng/mL) Standard Deviation 111.9
Plasma Concentration of M2951 Day 1: 4 hours post-dose	—	47.3 nanogram per milliliter (ng/mL) Standard Deviation 41.62
Plasma Concentration of M2951 Day 1: 6 hours post-dose	—	23.7 nanogram per milliliter (ng/mL) Standard Deviation 20.92
Plasma Concentration of M2951 Day 29: 0.25 hours post-dose	—	22.0 nanogram per milliliter (ng/mL) Standard Deviation 71.57
Plasma Concentration of M2951 Day 29: 0.5 hours post-dose	—	88.4 nanogram per milliliter (ng/mL) Standard Deviation 114.1
Plasma Concentration of M2951 Day 29: 2 hours post-dose	—	82.3 nanogram per milliliter (ng/mL) Standard Deviation 53.82
Plasma Concentration of M2951 Day 29: 4 hours post-dose	—	62.1 nanogram per milliliter (ng/mL) Standard Deviation 82.39
Plasma Concentration of M2951 Day 29: 6 hour post-dose	—	37.2 nanogram per milliliter (ng/mL) Standard Deviation 43.96
Plasma Concentration of M2951 Day 29: 1 hour post-dose	—	120 nanogram per milliliter (ng/mL) Standard Deviation 107.2

SECONDARY outcome

Timeframe: Pre-dose, 0.25, 0.5, 1.0, 2.0, 4.0, 6.0 hours post-dose at Day 1 and Day 29

Population: PK Analysis Set included all participants who receive at least 1 dose of M2951 and have at least 1 quantifiable M2951 plasma concentration at a scheduled PK time point post-dose. Here "Number Analyzed" signified those participants who were evaluable for this endpoint at the specified time point.

Outcome measures

Outcome measures
Measure	M2951: Double-Blind Treatment Period Participants received 50 milligrams (mg) M2951 orally twice daily up to Day 84 during the double-blind treatment period.	Placebo: Double-Blind Treatment Period n=33 Participants Participants received placebo matched to M2951 twice daily up to Day 84 during the double-blind treatment period.
Area Under the Concentration-Time Curve From Time Zero to 6 Hours (AUC 0-6h) of M2951 Day 1	—	431 hours*nanogram/milliliter Standard Deviation 390.9
Area Under the Concentration-Time Curve From Time Zero to 6 Hours (AUC 0-6h) of M2951 Day 29	—	414 hours*nanogram/milliliter Standard Deviation 268.4

SECONDARY outcome

Timeframe: Pre-dose, 0.25, 0.5, 1.0, 2.0, 4.0, 6.0 hours post-dose at Day 1 and Day 29

Population: PK Analysis Set included all participants who receive at least 1 dose of M2951 and have at least 1 quantifiable M2951 plasma concentration at a scheduled PK time point post-dose. Here "Number Analyzed" signified those participants who were evaluable for this endpoint at the specified time point.

Outcome measures

Outcome measures
Measure	M2951: Double-Blind Treatment Period Participants received 50 milligrams (mg) M2951 orally twice daily up to Day 84 during the double-blind treatment period.	Placebo: Double-Blind Treatment Period n=33 Participants Participants received placebo matched to M2951 twice daily up to Day 84 during the double-blind treatment period.
Maximum Observed Plasma Concentration (Cmax) of M2951 Day 1	—	206 ng/mL Standard Deviation 214.7
Maximum Observed Plasma Concentration (Cmax) of M2951 Day 29	—	171 ng/mL Standard Deviation 130.1

SECONDARY outcome

Timeframe: Pre-dose on Day 29

Population: PK Analysis Set included all participants who receive at least 1 dose of M2951 and have at least 1 quantifiable M2951 plasma concentration at a scheduled PK time point post-dose. Here, "Overall Number of Participants Analyzed" signified those participants who were evaluable for this outcome measure.

Outcome measures

Outcome measures
Measure	M2951: Double-Blind Treatment Period Participants received 50 milligrams (mg) M2951 orally twice daily up to Day 84 during the double-blind treatment period.	Placebo: Double-Blind Treatment Period n=28 Participants Participants received placebo matched to M2951 twice daily up to Day 84 during the double-blind treatment period.
Plasma Concentration Observed Immediately Before Dosing on Day 29 (Cpre) of M2951	—	5.47 ng/mL Standard Deviation 4.735

SECONDARY outcome

Timeframe: Pre-dose, 0.25, 0.5, 1.0, 2.0, 4.0, 6.0 hours post-dose at Day 1 and Day 29

Population: PK Analysis Set included all participants who receive at least 1 dose of M2951 and have at least 1 quantifiable M2951 plasma concentration at a scheduled PK time point post-dose. Here "Number Analyzed" signified those participants who were evaluable for this endpoint at the specified time point.

Outcome measures

Outcome measures
Measure	M2951: Double-Blind Treatment Period Participants received 50 milligrams (mg) M2951 orally twice daily up to Day 84 during the double-blind treatment period.	Placebo: Double-Blind Treatment Period n=33 Participants Participants received placebo matched to M2951 twice daily up to Day 84 during the double-blind treatment period.
Time to Reach Maximum Plasma Concentration (Tmax) of M2951 Day 1	—	1.00 hour Interval 0.5 to 4.0
Time to Reach Maximum Plasma Concentration (Tmax) of M2951 Day 29	—	1.00 hour Interval 0.5 to 6.0

SECONDARY outcome

Timeframe: Pre-dose, 0.25, 0.5, 1.0, 2.0, 4.0, 6.0 hours post-dose at Day 1 and Day 29

Population: PK Analysis Set included all participants who receive at least 1 dose of M2951 and have at least 1 quantifiable M2951 plasma concentration at a scheduled PK time point post-dose. Here, "Overall Number of Participants Analyzed" signified those participants who were evaluable for this outcome measure.

Accumulation ratio for AUC was calculated as AUC 0-6h, Day 29 divided by AUC 0-6h, Day 1

Outcome measures

Outcome measures
Measure	M2951: Double-Blind Treatment Period Participants received 50 milligrams (mg) M2951 orally twice daily up to Day 84 during the double-blind treatment period.	Placebo: Double-Blind Treatment Period n=26 Participants Participants received placebo matched to M2951 twice daily up to Day 84 during the double-blind treatment period.
Accumulation Ratio for Area Under the Concentration-Time Curve From Time Zero to 6 Hours (Racc [AUC0-6h]) of M2951	—	1.38 ratio Standard Deviation 1.134

SECONDARY outcome

Timeframe: Pre-dose, 0.25, 0.5, 1.0, 2.0, 4.0, 6.0 hours post-dose at Day 1 and Day 29

Population: PK Analysis Set included all participants who receive at least 1 dose of M2951 and have at least 1 quantifiable M2951 plasma concentration at a scheduled PK time point post-dose. Here, "Overall Number of Participants Analyzed" signified those participants who were evaluable for this outcome measure.

Accumulation ratio for Cmax , was calculated as Cmax, Day 29 divided by Cmax, Day1

Outcome measures

Outcome measures
Measure	M2951: Double-Blind Treatment Period Participants received 50 milligrams (mg) M2951 orally twice daily up to Day 84 during the double-blind treatment period.	Placebo: Double-Blind Treatment Period n=27 Participants Participants received placebo matched to M2951 twice daily up to Day 84 during the double-blind treatment period.
Accumulation Ratio for Observed Maximum Plasma Concentration (Racc [Cmax]) of M2951	—	1.52 ratio Standard Deviation 1.929

SECONDARY outcome

Timeframe: Baseline, Day 85

Population: PD Analysis Set included all participants who received at least 1 dose of M2951 or placebo and have at least 1 measured PD endpoint, not including BTK occupancy, at a scheduled PD time point post-dose. Here, "Overall Number of Participants Analyzed" signified those participants who were evaluable for this outcome measure.

Following immunoglobulin levels were measured: Immunoglobulin A , Immunoglobulin G, Immunoglobulin G Subclass 1, Immunoglobulin G Subclass 2, Immunoglobulin G Subclass 3, Immunoglobulin G Subclass 4, Immunoglobulin M.

Outcome measures

Outcome measures
Measure	M2951: Double-Blind Treatment Period n=12 Participants Participants received 50 milligrams (mg) M2951 orally twice daily up to Day 84 during the double-blind treatment period.	Placebo: Double-Blind Treatment Period n=10 Participants Participants received placebo matched to M2951 twice daily up to Day 84 during the double-blind treatment period.
Absolute Immunoglobulin Levels at Day 85 Immunoglobulin A	2.77 gram/Liter Standard Deviation 1.323	2.09 gram/Liter Standard Deviation 0.968
Absolute Immunoglobulin Levels at Day 85 Immunoglobulin G	9.88 gram/Liter Standard Deviation 2.498	10.61 gram/Liter Standard Deviation 3.897
Absolute Immunoglobulin Levels at Day 85 Immunoglobulin G Subclass 1	5.41 gram/Liter Standard Deviation 1.574	6.20 gram/Liter Standard Deviation 2.338
Absolute Immunoglobulin Levels at Day 85 Immunoglobulin G Subclass 2	3.74 gram/Liter Standard Deviation 1.205	3.59 gram/Liter Standard Deviation 1.644
Absolute Immunoglobulin Levels at Day 85 Immunoglobulin G Subclass 3	0.93 gram/Liter Standard Deviation 0.510	1.05 gram/Liter Standard Deviation 0.551
Absolute Immunoglobulin Levels at Day 85 Immunoglobulin G Subclass 4	0.684 gram/Liter Standard Deviation 0.6286	0.394 gram/Liter Standard Deviation 0.2474
Absolute Immunoglobulin Levels at Day 85 Immunoglobulin M	1.16 gram/Liter Standard Deviation 0.642	1.16 gram/Liter Standard Deviation 0.365

SECONDARY outcome

Timeframe: Baseline, Day 85

Population: PD Analysis Set included all participants who received at least 1 dose of M2951 or placebo and have at least 1 measured PD endpoint, not including BTK occupancy, at a scheduled PD time point post-dose. Here, "Overall Number of Participants Analyzed" signified those participants who were evaluable for this outcome measure.

Following immunoglobulin levels were measured: Immunoglobulin A , Immunoglobulin G, Immunoglobulin G Subclass 1, Immunoglobulin G Subclass 2, Immunoglobulin G Subclass 3, Immunoglobulin G Subclass 4, Immunoglobulin M.

Outcome measures

Outcome measures
Measure	M2951: Double-Blind Treatment Period n=12 Participants Participants received 50 milligrams (mg) M2951 orally twice daily up to Day 84 during the double-blind treatment period.	Placebo: Double-Blind Treatment Period n=10 Participants Participants received placebo matched to M2951 twice daily up to Day 84 during the double-blind treatment period.
Absolute Change From Baseline in Immunoglobulin Levels at Day 85 Immunoglobulin A	-0.04 gram/Liter Standard Deviation 0.133	-0.07 gram/Liter Standard Deviation 0.263
Absolute Change From Baseline in Immunoglobulin Levels at Day 85 Immunoglobulin G	-0.30 gram/Liter Standard Deviation 0.517	0.02 gram/Liter Standard Deviation 1.281
Absolute Change From Baseline in Immunoglobulin Levels at Day 85 Immunoglobulin G Subclass 1	-0.15 gram/Liter Standard Deviation 0.410	0.11 gram/Liter Standard Deviation 0.857
Absolute Change From Baseline in Immunoglobulin Levels at Day 85 Immunoglobulin G Subclass 2	-0.17 gram/Liter Standard Deviation 0.404	-0.13 gram/Liter Standard Deviation 0.477
Absolute Change From Baseline in Immunoglobulin Levels at Day 85 Immunoglobulin G Subclass 3	-0.04 gram/Liter Standard Deviation 0.209	0.07 gram/Liter Standard Deviation 0.214
Absolute Change From Baseline in Immunoglobulin Levels at Day 85 Immunoglobulin G Subclass 4	-0.046 gram/Liter Standard Deviation 0.2576	-0.028 gram/Liter Standard Deviation 0.1073
Absolute Change From Baseline in Immunoglobulin Levels at Day 85 Immunoglobulin M	-0.25 gram/Liter Standard Deviation 0.255	-0.04 gram/Liter Standard Deviation 0.177

SECONDARY outcome

Timeframe: Day 85

Population: PD Analysis Set included all participants who received at least 1 dose of M2951 or placebo and have at least 1 measured PD endpoint, not including BTK occupancy, at a scheduled PD time point post-dose. Here, "Overall Number of Participants Analyzed" signified those participants who were evaluable for this outcome measure.

Outcome measures

Outcome measures
Measure	M2951: Double-Blind Treatment Period n=12 Participants Participants received 50 milligrams (mg) M2951 orally twice daily up to Day 84 during the double-blind treatment period.	Placebo: Double-Blind Treatment Period n=12 Participants Participants received placebo matched to M2951 twice daily up to Day 84 during the double-blind treatment period.
Absolute B-Cell Levels at Day 85	204 cells per micro-liter Standard Deviation 154.0	243 cells per micro-liter Standard Deviation 265.0

SECONDARY outcome

Timeframe: Baseline, Day 85

Population: PD Analysis Set included all participants who received at least 1 dose of M2951 or placebo and have at least 1 measured PD endpoint, not including BTK occupancy, at a scheduled PD time point post-dose. Here, "Overall Number of Participants Analyzed" signified those participants who were evaluable for this outcome measure.

Outcome measures

Outcome measures
Measure	M2951: Double-Blind Treatment Period n=12 Participants Participants received 50 milligrams (mg) M2951 orally twice daily up to Day 84 during the double-blind treatment period.	Placebo: Double-Blind Treatment Period n=12 Participants Participants received placebo matched to M2951 twice daily up to Day 84 during the double-blind treatment period.
Absolute Change From Baseline in B-cell Levels at Day 85	11 cells per micro-liter Standard Deviation 73.2	76 cells per micro-liter Standard Deviation 242.0

Adverse Events

Placebo: Double-Blind Treatment Period

Serious events: 0 serious events

Other events: 13 other events

Deaths: 0 deaths

M2951: Double-Blind Treatment Period

Serious events: 1 serious events

Other events: 17 other events

Deaths: 0 deaths

Placebo/M2951: Open-Label Extension Period

Serious events: 0 serious events

Other events: 8 other events

Deaths: 0 deaths

M2951/M2951: Open-Label Extension Period

Serious events: 0 serious events

Other events: 10 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Placebo: Double-Blind Treatment Period n=32 participants at risk Participants received placebo matched to M2951 twice daily up to Day 84 during the double-blind treatment period.	M2951: Double-Blind Treatment Period n=33 participants at risk Participants received 50 milligrams (mg) M2951 orally twice daily up to Day 84 during the double-blind treatment period.	Placebo/M2951: Open-Label Extension Period n=18 participants at risk Participants who received placebo matched to M2951 in double-blind treatment period, received 50 mg M2951 orally twice daily up to 26-weeks during the open-label extension period.	M2951/M2951: Open-Label Extension Period n=21 participants at risk Participants who received M2951 in double-blind treatment period, received 50 mg M2951 orally twice daily up to 26-weeks during the open-label extension period.
Ear and labyrinth disorders Vestibular disorder	0.00% 0/32 • Double-Blind Period: Baseline up to 16 weeks; Open-Label Period: Baseline up to 30 weeks MedDRA version for the double-blind treatment period is version 20.0 and MedDRA version for the open-label extension period is version 20.1	3.0% 1/33 • Double-Blind Period: Baseline up to 16 weeks; Open-Label Period: Baseline up to 30 weeks MedDRA version for the double-blind treatment period is version 20.0 and MedDRA version for the open-label extension period is version 20.1	0.00% 0/18 • Double-Blind Period: Baseline up to 16 weeks; Open-Label Period: Baseline up to 30 weeks MedDRA version for the double-blind treatment period is version 20.0 and MedDRA version for the open-label extension period is version 20.1	0.00% 0/21 • Double-Blind Period: Baseline up to 16 weeks; Open-Label Period: Baseline up to 30 weeks MedDRA version for the double-blind treatment period is version 20.0 and MedDRA version for the open-label extension period is version 20.1
Nervous system disorders Vertigo CNS origin	0.00% 0/32 • Double-Blind Period: Baseline up to 16 weeks; Open-Label Period: Baseline up to 30 weeks MedDRA version for the double-blind treatment period is version 20.0 and MedDRA version for the open-label extension period is version 20.1	3.0% 1/33 • Double-Blind Period: Baseline up to 16 weeks; Open-Label Period: Baseline up to 30 weeks MedDRA version for the double-blind treatment period is version 20.0 and MedDRA version for the open-label extension period is version 20.1	0.00% 0/18 • Double-Blind Period: Baseline up to 16 weeks; Open-Label Period: Baseline up to 30 weeks MedDRA version for the double-blind treatment period is version 20.0 and MedDRA version for the open-label extension period is version 20.1	0.00% 0/21 • Double-Blind Period: Baseline up to 16 weeks; Open-Label Period: Baseline up to 30 weeks MedDRA version for the double-blind treatment period is version 20.0 and MedDRA version for the open-label extension period is version 20.1

Other adverse events

Additional Information

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Phone: +49-6151-72-5200

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place