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| ID | Type | Description | Link |
|---|---|---|---|
| 2016-000064-42 | EudraCT Number |
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| Name | Class |
|---|---|
| Merck KGaA, Darmstadt, Germany | INDUSTRY |
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M2951 is an investigational drug under evaluation for treatment of autoimmune and inflammatory disorders. The purpose of the study is to assess the efficacy of M2951 in participants with rheumatoid arthritis (RA) currently treated with stable dose of methotrexate (MTX).
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Placebo: Double-Blind Treatment Period | Placebo Comparator |
| |
| M2951: Double-Blind Treatment Period | Experimental |
| |
| Placebo/M2951: Open Label Extension Period | Experimental |
| |
| M2951/M2951: Open Label Extension Period | Experimental |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Placebo | Drug | Participants received placebo matched to M2951 twice daily up to Day 84 during the double-blind treatment period. |
|
| Measure | Description | Time Frame |
|---|---|---|
| Proportion of Participants Who Achieved American College of Rheumatology-20 (ACR20) Response | 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. | Day 84 |
| Measure | Description | Time Frame |
|---|---|---|
| Mean Change From Baseline in High-Sensitivity C-Reactive Protein (hsCRP) at Day 28 | Mean change in the hsCRP concentration from baseline at Day 28 was reported. | Baseline, Day 28 |
| Proportion of Participants Achieving American College of Rheumatology-50 (ACR50) Response |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Medical Responsible | EMD Serono Inc., a business of Merck KGaA, Darmstadt, Germany | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| U.S. Medical Information | Billerica | Massachusetts | United States | |||
| Merck KGaA Communication Center |
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.
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| ID | Title | Description |
|---|---|---|
| FG000 | Placebo: Double-Blind Treatment Period | Participants received placebo matched to M2951 twice daily up to Day 84 during the double-blind treatment period. |
| FG001 | M2951: Double-Blind Treatment Period | Participants received 50 milligrams (mg) M2951 orally twice daily up to Day 84 during the double-blind treatment period. |
| FG002 | 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. |
| FG003 | 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. |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Double-Blind Treatment Period (12 Weeks) |
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| ||||||||||||||||||
| Open-Label Extension Period (26 Weeks) |
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The Safety Analysis Set included all participants who received at least 1 dose of M2951 or placebo.
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| ID | Title | Description |
|---|---|---|
| BG000 | Placebo: Double-Blind Treatment Period | Participants received placebo matched to M2951 twice daily up to Day 84 during the double-blind treatment period. |
| BG001 | M2951: Double-Blind Treatment Period |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Proportion of Participants Who Achieved American College of Rheumatology-20 (ACR20) Response | 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. | 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. | Posted | Number | proportion of participants | Day 84 |
|
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
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Placebo: Double-Blind Treatment Period | Participants received placebo matched to M2951 twice daily up to Day 84 during the double-blind treatment period. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Vestibular disorder | Ear and labyrinth disorders | MedDRA | Non-systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Nausea | Gastrointestinal disorders | MedDRA | Non-systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Merck KGaA Communication Center | Merck Healthcare, a business of Merck KGaA, Darmstadt, Germany | +49-6151-72-5200 | service@merckgroup.com |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| SAP | No | Yes | No | Statistical Analysis Plan | Apr 18, 2017 | Apr 30, 2018 | SAP_001.pdf |
| Prot | Yes | No | No | Study Protocol | Sep 2, 2016 | Jun 18, 2018 | Prot_002.pdf |
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| ID | Term |
|---|---|
| D001172 | Arthritis, Rheumatoid |
| ID | Term |
|---|---|
| D001168 | Arthritis |
| D007592 | Joint Diseases |
| D009140 | Musculoskeletal Diseases |
| D012216 | Rheumatic Diseases |
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| ID | Term |
|---|---|
| C000632111 | evobrutinib |
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| M2951 | Drug | Participants received 50 milligrams (mg) M2951 orally twice daily up to Day 84 during the double-blind treatment period. |
|
|
| M2951 | Drug | Participants who received placebo matched to M2951 or M2951 in double-blind treatment period, received 50 mg M2951 orally twice daily up to 26-weeks during the open label extension period. |
|
|
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. |
| Day 28, Day 56 and Day 84 |
| Proportion of Participants Achieving American College of Rheumatology-70 (ACR70) Response | 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. | Day 28, Day 56 and Day 84 |
| Mean Change From Baseline in High-Sensitivity C-Reactive Protein (hsCRP) at Day 84 | Mean change in the hsCRP concentration from baseline at Day 84 was reported. | Baseline, Day 84 |
| 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 | 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. | Baseline, Day 28 and Day 84 |
| Proportion of Participants With Disease Activity Score- High Sensitivity C-Reactive Protein (DAS28-hsCRP) Value Less Than (<) 3.2 | 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. | Day 84 |
| Proportion of Participants With Disease Activity Score- High Sensitivity C-Reactive Protein (DAS28-hsCRP) Value Less Than (<) 2.6 | 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. | Day 84 |
| Change From Baseline in Erythrocyte Sedimentation Rate (ESR) at Day 28 and 84 | 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. | Baseline, Day 28 and Day 84 |
| Change From Baseline in Anti-cyclic Citrullinated Peptide (Anti-CCP) Antibody Levels at Day 28 and 84 | Anti-cyclic citrullinated peptide (anti-CCP) is an antibody present in most rheumatoid arthritis participants. | Baseline, Day 28 and Day 84 |
| Change From Baseline in Rheumatoid Factor (RF) at Day 28 and 84 | Rheumatoid Factor is an anti-body present in the blood. | Baseline, Day 28 and Day 84 |
| Change From Baseline in Global Assessment of Disease Activity Based on Visual Analog Scale (VAS) Score at Day 84 | 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). | Baseline, Day 84 |
| Change From Baseline in Self-assessment of Pain Based on Visual Analog Scale (VAS) Score at Day 84 | 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. | Baseline, Day 84 |
| Change From Baseline in Self-assessment of Disability Using Health Assessment Questionnaire - Disability Index (HAQ-DI) Score at Day 84 | 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. | Baseline, Day 84 |
| Change From Baseline in Physician's Global Assessment of Disease Activity Scale Based on Visual Analog Scale (VAS) Score at Day 84 | 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). | Baseline, Day 84 |
| Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | 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. | Baseline up to 16 Weeks |
| Number of Participants With Treatment Emergent Adverse Events (TEAEs) by Severity | 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. | Baseline up to 16 Weeks |
| Number of Participants With Grade 3 or Higher Clinically Significant Abnormality for Hematology, Biochemistry, Urinalysis or Coagulation | 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. | Baseline up to 16 Weeks |
| Number of Participants With Clinically Significant Vital Signs Abnormalities | Vital sign assessment included blood pressure, pulse rate, respiratory rate and temperature. Clinical significance was determined by the investigator. | Baseline up to 16 Weeks |
| Number of Participants With Clinically Significant 12-lead Electrocardiogram (ECG) Findings | 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. | Baseline up to 16 Weeks |
| Plasma Concentration of M2951 | 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 |
| Area Under the Concentration-Time Curve From Time Zero to 6 Hours (AUC 0-6h) of M2951 | Pre-dose, 0.25, 0.5, 1.0, 2.0, 4.0, 6.0 hours post-dose at Day 1 and Day 29 |
| Maximum Observed Plasma Concentration (Cmax) of M2951 | Pre-dose, 0.25, 0.5, 1.0, 2.0, 4.0, 6.0 hours post-dose at Day 1 and Day 29 |
| Plasma Concentration Observed Immediately Before Dosing on Day 29 (Cpre) of M2951 | Pre-dose on Day 29 |
| Time to Reach Maximum Plasma Concentration (Tmax) of M2951 | Pre-dose, 0.25, 0.5, 1.0, 2.0, 4.0, 6.0 hours post-dose at Day 1 and Day 29 |
| Accumulation Ratio for Area Under the Concentration-Time Curve From Time Zero to 6 Hours (Racc [AUC0-6h]) of M2951 | Accumulation ratio for AUC was calculated as AUC 0-6h, Day 29 divided by AUC 0-6h, Day 1 | Pre-dose, 0.25, 0.5, 1.0, 2.0, 4.0, 6.0 hours post-dose at Day 1 and Day 29 |
| Accumulation Ratio for Observed Maximum Plasma Concentration (Racc [Cmax]) of M2951 | Accumulation ratio for Cmax , was calculated as Cmax, Day 29 divided by Cmax, Day1 | Pre-dose, 0.25, 0.5, 1.0, 2.0, 4.0, 6.0 hours post-dose at Day 1 and Day 29 |
| Absolute Immunoglobulin Levels at Day 85 | 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. | Baseline, Day 85 |
| Absolute Change From Baseline in Immunoglobulin Levels at Day 85 | 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. | Baseline, Day 85 |
| Absolute B-Cell Levels at Day 85 | Day 85 |
| Absolute Change From Baseline in B-cell Levels at Day 85 | Baseline, Day 85 |
| Darmstadt |
| Germany |
| Withdrawal by Subject |
|
| Other |
|
| Lack of Efficacy |
|
| COMPLETED |
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| NOT COMPLETED |
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|
Participants received 50 milligrams (mg) M2951 orally twice daily up to Day 84 during the double-blind treatment period.
| BG002 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| OG000 |
| Placebo: Double-Blind Treatment Period |
Participants received placebo matched to M2951 twice daily up to Day 84 during the double-blind treatment period. |
| OG001 | M2951: Double-Blind Treatment Period | Participants received 50 milligrams (mg) M2951 orally twice daily up to Day 84 during the double-blind treatment period. |
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| Secondary | Mean Change From Baseline in High-Sensitivity C-Reactive Protein (hsCRP) at Day 28 | Mean change in the hsCRP concentration from baseline at Day 28 was reported. | 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. | Posted | Mean | Standard Error | milligram/milliliter (mg/mL) | Baseline, Day 28 |
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| Secondary | Proportion of Participants Achieving American College of Rheumatology-50 (ACR50) Response | 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. | 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. | Posted | Number | proportion of participants | Day 28, Day 56 and Day 84 |
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| Secondary | Proportion of Participants Achieving American College of Rheumatology-70 (ACR70) Response | 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. | 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. | Posted | Number | proportion of participants | Day 28, Day 56 and Day 84 |
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| Secondary | Mean Change From Baseline in High-Sensitivity C-Reactive Protein (hsCRP) at Day 84 | Mean change in the hsCRP concentration from baseline at Day 84 was reported. | 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. | Posted | Mean | Standard Error | mg/mL | Baseline, Day 84 |
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| Secondary | 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 | 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. | 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. | Posted | Mean | Standard Error | units on a scale | Baseline, Day 28 and Day 84 |
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| Secondary | Proportion of Participants With Disease Activity Score- High Sensitivity C-Reactive Protein (DAS28-hsCRP) Value Less Than (<) 3.2 | 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. | 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. | Posted | Number | proportion of participants | Day 84 |
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| Secondary | Proportion of Participants With Disease Activity Score- High Sensitivity C-Reactive Protein (DAS28-hsCRP) Value Less Than (<) 2.6 | 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. | 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. | Posted | Number | proportion of participants | Day 84 |
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| Secondary | Change From Baseline in Erythrocyte Sedimentation Rate (ESR) at Day 28 and 84 | 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. | 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. | Posted | Mean | Standard Deviation | millimeter/hour (mm/hour) | Baseline, Day 28 and Day 84 |
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| Secondary | Change From Baseline in Anti-cyclic Citrullinated Peptide (Anti-CCP) Antibody Levels at Day 28 and 84 | Anti-cyclic citrullinated peptide (anti-CCP) is an antibody present in most rheumatoid arthritis participants. | 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. | Posted | Mean | Standard Deviation | units/milliliter | Baseline, Day 28 and Day 84 |
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| Secondary | Change From Baseline in Rheumatoid Factor (RF) at Day 28 and 84 | Rheumatoid Factor is an anti-body present in the blood. | 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. | Posted | Mean | Standard Deviation | kiloUnit/Liter (kU/L) | Baseline, Day 28 and Day 84 |
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| Secondary | Change From Baseline in Global Assessment of Disease Activity Based on Visual Analog Scale (VAS) Score at Day 84 | 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). | 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. | Posted | Mean | Standard Deviation | millimeter | Baseline, Day 84 |
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| Secondary | Change From Baseline in Self-assessment of Pain Based on Visual Analog Scale (VAS) Score at Day 84 | 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. | 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. | Posted | Mean | Standard Deviation | millimeter | Baseline, Day 84 |
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| Secondary | Change From Baseline in Self-assessment of Disability Using Health Assessment Questionnaire - Disability Index (HAQ-DI) Score at Day 84 | 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. | 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. | Posted | Mean | Standard Deviation | units on a scale | Baseline, Day 84 |
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| Secondary | Change From Baseline in Physician's Global Assessment of Disease Activity Scale Based on Visual Analog Scale (VAS) Score at Day 84 | 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). | 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. | Posted | Mean | Standard Deviation | millimeter | Baseline, Day 84 |
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| Secondary | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | 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. | The Safety Analysis Set included all participants who received at least 1 dose of M2951 or placebo. | Posted | Count of Participants | Participants | Baseline up to 16 Weeks |
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| Secondary | Number of Participants With Treatment Emergent Adverse Events (TEAEs) by Severity | 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. | The Safety Analysis Set included all participants who received at least 1 dose of M2951 or placebo. | Posted | Count of Participants | Participants | Baseline up to 16 Weeks |
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| Secondary | Number of Participants With Grade 3 or Higher Clinically Significant Abnormality for Hematology, Biochemistry, Urinalysis or Coagulation | 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. | The Safety Analysis Set included all participants who received at least 1 dose of M2951 or placebo. | Posted | Count of Participants | Participants | Baseline up to 16 Weeks |
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| Secondary | Number of Participants With Clinically Significant Vital Signs Abnormalities | Vital sign assessment included blood pressure, pulse rate, respiratory rate and temperature. Clinical significance was determined by the investigator. | The Safety Analysis Set included all participants who received at least 1 dose of M2951 or placebo. | Posted | Count of Participants | Participants | Baseline up to 16 Weeks |
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| Secondary | Number of Participants With Clinically Significant 12-lead Electrocardiogram (ECG) Findings | 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. | The Safety Analysis Set included all participants who received at least 1 dose of M2951 or placebo. | Posted | Count of Participants | Participants | Baseline up to 16 Weeks |
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| Secondary | Plasma Concentration of M2951 | 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. | Posted | Mean | Standard Deviation | nanogram per milliliter (ng/mL) | 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 |
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| Secondary | Area Under the Concentration-Time Curve From Time Zero to 6 Hours (AUC 0-6h) of M2951 | 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. | Posted | Mean | Standard Deviation | hours*nanogram/milliliter | Pre-dose, 0.25, 0.5, 1.0, 2.0, 4.0, 6.0 hours post-dose at Day 1 and Day 29 |
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| Secondary | Maximum Observed Plasma Concentration (Cmax) of M2951 | 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. | Posted | Mean | Standard Deviation | ng/mL | Pre-dose, 0.25, 0.5, 1.0, 2.0, 4.0, 6.0 hours post-dose at Day 1 and Day 29 |
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| Secondary | Plasma Concentration Observed Immediately Before Dosing on Day 29 (Cpre) of M2951 | 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. | Posted | Mean | Standard Deviation | ng/mL | Pre-dose on Day 29 |
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| Secondary | Time to Reach Maximum Plasma Concentration (Tmax) of M2951 | 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. | Posted | Median | Full Range | hour | Pre-dose, 0.25, 0.5, 1.0, 2.0, 4.0, 6.0 hours post-dose at Day 1 and Day 29 |
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| Secondary | Accumulation Ratio for Area Under the Concentration-Time Curve From Time Zero to 6 Hours (Racc [AUC0-6h]) of M2951 | Accumulation ratio for AUC was calculated as AUC 0-6h, Day 29 divided by AUC 0-6h, Day 1 | 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. | Posted | Mean | Standard Deviation | ratio | Pre-dose, 0.25, 0.5, 1.0, 2.0, 4.0, 6.0 hours post-dose at Day 1 and Day 29 |
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| Secondary | Accumulation Ratio for Observed Maximum Plasma Concentration (Racc [Cmax]) of M2951 | Accumulation ratio for Cmax , was calculated as Cmax, Day 29 divided by Cmax, Day1 | 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. | Posted | Mean | Standard Deviation | ratio | Pre-dose, 0.25, 0.5, 1.0, 2.0, 4.0, 6.0 hours post-dose at Day 1 and Day 29 |
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| Secondary | Absolute Immunoglobulin Levels at Day 85 | 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. | 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. | Posted | Mean | Standard Deviation | gram/Liter | Baseline, Day 85 |
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| Secondary | Absolute Change From Baseline in Immunoglobulin Levels at Day 85 | 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. | 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. | Posted | Mean | Standard Deviation | gram/Liter | Baseline, Day 85 |
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| Secondary | Absolute B-Cell Levels at Day 85 | 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. | Posted | Mean | Standard Deviation | cells per micro-liter | Day 85 |
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| Secondary | Absolute Change From Baseline in B-cell Levels at Day 85 | 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. | Posted | Mean | Standard Deviation | cells per micro-liter | Baseline, Day 85 |
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| 0 |
| 32 |
| 0 |
| 32 |
| 13 |
| 32 |
| EG001 | M2951: Double-Blind Treatment Period | Participants received 50 milligrams (mg) M2951 orally twice daily up to Day 84 during the double-blind treatment period. | 0 | 33 | 1 | 33 | 17 | 33 |
| EG002 | 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. | 0 | 18 | 0 | 18 | 8 | 18 |
| EG003 | 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. | 0 | 21 | 0 | 21 | 10 | 21 |
| Vertigo CNS origin | Nervous system disorders | MedDRA | Non-systematic Assessment |
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| Vomiting | Gastrointestinal disorders | MedDRA | Non-systematic Assessment |
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| Abdominal pain upper | Gastrointestinal disorders | MedDRA | Non-systematic Assessment |
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| Leukocytosis | Blood and lymphatic system disorders | MedDRA | Non-systematic Assessment |
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| Neutropenia | Blood and lymphatic system disorders | MedDRA | Non-systematic Assessment |
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| Viral upper respiratory tract infection | Infections and infestations | MedDRA | Non-systematic Assessment |
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| Respiratory tract infection | Infections and infestations | MedDRA | Non-systematic Assessment |
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| Gastroenteritis | Infections and infestations | MedDRA | Non-systematic Assessment |
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| Nasopharyngitis | Infections and infestations | MedDRA | Non-systematic Assessment |
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| Lipase increased | Investigations | MedDRA | Non-systematic Assessment |
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| Blood glucose increased | Investigations | MedDRA | Non-systematic Assessment |
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| Alanine aminotransferase increased | Investigations | MedDRA | Non-systematic Assessment |
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| Amylase increased | Investigations | MedDRA | Non-systematic Assessment |
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| Aspartate aminotransferase increased | Investigations | MedDRA | Non-systematic Assessment |
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| Pain in extremity | Musculoskeletal and connective tissue disorders | MedDRA | Non-systematic Assessment |
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| Rheumatoid arthritis | Musculoskeletal and connective tissue disorders | MedDRA | Non-systematic Assessment |
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| Headache | Nervous system disorders | MedDRA | Non-systematic Assessment |
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| Anxiety | Psychiatric disorders | MedDRA | Non-systematic Assessment |
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| Oropharyngeal pain | Respiratory, thoracic and mediastinal disorders | MedDRA | Non-systematic Assessment |
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| Hypertension | Vascular disorders | MedDRA | Non-systematic Assessment |
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Not provided
Not provided
| D003240 |
| Connective Tissue Diseases |
| D017437 | Skin and Connective Tissue Diseases |
| D001327 | Autoimmune Diseases |
| D007154 | Immune System Diseases |
| Day 84 |
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| Difference in Proportion of Responders |
| -0.04 |
| 2-Sided |
| 80 |
| -0.18 |
| 0.09 |
| Superiority |
| Day 84 | Difference in Proportion of Responders | -0.01 | 2-Sided | 80 | -0.15 | 0.12 | Superiority |
| Day 84 |
|
| Difference in Proportion of Responders |
| 0.03 |
| 2-Sided |
| 80 |
| -0.05 |
| 0.11 |
| Superiority |
| Day 84 | Difference in Proportion of Responders | -0.04 | 2-Sided | 80 | -0.15 | 0.07 | Superiority |
| Difference in Mean Changes |
| 0.07 |
| 2-Sided |
| 80 |
| -0.29 |
| 0.43 |
| Superiority |
| Change at Day 84 |
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| Change at Day 84 |
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| Change at Day 84 |
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| Coagulation |
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| Urinalysis |
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| Day 1: 0.5 hours post-dose |
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| Day 1: 1 hour post-dose |
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| Day 1: 2 hours post-dose |
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| Day 1: 4 hours post-dose |
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| Day 1: 6 hours post-dose |
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| Day 29: 0.25 hours post-dose |
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| Day 29: 0.5 hours post-dose |
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| Day 29: 1 hour post-dose |
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| Day 29: 2 hours post-dose |
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| Day 29: 4 hours post-dose |
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| Day 29: 6 hour post-dose |
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| Immunoglobulin G Subclass 1 |
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| Immunoglobulin G Subclass 2 |
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| Immunoglobulin G Subclass 3 |
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| Immunoglobulin G Subclass 4 |
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| Immunoglobulin M |
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| Immunoglobulin G Subclass 1 |
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| Immunoglobulin G Subclass 2 |
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| Immunoglobulin G Subclass 3 |
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| Immunoglobulin G Subclass 4 |
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| Immunoglobulin M |
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