Rheumatoid Arthritis
Conditions
Keywords
Rheumatoid Arthritis, M2951, Bruton's Tyrosine Kinase (BTK)
Brief summary
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).
Interventions
DRUGPlacebo
Participants received placebo matched to M2951 twice daily up to Day 84 during the double-blind treatment period.
DRUGM2951
Participants received 50 milligrams (mg) M2951 orally twice daily up to Day 84 during the double-blind treatment period.
Sponsors
Merck KGaA, Darmstadt, Germany
EMD Serono Research & Development Institute, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Men or women 18 to 75 years of age at the time of informed consent signature * Confirmed diagnosis of RA according to 2010 American College of Rheumatology (ACR)/The European League Against Rheumatism (EULAR) RA classification criteria of at least 6 months duration * Positive RF and/or anti-CCP (anti-cyclic citrullinated peptide) * Persistently active disease defined as greater than equal to (\>=) 6 swollen joints (of 66 counted) and \>= 6 tender joints (of 68 counted) * High-sensitivity C-reactive protein (hsCRP) \>= 3.6 milligram per liter (mg/L) * Treatment for \>= 12 weeks with 10 to 25 mg/week MTX at a stable dose for at least 4 weeks prior to dosing with the investigational medicinal product (IMP) and maintained throughout the trial * Women of childbearing potential must use acceptable methods of contraception for 4 weeks prior to randomization, throughout the trial, and for 90 days after the last dose of IMP. For the purposes of this trial * Females who are postmenopausal (age-related amenorrhea \>= 12 consecutive months and increased follicle-stimulating hormone \[FSH\] greater than (\>) 40 milli international units per milliliter \[mIU/mL\]), or who have undergone hysterectomy or bilateral oophorectomy are exempt from pregnancy testing. If necessary to confirm postmenopausal status, an FSH will be drawn at Screening * Acceptable contraception is defined as use of either 2 barrier methods (eg, female diaphragm and male condom), or 1 barrier method in conjunction with one of the following: spermicide, an intrauterine device, or hormonal contraceptives (implant or oral) * Women of childbearing potential must have a negative serum pregnancy test at the Screening Visit and a negative urine pregnancy test at Day 1/randomization before dosing.
Exclusion criteria
* Use of oral corticosteroids \> 10 mg daily prednisone equivalent, use of injectable corticosteroids, or change in dose of corticosteroids within 2 weeks prior to Screening or during Screening * Initiation or change in dose for nonsteroidal anti-inflammatory drugs (NSAIDs) within 2 weeks prior to Screening * Treatment with tofacitinib, other Bruton's Tyrosine Kinase (BTK) inhibitors, or a biologic disease-modifying antirheumatic drug (DMARD; eg, anti-tumor necrosis factor alpha \[anti-TNF-α\], tocilizumab \[anti-interleukin-6 receptor\], abatacept \[CTLA4-Fc\]), or other immunosuppressive drugs(sulfasalazine would be acceptable at a stable dose) other than methotrexate within 3 months prior to Screening or during Screening * Treatment with anti-CD20 therapy (eg, rituximab) within 12 months prior to Screening or during Screening * Immunologic disorder other than Rheumatoid Arthritis (RA), with the exception of secondary Sjogren's syndrome associated with RA, and well-controlled diabetes or thyroid disorder, or any other condition requiring oral, intravenous, intramuscular, or intra-articular corticosteroid therapy * Vaccination with live or live-attenuated virus vaccine within 1 month prior to Screening * Active, clinically significant, viral, bacterial, or fungal infection, or any major episode of infection requiring hospitalization or treatment with parenteral anti-infectives within 4 weeks of Screening or during Screening, or completion of oral anti-infectives within 2 weeks before or during Screening, or a history of recurrent infections (ie, 3 or more of the same type of infection in a 12-month rolling period). Vaginal candidiasis, onychomycosis, and genital or oral herpes simplex virus considered by the Investigator to be sufficiently controlled would not be exclusionary * History of or positive testing for human immunodeficiency virus (HIV), hepatitis C antibody and/or polymerase chain reaction, hepatitis B surface antigen (HBsAg) (+) and/or hepatitis B core total, and/or IgM antibody (+) at Screening * History of or current diagnosis of active tuberculosis (TB); undergoing treatment for latent TB infection (LTBI); untreated LTBI (as determined by documented results within 3 months of the Screening Visit of a positive TB skin test with purified protein derivative with induration \>= 5 millimeter (mm), a positive QuantiFERON-TB test or positive or borderline T-SPOT \[Elispot\] test); or positive QuantiFERON-TB test at Screening. Participants with documented completed appropriate LTBI treatment would not be excluded and are not required to be tested * Participants with current household contacts with active TB will also be excluded * Indeterminate QuantiFERON-TB or T-SPOT tests may be repeated once, and will be considered positive if retest results are positive or indeterminate * History of cancer, except adequately treated basal cell or squamous cell carcinomas of the skin (no more than 3 lesions requiring treatment in lifetime) or carcinoma in situ/cervical intraepithelial neoplasia of the uterine cervix, unless considered cured \> 5 years * Clinically significant abnormality on electrocardiogram (ECG), or an active infective process or any other clinically significant abnormality on Screening chest X-ray (CXR) taken within 4 weeks of the first dose, per Investigator opinion. If a CXR has been taken within the previous 3 months and results are available and normal, the CXR does not need to be carried out * B cell (CD19) count less than (\<) 50% of the lower limit of normal at Screening * Significant cytopenia including absolute neutrophil count \< 1,500/ mm\^3, platelet count \< 100,000/mm\^3, or absolute lymphocyte count \< 1,000/mm\^3
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Participants Who Achieved American College of Rheumatology-20 (ACR20) Response | Day 84 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Participants Achieving American College of Rheumatology-50 (ACR50) Response | Day 28, Day 56 and Day 84 | 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. |
| Proportion of Participants Achieving American College of Rheumatology-70 (ACR70) Response | Day 28, Day 56 and Day 84 | 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. |
| Mean Change From Baseline in High-Sensitivity C-Reactive Protein (hsCRP) at Day 84 | Baseline, Day 84 | Mean change in the hsCRP concentration from baseline at Day 84 was reported. |
| 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 | Baseline, Day 28 and Day 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. |
| Proportion of Participants With Disease Activity Score- High Sensitivity C-Reactive Protein (DAS28-hsCRP) Value Less Than (<) 3.2 | Day 84 | 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. |
| Proportion of Participants With Disease Activity Score- High Sensitivity C-Reactive Protein (DAS28-hsCRP) Value Less Than (<) 2.6 | Day 84 | 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. |
| Change From Baseline in Erythrocyte Sedimentation Rate (ESR) at Day 28 and 84 | Baseline, Day 28 and Day 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. |
| Change From Baseline in Anti-cyclic Citrullinated Peptide (Anti-CCP) Antibody Levels at Day 28 and 84 | Baseline, Day 28 and Day 84 | Anti-cyclic citrullinated peptide (anti-CCP) is an antibody present in most rheumatoid arthritis participants. |
| Change From Baseline in Rheumatoid Factor (RF) at Day 28 and 84 | Baseline, Day 28 and Day 84 | Rheumatoid Factor is an anti-body present in the blood. |
| Change From Baseline in Global Assessment of Disease Activity Based on Visual Analog Scale (VAS) Score at Day 84 | Baseline, 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). |
| Change From Baseline in Self-assessment of Pain Based on Visual Analog Scale (VAS) Score at Day 84 | Baseline, 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. |
| Change From Baseline in Self-assessment of Disability Using Health Assessment Questionnaire - Disability Index (HAQ-DI) Score at Day 84 | Baseline, 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. |
| Change From Baseline in Physician's Global Assessment of Disease Activity Scale Based on Visual Analog Scale (VAS) Score at Day 84 | Baseline, 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). |
| Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | Baseline up to 16 Weeks | 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. |
| Mean Change From Baseline in High-Sensitivity C-Reactive Protein (hsCRP) at Day 28 | Baseline, Day 28 | Mean change in the hsCRP concentration from baseline at Day 28 was reported. |
| Number of Participants With Grade 3 or Higher Clinically Significant Abnormality for Hematology, Biochemistry, Urinalysis or Coagulation | Baseline up to 16 Weeks | 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. |
| Number of Participants With Clinically Significant Vital Signs Abnormalities | Baseline up to 16 Weeks | Vital sign assessment included blood pressure, pulse rate, respiratory rate and temperature. Clinical significance was determined by the investigator. |
| Number of Participants With Clinically Significant 12-lead Electrocardiogram (ECG) Findings | Baseline up to 16 Weeks | 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. |
| 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 | 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 AUC was calculated as AUC 0-6h, Day 29 divided by AUC 0-6h, Day 1 |
| Accumulation Ratio for Observed Maximum Plasma Concentration (Racc [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 | Accumulation ratio for Cmax , was calculated as Cmax, Day 29 divided by Cmax, Day1 |
| Absolute Immunoglobulin Levels at Day 85 | Baseline, 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. |
| Absolute Change From Baseline in Immunoglobulin Levels at Day 85 | Baseline, 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. |
| Absolute B-Cell Levels at Day 85 | Day 85 | — |
| Absolute Change From Baseline in B-cell Levels at Day 85 | Baseline, Day 85 | — |
| Number of Participants With Treatment Emergent Adverse Events (TEAEs) by Severity | Baseline up to 16 Weeks | 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. |
Countries
Germany, United States
Participant flow
Pre-assignment details
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.
Participants by arm
| Arm | Count |
|---|---|
| Placebo: Double-Blind Treatment Period Participants received placebo matched to M2951 twice daily up to Day 84 during the double-blind treatment period. | 32 |
| M2951: Double-Blind Treatment Period Participants received 50 milligrams (mg) M2951 orally twice daily up to Day 84 during the double-blind treatment period. | 33 |
| Total | 65 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Double-Blind Treatment Period (12 Weeks) | Adverse Event | 3 | 5 | 0 | 0 |
| Double-Blind Treatment Period (12 Weeks) | Lack of Efficacy | 1 | 0 | 0 | 0 |
| Double-Blind Treatment Period (12 Weeks) | Other | 2 | 0 | 0 | 0 |
| Double-Blind Treatment Period (12 Weeks) | Withdrawal by Subject | 2 | 1 | 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
| Characteristic | Total | M2951: Double-Blind Treatment Period | Placebo: Double-Blind Treatment Period |
|---|---|---|---|
| Age, Continuous | 53.4 years STANDARD_DEVIATION 11.39 | 53.8 years STANDARD_DEVIATION 10.73 | 53.1 years STANDARD_DEVIATION 12.19 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 1 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 63 Participants | 32 Participants | 31 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 62 Participants | 31 Participants | 31 Participants |
| Sex: Female, Male Female | 49 Participants | 24 Participants | 25 Participants |
| Sex: Female, Male Male | 16 Participants | 9 Participants | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 32 | 0 / 33 | 0 / 18 | 0 / 21 |
| other Total, other adverse events | 13 / 32 | 17 / 33 | 8 / 18 | 10 / 21 |
| serious Total, serious adverse events | 0 / 32 | 1 / 33 | 0 / 18 | 0 / 21 |
Outcome results
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.
Time frame: 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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo: Double-Blind Treatment Period | Proportion of Participants Who Achieved American College of Rheumatology-20 (ACR20) Response | 0.42 proportion of participants |
| M2951: Double-Blind Treatment Period | Proportion of Participants Who Achieved American College of Rheumatology-20 (ACR20) Response | 0.52 proportion of participants |
80% CI: [-0.07, 0.25]
Secondary
Absolute B-Cell Levels at Day 85
Time frame: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo: Double-Blind Treatment Period | Absolute B-Cell Levels at Day 85 | 243 cells per micro-liter | Standard Deviation 265 |
| M2951: Double-Blind Treatment Period | Absolute B-Cell Levels at Day 85 | 204 cells per micro-liter | Standard Deviation 154 |
Secondary
Absolute Change From Baseline in B-cell Levels at Day 85
Time frame: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo: Double-Blind Treatment Period | Absolute Change From Baseline in B-cell Levels at Day 85 | 76 cells per micro-liter | Standard Deviation 242 |
| M2951: Double-Blind Treatment Period | Absolute Change From Baseline in B-cell Levels at Day 85 | 11 cells per micro-liter | Standard Deviation 73.2 |
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.
Time frame: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo: Double-Blind Treatment Period | Absolute Change From Baseline in Immunoglobulin Levels at Day 85 | Immunoglobulin M | -0.04 gram/Liter | Standard Deviation 0.177 |
| Placebo: Double-Blind Treatment Period | Absolute Change From Baseline in Immunoglobulin Levels at Day 85 | Immunoglobulin A | -0.07 gram/Liter | Standard Deviation 0.263 |
| Placebo: Double-Blind Treatment Period | Absolute Change From Baseline in Immunoglobulin Levels at Day 85 | Immunoglobulin G Subclass 1 | 0.11 gram/Liter | Standard Deviation 0.857 |
| Placebo: Double-Blind Treatment Period | Absolute Change From Baseline in Immunoglobulin Levels at Day 85 | Immunoglobulin G Subclass 2 | -0.13 gram/Liter | Standard Deviation 0.477 |
| Placebo: Double-Blind Treatment Period | Absolute Change From Baseline in Immunoglobulin Levels at Day 85 | Immunoglobulin G Subclass 3 | 0.07 gram/Liter | Standard Deviation 0.214 |
| Placebo: Double-Blind Treatment Period | Absolute Change From Baseline in Immunoglobulin Levels at Day 85 | Immunoglobulin G Subclass 4 | -0.028 gram/Liter | Standard Deviation 0.1073 |
| Placebo: Double-Blind Treatment Period | Absolute Change From Baseline in Immunoglobulin Levels at Day 85 | Immunoglobulin G | 0.02 gram/Liter | Standard Deviation 1.281 |
| M2951: Double-Blind Treatment Period | Absolute Change From Baseline in Immunoglobulin Levels at Day 85 | Immunoglobulin G Subclass 3 | -0.04 gram/Liter | Standard Deviation 0.209 |
| M2951: Double-Blind Treatment Period | Absolute Change From Baseline in Immunoglobulin Levels at Day 85 | Immunoglobulin G | -0.30 gram/Liter | Standard Deviation 0.517 |
| M2951: Double-Blind Treatment Period | Absolute Change From Baseline in Immunoglobulin Levels at Day 85 | Immunoglobulin M | -0.25 gram/Liter | Standard Deviation 0.255 |
| M2951: Double-Blind Treatment Period | Absolute Change From Baseline in Immunoglobulin Levels at Day 85 | Immunoglobulin G Subclass 2 | -0.17 gram/Liter | Standard Deviation 0.404 |
| M2951: Double-Blind Treatment Period | Absolute Change From Baseline in Immunoglobulin Levels at Day 85 | Immunoglobulin A | -0.04 gram/Liter | Standard Deviation 0.133 |
| M2951: Double-Blind Treatment Period | Absolute Change From Baseline in Immunoglobulin Levels at Day 85 | Immunoglobulin G Subclass 4 | -0.046 gram/Liter | Standard Deviation 0.2576 |
| M2951: Double-Blind Treatment Period | Absolute Change From Baseline in Immunoglobulin Levels at Day 85 | Immunoglobulin G Subclass 1 | -0.15 gram/Liter | Standard Deviation 0.41 |
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.
Time frame: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo: Double-Blind Treatment Period | Absolute Immunoglobulin Levels at Day 85 | Immunoglobulin G Subclass 3 | 1.05 gram/Liter | Standard Deviation 0.551 |
| Placebo: Double-Blind Treatment Period | Absolute Immunoglobulin Levels at Day 85 | Immunoglobulin G Subclass 1 | 6.20 gram/Liter | Standard Deviation 2.338 |
| Placebo: Double-Blind Treatment Period | Absolute Immunoglobulin Levels at Day 85 | Immunoglobulin M | 1.16 gram/Liter | Standard Deviation 0.365 |
| Placebo: Double-Blind Treatment Period | Absolute Immunoglobulin Levels at Day 85 | Immunoglobulin G Subclass 2 | 3.59 gram/Liter | Standard Deviation 1.644 |
| Placebo: Double-Blind Treatment Period | Absolute Immunoglobulin Levels at Day 85 | Immunoglobulin G | 10.61 gram/Liter | Standard Deviation 3.897 |
| Placebo: Double-Blind Treatment Period | Absolute Immunoglobulin Levels at Day 85 | Immunoglobulin G Subclass 4 | 0.394 gram/Liter | Standard Deviation 0.2474 |
| Placebo: Double-Blind Treatment Period | Absolute Immunoglobulin Levels at Day 85 | Immunoglobulin A | 2.09 gram/Liter | Standard Deviation 0.968 |
| M2951: Double-Blind Treatment Period | Absolute Immunoglobulin Levels at Day 85 | Immunoglobulin G Subclass 4 | 0.684 gram/Liter | Standard Deviation 0.6286 |
| M2951: Double-Blind Treatment Period | Absolute Immunoglobulin Levels at Day 85 | Immunoglobulin G Subclass 2 | 3.74 gram/Liter | Standard Deviation 1.205 |
| M2951: Double-Blind Treatment Period | Absolute Immunoglobulin Levels at Day 85 | Immunoglobulin M | 1.16 gram/Liter | Standard Deviation 0.642 |
| M2951: Double-Blind Treatment Period | Absolute Immunoglobulin Levels at Day 85 | Immunoglobulin A | 2.77 gram/Liter | Standard Deviation 1.323 |
| M2951: Double-Blind Treatment Period | Absolute Immunoglobulin Levels at Day 85 | Immunoglobulin G | 9.88 gram/Liter | Standard Deviation 2.498 |
| M2951: Double-Blind Treatment Period | Absolute Immunoglobulin Levels at Day 85 | Immunoglobulin G Subclass 1 | 5.41 gram/Liter | Standard Deviation 1.574 |
| M2951: Double-Blind Treatment Period | Absolute Immunoglobulin Levels at Day 85 | Immunoglobulin G Subclass 3 | 0.93 gram/Liter | Standard Deviation 0.51 |
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
Time frame: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo: 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
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
Time frame: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo: Double-Blind Treatment Period | Accumulation Ratio for Observed Maximum Plasma Concentration (Racc [Cmax]) of M2951 | 1.52 ratio | Standard Deviation 1.929 |
Secondary
Area Under the Concentration-Time Curve From Time Zero to 6 Hours (AUC 0-6h) of M2951
Time frame: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo: 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 |
| Placebo: Double-Blind Treatment Period | 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
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.
Time frame: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo: 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 | 168 units/milliliter | Standard Deviation 991.1 |
| Placebo: Double-Blind Treatment Period | Change From Baseline in Anti-cyclic Citrullinated Peptide (Anti-CCP) Antibody Levels at Day 28 and 84 | Change at Day 84 | 301 units/milliliter | Standard Deviation 1282.6 |
| M2951: 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 |
| M2951: Double-Blind Treatment Period | 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 |
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.
Time frame: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo: Double-Blind Treatment Period | Change From Baseline in Erythrocyte Sedimentation Rate (ESR) at Day 28 and 84 | Change at Day 28 | -3 millimeter/hour (mm/hour) | Standard Deviation 36.9 |
| Placebo: Double-Blind Treatment Period | Change From Baseline in Erythrocyte Sedimentation Rate (ESR) at Day 28 and 84 | Change at Day 84 | -3 millimeter/hour (mm/hour) | Standard Deviation 21 |
| M2951: Double-Blind Treatment Period | 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 |
| M2951: 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 |
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).
Time frame: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo: Double-Blind Treatment Period | Change From Baseline in Global Assessment of Disease Activity Based on Visual Analog Scale (VAS) Score at Day 84 | -21 millimeter | Standard Deviation 23.5 |
| M2951: 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 |
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).
Time frame: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo: 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 | -33 millimeter | Standard Deviation 20.3 |
| M2951: 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 |
Secondary
Change From Baseline in Rheumatoid Factor (RF) at Day 28 and 84
Rheumatoid Factor is an anti-body present in the blood.
Time frame: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo: Double-Blind Treatment Period | Change From Baseline in Rheumatoid Factor (RF) at Day 28 and 84 | Change at Day 28 | -30 kiloUnit/Liter (kU/L) | Standard Deviation 124.2 |
| Placebo: Double-Blind Treatment Period | Change From Baseline in Rheumatoid Factor (RF) at Day 28 and 84 | Change at Day 84 | -34 kiloUnit/Liter (kU/L) | Standard Deviation 132.1 |
| M2951: 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 |
| M2951: Double-Blind Treatment Period | 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 |
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.
Time frame: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo: 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 0.44 |
| M2951: 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 |
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.
Time frame: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo: Double-Blind Treatment Period | Change From Baseline in Self-assessment of Pain Based on Visual Analog Scale (VAS) Score at Day 84 | -19 millimeter | Standard Deviation 21.8 |
| M2951: 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 |
Secondary
Maximum Observed Plasma Concentration (Cmax) of M2951
Time frame: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo: Double-Blind Treatment Period | Maximum Observed Plasma Concentration (Cmax) of M2951 | Day 1 | 206 ng/mL | Standard Deviation 214.7 |
| Placebo: Double-Blind Treatment Period | Maximum Observed Plasma Concentration (Cmax) of M2951 | Day 29 | 171 ng/mL | Standard Deviation 130.1 |
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.
Time frame: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo: 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 84 | -1.35 units on a scale | Standard Error 0.2 |
| Placebo: 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 | -0.79 units on a scale | Standard Error 0.14 |
| M2951: 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 |
| M2951: 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 84 | -1.28 units on a scale | Standard Error 0.19 |
Comparison: Day 2880% CI: [-0.33, 0.16]
Comparison: Day 8480% CI: [-0.29, 0.43]
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.
Time frame: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo: Double-Blind Treatment Period | Mean Change From Baseline in High-Sensitivity C-Reactive Protein (hsCRP) at Day 28 | -0.80 milligram/milliliter (mg/mL) | Standard Error 2 |
| M2951: 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 |
80% CI: [-5.54, 1.69]
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.
Time frame: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo: Double-Blind Treatment Period | Mean Change From Baseline in High-Sensitivity C-Reactive Protein (hsCRP) at Day 84 | -2.14 mg/mL | Standard Error 2.2 |
| M2951: 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 |
80% CI: [-5.37, 2.58]
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.
Time frame: Baseline up to 16 Weeks
Population: The Safety Analysis Set included all participants who received at least 1 dose of M2951 or placebo.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo: Double-Blind Treatment Period | Number of Participants With Clinically Significant 12-lead Electrocardiogram (ECG) Findings | 0 Participants |
| M2951: Double-Blind Treatment Period | Number of Participants With Clinically Significant 12-lead Electrocardiogram (ECG) Findings | 0 Participants |
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.
Time frame: Baseline up to 16 Weeks
Population: The Safety Analysis Set included all participants who received at least 1 dose of M2951 or placebo.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo: Double-Blind Treatment Period | Number of Participants With Clinically Significant Vital Signs Abnormalities | 0 Participants |
| M2951: Double-Blind Treatment Period | Number of Participants With Clinically Significant Vital Signs Abnormalities | 0 Participants |
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.
Time frame: Baseline up to 16 Weeks
Population: The Safety Analysis Set included all participants who received at least 1 dose of M2951 or placebo.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo: Double-Blind Treatment Period | Number of Participants With Grade 3 or Higher Clinically Significant Abnormality for Hematology, Biochemistry, Urinalysis or Coagulation | Hematology | 2 Participants |
| Placebo: Double-Blind Treatment Period | Number of Participants With Grade 3 or Higher Clinically Significant Abnormality for Hematology, Biochemistry, Urinalysis or Coagulation | Coagulation | 0 Participants |
| Placebo: Double-Blind Treatment Period | Number of Participants With Grade 3 or Higher Clinically Significant Abnormality for Hematology, Biochemistry, Urinalysis or Coagulation | Urinalysis | 0 Participants |
| Placebo: Double-Blind Treatment Period | Number of Participants With Grade 3 or Higher Clinically Significant Abnormality for Hematology, Biochemistry, Urinalysis or Coagulation | Biochemistry | 4 Participants |
| M2951: Double-Blind Treatment Period | Number of Participants With Grade 3 or Higher Clinically Significant Abnormality for Hematology, Biochemistry, Urinalysis or Coagulation | Urinalysis | 0 Participants |
| M2951: Double-Blind Treatment Period | Number of Participants With Grade 3 or Higher Clinically Significant Abnormality for Hematology, Biochemistry, Urinalysis or Coagulation | Biochemistry | 2 Participants |
| M2951: Double-Blind Treatment Period | Number of Participants With Grade 3 or Higher Clinically Significant Abnormality for Hematology, Biochemistry, Urinalysis or Coagulation | Coagulation | 0 Participants |
| M2951: Double-Blind Treatment Period | Number of Participants With Grade 3 or Higher Clinically Significant Abnormality for Hematology, Biochemistry, Urinalysis or Coagulation | Hematology | 0 Participants |
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.
Time frame: Baseline up to 16 Weeks
Population: The Safety Analysis Set included all participants who received at least 1 dose of M2951 or placebo.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo: Double-Blind Treatment Period | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | TEAEs | 16 Participants |
| Placebo: Double-Blind Treatment Period | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | SAEs | 0 Participants |
| M2951: Double-Blind Treatment Period | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | TEAEs | 22 Participants |
| M2951: Double-Blind Treatment Period | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | SAEs | 1 Participants |
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.
Time frame: Baseline up to 16 Weeks
Population: The Safety Analysis Set included all participants who received at least 1 dose of M2951 or placebo.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo: Double-Blind Treatment Period | Number of Participants With Treatment Emergent Adverse Events (TEAEs) by Severity | NCI-CTCAE Severity grade >=4 | 0 Participants |
| Placebo: Double-Blind Treatment Period | Number of Participants With Treatment Emergent Adverse Events (TEAEs) by Severity | NCI-CTCAE Severity grade >=3 | 2 Participants |
| M2951: Double-Blind Treatment Period | Number of Participants With Treatment Emergent Adverse Events (TEAEs) by Severity | NCI-CTCAE Severity grade >=3 | 3 Participants |
| M2951: Double-Blind Treatment Period | Number of Participants With Treatment Emergent Adverse Events (TEAEs) by Severity | NCI-CTCAE Severity grade >=4 | 1 Participants |
Secondary
Plasma Concentration Observed Immediately Before Dosing on Day 29 (Cpre) of M2951
Time frame: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo: 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
Plasma Concentration of M2951
Time frame: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo: Double-Blind Treatment Period | Plasma Concentration of M2951 | Day 1: Pre-Dose: | 0.00 nanogram per milliliter (ng/mL) | — |
| Placebo: Double-Blind Treatment Period | Plasma Concentration of M2951 | Day 1: 0.25 hours post-dose | 10.3 nanogram per milliliter (ng/mL) | Standard Deviation 23.37 |
| Placebo: Double-Blind Treatment Period | Plasma Concentration of M2951 | Day 1: 0.5 hours post-dose | 80.5 nanogram per milliliter (ng/mL) | Standard Deviation 136.9 |
| Placebo: Double-Blind Treatment Period | Plasma Concentration of M2951 | Day 1: 1 hour post-dose | 160 nanogram per milliliter (ng/mL) | Standard Deviation 219.7 |
| Placebo: Double-Blind Treatment Period | Plasma Concentration of M2951 | Day 1: 2 hours post-dose | 125 nanogram per milliliter (ng/mL) | Standard Deviation 111.9 |
| Placebo: Double-Blind Treatment Period | Plasma Concentration of M2951 | Day 1: 4 hours post-dose | 47.3 nanogram per milliliter (ng/mL) | Standard Deviation 41.62 |
| Placebo: Double-Blind Treatment Period | Plasma Concentration of M2951 | Day 1: 6 hours post-dose | 23.7 nanogram per milliliter (ng/mL) | Standard Deviation 20.92 |
| Placebo: Double-Blind Treatment Period | Plasma Concentration of M2951 | Day 29: 0.25 hours post-dose | 22.0 nanogram per milliliter (ng/mL) | Standard Deviation 71.57 |
| Placebo: Double-Blind Treatment Period | Plasma Concentration of M2951 | Day 29: 0.5 hours post-dose | 88.4 nanogram per milliliter (ng/mL) | Standard Deviation 114.1 |
| Placebo: Double-Blind Treatment Period | Plasma Concentration of M2951 | Day 29: 1 hour post-dose | 120 nanogram per milliliter (ng/mL) | Standard Deviation 107.2 |
| Placebo: Double-Blind Treatment Period | Plasma Concentration of M2951 | Day 29: 2 hours post-dose | 82.3 nanogram per milliliter (ng/mL) | Standard Deviation 53.82 |
| Placebo: Double-Blind Treatment Period | Plasma Concentration of M2951 | Day 29: 4 hours post-dose | 62.1 nanogram per milliliter (ng/mL) | Standard Deviation 82.39 |
| Placebo: Double-Blind Treatment Period | Plasma Concentration of M2951 | Day 29: 6 hour post-dose | 37.2 nanogram per milliliter (ng/mL) | Standard Deviation 43.96 |
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.
Time frame: 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.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo: Double-Blind Treatment Period | Proportion of Participants Achieving American College of Rheumatology-50 (ACR50) Response | Day 56 | 0.23 proportion of participants |
| Placebo: Double-Blind Treatment Period | Proportion of Participants Achieving American College of Rheumatology-50 (ACR50) Response | Day 28 | 0.10 proportion of participants |
| Placebo: Double-Blind Treatment Period | Proportion of Participants Achieving American College of Rheumatology-50 (ACR50) Response | Day 84 | 0.23 proportion of participants |
| M2951: Double-Blind Treatment Period | Proportion of Participants Achieving American College of Rheumatology-50 (ACR50) Response | Day 28 | 0.06 proportion of participants |
| M2951: Double-Blind Treatment Period | Proportion of Participants Achieving American College of Rheumatology-50 (ACR50) Response | Day 56 | 0.18 proportion of participants |
| M2951: Double-Blind Treatment Period | Proportion of Participants Achieving American College of Rheumatology-50 (ACR50) Response | Day 84 | 0.21 proportion of participants |
Comparison: Day 2880% CI: [-0.13, 0.06]
Comparison: Day 5680% CI: [-0.18, 0.09]
Comparison: Day 8480% CI: [-0.15, 0.12]
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.
Time frame: 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.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo: Double-Blind Treatment Period | Proportion of Participants Achieving American College of Rheumatology-70 (ACR70) Response | Day 84 | 0.13 proportion of participants |
| Placebo: Double-Blind Treatment Period | Proportion of Participants Achieving American College of Rheumatology-70 (ACR70) Response | Day 28 | 0.00 proportion of participants |
| Placebo: Double-Blind Treatment Period | Proportion of Participants Achieving American College of Rheumatology-70 (ACR70) Response | Day 56 | 0.03 proportion of participants |
| M2951: Double-Blind Treatment Period | Proportion of Participants Achieving American College of Rheumatology-70 (ACR70) Response | Day 28 | 0.06 proportion of participants |
| M2951: Double-Blind Treatment Period | Proportion of Participants Achieving American College of Rheumatology-70 (ACR70) Response | Day 56 | 0.06 proportion of participants |
| M2951: Double-Blind Treatment Period | Proportion of Participants Achieving American College of Rheumatology-70 (ACR70) Response | Day 84 | 0.09 proportion of participants |
Comparison: Day 2880% CI: [0.01, 0.14]
Comparison: Day 5680% CI: [-0.05, 0.11]
Comparison: Day 8480% CI: [-0.15, 0.07]
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.
Time frame: 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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo: Double-Blind Treatment Period | Proportion of Participants With Disease Activity Score- High Sensitivity C-Reactive Protein (DAS28-hsCRP) Value Less Than (<) 2.6 | 0.10 proportion of participants |
| M2951: 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 |
80% CI: [-0.13, 0.06]
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.
Time frame: 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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo: Double-Blind Treatment Period | Proportion of Participants With Disease Activity Score- High Sensitivity C-Reactive Protein (DAS28-hsCRP) Value Less Than (<) 3.2 | 0.13 proportion of participants |
| M2951: 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 |
80% CI: [-0.04, 0.21]
Secondary
Time to Reach Maximum Plasma Concentration (Tmax) of M2951
Time frame: 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.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Placebo: Double-Blind Treatment Period | Time to Reach Maximum Plasma Concentration (Tmax) of M2951 | Day 1 | 1.00 hour |
| Placebo: Double-Blind Treatment Period | Time to Reach Maximum Plasma Concentration (Tmax) of M2951 | Day 29 | 1.00 hour |