A Phase II, Randomized, Double-Blind, Placebo-Controlled Dose-Ranging Study To Evaluate the Safety and Efficacy of M2951 in Subjects With SLE
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 入组人数
- 469
- 试验地点
- 156
- 主要终点
- DBPC Period: Number of Participants With Response Based on Systemic Lupus Erythematosus Responder Index 4 (SRI-4) at Week 52
研究概览
简要总结
M2951 is an investigational drug under evaluation for treatment of autoimmune and inflammatory disorders. The purpose of the study was to assess the Safety and Efficacy of M2951 in participants with Systemic Lupus Erythematosus (SLE).
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Eligible male and female participants, aged 18 to 75 years
- •Must have diagnosis of SLE with either the Systemic Lupus International Collaborating Clinics (SLICC) criteria for SLE, or at least four of the 11 American College of Rheumatology (ACR) classification criteria for SLE, of at least six months duration prior to Screening
- •SLEDAI-2K total score greater than or equal to (>=) 6 (including clinical SLEDAI greater than or equal to (>=) 4) at Screening Visit
- •And be positive for anti-double-stranded Deoxyribonucleic Acid (DNA) and/or anti-nuclear antibody (ANA greater than or equal to (>=) 1:80) and/or anti-Smith (anti-Sm) antibody at the time of Screening
- •Other protocol defined inclusion criteria could apply
排除标准
- •Participants are not eligible for this study if they have active, clinically significant interstitial lung disease or pulmonary arterial hypertension
- •Proteinuria (urine protein to creatinine ratio [UPCR] > 4 mg/mg)
- •Acutely worsened renal function
- •Central nervous system SLE
- •Or within two weeks prior to Screening or during Screening: use of oral corticosteroids greater than (>) 30 mg daily prednisone equivalent
- •Use of injectable corticosteroids, or change in dose of corticosteroids.
- •Other protocol defined exclusion criteria could apply
研究组 & 干预措施
LTE Period: M2951 25 mg QD/ M2951 50 mg BID
干预措施: M2951 (Drug)
Double-Blind Placebo-Controlled (DBPC) Period: Placebo
干预措施: Placebo (Drug)
DBPC Period: M2951 25 mg QD
干预措施: M2951 (Drug)
DBPC Period: M2951 75 mg QD
干预措施: M2951 (Drug)
DBPC Period: M2951 50 mg BID
干预措施: M2951 (Drug)
Long-Term Extension (LTE) Period: Placebo/ M2951 50 mg BID
干预措施: M2951 (Drug)
LTE Period: M2951 75 mg QD/ M2951 50 mg BID
干预措施: M2951 (Drug)
LTE Period: M2951 50 mg BID/ M2951 50 mg BID
干预措施: M2951 (Drug)
结局指标
主要结局
DBPC Period: Number of Participants With Response Based on Systemic Lupus Erythematosus Responder Index 4 (SRI-4) at Week 52
时间窗: Week 52
SRI-4 response was defined as greater than or equal to (\>=) 4-point reduction in Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) total score, no new British Isles Lupus Assessment Group (BILAG) A and no more than 1 new BILAG B domain score, no worsening (less than 10 percent increase) from baseline in Physician's Global Assessment of Disease Activity (PGA) and no treatment failure. SLEDAI-2K assessment consists of 24 items with total score of 0(no symptoms) to 105 (presence of all defined symptoms) with higher scores representing increased disease activity. BILAG Index: assessing clinical signs, symptoms, or laboratory parameters related to Systemic Lupus Erythematosus (SLE) divided into 9 organ systems. For each organ system A=severe disease, B=moderate disease, C=mild stable disease, D=inactive, but previously active, E=inactive and never affected. The PGA assess disease activity on a visual analogue scale =from 0(very well) to 100(very poor).
DBPC Period: Mean Absolute Value of Serum Immunoglobulin (Ig) Levels (IgG, IgA, IgM) at Week 24
时间窗: Week 24
Mean absolute value of serum levels of IgG, IgA, IgM were assessed at Week 24.
DBPC Period: Number of Participants With Response Based on Systemic Lupus Erythematosus Responder Index 6 (SRI-6) at Week 52
时间窗: Week 52
SRI-6 response was defined as \>= 6-point reduction in SLEDAI-2K total score, no new BILAG A and no more than 1 new BILAG B domain score and no worsening (less than 10 percent increase) from baseline in Physician's Global Assessment of Disease Activity (PGA) and treatment failure. SLEDAI-2K assessment consists of 24 items with total score of 0 (no symptoms) to 105 (presence of all defined symptoms) with higher scores representing increased disease activity. BILAG Index: assessing clinical signs, symptoms, or laboratory parameters related to SLE, divided into 9 organ systems. For each organ system :A=severe disease, B=moderate disease, C=mild stable disease, D=inactive, but previously active, E=inactive and never affected. The PGA assess disease activity on a visual analogue scale =from 0(very well) to 100(very poor).
DBPC Period: Number of Participants With Clinically Significant Changes From Baseline in 12-Lead Electrocardiogram (ECG) Findings
时间窗: Baseline up to Week 56
12-lead ECG recordings included rhythm, heart rate (as measured by RR interval), PR interval, QRS duration, and QT interval. The corrected QT interval (QTcF) was calculated using Fridericia's formula. 12-lead ECG recordings were obtained after the participants have rested for at least 10 minutes in semisupine position. Clinical significance was determined by the investigator. The number of participants with clinically significant changes from baseline in 12-lead ECG findings were reported.
DBPC Period: Mean Absolute Value of Serum Immunoglobulin (Ig) Levels (IgG, IgA, IgM) at Week 52
时间窗: Week 52
Mean absolute value of serum levels of IgG, IgA, IgM were assessed at Week 52
DBPC Period: Mean Absolute Total B Cell Count at Week 24
时间窗: Week 24
Mean absolute total B cell count were assessed. Flow cytometry analysis of lymphocyte populations using four-color fluorescence activated cell sorting was performed for the analysis of B cell counts.
DBPC Period: Change From Baseline in Serum Immunoglobulin (Ig) Levels (IgG, IgA, IgM) at Week 12
时间窗: Baseline and Week 12
Change from baseline in the serum levels of IgG, IgA, IgM were assessed.
DBPC Period: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs According to National Cancer Institute-Common Terminology Criteria for Adverse Events Version 4.03 (NCI-CTCAE v4.03)
时间窗: Baseline up to Week 56
Adverse event (AE) was defined as any untoward medical occurrence in a participant, which does not necessarily have causal relationship with treatment. A serious AE was defined as an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged in participant hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. TEAEs: events between first dose of study drug that were absent before treatment/that worsened relative to pre-treatment state up to 56 weeks. TEAEs included both serious TEAEs and non-serious TEAEs. Number of participants with TEAEs and serious TEAEs were reported.
DBPC Period: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) by Severity According to National Cancer Institute-Common Terminology Criteria for Adverse Events Version 4.03 (NCI-CTCAE v4.03)
时间窗: Baseline up to Week 56
Severity of TEAEs were graded using NCI-CTCAE v4.03 toxicity grades, as follows: Grade 1= Mild; Grade 2 = Moderate; Grade 3 = Severe; Grade 4 = Life-threatening and Grade 5 = Death. Number of participants with TEAEs by severity were reported.
DBPC Period: Number of Participants With Clinically Significant Change From Baseline in Vital Signs
时间窗: Baseline up to Week 56
Vital signs included body temperature, systolic and diastolic blood pressure, pulse rate, respiratory rate, weight and height. Clinical significance was determined by the investigator. The number of participants with clinically significant changes from baseline in vital signs were reported.
DBPC Period: Mean Absolute Value of Serum Immunoglobulin (Ig) Levels (IgG, IgA, IgM) at Week 4
时间窗: Week 4
Mean absolute value of serum levels of IgG, IgA, IgM were assessed at Week 4.
DBPC Period: Mean Absolute Value of Serum Immunoglobulin (Ig) Levels (IgG, IgA, IgM) at Week 56
时间窗: Week 56
Mean absolute value of serum levels of IgG, IgA, IgM were assessed at Week 56
DBPC Period: Change From Baseline in Serum Immunoglobulin (Ig) Levels (IgG, IgA, IgM) at Week 2
时间窗: Baseline and Week 2
Change from baseline in the serum levels of IgG, IgA, IgM were assessed.
DBPC Period: Change From Baseline in Total B Cell Count at Week 4
时间窗: Baseline and Week 4
Change from baseline in Total B cell count were assessed. Flow cytometry analysis of lymphocyte populations using four-color fluorescence-activated cell sorting was performed for the analysis of B cell counts.
DBPC Period: Mean Absolute Value of Serum Immunoglobulin (Ig) Levels (IgG, IgA, IgM) at Week 12
时间窗: Week 12
Mean absolute value of serum levels of IgG, IgA, IgM were assessed at Week 12.
DBPC Period: Mean Absolute Total B Cell Count at Week 4
时间窗: Week 4
Mean total B cell count were assessed. Flow cytometry analysis of lymphocyte populations using four-color fluorescence activated cell sorting was performed for the analysis of B cell counts.
DBPC Period: Mean Absolute Total B Cell Count at Week 52
时间窗: Week 52
Mean absolute total B cell count were assessed. Flow cytometry analysis of lymphocyte populations using four-color fluorescence activated cell sorting was performed for the analysis of B cell counts.
DBPC Period: Mean Absolute Total B Cell Count at Week 56
时间窗: Week 56
Mean absolute total B cell count were assessed. Flow cytometry analysis of lymphocyte populations using four-color fluorescence activated cell sorting was performed for the analysis of B cell counts.
DBPC Period: Change From Baseline in Serum Immunoglobulin (Ig) Levels (IgG, IgA, IgM) at Week 36
时间窗: Baseline and Week 36
Change from baseline in the serum levels of IgG, IgA, IgM were assessed.
DBPC Period: Change From Baseline in Total B Cell Count at Week 52
时间窗: Baseline and Week 52
Change from baseline in Total B cell count were assessed. Flow cytometry analysis of lymphocyte populations using four-color fluorescence-activated cell sorting was performed for the analysis of B cell counts.
DBPC Period: Number of Participants With Clinically Significant Changes From Baseline in Laboratory Parameters
时间窗: Baseline up to Week 56
Laboratory investigation included hematology, biochemistry, urinalysis and coagulation. Clinical significance was determined by the investigator. The number of participants with clinically significant changes from baseline in laboratory parameters were reported.
DBPC Period: Mean Absolute Value of Serum Immunoglobulin (Ig) Levels (IgG, IgA, IgM) at Week 2
时间窗: Week 2
Mean absolute value of serum levels of IgG, IgA, IgM were assessed at Week 2.
DBPC Period: Mean Absolute Value of Serum Immunoglobulin (Ig) Levels (IgG, IgA, IgM) at Week 36
时间窗: Week 36
Mean absolute value of serum levels of IgG, IgA, IgM were assessed at Week 36.
DBPC Period: Change From Baseline in Serum Immunoglobulin (Ig) Levels (IgG, IgA, IgM) at Week 56
时间窗: Baseline and Week 56
Change from baseline in the serum levels of IgG, IgA, IgM were assessed.
DBPC Period: Change From Baseline in Serum Immunoglobulin (Ig) Levels (IgG, IgA, IgM) at Week 4
时间窗: Baseline and Week 4
Change from baseline in the serum levels of IgG, IgA, IgM were assessed.
DBPC Period: Change From Baseline in Serum Immunoglobulin (Ig) Levels (IgG, IgA, IgM) at Week 24
时间窗: Baseline and Week 24
Change from baseline in the serum levels of IgG, IgA, IgM were assessed.
DBPC Period: Change From Baseline in Serum Immunoglobulin (Ig) Levels (IgG, IgA, IgM) at Week 52
时间窗: Baseline and Week 52
Change from baseline in the serum levels of IgG, IgA, IgM were assessed.
DBPC Period: Change From Baseline in Total B Cell Count at Week 24
时间窗: Baseline and Week 24
Change from baseline in Total B cell count were assessed. Flow cytometry analysis of lymphocyte populations using four-color fluorescence-activated cell sorting was performed for the analysis of B cell counts.
DBPC Period: Change From Baseline in Total B Cell Count at Week 56
时间窗: Baseline and Week 56
Change from baseline in Total B cell count were assessed. Flow cytometry analysis of lymphocyte populations using four-color fluorescence-activated cell sorting was performed for the analysis of B cell counts.
次要结局
- DBPC Period: Number of Participants With Low Disease Activity Status, Defined by Clinical Systemic Lupus Erythematosus Disease Activity Index-2000 (SLEDAI-2K) Score of Less Than or Equal (<= ) 2 at Week 52(Week 52)
- DBPC Period: Number of Participants With Response Based on BILAG-Based Composite Lupus Assessment (BICLA) at Week 52(Week 52)
- DBPC Period: Time to First Severe British Isles Lupus Assessment Group (BILAG) A Flare(Baseline up to Week 56)
- DBPC Period: Number of Participants With Response Based on Systemic Lupus Erythematosus Responder Index 4 (SRI-4) at Week 52 in Serologically Active (SA) Subgroup(Week 52)
- DBPC Period: Number of Participants With Response Based on Systemic Lupus Erythematosus Responder Index 6 (SRI-6) at Week 52 in Serologically Active Subgroup(Week 52)
- DBPC Period: Time to First British Isles Lupus Assessment Group (BILAG) A or 2B Moderate to Severe Flare(Baseline up to Week 56)
- DBPC Period: Number of Participants With British Isles Lupus Assessment Group (BILAG) 2004 Flare-Free Status During the 52-Week Treatment Period(up to Week 52)
- DBPC Period: Change From Baseline in European Quality of Life 5-dimensions (EQ-5D-5L) Health Outcome Questionnaire at Week 4, 8, 12, 16, 24, 32, 40 and 52(Baseline, Week 4, 8, 12, 16, 24, 32, 40, and 52)
- DBPC Period: Cumulative Prednisone Equivalent Corticosteroid (CS) Dose at Week 52(Week 52)
- DBPC Period: Number of Participants With a Sustained Reduction of Oral Corticosteroids (OCS) Dose to 7.5 mg Prednisone Equivalent Per Day or Less With Response Based on Systemic Lupus Erythematosus Responder Index 6 (SRI-6) at Week 52(Week 52)
- DBPC Period: Change From Baseline in Systemic Lupus Erythematosus Disease Activity Index-2000 (SLEDAI-2K) Score at Week 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48 and 52(Baseline, Week 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48 and 52)
- DBPC Period: Change From Baseline in Cutaneous Lupus Erythematosus Disease Area and Severity Index Activity (CLASI-A) Score at Week 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48 and 52(Baseline, Week 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48 and 52)
- DBPC Period: Change From Baseline in Lupus Quality of Life (LupusQoL) Questionnaire Score at Week 4, 8, 12, 16, 24, 32, 40 and 52(Baseline, Week 4, 8, 12, 16, 24, 32, 40, and 52)
- DBPC Period: Change From Baseline in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) Score at Week 4, 8, 12, 16, 24, 32, 40 and 52(Baseline, Week 4, 8, 12, 16, 24, 32, 40, and 52)
- DBPC Period: Number of Participants With Lupus Low Disease Activity State (LLDAS) at Week 52(Week 52)
- DBPC Period: Annualized Flare Rate(Baseline up to Week 52)
- DBPC Period: Number of Participants With Low Disease Activity Status, Defined by Systemic Lupus Erythematosus Disease Activity Index-2000 (SLEDAI-2K) Score of Less Than or Equal (<= ) 2 at Week 52(Week 52)
- DBPC Period: Change From Baseline in British Isles Lupus Assessment Group (BILAG)-2004 Score at Week 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48 and 52(Baseline, Week 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48 and 52)
- DBPC Period: Change From Baseline in Physician's Global Assessment (PGA) Score at Week 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48 and 52(Baseline, Week 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48 and 52)
- DBPC Period: Change From Baseline in European Quality of Life 5-dimensions (EQ-5D-5L) Visual Analog Scale (VAS) at Week 4, 8, 12, 16, 24, 32, 40 and 52(Baseline, Week 4, 8, 12, 16, 24, 32, 40, and 52)
- DBPC Period: Change From Baseline in Study 36-Item Short Form Health Survey Version 2 (SF-36v2) Physical Component Summary Score and Mental Component Summary Scores at Week 4, 8, 12, 16, 24, 32, 40 and 52(Baseline, Week 4, 8, 12, 16, 24, 32, 40 and 52)
- DBPC Period: Number of Participants With Patient Global Impression of Change (PGIC) Scale Score of Any Improvement, no Change and Any Worsening(Week 4, 8, 12, 16, 24, 32, 40, and 52)
- DBPC Period: Number of Participants With a Sustained Reduction of Oral Corticosteroids (OCS) Dose to 7.5 mg Prednisone Equivalent Per Day or Less With Response Based on SRI-4 at Week 52 in Serologically Active Subgroup(Week 52)
- DBPC Period: Number of Participants With Change From Baseline in Prednisone Equivalent Corticosteroid (CS) Dose by >=25% to a Dose of <=7.5 Milligram Per Day (mg/Day), With no BILAG A or 2B Flare in Disease Activity at Week 52(Baseline and Week 52)
- DBPC Period: Number of Participants With Reduction From Baseline in Prednisone Equivalent Corticosteroid (CS) Daily Dose by > 0 to 25%, >25% to 50%, >50% to 100% or an Increase at Week 1, 2, 4, 6, 8, 10, 12, 14, 16, 20, 24, 28, 32, 36, 40, 44, 48 and 52(Baseline, Week 1, 2, 4, 6, 8, 10, 12, 14, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52)
- DBPC Period: Number of Participants With a Sustained Reduction of Oral Corticosteroids (OCS) Dose to 7.5 mg Prednisone Equivalent Per Day or Less With Response Based on Systemic Lupus Erythematosus Responder Index 4 (SRI-4) at Week 52(Week 52)
- DBPC Period: Change From Baseline to Week 52 in Prednisone Equivalent Corticosteroid (CS) Daily Dose at at Week 1, 2, 4, 6, 8, 10, 12, 14, 16, 20, 24, 28, 32, 36, 40, 44, 48 and 52(Baseline, Week 1, 2, 4, 6, 8, 10, 12, 14, 16, 20, 24, 28, 32, 36, 40, 44, 48 and 52)