A Phase Ib, Randomized, Double-blind, Placebo Controlled Study to Evaluate the Safety and Pharmacokinetics of Multiple Ascending Doses of M5049 Administered Orally in SLE and CLE Participants Treated With Standard of Care
Overview
- Phase
- Phase 1
- Intervention
- M5049
- Conditions
- Systemic Lupus Erythematosus
- Sponsor
- Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany
- Enrollment
- 25
- Locations
- 12
- Primary Endpoint
- Part A: Cohort 3 and 4; Part B: Cohort 5: Number of Participants with Treatment-Emergent Adverse Events (TEAEs) Based on Severity
- Status
- Completed
- Last Updated
- 2 years ago
Overview
Brief Summary
This study is to evaluate the safety, tolerability and pharmacokinetics (PK) of orally administered M5049 in participants with systemic lupus erythematosus (SLE) or cutaneous lupus erythematosus (CLE).
Investigators
Eligibility Criteria
Inclusion Criteria
- •Active systemic lupus erythematosus (SLE) with a Cutaneous lupus erythematosus disease area and activity index (CLASI-A) greater than or equal to \[\>= \] 6 and/or at least one active SLE clinical manifestation according to Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K)
- •Active cutaneous lupus erythematosus (CLE) (subacute cutaneous lupus erythematosus and/or discoid lupus erythematosus) with a CLASI-A \>= 6
- •Other protocol defined inclusion criteria could apply
Exclusion Criteria
- •Autoimmune or rheumatic disease other than SLE or CLE
- •Dermatological diseases other than cutaneous manifestations of SLE or CLE
- •Uncontrolled medical conditions including significant cardiovascular events, active lupus nephritis, and active neurological disorder
- •Ongoing or active clinically significant viral, bacterial or fungal infection
- •History of uncontrolled seizures or other neurological disorder
- •History of or positive for human immunodeficiency virus, hepatitis C virus, or hepatitis B virus
- •History of malignancy
- •Other protocol defined exclusion criteria could apply
Arms & Interventions
Part A (Cohort 1): M5049 Dose A
Intervention: M5049
Part A (Cohort 2): M5049 Dose B
Intervention: M5049
Part A (Cohort 3): M5049 Dose C
Intervention: M5049
Part A (Cohort 4): M5049 Dose D
Intervention: M5049
Part A: Placebo
Intervention: Placebo
Part B (Cohort 5): M5049 Dose E
Intervention: M5049
Part B: Placebo
Intervention: Placebo
Outcomes
Primary Outcomes
Part A: Cohort 3 and 4; Part B: Cohort 5: Number of Participants with Treatment-Emergent Adverse Events (TEAEs) Based on Severity
Time Frame: Up to Day 186
Part A: Cohort 3 and 4; Part B: Cohort 5: Number of Participants with Clinically Significant Changes from Baseline in Laboratory Parameters, Vital Signs, Electroencephalogram (EEG) and Electrocardiogram (ECG) Findings
Time Frame: Up to Day 186
Part A: Cohort 1 and 2: Number of Participants with Confirmed Signs and Symptoms of Prodromal Seizure
Time Frame: Up to Day 102
Part A: Cohort 1 and 2: Number of Participants with Clinically Significant Changes from Baseline in Laboratory Parameters, Vital Signs, Electroencephalogram (EEG) and Electrocardiogram (ECG) Findings
Time Frame: Up to Day 102
Part A: Cohort 1 and 2: Number of Participants with Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs and Adverse Event of Special Interest (AESI), TEAEs Leading to Permanent Treatment Discontinuation and Treatment-Related TEAEs
Time Frame: Up to Day 102
Part A: Cohort 3 and 4; Part B: Cohort 5: Number of Participants with Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs and Adverse Event of Special Interest (AESI), TEAEs Leading to Permanent Treatment Discontinuation and Treatment-Related TEAEs
Time Frame: Up to Day 186
Part A: Cohort 1 and 2: Number of Participants with Treatment-Emergent Adverse Events (TEAEs) Based on Severity
Time Frame: Up to Day 102
Part A: Cohort 3 and 4; Part B: Cohort 5: Number of Participants with Confirmed Signs and Symptoms of Prodromal Seizure
Time Frame: Up to Day 186
Part A: Cohort 1 and 2: Number of Participants with Suicidal Behavior and Suicidal Ideation as Assessed by Columbia-Suicide Severity Rating Scale (C-SSRS)
Time Frame: Up to Day 102
Secondary Outcomes
- Part A and Part B: Apparent Terminal Half-life (t1/2) of M5049(Day 1 and Day 29)
- Part A and Part B: Total Body Clearance (CL/f) of M5049(Day 1)
- Part A and Part B: Dose Normalized Maximum Observed Plasma Concentration (Cmax/Dose) of M5049(Day 1 and Day 29)
- Part A and Part B: Time to Reach Maximum Plasma Concentration (tmax) of M5049(Pre-dose up to Day 85 for Cohort 1 and 2 of Part A, up to Day 169 for Cohort 3, 4 of Part A and Cohort 5 of Part B)
- Part A and Part B: Accumulation Ratio for Maximum Observed Plasma Concentration (Racc Cmax) of M5049(Pre-dose up to Day 85 for Cohort 1 and 2 of Part A, up to Day 169 for Cohort 3, 4 of Part A and Cohort 5 of Part B)
- Part A and Part B: Dose Normalized Area Under Plasma Concentration-Time Curve from Time Zero to 12 Hours Post-Dose (AUC0-12h/Dose) of M5049(Day 29)
- Part A and Part B: Apparent Volume of Distribution (Vz/f) of M5049(Day 1)
- Part A and Part B: Change from Baseline in 28-Joint Count(Baseline (Day 1) through Day 85 for Cohort 1 and 2 of Part A, Day 169 for Cohort 3, 4 of Part A and Cohort 5 of Part B)
- Part A and Part B: Dose Normalized Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Sampling Time (AUC0-t/Dose) of M5049(Day 1 and Day 29)
- Part A and Part B: Elimination Rate Constant (Lambda z) of M5049(Day 1 and Day 29)
- Part A and Part B: Change from Baseline in Cutaneous Lupus Erythematosus Disease Area and Activity Index (CLASI-A)(Baseline (Day 1) through Day 85 for Cohort 1 and 2 of Part A, Day 169 for Cohort 3, 4 of Part A and Cohort 5 of Part B)
- Part A and Part B: Change from Baseline in Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K)(Baseline (Day 1) through Day 85 for Cohort 1 and 2 of Part A, Day 169 for Cohort 3, 4 of Part A and Cohort 5 of Part B)
- Part A and Part B: Maximum Observed Plasma Concentration (Cmax) of M5049(Pre-dose up to Day 85 for Cohort 1 and 2 of Part A, up to Day 169 for Cohort 3, 4 of Part A and Cohort 5 of Part B)
- Part A and Part B: Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Sampling Time (AUC0-t) of M5049(Pre-dose up to Day 85 for Cohort 1 and 2 of Part A, up to Day 169 for Cohort 3, 4 of Part A and Cohort 5 of Part B)
- Part A and Part B: Change from Baseline in Physician Global Assessment (PGA) Score(Baseline (Day 1) through Day 85 for Cohort 1 and 2 of Part A, Day 169 for Cohort 3, 4 of Part A and Cohort 5 of Part B)
- Part A and Part B: Area Under the Plasma Concentration-Time Curve From Time Zero to 12 Hours Post-Dose (AUC0-12h) of M5049(Day 29)
- Part A and Part B: Area Under Plasma Concentration-Time Curve from Time Zero Extrapolated to Infinity (AUC0-inf) of M5049(Day 1)
- Part A and Part B: Dose Normalized Area Under Plasma Concentration-Time Curve from Time Zero Extrapolated to Infinity (AUC0-inf/Dose) of M5049(Day 1)