Clinical trial NCT04647708: Study of M5049 in CLE and SLE Participants
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Systemic Lupus Erythematosus
Cutaneous Lupus Erythematosus
Keywords: Lupus Erythematosus, Systemic
Lupus Erythematosus, Cutaneous
Autoimmune Diseases
Lead sponsor: Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany
Sponsor class: INDUSTRY
First posted: 2020-12-01
Enrollment: 25
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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).


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

Primary outcomes:
measure: 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
timeFrame: Up to Day 102
measure: 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
timeFrame: Up to Day 186
measure: Part A: Cohort 1 and 2: Number of Participants with Treatment-Emergent Adverse Events (TEAEs) Based on Severity
timeFrame: Up to Day 102
measure: Part A: Cohort 3 and 4; Part B: Cohort 5: Number of Participants with Treatment-Emergent Adverse Events (TEAEs) Based on Severity
timeFrame: Up to Day 186
measure: 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
timeFrame: Up to Day 102
measure: 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
timeFrame: Up to Day 186
measure: Part A: Cohort 1 and 2: Number of Participants with Confirmed Signs and Symptoms of Prodromal Seizure
timeFrame: Up to Day 102
measure: Part A: Cohort 3 and 4; Part B: Cohort 5: Number of Participants with Confirmed Signs and Symptoms of Prodromal Seizure
timeFrame: Up to Day 186
measure: 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)
timeFrame: Up to Day 102
Secondary outcomes:
measure: Part A and Part B: Maximum Observed Plasma Concentration (Cmax) of M5049
timeFrame: 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
measure: Part A and Part B: Dose Normalized Maximum Observed Plasma Concentration (Cmax/Dose) of M5049
timeFrame: Day 1 and Day 29
measure: Part A and Part B: Time to Reach Maximum Plasma Concentration (tmax) of M5049
timeFrame: 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
measure: Part A and Part B: Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Sampling Time (AUC0-t) of M5049
timeFrame: 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
measure: 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
timeFrame: Day 1 and Day 29
measure: Part A and Part B: Accumulation Ratio for Maximum Observed Plasma Concentration (Racc Cmax) of M5049
timeFrame: 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
measure: Part A and Part B: Elimination Rate Constant (Lambda z) of M5049
timeFrame: Day 1 and Day 29
measure: Part A and Part B: Apparent Terminal Half-life (t1/2) of M5049
timeFrame: Day 1 and Day 29
measure: Part A and Part B: Area Under the Plasma Concentration-Time Curve From Time Zero to 12 Hours Post-Dose (AUC0-12h) of M5049
timeFrame: Day 29
measure: 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
timeFrame: Day 29
measure: Part A and Part B: Total Body Clearance (CL/f) of M5049
timeFrame: Day 1
measure: Part A and Part B: Apparent Volume of Distribution (Vz/f) of M5049
timeFrame: Day 1
measure: Part A and Part B: Area Under Plasma Concentration-Time Curve from Time Zero Extrapolated to Infinity (AUC0-inf) of M5049
timeFrame: Day 1
measure: Part A and Part B: Dose Normalized Area Under Plasma Concentration-Time Curve from Time Zero Extrapolated to Infinity (AUC0-inf/Dose) of M5049
timeFrame: Day 1
measure: Part A and Part B: Change from Baseline in Cutaneous Lupus Erythematosus Disease Area and Activity Index (CLASI-A)
timeFrame: 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
measure: Part A and Part B: Change from Baseline in Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K)
timeFrame: 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
measure: Part A and Part B: Change from Baseline in 28-Joint Count
timeFrame: 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
measure: Part A and Part B: Change from Baseline in Physician Global Assessment (PGA) Score
timeFrame: 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
Other outcomes:
Locations:
city: Pleven
country: Bulgaria
facility: Medical center Medconsult Pleven OOD
city: Sevlievo
country: Bulgaria
facility: Medical Center-1-Sevlievo EOOD
city: Sofia
country: Bulgaria
facility: Military Medical Academy - MHAT - Sofia
city: Sofia
country: Bulgaria
facility: UMHAT "Sv. Ivan Rilski", EAD
city: Erfurt
country: Germany
facility: SocraTec R&D GmbH
city: Frankfurt
country: Germany
facility: Fraunhofer ITMP (Fraunhofer Institute for Translational Medicine and Pharmacology)
city: Chisinau
country: Moldova, Republic of
facility: ARENSIA Exploratory Medicine Phase I Unit, Clinical Republican Hospital
city: Skopje
country: North Macedonia
facility: PHI University Clinic of Rheumatology Skopje
city: Sevilla
country: Spain
facility: Hospital Universitario Nuestra Señora de Valme
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen del Rocio
city: Valladolid
country: Spain
facility: Hospital Universitario Rio Hortega - Servicio de Medicina Interna
city: Kyiv
country: Ukraine
facility: Medical Center of Limited Liability Company "Harmoniya krasy", Department of clinical trials
Study officials:
affiliation: Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany
name: Medical Responsible
role: STUDY_DIRECTOR
References:
citation: Klopp-Schulze L, Shaw JV, Dong JQ, Khandelwal A, Vazquez-Mateo C, Goteti K. Applying Modeling and Simulations for Rational Dose Selection of Novel Toll-Like Receptor 7/8 Inhibitor Enpatoran for Indications of High Medical Need. Clin Pharmacol Ther. 2022 Aug;112(2):297-306. doi: 10.1002/cpt.2606. Epub 2022 May 21.