A TQT Study of Effect of M2951 on Cardiac Repolarization

Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany36 enrolled

Overview

The purpose of this study is to assess potential effects of M2951 on cardiac repolarization (i.e. prolongation of QT interval).

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

OTHER

Masking

QUADRUPLE

Enrollment

Conditions

Healthy

Interventions

Placebo matched to M2951DRUG

Participants will receive single oral dose of placebo matched to M2951 in either of study periods (period 1 or period 2 or period 3 or period 4) under fasted conditions.

MoxifloxacinDRUG

Participants will receive single oral dose of moxifloxacin in either of study periods (period 1 or period 2 or period 3 or period 4) under fasted conditions.

M2951 Low DoseDRUG

Participants will receive single oral low dose of M2951 in either of study periods (period 1 or period 2 or period 3 or period 4) under fasted conditions.

Eligibility

Sex: ALLMin age: 18 YearsMax age: 55 YearsHealthy volunteers:

Medical Language ↔ Plain English

Inclusion Criteria: * Participants are overtly healthy as determined by medical evaluation, including no clinically significant abnormality identified on physical examination or laboratory evaluation and no active clinically significant disorder, condition, infection, or disease that would pose a risk to participant safety or interfere with the study evaluation, procedures, or completion * Participants have a body weight within 50.0 and 100.0 kilograms (kg) (inclusive) and body mass index (BMI) within the range 19.0 and 30.0 kilograms per square meter (kg/m\^2) (inclusive) * Participants are stable nonsmokers for at least 3 months preceding the first administration of study intervention Exclusion Criteria: * Participants with history or presence of clinically relevant respiratory, gastrointestinal, renal, hepatic, hematological, lymphatic, neurological, cardiovascular, musculoskeletal, genitourinary, immunological, dermatological, connective tissue, psychiatric (due to rare risk of hallucinations, agitation, and activation of psychosis), and other diseases or disorders, and epilepsy, as determined by medical evaluation * Participants with diagnosis of hemochromatosis, Wilson´s disease, alpha 1 antitrypsin deficiency, or any other chronic liver disease including Gilbert's disease will be excluded from the study. Prior history of cholecystectomy or splenectomy, and any clinically relevant surgery within 6 months prior to the first administration of study intervention * Participants with history of any malignancy * Participants with history of seizures * Participants with history of pharmacologically treated psychiatric disease

Locations (1)

Nuvisan GmbH

Neu-Ulm, Germany

Outcomes

Primary Outcomes

Placebo-corrected Change From Baseline in Corrected QT Interval by Fridericia' Formula (QTcF) for Evobrutinib

A linear mixed-effects model was used to analyze the relationship between evobrutinib and MSC2729909A concentrations and ΔQTc. Based on this model, drug-induced ΔΔQTc and its two-sided 90% CI was predicted over the clinical concentration range and at concentrations corresponding to the observed geometric mean Cmax following administration of 45 mg and 225 mg evobrutinib. The higher geometric mean Cmax calculated based on the PK and ECG Analysis Sets was considered.

Time frame: Baseline and from 1 hour before any administration until 24 hours post-administration at the following timepoints: -1-hour, 5 min, 10 min, 20 min, 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hours

Secondary Outcomes

Placebo-corrected Change From Baseline in Corrected QT Interval by Fridericia' Formula (QTcF) for Moxifloxacin

A linear mixed-effects model was used to analyze the relationship between moxifloxacin concentrations and ΔQTc. Based on this model, drug-induced ΔΔQTc and its two-sided 90% CI was predicted. The higher geometric mean Cmax calculated based on the PK and ECG Analysis Sets was considered.

Time frame: From 1 hour before any administration until 24 hours post-administration at the following timepoints: -1-hour, 5 min, 10 min, 20 min, 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hours

Number of Participants With Treatment-Emergent Adverse Events (TEAEs)

An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product, regardless of causal relationship with this treatment.Therefore, an AE can be any unfavorable and unintended sign (including an abnormallaboratory finding), symptom, or disease temporally associated with the use of amedicinal product, regardless if it is considered related to the medicinal product.Serious AE: AE that resulted in any of the following outcomes: death; life threatening;persistent/significant disability/incapacity; initial/prolonged inpatient hospitalization;congenital anomaly/birth defect. TEAEs are defined as AEs that were reported orworsened on or after start of study drug dosing through the Safety Follow-up Visit.TEAEs included both serious TEAEs and non-serious TEAEs. Treatment related AEs:reasonably related to the study drug/study treatment.

Data from ClinicalTrials.gov

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Participants will receive single oral high dose of M2951 in either of study periods (period 1 or period 2 or period 3 or period 4) under fasted conditions.

Time frame: Up to 3 months

Number of Participants With Treatment-Emergent Adverse Events (TEAEs) Based on Severity

Severity of adverse events (AE) were assessed by the investigator. The Investigator assessed the intensity of each AE and SAE reported during the study and assigned it to 1 of the following categories: 1\. Mild: A type of adverse event that is usually transient and may require only minimal treatment or therapeutic intervention. The event does not generally interfere with usual activities of daily living. 2. Moderate: A type of adverse event that is usually alleviated with additional specific therapeutic intervention. The event interferes with usual activities of daily living, causing discomfort but poses no significant or permanent risk of harm to the research participant. 3. Severe: A type of adverse event that interrupts usual activities of daily living, or significantly affects clinical status, or may require intensive therapeutic intervention. Number of participants with severe adverse events were reported.

Time frame: Up to 3 months

Number of Participants With Clinically Significant Abnormalities From Baseline in Safety Laboratory Tests

The laboratory measurements included hematology, blood chemistry and urinalysis. Number of participants with clinically significant abnormalities from baseline were reported. Clinically Significance was decided by investigator.

Time frame: Up to Day 29

Number of Participants With Clinically Significant Abnormalities From Baseline in Vital Signs

Vital sign assessment included blood pressure, pulse rate, body temperature and respiration (frequency per minute). Number of participants with clinically significant abnormalities in vital signs were reported. Clinically significance was decided by investigator.

Time frame: Up to Day 29

Number of Participants With Clinically Significant Changes From Baseline in Electroencephalogram (EEG) and Electrocardiogram (ECG) Findings

The 12-lead ECG recordings were obtained after 5 minutes of rest in a semi-supine position. ECG recordings included rhythm, ventricular rate, PR interval, QRS duration, QT and QTc intervals. Number of participants with clinically significant abnormalities were reported. Clinically significance was decided by investigator.

Time frame: Up to Day 29

Area Under the Blood-Concentration Time Curve From Time Zero to 24 Hours Post-Dose (AUC 0-24) of Evobrutinib

AUC from time zero to 24 hours post dose, calculated using the mixed log linear trapezoidal rule (linear up, log down) using the nominal dosing interval.