Study of the Electrocardiographic Effects of Ponesimod in Healthy Male and Female Subjects

Actelion Pharmaceuticals

Status and phase: Completed; Phase 1

Conditions: Healthy

Treatments: Drug: Ponesimod 100 mg; Drug: Ponesimod 80 mg; Drug: Moxifloxacin Placebo; Drug: Moxifloxacin 400 mg; Drug: Ponesimod 20 mg; Drug: Ponesimod 40 mg; Drug: Ponesimod 10 mg; Drug: Ponesimod 60 mg; Drug: Ponesimod Placebo

Study type: Interventional

Funder types: Industry

Identifiers

NCT02136888

AC-058-110

Details and patient eligibility

About

The aim of this study is to demonstrate that therapeutic and supratherapeutic plasma exposures to ponesimod do not have an effect on cardiac repolarization exceeding the threshold of regulatory concern as measured by the QTc (interval from beginning of the Q wave until end of the T wave corrected for heart rate) interval duration after administration of multiple oral doses of 40 mg and 100 mg to healthy male and female subjects.

Full description

This is a Phase 1, single-center, double-blind, randomized, placebo and positive-controlled, double-dummy, parallel group, multiple-dose, up-titration study of the electrocardiographic effects of ponesimod in healthy male and female subjects with a nested cross-over comparison between moxifloxacin and placebo.

Subjects will be randomly assigned to Group A (ponesimod treatment group) or Group B (placebo treatment group) in a 1:1 ratio. Subjects in Group B will be further randomized in a 1:1 ratio to one of the following sequences: 400 mg moxifloxacin followed by moxifloxacin-matching placebo or moxifloxacin matching placebo followed by 400 mg moxifloxacin.

Enrollment: 116 patients

Sex: All

Ages: 18 to 45 years old

Volunteers: Accepts Healthy Volunteers

Inclusion criteria

• Signed informed consent prior to any study-mandated procedure.
• Body mass index between 18.0 and 30.0 kg/m^2 (inclusive) at screening.
• Healthy on the basis of medical history and the assessments performed at screening.
• Women of childbearing potential must have a negative serum pregnancy test at screening and a negative urine pregnancy test prior to the first drug administration.
• Systolic blood pressure between 90 and 150 mmHg and diastolic blood pressure between 50 and 90 mmHg.
• 12-lead electrocardiogram (ECG) and 24-hour Holter ECG, without clinically relevant abnormalities at screening.
• Hematology and clinical chemistry test results not deviating from the normal range to a clinically relevant extent at screening.
• Negative results from urine drug screen at screening.
• Ability to communicate well with the investigator and to understand and comply with the requirements of the study.

Exclusion criteria

• Pregnant or lactating women.
• Known hypersensitivity to moxifloxacin or to any excipients of the drug formulations.
• Veins unsuitable for intravenous puncture on either arm.
• Treatment with another investigational drug within 3 months prior to screening.
• Excessive caffeine consumption, defined as ≥ 800 mg per day at screening.
• History or clinical evidence of any disease and/or existence of any surgical or medical condition which might interfere with the absorption, distribution, metabolism or excretion of the study drugs.
• Smoking within 3 months prior to screening.
• Any immunosuppressive treatment within 6 weeks before study drug administration.
• Previous treatment with any prescribed or over-the-counter medications within 2 weeks prior to screening or five half-lives of the drug, whichever is longer.
• Donation of blood, plasma or platelets within 3 months prior to screening or donations made on more than two occasions within the 12 months preceding the first dose administration.
• Lymphopenia (< 1,000 cells/μL^9).
• Viral, systemic, fungal, bacterial or protozoal infection within 4 weeks before the first study drug administration.
• History or clinical evidence suggestive of active or latent tuberculosis at screening.
• Positive hepatitis B surface antigen or hepatitis C antibody tests at screening.
• Positive results from human immunodeficiency virus serology at screening.
• FEV1 or FVC < 80% of the predicted value, or FEV1/FVC ratio < 0.7 at screening.
• History of asthma or chronic obstructive pulmonary disease.
• History of atrioventricular block on ECG.
• Any cardiac condition or illness (including ECG abnormalities based on standard 12-lead ECG or on 24-hour Holter ECG at screening) with a potential to increase the cardiac risk of the subject or that may affect QTc interval analysis.
• QTc interval > 450 milliseconds or > 470 milliseconds for male or female subjects, respectively (using the ECG machine heart rate correction method) at screening.
• Heart rate < 50 beats per minute (bpm) at screening or Day -1 pre-dose on 12-lead ECG.
• Subjects with personal or family history of long QT syndrome or hypokalemia.
• History of fainting, collapse, syncope, orthostatic hypotension, or vasovagal reactions.
• History or presence of macular edema.
• History or clinical evidence of alcoholism or drug abuse within the 3-year period prior to screening.
• Legal incapacity or limited legal capacity at screening.
• Any circumstances or conditions, which, in the opinion of the investigator, may affect the subject's full participation in the study or compliance with the protocol.

Trial design

116 participants in 2 patient groups

Group A

Experimental group

Description:

Ponesimod will be administered orally, once daily for 22 days starting on Day 2, and will comprise the following multiple-dose up-titration: 3 days of 10 mg (Days 2 to 4), 3 days of 20 mg (Days 5 to 7), 5 days of 40 mg (Days 8 to 12), 3 days of 60 mg (Days 13 to 15), 3 days of 80 mg (Days 16 to 18), and 5 days of 100 mg (19 to 23). Placebo matched for ponesimod will be given on Day -1. Placebo tablets matched for moxifloxacin will be administered on Days 1 and 24.

Treatment:

Drug: Ponesimod 60 mg

Drug: Moxifloxacin Placebo

Drug: Ponesimod 10 mg

Drug: Ponesimod 40 mg

Drug: Ponesimod Placebo

Drug: Ponesimod 20 mg

Drug: Ponesimod 80 mg

Drug: Ponesimod 100 mg

Group B

Experimental group

Description:

Placebo matched for ponesimod will be administered orally, once daily on Day -1 and on Day 2 through Day 23. In half of Group B subjects, 400 mg moxifloxacin will be administered orally on Day 1 and a matching placebo tablet on Day 24. In the other half of Group B subjects, a matching placebo tablet will be administered on Day 1 and 400 mg moxifloxacin on Day 24.

Treatment:

Drug: Moxifloxacin Placebo

Drug: Ponesimod Placebo

Drug: Moxifloxacin 400 mg