Clinical trial NCT02136888: Study of the Electrocardiographic Effects of Ponesimod in Healthy Male and Female Subjects
Official title: A Single-center, Double-blind, Randomized, Placebo- and Positive-controlled, Parallel-group, Multiple-dose, Up-titration Study of the Electrocardiographic Effects of Ponesimod in Healthy Male and Female Subjects
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Healthy
Keywords: Ponesimod
Safety
Lead sponsor: Actelion
Sponsor class: INDUSTRY
First posted: 2014-05-13
Enrollment: 116
Sex: ALL
Minimum age (years): 18
Maximum age (years): 45
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL

Brief summary: 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.

Detailed 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Baseline-adjusted, placebo-corrected effect on QTc interval (time interval from beginning of the Q wave until end of the T wave (ΔΔQTc interval)) on Day 12 (after 5 days of 40 mg ponesimod)
timeFrame: 12 Days
measure: Baseline-adjusted, placebo-corrected effect on QTc interval (time interval from beginning of the Q wave until end of the T wave (ΔΔQTc interval)) on Day 23 (after 5 days of 100 mg ponesimod)
timeFrame: 23 Days
Secondary outcomes:
measure: Baseline-adjusted, placebo-corrected effect on QT beat-to-beat interval (QTbtb interval) on Day 12 (after 5 days of 40 mg ponesimod)
timeFrame: 12 Days
measure: Baseline-adjusted, placebo-corrected effect on QT beat-to-beat interval (QTbtb interval) on Day 23 (after 5 days of 100 mg ponesimod)
timeFrame: 23 Days
measure: Baseline-adjusted, placebo-corrected effect on heart rate on Day 12 (after 5 days of 40 mg ponesimod)
timeFrame: 12 Days
measure: Baseline-adjusted, placebo-corrected effect on heart rate on Day 23 (after 5 days of 100 mg ponesimod)
timeFrame: 23 Days
measure: Baseline-adjusted, placebo-corrected effect on the R-to-R interval (interval from the peak of one QRS complex to the peak of the next (RR interval)) on Day 12 (after 5 days of 40 mg ponesimod)
timeFrame: 12 Days
measure: Baseline-adjusted, placebo-corrected effect on the R-to-R interval (interval from the peak of one QRS complex to the peak of the next (RR interval)) on Day 23 (after 5 days of 100 mg ponesimod)
timeFrame: 23 Days
measure: Baseline-adjusted, placebo-corrected effect on the PR interval (time interval from the beginning of the P wave to the beginning of the QRS complex) on Day 12 (after 5 days of 40 mg ponesimod)
timeFrame: 12 Days
measure: Baseline-adjusted, placebo-corrected effect on the PR interval (time interval from the beginning of the P wave to the beginning of the QRS complex) on Day 23 (after 5 days of 100 mg ponesimod)
timeFrame: 23 Days
measure: Baseline-adjusted, placebo-corrected effect on QRS duration (time interval from the beginning of the Q wave to the end of the S wave) on Day 12 (after 5 days of 40 mg ponesimod)
timeFrame: 12 Days
measure: Baseline-adjusted, placebo-corrected effect on QRS duration (time interval from the beginning of the Q wave to the end of the S wave) on Day 23 (after 5 days of 100 mg ponesimod)
timeFrame: 23 Days
measure: Frequency of T-wave morphology changes on Day 12 (after 5 days of 40 mg ponesimod)
timeFrame: 12 Days
measure: Frequency of T-wave morphology changes on Day 23 (after 5 days of 100 mg ponesimod)
timeFrame: 23 Days
measure: Change in systolic blood pressure from baseline up to end of study
timeFrame: 31 Days
measure: Change in diastolic blood pressure from baseline up to end of study
timeFrame: 31 Days
measure: Change in heart rate from baseline up to end of study
timeFrame: 31 Days
measure: Change in QTc interval according to Bazett's correction (QTcB interval) from baseline up to end of study
timeFrame: 31 Days
measure: Change in QTc interval according to Fridericia's correction (QTcF interval) from baseline up to end of study
timeFrame: 31 Days
measure: Change in forced expiratory volume in 1 second (FEV1) from baseline to end of study
timeFrame: 31 Days
measure: Change in forced vital capacity (FVC) from baseline to end of study
timeFrame: 31 Days
measure: Incidence of treatment emergent pulmonary function test decreases of >30% from baseline up to end of study
timeFrame: 31 Days
measure: Area under the plasma concentration-time curve of ponesimod from time zero over the dosing interval (τ) (AUCτ) after 5 days of dosing with 40 mg ponesimod
timeFrame: 12 Days
measure: Maximum plasma concentration (Cmax) of ponesimod after 5 days of dosing with 40 mg ponesimod
timeFrame: 12 Days
measure: Time to maximum plasma concentration (tmax) of ponesimod after 5 days of dosing with 40 mg ponesimod
timeFrame: 12 Days
measure: Trough plasma concentration of ponesimod on Days 5, 8, 16, and 19 (Ctrough)
timeFrame: 19 Days
measure: Area under the plasma concentration-time curve of the ponesimod metabolite ACT-204426 from time zero over the dosing interval (τ) (AUCτ) after 5 days of dosing with 40 mg ponesimod
timeFrame: 12 Days
measure: Maximum plasma concentration (Cmax) of the ponesimod metabolite ACT-204426 after 5 days of dosing with 40 mg ponesimod
timeFrame: 12 Days
measure: Time to maximum plasma concentration (tmax) of the ponesimod metabolite ACT-204426 after 5 days of dosing with 40 mg ponesimod
timeFrame: 12 Days
measure: Area under the plasma concentration-time curve of the ponesimod metabolite ACT-338375 from time zero over the dosing interval (τ) (AUCτ) after 5 days of dosing with 40 mg ponesimod
timeFrame: 12 Days
measure: Maximum plasma concentration (Cmax) of the ponesimod metabolite ACT-338375 after 5 days of dosing with 40 mg ponesimod
timeFrame: 12 Days
measure: Time to maximum plasma concentration (tmax) of the ponesimod metabolite ACT-338375 after 5 days of dosing with 40 mg ponesimod
timeFrame: 12 Days
measure: Area under the plasma concentration-time curve of ponesimod from time zero over the dosing interval (τ) (AUCτ) after 5 days of dosing with 100 mg ponesimod
timeFrame: 23 Days
measure: Maximum plasma concentration (Cmax) of ponesimod after 5 days of dosing with 100 mg ponesimod
timeFrame: 23 Days
measure: Time to maximum plasma concentration (tmax) of ponesimod after 5 days of dosing with 100 mg ponesimod
timeFrame: 23 Days
measure: Area under the plasma concentration-time curve of the ponesimod metabolite ACT-204426 from time zero over the dosing interval (τ) (AUCτ) after 5 days of dosing with 100 mg ponesimod
timeFrame: 23 Days
measure: Maximum plasma concentration (Cmax) of the ponesimod metabolite ACT-204426 after 5 days of dosing with 100 mg ponesimod
timeFrame: 23 Days
measure: Time to maximum plasma concentration (tmax) of the ponesimod metabolite ACT-204426 after 5 days of dosing with 100 mg ponesimod
timeFrame: 23 Days
measure: Area under the plasma concentration-time curve of the ponesimod metabolite ACT-338375 from time zero over the dosing interval (τ) (AUCτ) after 5 days of dosing with 100 mg ponesimod
timeFrame: 23 Days
measure: Maximum plasma concentration (Cmax) of the ponesimod metabolite ACT-338375 after 5 days of dosing with 100 mg ponesimod
timeFrame: 23 Days
measure: Time to maximum plasma concentration (tmax) of the ponesimod metabolite ACT-338375 after 5 days of dosing with 100 mg ponesimod
timeFrame: 23 Days
Other outcomes:
Locations:
city: Evansville
country: United States
facility: Covance Clinical Research Unit (CRU)
state: Indiana
Study officials:
affiliation: Actelion
name: Patrick Brossard, PhD
role: STUDY_DIRECTOR
References:
citation: Hoch M, Darpo B, Brossard P, Zhou M, Stoltz R, Dingemanse J. Effect of ponesimod, a selective S1P1 receptor modulator, on the QT interval in healthy individuals. Basic Clin Pharmacol Toxicol. 2015 May;116(5):429-37. doi: 10.1111/bcpt.12336. Epub 2014 Nov 8.