HealthyPhase 1NCT02136888
Study of the Electrocardiographic Effects of Ponesimod in Healthy Male and Female Subjects
A Phase 1 study testing Ponesimod 10 mg, Ponesimod 20 mg and Ponesimod 40 mg in people with Healthy, run by Actelion at 1 site in United States.
Trial 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)… Read more about this study
- Who is it for?
- Ages 18 to 45 yearsHealthy volunteers can take part
- Conditions the study is for
- Healthy
- What is being tested?
- Ponesimod 10 mg, Ponesimod 20 mg and Ponesimod 40 mg
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 116 participants
- Where
- 1 siteUnited States
- Study dates
- Aug 2011to Feb 2012
- Phase
- Phase 1
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 45 years
- All sexes
- Healthy volunteers accepted
- Adult
Who may be able to join
- 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.
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- 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.
Who cannot join
- 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.
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- 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 locations and contacts
1 site in 1 country.
United States1 site
Covance Clinical Research Unit (CRU)
Evansville, Indiana, 47710
About this study
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
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.
Read the 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.
- Conditions
- Healthy
- Being tested
- Ponesimod Placebo, Moxifloxacin Placebo, Ponesimod 10 mg, Ponesimod 20 mg, Ponesimod 40 mg
- Keywords
- Ponesimod, Safety
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Ponesimod PlaceboDrug
Moxifloxacin PlaceboDrug
Ponesimod 10 mgDrug
Also called ACT-128800
Ponesimod 20 mgDrug
Also called ACT-128800
Ponesimod 40 mgDrug
Also called ACT-128800
Ponesimod 60 mgDrug
Also called ACT-128800
Ponesimod 80 mgDrug
Also called ACT-128800
Ponesimod 100 mgDrug
Also called ACT-128800
Moxifloxacin 400 mgDrug
| Study group | Role | What they receive |
|---|---|---|
| Group A | Experimental | 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. Receives: Drug: Ponesimod Placebo; Drug: Moxifloxacin Placebo; Drug: Ponesimod 10 mg; Drug: Ponesimod 20 mg; Drug: Ponesimod 40 mg; Drug: Ponesimod 60 mg; Drug: Ponesimod 80 mg; Drug: Ponesimod 100 mg |
| Group B | Experimental | 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. Receives: Drug: Ponesimod Placebo; Drug: Moxifloxacin Placebo; Drug: Moxifloxacin 400 mg |
What is being measured
The primary outcome is the main question the study is designed to answer.
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)
Replicate electrocardiograms (ECGs) (at least 3 and up to 10) for the determination of ΔΔQTc interval will be extracted from the continuous digital 12-lead ECG recording within 20 minutes prior to dosing and then at 1, 2, 2.5, 3, 4, 5, 6, 8, 9, 10, 11, and 12 hours (total of 13 time points) post-dose on Days -1, 1, and 12.
Measured: 12 Days
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)
Replicate electrocardiograms (ECGs) (at least 3 and up to 10) for the determination of ΔΔQTc interval will be extracted from the continuous digital 12-lead ECG recording within 20 minutes prior to dosing and then at 1, 2, 2.5, 3, 4, 5, 6, 8, 9, 10, 11, and 12 hours (total of 13 time points) post-dose on Days -1, 1, and 23.
Measured: 23 Days
Secondary outcomes (39)
Baseline-adjusted, placebo-corrected effect on QT beat-to-beat interval (QTbtb interval) on Day 12 (after 5 days of 40 mg ponesimod)
Replicate electrocardiograms (ECGs) (at least 3 and up to 10) for the determination of QTbtb interval will be extracted from the continuous digital 12-lead ECG recording within 20 minutes prior to dosing and then at 1, 2, 2.5, 3, 4, 5, 6, 8, 9, 10, 11, and 12 hours (total of 13 time points) post-dose on Days -1, 1, and 12.
Measured: 12 Days
Baseline-adjusted, placebo-corrected effect on QT beat-to-beat interval (QTbtb interval) on Day 23 (after 5 days of 100 mg ponesimod)
Replicate electrocardiograms (ECGs) (at least 3 and up to 10) for the determination of QTbtb interval will be extracted from the continuous digital 12-lead ECG recording within 20 minutes prior to dosing and then at 1, 2, 2.5, 3, 4, 5, 6, 8, 9, 10, 11, and 12 hours (total of 13 time points) post-dose on Days -1, 1, and 23.
Measured: 23 Days
Baseline-adjusted, placebo-corrected effect on heart rate on Day 12 (after 5 days of 40 mg ponesimod)
Replicate electrocardiograms (ECGs) (at least 3 and up to 10) for the determination of heart rate will be extracted from the continuous digital 12-lead ECG recording within 20 minutes prior to dosing and then at 1, 2, 2.5, 3, 4, 5, 6, 8, 9, 10, 11, and 12 hours (total of 13 time points) post-dose on Days -1, 1, and 12.
Measured: 12 Days
Baseline-adjusted, placebo-corrected effect on heart rate on Day 23 (after 5 days of 100 mg ponesimod)
Replicate electrocardiograms (ECGs) (at least 3 and up to 10) for the determination of heart rate will be extracted from the continuous digital 12-lead ECG recording within 20 minutes prior to dosing and then at 1, 2, 2.5, 3, 4, 5, 6, 8, 9, 10, 11, and 12 hours (total of 13 time points) post-dose on Days -1, 1, and 23.
Measured: 23 Days
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)
Replicate electrocardiograms (ECGs) (at least 3 and up to 10) for the determination of RR interval will be extracted from the continuous digital 12-lead ECG recording within 20 minutes prior to dosing and then at 1, 2, 2.5, 3, 4, 5, 6, 8, 9, 10, 11, and 12 hours (total of 13 time points) post-dose on Days -1, 1, and 12.
Measured: 12 Days
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)
Replicate electrocardiograms (ECGs) (at least 3 and up to 10) for the determination of RR interval will be extracted from the continuous digital 12-lead ECG recording within 20 minutes prior to dosing and then at 1, 2, 2.5, 3, 4, 5, 6, 8, 9, 10, 11, and 12 hours (total of 13 time points) post-dose on Days -1, 1, and 23.
Measured: 23 Days
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)
Replicate electrocardiograms (ECGs) (at least 3 and up to 10) for the determination of PR interval will be extracted from the continuous digital 12-lead ECG recording within 20 minutes prior to dosing and then at 1, 2, 2.5, 3, 4, 5, 6, 8, 9, 10, 11, and 12 hours (total of 13 time points) post-dose on Days -1, 1, and 12.
Measured: 12 Days
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)
Replicate electrocardiograms (ECGs) (at least 3 and up to 10) for the determination of PR interval will be extracted from the continuous digital 12-lead ECG recording within 20 minutes prior to dosing and then at 1, 2, 2.5, 3, 4, 5, 6, 8, 9, 10, 11, and 12 hours (total of 13 time points) post-dose on Days -1, 1, and 23.
Measured: 23 Days
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)
Replicate electrocardiograms (ECGs) (at least 3 and up to 10) for the determination of QRS duration will be extracted from the continuous digital 12-lead ECG recording within 20 minutes prior to dosing and then at 1, 2, 2.5, 3, 4, 5, 6, 8, 9, 10, 11, and 12 hours (total of 13 time points) post-dose on Days -1, 1, and 12.
Measured: 12 Days
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)
Replicate electrocardiograms (ECGs) (at least 3 and up to 10) for the determination of QRS duration will be extracted from the continuous digital 12-lead ECG recording within 20 minutes prior to dosing and then at 1, 2, 2.5, 3, 4, 5, 6, 8, 9, 10, 11, and 12 hours (total of 13 time points) post-dose on Days -1, 1, and 23.
Measured: 23 Days
Frequency of T-wave morphology changes on Day 12 (after 5 days of 40 mg ponesimod)
Replicate electrocardiograms (ECGs) (at least 3 and up to 10) for the determination of T-wave morphology changes will be extracted from the continuous digital 12-lead ECG recording within 20 minutes prior to dosing and then at 1, 2, 2.5, 3, 4, 5, 6, 8, 9, 10, 11, and 12 hours (total of 13 time points) post-dose on Days -1, 1, and 12.
Measured: 12 Days
Frequency of T-wave morphology changes on Day 23 (after 5 days of 100 mg ponesimod)
Replicate electrocardiograms (ECGs) (at least 3 and up to 10) for the determination of T-wave morphology changes will be extracted from the continuous digital 12-lead ECG recording within 20 minutes prior to dosing and then at 1, 2, 2.5, 3, 4, 5, 6, 8, 9, 10, 11, and 12 hours (total of 13 time points) post-dose on Days -1, 1, and 23.
Measured: 23 Days
Change in systolic blood pressure from baseline up to end of study
Blood pressure will be measured using an automatic oscillometric device, always on the dominant arm (i.e., dominant arm right = writing with right hand). Measurements should be recorded from the subject in the supine position after having rested for a 5-minute period.
Measured: 31 Days
Change in diastolic blood pressure from baseline up to end of study
Blood pressure will be measured using an automatic oscillometric device, always on the dominant arm (i.e., dominant arm right = writing with right hand). Measurements should be recorded from the subject in the supine position after having rested for a 5-minute period.
Measured: 31 Days
Change in heart rate from baseline up to end of study
Heart rate will be measured using an automatic oscillometric device, always on the dominant arm (i.e., dominant arm right = writing with right hand). Measurements should be recorded from the subject in the supine position after having rested for a 5-minute period.
Measured: 31 Days
Change in QTc interval according to Bazett's correction (QTcB interval) from baseline up to end of study
QTcB interval will be determined from standard 12-lead ECG recordings. The QTcB interval is the QT interval corrected for heart rate with Bazett's formula (QTcB = QT/RR^0.5 where RR is 60/heart rate)
Measured: 31 Days
Change in QTc interval according to Fridericia's correction (QTcF interval) from baseline up to end of study
QTcF interval will be determined from standard 12-lead ECG recordings. The QTcF interval is the QT interval corrected for heart rate with Fridericia's formula (QTcB = QT/RR^0.5 where RR is 60/heart rate)
Measured: 31 Days
Change in forced expiratory volume in 1 second (FEV1) from baseline to end of study
FEV1 will be measured according to the American Thoracic Society/European Respiratory Society guidelines. Three good test breaths will be measured; the highest FEV1 value will be recorded. The spirometry device must be calibrated and the assessor trained.
Measured: 31 Days
Change in forced vital capacity (FVC) from baseline to end of study
FVC will be measured according to the American Thoracic Society/European Respiratory Society guidelines. Three good test breaths will be measured; the highest FVC value will be recorded. The spirometry device must be calibrated and the assessor trained.
Measured: 31 Days
Incidence of treatment emergent pulmonary function test decreases of >30% from baseline up to end of study
Pulmonary function tests will be performed according to the American Thoracic Society/European Respiratory Society guidelines. Three good test breaths will be measured; the highest values will be recorded. The spirometry device must be calibrated and the assessor trained.
Measured: 31 Days
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
Plasma concentrations of ponesimod will be measured at pre-dose and at 1, 2, 2.5, 3, 4, 5, 6, 8, 9, 10, 11, and 12 hours post-dose on Day 12 (after 5 days of dosing with 40 mg ponesimod). AUCτ will be calculated according to the linear trapezoidal rule using the measured concentration-time values above the limit of quantification (LOQ).
Measured: 12 Days
Maximum plasma concentration (Cmax) of ponesimod after 5 days of dosing with 40 mg ponesimod
Plasma concentrations of ponesimod will be measured at pre-dose and at 1, 2, 2.5, 3, 4, 5, 6, 8, 9, 10, 11, and 12 hours post-dose on Day 12 (after 5 days of dosing with 40 mg ponesimod). The measured individual plasma concentrations will be used to directly obtain Cmax.
Measured: 12 Days
Time to maximum plasma concentration (tmax) of ponesimod after 5 days of dosing with 40 mg ponesimod
Plasma concentrations of ponesimod will be measured at pre-dose and at 1, 2, 2.5, 3, 4, 5, 6, 8, 9, 10, 11, and 12 hours post-dose on Day 12 (after 5 days of dosing with 40 mg ponesimod). The measured individual plasma concentrations will be used to directly obtain tmax.
Measured: 12 Days
Trough plasma concentration of ponesimod on Days 5, 8, 16, and 19 (Ctrough)
Plasma concentrations of ponesimod will be measured on Days 5, 8, 16, and 19 immediately before administration of the study drug.The measured individual plasma concentrations will be used to directly obtain Ctrough.
Measured: 19 Days
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
Plasma concentrations of ACT-204426 will be measured at pre-dose and at 1, 2, 2.5, 3, 4, 5, 6, 8, 9, 10, 11, and 12 hours post-dose on Day 12 (after 5 days of dosing with 40 mg ponesimod). AUCτ will be calculated according to the linear trapezoidal rule using the measured concentration-time values above the limit of quantification (LOQ).
Measured: 12 Days
Maximum plasma concentration (Cmax) of the ponesimod metabolite ACT-204426 after 5 days of dosing with 40 mg ponesimod
Plasma concentrations of ACT-204426 will be measured at pre-dose and at 1, 2, 2.5, 3, 4, 5, 6, 8, 9, 10, 11, and 12 hours post-dose on Day 12 (after 5 days of dosing with 40 mg ponesimod). The measured individual plasma concentrations will be used to directly obtain Cmax.
Measured: 12 Days
Time to maximum plasma concentration (tmax) of the ponesimod metabolite ACT-204426 after 5 days of dosing with 40 mg ponesimod
Plasma concentrations of ACT-204426 will be measured at pre-dose and at 1, 2, 2.5, 3, 4, 5, 6, 8, 9, 10, 11, and 12 hours post-dose on Day 12 (after 5 days of dosing with 40 mg ponesimod). The measured individual plasma concentrations will be used to directly obtain tmax.
Measured: 12 Days
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
Plasma concentrations of ACT-338375 will be measured at pre-dose and at 1, 2, 2.5, 3, 4, 5, 6, 8, 9, 10, 11, and 12 hours post-dose on Day 12 (after 5 days of dosing with 40 mg ponesimod). AUCτ will be calculated according to the linear trapezoidal rule using the measured concentration-time values above the limit of quantification (LOQ).
Measured: 12 Days
Maximum plasma concentration (Cmax) of the ponesimod metabolite ACT-338375 after 5 days of dosing with 40 mg ponesimod
Plasma concentrations of ACT-338375 will be measured at pre-dose and at 1, 2, 2.5, 3, 4, 5, 6, 8, 9, 10, 11, and 12 hours post-dose on Day 12 (after 5 days of dosing with 40 mg ponesimod). The measured individual plasma concentrations will be used to directly obtain Cmax.
Measured: 12 Days
Time to maximum plasma concentration (tmax) of the ponesimod metabolite ACT-338375 after 5 days of dosing with 40 mg ponesimod
Plasma concentrations of ACT-338375 will be measured at pre-dose and at 1, 2, 2.5, 3, 4, 5, 6, 8, 9, 10, 11, and 12 hours post-dose on Day 12 (after 5 days of dosing with 40 mg ponesimod). The measured individual plasma concentrations will be used to directly obtain tmax.
Measured: 12 Days
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
Plasma concentrations of ponesimod will be measured at pre-dose and at 1, 2, 2.5, 3, 4, 5, 6, 8, 9, 10, 11, and 12 hours post-dose on Day 23 (after 5 days of dosing with 100 mg ponesimod). AUCτ will be calculated according to the linear trapezoidal rule using the measured concentration-time values above the limit of quantification (LOQ).
Measured: 23 Days
Maximum plasma concentration (Cmax) of ponesimod after 5 days of dosing with 100 mg ponesimod
Plasma concentrations of ponesimod will be measured at pre-dose and at 1, 2, 2.5, 3, 4, 5, 6, 8, 9, 10, 11, and 12 hours post-dose on Day 23 (after 5 days of dosing with 100 mg ponesimod). The measured individual plasma concentrations will be used to directly obtain Cmax.
Measured: 23 Days
Time to maximum plasma concentration (tmax) of ponesimod after 5 days of dosing with 100 mg ponesimod
Plasma concentrations of ponesimod will be measured at pre-dose and at 1, 2, 2.5, 3, 4, 5, 6, 8, 9, 10, 11, and 12 hours post-dose on Day 23 (after 5 days of dosing with 100 mg ponesimod). The measured individual plasma concentrations will be used to directly obtain tmax.
Measured: 23 Days
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
Plasma concentrations of ACT-204426 will be measured at pre-dose and at 1, 2, 2.5, 3, 4, 5, 6, 8, 9, 10, 11, and 12 hours post-dose on Day 23 (after 5 days of dosing with 100 mg ponesimod). AUCτ will be calculated according to the linear trapezoidal rule using the measured concentration-time values above the limit of quantification (LOQ).
Measured: 23 Days
Maximum plasma concentration (Cmax) of the ponesimod metabolite ACT-204426 after 5 days of dosing with 100 mg ponesimod
Plasma concentrations of ACT-204426 will be measured at pre-dose and at 1, 2, 2.5, 3, 4, 5, 6, 8, 9, 10, 11, and 12 hours post-dose on Day 23 (after 5 days of dosing with 100 mg ponesimod). The measured individual plasma concentrations will be used to directly obtain Cmax.
Measured: 23 Days
Time to maximum plasma concentration (tmax) of the ponesimod metabolite ACT-204426 after 5 days of dosing with 100 mg ponesimod
Plasma concentrations of ACT-204426 will be measured at pre-dose and at 1, 2, 2.5, 3, 4, 5, 6, 8, 9, 10, 11, and 12 hours post-dose on Day 23 (after 5 days of dosing with 100 mg ponesimod). The measured individual plasma concentrations will be used to directly obtain tmax.
Measured: 23 Days
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
Plasma concentrations of ACT-338375 will be measured at pre-dose and at 1, 2, 2.5, 3, 4, 5, 6, 8, 9, 10, 11, and 12 hours post-dose on Day 23 (after 5 days of dosing with 100 mg ponesimod). AUCτ will be calculated according to the linear trapezoidal rule using the measured concentration-time values above the limit of quantification (LOQ).
Measured: 23 Days
Maximum plasma concentration (Cmax) of the ponesimod metabolite ACT-338375 after 5 days of dosing with 100 mg ponesimod
Plasma concentrations of ACT-338375 will be measured at pre-dose and at 1, 2, 2.5, 3, 4, 5, 6, 8, 9, 10, 11, and 12 hours post-dose on Day 23 (after 5 days of dosing with 100 mg ponesimod). The measured individual plasma concentrations will be used to directly obtain Cmax.
Measured: 23 Days
Time to maximum plasma concentration (tmax) of the ponesimod metabolite ACT-338375 after 5 days of dosing with 100 mg ponesimod
Plasma concentrations of ACT-338375 will be measured at pre-dose and at 1, 2, 2.5, 3, 4, 5, 6, 8, 9, 10, 11, and 12 hours post-dose on Day 23 (after 5 days of dosing with 100 mg ponesimod). The measured individual plasma concentrations will be used to directly obtain tmax.
Measured: 23 Days
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted13 May 2014 (estimated)
- Study startAug 2011
- Primary completionFeb 2012
- Study completionFeb 2012
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for HealthyStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind
- Who is masked
- Participant, Investigator, Outcomes assessor
- Enrolment
- 116 participants (actual)
Sponsor and investigators
- Lead sponsor
- Actelion
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Patrick Brossard, PhD, Study director, Actelion
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02136888
- Sponsor's protocol ID
- AC-058-110
- Status last verified
- May 2014
- First submitted
- 9 May 2014
- Last updated
- 13 May 2014
- Results posted
- No
- Data monitoring committee
- No
Publications
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.
PubMed 25287214
Study at a glance
From the registry record, last updated by the sponsor on 13 May 2014. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT02136888
- Acronym / sponsor ID
- AC-058-110
- Conditions
- Healthy
- Keywords
- Ponesimod, Safety
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 116 participants (actual)
- Lead sponsor
- ActelionIndustry (pharma, biotech, devices)
- Study start
- Aug 2011
- Primary completion
- Feb 2012 (actual)
- Study completion
- Feb 2012 (actual)
- First posted
- 13 May 2014 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind (participant, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Group A | Experimental | Drug: Ponesimod Placebo, Drug: Moxifloxacin Placebo, Drug: Ponesimod 10 mg, Drug: Ponesimod 20 mg, Drug: Ponesimod 40 mg, Drug: Ponesimod 60 mg, Drug: Ponesimod 80 mg, Drug: Ponesimod 100 mgPonesimod 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. |
| Group B | Experimental | Drug: Ponesimod Placebo, Drug: Moxifloxacin Placebo, Drug: Moxifloxacin 400 mgPlacebo 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. |
Who may qualify
- Ages
- 18 to 45 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (9 listed)
- 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.
Key exclusion criteria (27 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Ponesimod Placebo | Drug | Group A, Group B |
| Moxifloxacin Placebo | Drug | Group A, Group B |
| Ponesimod 10 mgAlso: ACT-128800 | Drug | Group A |
| Ponesimod 20 mgAlso: ACT-128800 | Drug | Group A |
| Ponesimod 40 mgAlso: ACT-128800 | Drug | Group A |
| Ponesimod 60 mgAlso: ACT-128800 | Drug | Group A |
| Ponesimod 80 mgAlso: ACT-128800 | Drug | Group A |
| Ponesimod 100 mgAlso: ACT-128800 | Drug | Group A |
| Moxifloxacin 400 mg | Drug | Group B |
Primary outcome
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)
Time frame: 12 Days
Replicate electrocardiograms (ECGs) (at least 3 and up to 10) for the determination of ΔΔQTc interval will be extracted from the continuous digital 12-lead ECG recording within 20 minutes prior to dosing and then at 1, 2, 2.5, 3, 4, 5, 6, 8, 9, 10, 11, and 12 hours (total of 13 time points) post-dose on Days -1, 1, and 12.
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)
Time frame: 23 Days
Replicate electrocardiograms (ECGs) (at least 3 and up to 10) for the determination of ΔΔQTc interval will be extracted from the continuous digital 12-lead ECG recording within 20 minutes prior to dosing and then at 1, 2, 2.5, 3, 4, 5, 6, 8, 9, 10, 11, and 12 hours (total of 13 time points) post-dose on Days -1, 1, and 23.
39 secondary outcomes
Baseline-adjusted, placebo-corrected effect on QT beat-to-beat interval (QTbtb interval) on Day 12 (after 5 days of 40 mg ponesimod)
Time frame: 12 Days
Baseline-adjusted, placebo-corrected effect on QT beat-to-beat interval (QTbtb interval) on Day 23 (after 5 days of 100 mg ponesimod)
Time frame: 23 Days
Baseline-adjusted, placebo-corrected effect on heart rate on Day 12 (after 5 days of 40 mg ponesimod)
Time frame: 12 Days
Baseline-adjusted, placebo-corrected effect on heart rate on Day 23 (after 5 days of 100 mg ponesimod)
Time frame: 23 Days
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)
Time frame: 12 Days
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)
Time frame: 23 Days
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)
Time frame: 12 Days
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)
Time frame: 23 Days
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)
Time frame: 12 Days
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)
Time frame: 23 Days
Frequency of T-wave morphology changes on Day 12 (after 5 days of 40 mg ponesimod)
Time frame: 12 Days
Frequency of T-wave morphology changes on Day 23 (after 5 days of 100 mg ponesimod)
Time frame: 23 Days
Change in systolic blood pressure from baseline up to end of study
Time frame: 31 Days
Change in diastolic blood pressure from baseline up to end of study
Time frame: 31 Days
Change in heart rate from baseline up to end of study
Time frame: 31 Days
Change in QTc interval according to Bazett's correction (QTcB interval) from baseline up to end of study
Time frame: 31 Days
Change in QTc interval according to Fridericia's correction (QTcF interval) from baseline up to end of study
Time frame: 31 Days
Change in forced expiratory volume in 1 second (FEV1) from baseline to end of study
Time frame: 31 Days
Change in forced vital capacity (FVC) from baseline to end of study
Time frame: 31 Days
Incidence of treatment emergent pulmonary function test decreases of >30% from baseline up to end of study
Time frame: 31 Days
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
Time frame: 12 Days
Maximum plasma concentration (Cmax) of ponesimod after 5 days of dosing with 40 mg ponesimod
Time frame: 12 Days
Time to maximum plasma concentration (tmax) of ponesimod after 5 days of dosing with 40 mg ponesimod
Time frame: 12 Days
Trough plasma concentration of ponesimod on Days 5, 8, 16, and 19 (Ctrough)
Time frame: 19 Days
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
Time frame: 12 Days
Maximum plasma concentration (Cmax) of the ponesimod metabolite ACT-204426 after 5 days of dosing with 40 mg ponesimod
Time frame: 12 Days
Time to maximum plasma concentration (tmax) of the ponesimod metabolite ACT-204426 after 5 days of dosing with 40 mg ponesimod
Time frame: 12 Days
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
Time frame: 12 Days
Maximum plasma concentration (Cmax) of the ponesimod metabolite ACT-338375 after 5 days of dosing with 40 mg ponesimod
Time frame: 12 Days
Time to maximum plasma concentration (tmax) of the ponesimod metabolite ACT-338375 after 5 days of dosing with 40 mg ponesimod
Time frame: 12 Days
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
Time frame: 23 Days
Maximum plasma concentration (Cmax) of ponesimod after 5 days of dosing with 100 mg ponesimod
Time frame: 23 Days
Time to maximum plasma concentration (tmax) of ponesimod after 5 days of dosing with 100 mg ponesimod
Time frame: 23 Days
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
Time frame: 23 Days
Maximum plasma concentration (Cmax) of the ponesimod metabolite ACT-204426 after 5 days of dosing with 100 mg ponesimod
Time frame: 23 Days
Time to maximum plasma concentration (tmax) of the ponesimod metabolite ACT-204426 after 5 days of dosing with 100 mg ponesimod
Time frame: 23 Days
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
Time frame: 23 Days
Maximum plasma concentration (Cmax) of the ponesimod metabolite ACT-338375 after 5 days of dosing with 100 mg ponesimod
Time frame: 23 Days
Time to maximum plasma concentration (tmax) of the ponesimod metabolite ACT-338375 after 5 days of dosing with 100 mg ponesimod
Time frame: 23 Days
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 13 May 2014.
- Derived from this study: PubMed 25287214Hoch 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Patrick Brossard, PhD study director
Actelion
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Ponesimod 10 mg, Ponesimod 20 mg and Ponesimod 40 mg in people with Healthy, run by Actelion at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 9 inclusion and 27 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 13 May 2014. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome 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) (time frame: 12 Days). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02136888, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 13 May 2014.