Clinical trial NCT03882255: A Study of Ponesimod in Healthy Adult Participants Receiving Propranolol at Steady State
Official title: A Randomized, Double-blind, Parallel-group, 2-period, Placebo-controlled, Phase 1 Study to Investigate the Effects on Heart Rate, Blood Pressure, and Pharmacokinetic Interactions of the Up-titration Regimen of Ponesimod in Healthy Adult Subjects Receiving Propranolol at Steady State
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Healthy
Lead sponsor: Janssen Pharmaceutica N.V., Belgium
Sponsor class: INDUSTRY
First posted: 2019-03-20
Enrollment: 52
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: OTHER

Brief summary: The primary purpose of this study is to evaluate the effect of the up-titration regimen of ponesimod on heart rate (HR) and other electrocardiogram (ECG) parameters when administrated to healthy adult participants receiving propranolol at steady state.


Eligibility criteria: Inclusion Criteria:

* Systolic blood pressure (SBP) 90 to 140 millimeters of mercury (mmHg) and diastolic blood pressure (DBP) 50 to 90 mmHg measured on the right arm in supine position after at least 5 minutes rest in the supine position at screening, on Day 1 of the Treatment Period 1, and on Day -2 of Treatment Period 2
* Body mass index (BMI) between 18.0 and 30.0 kilogram per meter square (kg/m\^2 ) (inclusive) at screening and body weight not less than 50.0 kg
* 12-lead safety electrocardiogram (ECG) without clinically relevant abnormalities at screening, on Day 1 of the Treatment Period 1, and on Day-2 of Treatment Period 2, including:

  1. QT interval corrected for heart rate using the Fridericia correction (QTcF) of less than or equal to (=\<) 450 millisecond (ms) for male participants and =\< 470 ms for female participants
  2. Heart rate (HR) 55 to 100 Beats per minute (bpm) (inclusive)
  3. QRS interval less than (\<) 120 ms
  4. PR interval =\< 200 ms
  5. ECG morphology consistent with healthy cardiac conduction and function
* Female participant must have a negative highly sensitive serum (beta human chorionic gonadotropin \[beta- hCG\]) pregnancy test at screening and a negative urine pregnancy test on Day 1 of Treatment Period 1 and Day 2 of Treatment Period 2
* Negative results from urine drug screen at screening, on Day -1 of Treatment Period 1, and on Day -2 of Treatment Period 2

Exclusion Criteria:

* Any cardiac condition or illness (including ECG abnormalities) with a potential to increase the cardiac risk of the participant based on medical history, physical examination, 12-lead safety ECG, or 24-hour Holter ECG at screening, including:

  1. 24-hour Holter ECG with clinically relevant abnormalities
  2. History or evidence of Atrioventricular (AV) block second degree or higher
  3. Any cardiac condition or illness (including ECG abnormalities based on standard 12-lead safety ECG or d- 24-hour Holter ECG) with a potential to increase the cardiac risk of the participant
* Family history of sick-sinus syndrome
* Hepatitis A antibody immunoglobulin M (IgM) positive, positive hepatitis B surface antigen (HBsAg) or hepatitis C antibody (anti-hepatitis C virus \[anti-HCV\]) tests, or other clinically active liver disease at screening
* Known hypersensitivity to any excipients of the ponesimod drug formulation (lactose, microcrystalline cellulose, povidone, sodium lauryl sulfate, croscarmellose sodium, colloidal anhydrous silica, magnesium stearate, opadry II brown), or lactose
* History of significant propranolol side effects or known hypersensitivity to propranolol or to any of its excipients

Primary outcomes:
measure: Maximum Decrease from Baseline in Mean Hourly Heart Rate (HR) (Emax HR) on Day 5
timeFrame: Baseline and Day 5
measure: Maximum Decrease from Baseline in Mean Hourly Heart Rate (HR) (Emax HR) on Day 19
timeFrame: Baseline and Day 19
measure: Minimum of the Mean Hourly HR for each day (HR nadir) on Day 5
timeFrame: Day 5
measure: Minimum of the Mean Hourly HR for each day (HR nadir) on Day 19
timeFrame: Day 19
Secondary outcomes:
measure: Maximum Decrease from Baseline in Mean Hourly Heart Rate (HR) (Emax HR) on Days 4,16, and 19
timeFrame: Baseline, Days 4, 16, and 19
measure: Minimum of the Mean Arterial Blood Pressure
timeFrame: Days 4, 5, 16, and 19
measure: Change from Baseline in Average Heart Rate
timeFrame: Baseline, Days 4, 5, 16, and 19
measure: Change from Baseline in Average PR Interval
timeFrame: Baseline, Days 4, 5, 16, and 19
measure: Maximum Observed Plasma Analyte Concentration (Cmax) of Ponesimod
timeFrame: Days 5, 9 (Predose; 1, 2, 3, 4, 5, 6, 8, 10, 12 and 24 hours postdose)
measure: Maximum Observed Plasma Analyte Concentration (Tmax) of Ponesimod
timeFrame: Days 5, 19 (Predose; 1, 2, 3, 4, 5, 6, 8, 10, 12 and 24 hours postdose)
measure: Area Under the Plasma Analyte Concentration-Time Curve (AUC [0-24]) of Ponesimod
timeFrame: Day 5 (Predose; 1, 2, 3, 4, 5, 6, 8, 10, 12 and 24 Hours postdose)
measure: Trough Plasma Analyte Concentration (Ctrough) of Ponesimod
timeFrame: Day 19 (Predose; 1, 2, 3, 4, 5, 6, 8, 10, 12 and 24 hours postdose)
measure: Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau)
timeFrame: Day 19 (Predose; 1, 2, 3, 4, 5, 6, 8, 10, 12 and 24 hours postdose)
measure: Maximum Observed Plasma Analyte Concentration (Cmax) of Propranolol and 4 hydroxypropranolol
timeFrame: Days 4, 5, and 19 (Predose; 1, 2, 3, 4, 5, 6, 8, 10, 12 and 24 hours postdose)
measure: Maximum Observed Plasma Analyte Concentration (Tmax) of Propranolol and 4 hydroxypropranolol
timeFrame: Days 4, 5, and 19 (Predose; 1, 2, 3, 4, 5, 6, 8, 10, 12 and 24 hours postdose)
measure: Trough Plasma Analyte Concentration (Ctrough) of Propranolol and 4 hydroxypropranolol
timeFrame: Days 4, 5, and 19 (Predose; 1, 2, 3, 4, 5, 6, 8, 10, 12 and 24 hours postdose)
measure: Area Under the Curve from Time Zero to End of Dosing Interval (AUCtau) of Propranolol and 4 hydroxypropranolol
timeFrame: Days 4, 5, and 19 (Predose; 1, 2, 3, 4, 5, 6, 8, 10, 12 and 24 hours postdose)
measure: Total apparent Oral Clearance of Propranolol
timeFrame: Days 4, 5, and 19 (Predose; 1, 2, 3, 4, 5, 6, 8, 10, 12 and 24 hours postdose)
measure: Number of Participants with Adverse Events as a Measure of Safety and Tolerability
timeFrame: Approximately 2.5 months
Other outcomes:
Locations:
city: Antwerpen
country: Belgium
facility: SGS Clinical Pharmacology Unit (located in ZNA Stuivenberg)
Study officials:
affiliation: Janssen Pharmaceutica N.V., Belgium
name: Janssen Pharmaceutica N.V., Belgium Clinical Trial
role: STUDY_DIRECTOR
References: