A Study of Ponesimod in Healthy Adult Participants Receiving Propranolol at Steady State

Healthy Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03882255
• Other study ID #: CR108589
• Secondary ID: 2018-003550-24AC
• Status: Completed
• Phase: Phase 1
• Start date: March 20, 2019
• Est. completion date: August 26, 2019

Study information

• Verified date: October 2019
• Source: Janssen Pharmaceutica N.V., Belgium
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 52
• Est. completion date: August 26, 2019
• Est. primary completion date: August 26, 2019
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 55 Years

Eligibility

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

Related Conditions & MeSH terms

• Healthy

Intervention

Drug:
• Ponesimod dose range (2 - 20 mg)
Participants will receive ponesimod oral tablet at a dose of 2 mg in Treatment period 1 and as an up-titrating regimen (dose range: 2mg-20mg) in Treatments period 2.
• Placebo Propranolol
Participants will be administered placebo propranolol oral capsule from Day 1 to Day 19 in Treatment A of Treatment period 2.
• Propranolol 80 mg
Participants will receive propranolol 80 mg long acting oral capsule from Day 1 to Day 19 in Treatment B of Treatment period 2.

Locations

Country	Name	City	State
Belgium	SGS Clinical Pharmacology Unit (located in ZNA Stuivenberg)	Antwerpen

Sponsors (1)

Lead Sponsor	Collaborator
Janssen Pharmaceutica N.V., Belgium

Country where clinical trial is conducted

Belgium, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Maximum Decrease from Baseline in Mean Hourly Heart Rate (HR) (Emax HR) on Day 5	Emax HR is defined as the maximum decrease from baseline in mean hourly HR.	Baseline and Day 5
Primary	Maximum Decrease from Baseline in Mean Hourly Heart Rate (HR) (Emax HR) on Day 19	Emax HR is defined as the maximum decrease from baseline in mean hourly HR.	Baseline and Day 19
Primary	Minimum of the Mean Hourly HR for each day (HR nadir) on Day 5	HR nadir will be defined as the minimum of the mean hourly HR for each day and will be summarized by descriptive statistics.	Day 5
Primary	Minimum of the Mean Hourly HR for each day (HR nadir) on Day 19	HR nadir will be defined as the minimum of the mean hourly HR for each day and will be summarized by descriptive statistics.	Day 19
Secondary	Maximum Decrease from Baseline in Mean Hourly Heart Rate (HR) (Emax HR) on Days 4,16, and 19	Emax HR is defined as the maximum decrease from baseline in mean hourly HR.	Baseline, Days 4, 16, and 19
Secondary	Minimum of the Mean Arterial Blood Pressure	Minimum of the Mean arterial blood pressure (MAP) will be assessed. The MAP will be derived from the systolic blood pressure (SBP) and diastolic blood pressure (DBP) for each participant at the same time point as follows: MAP = 1/3 SBP + 2/3 DBP.	Days 4, 5, 16, and 19
Secondary	Change from Baseline in Average Heart Rate	Change from baseline in average heart rate on Days 4, 5, 16 and 19 will be assessed in Treatment Period 2.	Baseline, Days 4, 5, 16, and 19
Secondary	Change from Baseline in Average PR Interval	Change from baseline in PR interval on Days 4, 5, 16 and 19 will be assessed in Treatment Period 2. PR intervals will be derived from 12-lead safety electrocardiogram (ECG).	Baseline, Days 4, 5, 16, and 19
Secondary	Maximum Observed Plasma Analyte Concentration (Cmax) of Ponesimod	Cmax is defined as maximum observed plasma analyte concentration.	Days 5, 9 (Predose; 1, 2, 3, 4, 5, 6, 8, 10, 12 and 24 hours postdose)
Secondary	Maximum Observed Plasma Analyte Concentration (Tmax) of Ponesimod	Tmax is defined as maximum observed plasma analyte concentration.	Days 5, 19 (Predose; 1, 2, 3, 4, 5, 6, 8, 10, 12 and 24 hours postdose)
Secondary	Area Under the Plasma Analyte Concentration-Time Curve (AUC [0-24]) of Ponesimod	(AUC [0-24]) is defined as area under the plasma analyte concentration-time curve (AUC) from time 0 to 24 hours postdose, calculated by linear-linear trapezoidal summation.	Day 5 (Predose; 1, 2, 3, 4, 5, 6, 8, 10, 12 and 24 Hours postdose)
Secondary	Trough Plasma Analyte Concentration (Ctrough) of Ponesimod	(Ctrough) is defined as observed analyte concentration just prior to the beginning of a dosing interval.	Day 19 (Predose; 1, 2, 3, 4, 5, 6, 8, 10, 12 and 24 hours postdose)
Secondary	Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau)	The AUCtau is the measure of the plasma analyte concentration from time zero to end of dosing interval. AUC during a dosing interval (t) at steady state, calculated by linear-linear trapezoidal summation.	Day 19 (Predose; 1, 2, 3, 4, 5, 6, 8, 10, 12 and 24 hours postdose)
Secondary	Maximum Observed Plasma Analyte Concentration (Cmax) of Propranolol and 4 hydroxypropranolol	Cmax is defined as maximum observed plasma analyte concentration.	Days 4, 5, and 19 (Predose; 1, 2, 3, 4, 5, 6, 8, 10, 12 and 24 hours postdose)
Secondary	Maximum Observed Plasma Analyte Concentration (Tmax) of Propranolol and 4 hydroxypropranolol	Tmax is defined as maximum observed plasma analyte concentration.	Days 4, 5, and 19 (Predose; 1, 2, 3, 4, 5, 6, 8, 10, 12 and 24 hours postdose)
Secondary	Trough Plasma Analyte Concentration (Ctrough) of Propranolol and 4 hydroxypropranolol	(Ctrough) is defined as observed analyte concentration just prior to the beginning of a dosing interval.	Days 4, 5, and 19 (Predose; 1, 2, 3, 4, 5, 6, 8, 10, 12 and 24 hours postdose)
Secondary	Area Under the Curve from Time Zero to End of Dosing Interval (AUCtau) of Propranolol and 4 hydroxypropranolol	The AUCtau is the measure of the plasma analyte concentration from time zero to end of dosing interval. AUC during a dosing interval (t) at steady state, calculated by linear-linear trapezoidal summation.	Days 4, 5, and 19 (Predose; 1, 2, 3, 4, 5, 6, 8, 10, 12 and 24 hours postdose)
Secondary	Total apparent Oral Clearance of Propranolol	Total apparent clearance is defined as total apparent oral clearance at steady state, calculated as dose/AUC (tau).	Days 4, 5, and 19 (Predose; 1, 2, 3, 4, 5, 6, 8, 10, 12 and 24 hours postdose)
Secondary	Number of Participants with Adverse Events as a Measure of Safety and Tolerability	An adverse event is any adverse change, that is, any unfavorable and unintended sign, including an abnormal laboratory finding, symptom, or disease, that occurs in a participant during the course of the study, whether or not considered related to the study treatment.	Approximately 2.5 months

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