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
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- 入组人数
- 52
- 试验地点
- 1
- 主要终点
- Maximum Decrease from Baseline in Mean Hourly Heart Rate (HR) (Emax HR) on Day 5
研究概览
简要总结
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Other
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 18 Years 至 55 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •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:
- •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
- •Heart rate (HR) 55 to 100 Beats per minute (bpm) (inclusive)
- •QRS interval less than (<) 120 ms
- •PR interval =< 200 ms
- •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
排除标准
- •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:
- •24-hour Holter ECG with clinically relevant abnormalities
- •History or evidence of Atrioventricular (AV) block second degree or higher
- •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
研究组 & 干预措施
Treatment Period 1: Ponesimod (2 mg)
Participants will receive a single dose ponesimod 2 milligram (mg) oral tablet under fed conditions on Day 1. Participants not fulfilling discontinuation criteria can continue to Treatment Period 2 after a washout period of at least 7 days and a maximum of 14 days.
干预措施: Ponesimod dose range (2 - 20 mg) (Drug)
Treatment Period 2:Ponesimod, Propranolol, Placebo Propranolol
Participants who do not fulfill any of discontinuation criteria will be randomized to 1 of 2 Treatments (Treatment A or B) on Day 1. Treatment A: up-titration regimen of ponesimod (2mg-20mg) once daily from Day 5 to Day 19 plus placebo propranolol once daily from Day 1 to Day 19; Treatment B: up-titration regimen of ponesimod (2mg-20mg) once daily from Day 5 to Day 19 plus 80 mg propranolol once daily from Day 1 to Day 19.
干预措施: Ponesimod dose range (2 - 20 mg) (Drug)
Treatment Period 2:Ponesimod, Propranolol, Placebo Propranolol
Participants who do not fulfill any of discontinuation criteria will be randomized to 1 of 2 Treatments (Treatment A or B) on Day 1. Treatment A: up-titration regimen of ponesimod (2mg-20mg) once daily from Day 5 to Day 19 plus placebo propranolol once daily from Day 1 to Day 19; Treatment B: up-titration regimen of ponesimod (2mg-20mg) once daily from Day 5 to Day 19 plus 80 mg propranolol once daily from Day 1 to Day 19.
干预措施: Placebo Propranolol (Drug)
Treatment Period 2:Ponesimod, Propranolol, Placebo Propranolol
Participants who do not fulfill any of discontinuation criteria will be randomized to 1 of 2 Treatments (Treatment A or B) on Day 1. Treatment A: up-titration regimen of ponesimod (2mg-20mg) once daily from Day 5 to Day 19 plus placebo propranolol once daily from Day 1 to Day 19; Treatment B: up-titration regimen of ponesimod (2mg-20mg) once daily from Day 5 to Day 19 plus 80 mg propranolol once daily from Day 1 to Day 19.
干预措施: Propranolol 80 mg (Drug)
结局指标
主要结局
Maximum Decrease from Baseline in Mean Hourly Heart Rate (HR) (Emax HR) on Day 5
时间窗: Baseline and Day 5
Emax HR is defined as the maximum decrease from baseline in mean hourly HR.
Maximum Decrease from Baseline in Mean Hourly Heart Rate (HR) (Emax HR) on Day 19
时间窗: Baseline and Day 19
Emax HR is defined as the maximum decrease from baseline in mean hourly HR.
Minimum of the Mean Hourly HR for each day (HR nadir) on Day 5
时间窗: 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.
Minimum of the Mean Hourly HR for each day (HR nadir) on Day 19
时间窗: 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.
次要结局
- Change from Baseline in Average Heart Rate(Baseline, Days 4, 5, 16, and 19)
- Change from Baseline in Average PR Interval(Baseline, Days 4, 5, 16, and 19)
- Maximum Observed Plasma Analyte Concentration (Cmax) of Ponesimod(Days 5, 9 (Predose; 1, 2, 3, 4, 5, 6, 8, 10, 12 and 24 hours postdose))
- Maximum Decrease from Baseline in Mean Hourly Heart Rate (HR) (Emax HR) on Days 4,16, and 19(Baseline, Days 4, 16, and 19)
- Minimum of the Mean Arterial Blood Pressure(Days 4, 5, 16, and 19)
- Trough Plasma Analyte Concentration (Ctrough) of Ponesimod(Day 19 (Predose; 1, 2, 3, 4, 5, 6, 8, 10, 12 and 24 hours postdose))
- Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau)(Day 19 (Predose; 1, 2, 3, 4, 5, 6, 8, 10, 12 and 24 hours postdose))
- Maximum Observed Plasma Analyte Concentration (Cmax) of Propranolol and 4 hydroxypropranolol(Days 4, 5, and 19 (Predose; 1, 2, 3, 4, 5, 6, 8, 10, 12 and 24 hours postdose))
- Maximum Observed Plasma Analyte Concentration (Tmax) of Ponesimod(Days 5, 19 (Predose; 1, 2, 3, 4, 5, 6, 8, 10, 12 and 24 hours postdose))
- Area Under the Plasma Analyte Concentration-Time Curve (AUC [0-24]) of Ponesimod(Day 5 (Predose; 1, 2, 3, 4, 5, 6, 8, 10, 12 and 24 Hours postdose))
- Maximum Observed Plasma Analyte Concentration (Tmax) of Propranolol and 4 hydroxypropranolol(Days 4, 5, and 19 (Predose; 1, 2, 3, 4, 5, 6, 8, 10, 12 and 24 hours postdose))
- Trough Plasma Analyte Concentration (Ctrough) of Propranolol and 4 hydroxypropranolol(Days 4, 5, and 19 (Predose; 1, 2, 3, 4, 5, 6, 8, 10, 12 and 24 hours postdose))
- Area Under the Curve from Time Zero to End of Dosing Interval (AUCtau) of Propranolol and 4 hydroxypropranolol(Days 4, 5, and 19 (Predose; 1, 2, 3, 4, 5, 6, 8, 10, 12 and 24 hours postdose))
- Total apparent Oral Clearance of Propranolol(Days 4, 5, and 19 (Predose; 1, 2, 3, 4, 5, 6, 8, 10, 12 and 24 hours postdose))
- Number of Participants with Adverse Events as a Measure of Safety and Tolerability(Approximately 2.5 months)