A Randomized, Double-Blind, Placebo- and Positive-Controlled, Multiple Dose, Four Way Crossover Study to Evaluate the Effects of Tramadol Hydrochloride on Cardiac Repolarization in Healthy Subjects at Therapeutic and Supratherapeutic Dose Levels
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 68
- 主要终点
- Change From Baseline in QTc Interval
研究概览
简要总结
The purpose of this study is to assess the effects of multiple doses of an immediate release (IR) formulation of tramadol hydrochloride (HCl) at therapeutic and supratherapeutic levels in healthy adult participants on the electrocardiogram (ECG) QT interval corrected for heart rate (QTc).
详细描述
This is a randomized (study medication assigned by chance), double-blind (neither physician nor participant knows the treatment that the participant receives), 4-way crossover (method used to switch participants from one treatment arm to another), placebo- and positive-controlled (the experimental treatment or procedure is compared to an inactive substance and a standard treatment or procedure), single site, multiple dose study. The study has 3 phases: a Screening Phase (up to 35 days); a Double-blind Treatment Phase (4 treatment periods with a washout period of 7 to 15 days); and a Post-treatment Phase (Day 5 of Period 4 or at the time of early withdrawal). All eligible participants will receive each of the 4 treatments: tramadol HCl at therapeutic dose of 400 milligram per day (mg/day), tramadol HCl at supratherapeutic dose of 600 mg/day, placebo, and positive control moxifloxacin 400 mg; in any of the treatment period as per assigned treatment sequence. The total duration of each participant's participation will be up to a maximum of 100 days. Participants' safety will be monitored throughout the study.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Treatment
- 盲法
- Triple (Participant, Investigator, Outcomes Assessor)
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
- •Woman participant of child-bearing potential, must have a negative serum beta-human chorionic gonadotropin pregnancy test at Screening; and a negative urine pregnancy test on Day 1 of each treatment period
- •Standard electroencephalogram (EEG) that is normal, as assessed by a neurologist. The EEG will be performed under basic conditions and during hyperventilation and intermittent photic stimulation at Screening
- •Body mass index (BMI; weight [in kilogram]/height [in square meter]) between 18 and 30 kilogram per square meter (inclusive), and body weight not less than 50 kilogram at Screening
- •Blood pressure between 90 and 140 millimeter of mercury (mm Hg) systolic (inclusive) and no higher than 90 mm Hg diastolic
- •An average of triplicate 12-lead electrocardiogram (ECG) recordings (performed in a semi-supine position), completed within 4 minutes total, consistent with normal cardiac conduction and function at Screening, including: 1- Sinus rhythm with heart rate between 40 and 100 beats per minute (inclusive); 2- QTc interval between 350 to 450 milliseconds (inclusive); 3- QRS interval of less than 110 milliseconds; 4- PR interval less than 200 milliseconds; 5- ECG morphology consistent with healthy cardiac conduction and function
排除标准
- •Personal or family history of epileptic seizures or convulsions (genetic or idiopathic seizures), or have suffered from head trauma with loss of consciousness, central nervous system infection, or loss of consciousness of unknown origin
- •History of additional risk factors for torsades de pointes (TdP) or the presence of a family history of short QT syndrome, long QT syndrome, sudden unexplained death at a young age ( less than equal to 40 years), drowning or sudden infant death syndrome in a first degree relative (that is, biological parent, sibling, or child)
- •Clinically significant abnormal values for hematology, clinical chemistry, or urinalysis at Screening or before the first dose of study drug on Day -1 of each treatment period as assessed by the Investigator. Note that participants who have serum potassium, magnesium, or calcium levels outside of the local laboratory's reference range will be excluded
- •Clinically significant abnormal physical examination or vital signs at Screening or before the first dose of study drug on Day -1 of each treatment period as assessed by the Investigator
- •History of drug or alcohol abuse within 5 years before Screening or positive test result(s) for alcohol or drugs of abuse (such as barbiturates, opiates, cocaine, cannabinoids, amphetamines, hallucinogens, and benzodiazepines) at Screening or on Day -1 of each treatment period
研究组 & 干预措施
Treatment Sequence 1
Participants will receive treatment A (2*50 milligram [mg] tramadol hydrochloride [HCl] immediate release [IR] tablet + 1 tramadol HCl placebo every 6 hours on Days 1, 2, and 3, along with single dose of 2*50 mg tramadol HCl IR tablet + 1 tramadol HCl placebo + 1 moxifloxacin placebo on Day 4); treatment B (3*50 mg tramadol HCl IR tablet every 6 hours on Days 1, 2, and 3, along with single dose of 3*50 mg tramadol HCl IR tablet + 1 moxifloxacin placebo on Day 4); treatment C (3 tramadol HCl placebo every 6 hours on Days 1, 2, and 3, along with single dose of 3 tramadol HCl placebo + 1 moxifloxacin placebo on Day 4); and treatment D (3 tramadol HCl placebo every 6 hours on Days 1, 2, and 3, along with single dose of 3 tramadol HCl placebo + 1 moxifloxacin placebo on Day 4) in 4 treatment periods as per protocol defined sequence. A washout period of 7 to 15 days will be maintained between each treatment period.
干预措施: Tramadol HCl (Drug)
Treatment Sequence 1
Participants will receive treatment A (2*50 milligram [mg] tramadol hydrochloride [HCl] immediate release [IR] tablet + 1 tramadol HCl placebo every 6 hours on Days 1, 2, and 3, along with single dose of 2*50 mg tramadol HCl IR tablet + 1 tramadol HCl placebo + 1 moxifloxacin placebo on Day 4); treatment B (3*50 mg tramadol HCl IR tablet every 6 hours on Days 1, 2, and 3, along with single dose of 3*50 mg tramadol HCl IR tablet + 1 moxifloxacin placebo on Day 4); treatment C (3 tramadol HCl placebo every 6 hours on Days 1, 2, and 3, along with single dose of 3 tramadol HCl placebo + 1 moxifloxacin placebo on Day 4); and treatment D (3 tramadol HCl placebo every 6 hours on Days 1, 2, and 3, along with single dose of 3 tramadol HCl placebo + 1 moxifloxacin placebo on Day 4) in 4 treatment periods as per protocol defined sequence. A washout period of 7 to 15 days will be maintained between each treatment period.
干预措施: Moxifloxacin 400 mg (Drug)
Treatment Sequence 1
Participants will receive treatment A (2*50 milligram [mg] tramadol hydrochloride [HCl] immediate release [IR] tablet + 1 tramadol HCl placebo every 6 hours on Days 1, 2, and 3, along with single dose of 2*50 mg tramadol HCl IR tablet + 1 tramadol HCl placebo + 1 moxifloxacin placebo on Day 4); treatment B (3*50 mg tramadol HCl IR tablet every 6 hours on Days 1, 2, and 3, along with single dose of 3*50 mg tramadol HCl IR tablet + 1 moxifloxacin placebo on Day 4); treatment C (3 tramadol HCl placebo every 6 hours on Days 1, 2, and 3, along with single dose of 3 tramadol HCl placebo + 1 moxifloxacin placebo on Day 4); and treatment D (3 tramadol HCl placebo every 6 hours on Days 1, 2, and 3, along with single dose of 3 tramadol HCl placebo + 1 moxifloxacin placebo on Day 4) in 4 treatment periods as per protocol defined sequence. A washout period of 7 to 15 days will be maintained between each treatment period.
干预措施: Tramadol HCl Placebo (Drug)
Treatment Sequence 1
Participants will receive treatment A (2*50 milligram [mg] tramadol hydrochloride [HCl] immediate release [IR] tablet + 1 tramadol HCl placebo every 6 hours on Days 1, 2, and 3, along with single dose of 2*50 mg tramadol HCl IR tablet + 1 tramadol HCl placebo + 1 moxifloxacin placebo on Day 4); treatment B (3*50 mg tramadol HCl IR tablet every 6 hours on Days 1, 2, and 3, along with single dose of 3*50 mg tramadol HCl IR tablet + 1 moxifloxacin placebo on Day 4); treatment C (3 tramadol HCl placebo every 6 hours on Days 1, 2, and 3, along with single dose of 3 tramadol HCl placebo + 1 moxifloxacin placebo on Day 4); and treatment D (3 tramadol HCl placebo every 6 hours on Days 1, 2, and 3, along with single dose of 3 tramadol HCl placebo + 1 moxifloxacin placebo on Day 4) in 4 treatment periods as per protocol defined sequence. A washout period of 7 to 15 days will be maintained between each treatment period.
干预措施: Moxifloxacin Placebo (Drug)
Treatment Sequence 2
Participants will receive treatment A; treatment B; treatment C; and treatment D in 4 treatment periods as per protocol defined sequence. A washout period of 7 to 15 days will be maintained between each treatment period.
干预措施: Tramadol HCl (Drug)
Treatment Sequence 2
Participants will receive treatment A; treatment B; treatment C; and treatment D in 4 treatment periods as per protocol defined sequence. A washout period of 7 to 15 days will be maintained between each treatment period.
干预措施: Moxifloxacin 400 mg (Drug)
Treatment Sequence 2
Participants will receive treatment A; treatment B; treatment C; and treatment D in 4 treatment periods as per protocol defined sequence. A washout period of 7 to 15 days will be maintained between each treatment period.
干预措施: Tramadol HCl Placebo (Drug)
Treatment Sequence 2
Participants will receive treatment A; treatment B; treatment C; and treatment D in 4 treatment periods as per protocol defined sequence. A washout period of 7 to 15 days will be maintained between each treatment period.
干预措施: Moxifloxacin Placebo (Drug)
Treatment Sequence 3
Participants will receive treatment A; treatment B; treatment C; and treatment D in 4 treatment periods as per protocol defined sequence. A washout period of 7 to 15 days will be maintained between each treatment period.
干预措施: Tramadol HCl (Drug)
Treatment Sequence 3
Participants will receive treatment A; treatment B; treatment C; and treatment D in 4 treatment periods as per protocol defined sequence. A washout period of 7 to 15 days will be maintained between each treatment period.
干预措施: Moxifloxacin 400 mg (Drug)
Treatment Sequence 3
Participants will receive treatment A; treatment B; treatment C; and treatment D in 4 treatment periods as per protocol defined sequence. A washout period of 7 to 15 days will be maintained between each treatment period.
干预措施: Tramadol HCl Placebo (Drug)
Treatment Sequence 3
Participants will receive treatment A; treatment B; treatment C; and treatment D in 4 treatment periods as per protocol defined sequence. A washout period of 7 to 15 days will be maintained between each treatment period.
干预措施: Moxifloxacin Placebo (Drug)
Treatment Sequence 4
Participants will receive treatment A; treatment B; treatment C; and treatment D in 4 treatment periods as per protocol defined sequence. A washout period of 7 to 15 days will be maintained between each treatment period.
干预措施: Tramadol HCl (Drug)
Treatment Sequence 4
Participants will receive treatment A; treatment B; treatment C; and treatment D in 4 treatment periods as per protocol defined sequence. A washout period of 7 to 15 days will be maintained between each treatment period.
干预措施: Moxifloxacin 400 mg (Drug)
Treatment Sequence 4
Participants will receive treatment A; treatment B; treatment C; and treatment D in 4 treatment periods as per protocol defined sequence. A washout period of 7 to 15 days will be maintained between each treatment period.
干预措施: Tramadol HCl Placebo (Drug)
Treatment Sequence 4
Participants will receive treatment A; treatment B; treatment C; and treatment D in 4 treatment periods as per protocol defined sequence. A washout period of 7 to 15 days will be maintained between each treatment period.
干预措施: Moxifloxacin Placebo (Drug)
结局指标
主要结局
Change From Baseline in QTc Interval
时间窗: Baseline (pre-dose, Day1); pre-dose up to 24 hours post-dose on Day 4
The QT interval corrected for heart rate (QTc interval) using Fridericia, Bazett and study-specific power correction methods, will be measured by electrocardiograms (ECG).
次要结局
- Number of Participants With Adverse Events (AEs) or Serious Adverse Events (SAEs)(Screening up to end of study (30 days after the last dose of study drug or early withdrawal))
- Change From Baseline in HR, QRS, and PR Intervals(Baseline (pre-dose, Day1); pre-dose up to 24 hours post-dose on Day 4)
- Number of Participants with T-wave and U-wave Morphological Changes(Baseline (pre-dose, Day1); pre-dose up to 24 hours post-dose on Day 4)
- Maximum Plasma Concentration During a Dosing Interval at Steady State (Cmax,ss)(Pre-dose up to 24 hours post-dose on Day 4)
- Trough Plasma Concentration Before Dosing (pre-dose) At Steady State (Ctrough,ss)(Pre-dose up to 24 hours post-dose on Day 4)
- Time to Reach the Maximum Plasma Concentration at Steady State (Tmax,ss)(Pre-dose up to 24 hours post-dose on Day 4)
- Area Under the Plasma Concentration-Time Curve During a Dosing Interval (tau) at Steady State (AUCtau,ss)(Pre-dose up to 24 hours post-dose on Day 4)