A Phase 1 Study to Investigate the Safety, Tolerability, and Pharmacokinetic Profile of Single Ascending Doses of REL-1017 (d-Methadone) in Healthy Subjects
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 42
- 主要终点
- Adverse Events (AEs)
研究概览
简要总结
This study evaluated the safety, tolerance, and pharmacokinetics (PK) of d-methadone in a limited dose range, in single administrations in humans.
详细描述
This was a phase 1, single-center study carried out in healthy male and female subjects to investigate the safety, tolerability, and PK of d-methadone. This was a double-blind, randomized, placebo-controlled study in 6 sequential cohorts of healthy subjects. Single oral doses of d-methadone were investigated in sequential cohorts. The proposed doses were 5 mg, 20 mg, 60 mg, 100 mg, 200 mg, 300 mg, and 400 mg. The decision to enroll the sequential cohort at the next dose level was based on the safety data and available PK data from previous doses. Dose escalation depended on the emergence of dose-limiting AEs and review of the safety data. Progression to the next higher dose only occurred if the previous dose level was deemed to be safe and well tolerated by the investigator, safety review team, and sponsor. Of the 8 subjects in each cohort, 2 subjects received placebo and 6 subjects received d-methadone.
Subjects were admitted the day prior to receiving the study drug and remained in the clinical research unit (CRU) under clinical supervision for at least 72 hours post-dose. At the discretion of the investigator or designee, the confinement time could have been extended to ensure the safety of each subject. Visits 3 and 4 were follow-up visits approximately 6±2 days and 10±2 days, respectively, after drug administration.
Based on the blinded safety data from Cohorts 1 to 4, single doses of 5 mg, 20 mg, 60 mg, and 100 mg of d-methadone or placebo were well tolerated and there were no dose-limiting AEs.
During all cohorts, subjects were evaluated for safety (AEs, vital signs, electrocardiograms [ECGs], cardiac telemetry, pulse oximetry, clinical laboratory tests), tolerability, and PK. The following signs of opioid toxicity were deemed to be of special interest:
- sustained respiratory depression that results in oxygen saturation below 92%
- QTc prolongation (>500 ms or >70 ms above the baseline)
- protracted nausea and vomiting
- any AE deemed by the investigator to be dose-limiting Safety Analysis Safety and tolerability parameters were listed by treatment and subject and displayed in summary tables using descriptive statistics.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Basic Science
- 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
- •healthy male or female subjects, 18 to 55 years of age, inclusive
- •body mass index (BMI) within the range of 18.0 to 30.0 kg/m2, inclusive, and a minimum weight of 50.0 kg
- •non-smoker for at least 3 months and tested negative on a breath carbon monoxide (CO) test
- •male subjects of reproductive potential must have been using and willing to continue using medically acceptable contraception from screening and for at least 2 months after the last study drug administration
- •female subjects of childbearing potential must have been using and willing to continue using medically acceptable contraception for at least 1 month prior to screening (at least 3 months for oral, transdermal, vaginal ring contraceptives) and for at least 2 months after last study drug administration
- •female subjects of non-childbearing potential must have met the criteria defined in the clinical protocol
- •able to speak, read, and understand English sufficiently to allow completion of all study assessments
- •must have understood and provided written informed consent, prior to the initiation of any protocol-specific procedures
排除标准
- •self-reported substance or alcohol dependence (excluding nicotine and caffeine) within the past 2 years, and/or subjects who had ever been in a substance or alcohol rehabilitation program to treat their substance or alcohol dependence
- •subject-reported family history of substance abuse in an immediate family member (i.e., parent, sibling, or child)
- •history or presence of clinically significant abnormality as assessed by physical examination, medical history, 12-lead ECG, vital signs, or laboratory values, which in the opinion of the investigator would jeopardize the safety of the subject or the validity of the study results
- •chronic use of prescribed opioids (i.e., >120 days in a 6-month period) or any recreational use of opioids
- •evidence of clinically significant hepatic or renal impairment, including alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >1.5× upper limit of normal (ULN) or bilirubin >1× ULN
- •history or family history of sudden unexplained death or long QT syndrome
- •QT interval corrected using Fridericia's formula (QTcF) >450 ms in females or >430 ms in males
- •history of hypotension
- •history or presence of any condition in which an opioid was contraindicated (e.g., significant respiratory depression, acute or severe bronchial asthma or hypercarbia, bronchitis, or had/was suspected of having paralytic ileus)
- •history of status asthmaticus, chronic pulmonary disease, or severe allergic reaction (including anaphylaxis) to any substance
- •use of an opioid within the 6 months prior to screening
- •use of a prohibited medication
- •positive urine drug screen
- •positive breath alcohol test; subjects with a positive result may have been rescheduled at the investigator's discretion
- •female subjects who were currently pregnant (had a positive pregnancy test)
- •history of allergy or hypersensitivity to methadone or related drugs (e.g., opioids)
- •positive for hepatitis B, hepatitis C, or human immunodeficiency virus (HIV)
- •donation or loss of more than 500 mL of whole blood within 30 days prior to first drug administration
- •difficulty with venous access or unsuitable or unwilling to undergo catheter insertion
- •treatment with an investigational drug within 5 times the elimination half-life, if known (e.g., a marketed product) or within 30 days (if the elimination half-life is unknown) prior to first drug administration or was concurrently enrolled in any research judged not to be scientifically or medically compatible with this study
- •an employee of the sponsor or research site personnel directly affiliated with this study or their immediate family member, defined as a spouse, parent, sibling, or child, whether biological or legally adopted
- •a subject who, in the opinion of the investigator or designee, was considered unsuitable or unlikely to comply with the study protocol for any reason
研究组 & 干预措施
Arm 1
100 mL Ocean Spray® Diet Cranberry Juice
干预措施: Placebo (Drug)
Arm 2
REL-1017 5 mg in 100 mL of Ocean Spray® Diet Cranberry Juice
干预措施: REL-1017 (Drug)
Arm 3
REL-1017 20 mg in 100 mL of Ocean Spray® Diet Cranberry Juice
干预措施: REL-1017 (Drug)
Arm 4
REL-1017 60 mg in 100 mL of Ocean Spray® Diet Cranberry Juice
干预措施: REL-1017 (Drug)
Arm 5
REL-1017 100 mg in 100 mL of Ocean Spray® Diet Cranberry Juice
干预措施: REL-1017 (Drug)
Arm 6
REL-1017 150 mg in 100 mL of Ocean Spray® Diet Cranberry Juice
干预措施: REL-1017 (Drug)
结局指标
主要结局
Adverse Events (AEs)
时间窗: Change from pre-dose, 0.5, 1, 2, 3, 5, 8, 12, 24, 36, 48, 60, and 72 hours post-dose, and 7 and 11 days post-dose follow-up
Spontaneously reported and observed AEs were recorded throughout the study, and AEs were elicited using a non-leading question at designated time points. Regardless of seriousness, intensity, or presumed relationship to study drug, all AEs were recorded in the source documentation from the time of first contact with the subject (e.g., screening) until the end of the follow-up period of the study. AEs that occurred after medical screening and prior to administration of the first dose of study drug were recorded in the source documentation as baseline signs and symptoms.
次要结局
- Plasma levels(Pre-dose, 0.5, 1, 2, 3, 5, 8, 12, 24, 36, 48, 60, and 72 hours post-dose, and 7 and 11 days post-dose follow-up)