A Phase 1, Randomized, Open Label, Crossover Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of QEV-817 Oral Suspension in Healthy Volunteers
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 8
- 试验地点
- 2
- 主要终点
- Number of Participants with Treatment-Emergent Adverse Events (TEAEs)
研究概览
简要总结
This study has been designed to assess the safety, tolerability, and pharmacokinetics of a therapeutic dose of hydrocodone bitartrate with and without an oral dose of doxapram hydrochloride in healthy volunteers who are naltrexone-blocked.
详细描述
This is a Phase 1, single-center, randomized, open label, crossover study that will be conducted in male and female healthy volunteers. The study will be conducted at a single site in the US. The study consists of a 28-day Screening Period, a four-day treatment period, and a one-day safety follow-up period.
The study will be conducted in eight (8) healthy male and female subjects. Up to an additional five (5) subjects may be enrolled as alternates to replace dropouts. Subjects will be randomized (1:1) to one of two crossover treatment sequences.
Subjects will receive either a fixed therapeutic dose of oral hydrocodone bitartrate alone or in combination with a fixed dose of oral doxapram hydrochloride. Prior to treatment, all subjects will receive naltrexone (opioid antagonist) to block opioid effects (i.e., naltrexone block).
Safety will be evaluated by monitoring the nature, severity, and incidence of adverse events (AEs); and changes from baseline in physical examination, vital signs, 12-lead electrocardiogram (ECG) assessment, pulse oximetry, and clinical laboratory tests.
Pharmacokinetics of both drugs and their primary metabolites will be assessed in plasma samples collected through 24 hours post-dose from all subjects.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Basic Science
- 盲法
- None (Participant, Care Provider, 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
- •include but are not limited to:
- •Male or female aged 18-55 years, inclusive, on the day of screening.
- •Willing to abstain from alcohol and strenuous physical activity (i.e., strenuous, or unaccustomed weightlifting, running, bicycling, etc.) from 48 hours prior to study treatment administration until discharge from the clinical unit and prior to each outpatient visit.
- •Have normal laboratory values, as defined per protocol, at screening.
- •Absence of cardiac arrythmias, as well as corrected QT interval (QTc) < 450 ms in males and QTc < 460 ms in females based on 12-lead ECG findings at screening.
- •Body weight ≥50 kg and body mass index (BMI) within the range of 19-32 kg/m2 (inclusive).
- •Has never used opioids for non-therapeutic purposes (i.e., for recreational effects). Subjects with a history of valid medical use under prescription must have not used an opioid for at least three (3) months prior to Day
- •Women of childbearing potential (WOCBP), as defined in Section 10.4, must have a negative serum pregnancy test within one (1) week AND a negative urine pregnancy test on Day 2, prior to the start of study treatment; Must not be breastfeeding, lactating, or planning a pregnancy during the study and for at least 32 days (5 half-lives plus 30-days) after the last dose of study intervention
- •Postmenopausal females must have a documented serum follicle-stimulating hormone (FSH) level >40 mIU/mL (milli international units per milliliter) at screening to confirm menopause.
- •Male participants with female sexual partners who are WOCBP must agree to remain abstinent (complete avoidance of heterosexual intercourse) or use adequate contraceptive methods, defined as use of a condom by the male partner combined with use of a highly effective method of contraception by the female partner, during the treatment period and for at least 92 days (5 half-lives + 90-day spermatogenesis cycle) after the last dose of study intervention; must not donate sperm for at least 92 days (5 half-lives + 90-day spermatogenesis cycle) after the last dose of study intervention.
排除标准
- •include but are not limited to:
- •Female subject who is pregnant or lactating.
- •Have any vital sign abnormalities as described in the protocol.
- •Recreational opioid user who has used opioids for non-therapeutic purposes (i.e., for psychoactive effects) or who is physically dependent on any illicit or prescription opioid, and/or currently participating in a treatment program for individuals with opioid dependence.
- •Known allergy or history of significant adverse reaction to hydrocodone or its metabolites, other opioids, or related compounds, doxapram hydrochloride, naltrexone, naloxone, or to any of the excipients in QEV-
- •History of or currently has hypoventilation syndrome or sleep apnea and is on non-invasive ventilation (e.g., CPAP).
- •Clinically meaningful infection/injury/illness within one month prior to screening.
- •Active malignancy (excluding squamous or basal cell carcinoma of the skin) within 5 years of screening.
- •Subjects with hepatic impairment as defined by screening alanine transaminase (ALT), aspartate transaminase (AST) or total bilirubin >3× upper limit of normal (ULN).
- •Subjects with renal impairment as defined by screening estimated creatinine clearance/eGFR (estimated glomerular filtration rate) using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation is <60 mL/min/1.73 m
- •Donation of blood (>450 mL) or significant blood loss within 56 days.
- •Current (or recent history of) psychiatric illness or mental impairment.
- •Clinically meaningful current (or history of) unstable chronic disease; medical abnormality; or significant cardiovascular (including significant cardiovascular impairment, uncompensated heart failure, severe coronary artery disease, severe hypertension), endocrine, gastrointestinal, neurological disorder (including cognitive disorders); or metabolic disease.
- •Currently active (or history of) epilepsy, seizure disorder, serious head injury, cerebral vascular accident, or cerebral edema.
- •Current treatment with monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants, sympathomimetic drugs, neuromuscular blocking agents, narcotics, antihistamines, antipsychotics, antianxiety agents, or other central nervous system (CNS) depressants.
- •Use of any prescription or over the counter (OTC) medications including food supplements and herbal medications (e.g., St. John's wort), with the exception of contraceptive medications or a daily multivitamin, within fourteen (14) days prior to study treatment administration. Use of CYP3A4 inhibitors or inducers is prohibited within 28 days prior to the first treatment and throughout the treatment and follow-up periods.
- •A positive urine drug, cotinine, or alcohol test at screening, excluding tetrahydro-cannabinol (THC) or cannabinoid metabolites.
- •Smokers or use of tobacco-containing products within 6 weeks of study drug administration.
研究组 & 干预措施
Sequence A - Hydrocodone alone followed by combined (hydrocodone + doxapram)
Subjects randomized to Sequence A will first receive a single oral administration of hydrocodone bitartrate alone on Study Day-2 and then receive a combination of hydrocodone bitartrate and doxapram hydrocholoride on study Day-4 (after a 48 hour wash-out).
干预措施: Hydrocodone Bitartrate (Drug)
Sequence A - Hydrocodone alone followed by combined (hydrocodone + doxapram)
Subjects randomized to Sequence A will first receive a single oral administration of hydrocodone bitartrate alone on Study Day-2 and then receive a combination of hydrocodone bitartrate and doxapram hydrocholoride on study Day-4 (after a 48 hour wash-out).
干预措施: Hydrocodone Bitartrate + Doxapram Hydrochloride (Drug)
Sequence B - Combined (hydrocodone + doxapram) followed by hydrocodone alone
Subjects randomized to Sequence B will first receive a single combined administration of hydrocodone bitartrate and doxapram hydrocholoride on Study Day-2 and then receive hydrocodone alone on study Day-4 (after a 48 hour wash-out).
干预措施: Hydrocodone Bitartrate + Doxapram Hydrochloride (Drug)
Sequence B - Combined (hydrocodone + doxapram) followed by hydrocodone alone
Subjects randomized to Sequence B will first receive a single combined administration of hydrocodone bitartrate and doxapram hydrocholoride on Study Day-2 and then receive hydrocodone alone on study Day-4 (after a 48 hour wash-out).
干预措施: Hydrocodone Bitartrate (Drug)
结局指标
主要结局
Number of Participants with Treatment-Emergent Adverse Events (TEAEs)
时间窗: Day 1 to Day 5
Incidence, nature, and severity of TEAEs
Number of Participants with Abnormal Laboratory Assessments, 12-Lead Electrocardiogram (ECG), and Vital Signs
时间窗: Day 1 to Day 5
Changes from baseline in physical examination, vital signs, 12-lead ECG assessment and pulse oximetry
Number of Participants With Abnormal Laboratory Assessments, 12-Lead Electrocardiogram (ECG), and Vital Signs
时间窗: Day 1 to Day 5
Number of participants with clinically meaningful changes from baseline in physical examination, vital signs, 12-lead ECG assessment and/or pulse oximetry
次要结局
- Plasma PK Parameters (Tmax)(Day 2 and Day 4)
- Plasma PK Parameters (AUC0-inf)(Day 2 and Day 4)
- Plasma PK Parameters (Cmax)(Day 2 and Day 4)
- Plasma PK Parameter (AUC0-24h)(Day 2 and Day 4)
- Plasma PK Parameter (Tmax)(Day 2 and Day 4)