Phase 1, Randomized, Double-Blind, Active and Placebo Controlled, Dose Escalation Study to Evaluate the Safety, Pharmacokinetics and Pharmacodynamics of EXPAREL® Administered Via a Single Intrathecal Injection to Healthy Volunteers.
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 20
- 试验地点
- 1
- 主要终点
- Area under the plasma concentration-versus-time curve
研究概览
简要总结
Primary objective: To assess the safety and tolerability of EXPAREL® administered as a single intrathecal injection in healthy volunteers
Secondary objective: To characterize the pharmacokinetic (PK) and pharmacodynamic (PD) profile of EXPAREL® administered as a single intrathecal injection in healthy volunteers
详细描述
This is a Phase-1, single center, randomized, double-blind, active and placebo-controlled study in approximately 40 healthy adult subjects.
On Day 1, eligible subjects will be randomized in blocks of 5, in a ratio of 3:1:1 to receive EXPAREL® or bupivacaine or placebo (saline) injection, respectively. Starting with treatment Cohort 1, healthy volunteers will be randomized to the 3 treatment arms within cohorts. Each cohort will consist of 10 subjects (6 EXPAREL®, 2 bupivacaine and 2 placebo). In each cohort, all 10 subjects in each cohort will receive cerebrospinal fluid (CSF) taps. Within the EXPAREL® arm, subjects will be randomized 2:1 with 4 subjects undergoing CSF tap and 2 subjects not undergoing CSF tap in each cohort. Subjects who are not undergoing CSF tap, will still be injected with needles without draw of CSF to prevent subject bias. Such a randomization will allow for characterization of the complete pharmacodynamics profile of the drug without risk of drug removal in the CSF. For those subjects randomized to the EXPAREL® arm - the dose of EXPAREL® will be determined by the cohort. Starting at 1 mL (13.3 mg) for Cohort 1, the volume of EXPAREL® will be increased by 1 mL in each subsequent cohort for a maximum of 4 mL (53.2 mg). The decision to proceed to the next cohort will be made following a full review of the safety, PK, and PD (sensory and motor) data from current completed cohort(s). All subjects will remain in the EPRU for 5 days after drug administration and will be discharged on Day 6. Subjects will be instructed to return for a follow up visit on Day 9. Adverse events (AEs) and serious adverse events (SAEs) will be recorded from the time of consent through 30 days after drug administration.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
盲法说明
Each of the cohorts will be masked as to proceed to subsequent next dose escalation cohort.
入排标准
- 年龄范围
- 18 Years 至 50 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Healthy adult male or female volunteers ages ≥18 and ≤50 years old.
- •American Society of Anesthesiologists (ASA) physical status
- •Able to provide informed consent, adhere to the study schedule, and complete all study assessments.
排除标准
- •Allergy, hypersensitivity, intolerance, or contraindication to any of the study medications for which an alternative is not named in the protocol (eg, amide-type local anesthetics, opioids, bupivacaine, non-steroidal anti-inflammatory drugs [NSAIDs], spinal anesthesia).
- •Impaired renal or hepatic function (eg, serum creatinine level >2 mg/dL [176.8 μmol/L], blood urea nitrogen level >50 mg/dL [17.9 mmol/L], serum aspartate aminotransferase [AST] level >1.5 times the upper limit of normal [ULN], or serum alanine aminotransferase [ALT] level >1.5 times the ULN).
- •Subjects at an increased risk for bleeding or who have a coagulation disorder (defined as platelet count less than 80,000 × 103/mm3).
- •Concurrent painful physical condition that may require analgesic treatment (such as long-term, consistent use of opioids) in the post dosing period for pain and which may confound the post dosing assessments.
- •Women of childbearing potential must have a documented negative pregnancy test at screening and must be confirmed on the day of drug administration. If postmenopausal, must have a documented Follicle Stimulating Hormone (FSH) test confirming menopause at screening.
- •Currently pregnant, nursing, or planning to become pregnant during the study or within 30 days after completion of the study.
- •Positive serology test result for Human Immunodeficiency Virus (HIV), Hepatitis B virus, or Hepatitis C virus.
- •Clinically significant abnormal ECG that in the opinion of the investigator would preclude the subject from participation in the study.
- •Previous participation in a Pacira study.
- •History of, suspected, or known addiction to or abuse of illicit drug(s), prescription medicine(s), or alcohol within the past 2 years.
- •Administration of an investigational drug within 30 days or 5 elimination half-lives of such investigational drug, whichever is longer, prior to study drug administration, or planned administration of another investigational product or procedure during the subject's participation in this study
研究组 & 干预措施
EXPAREL®
For those subjects randomized to EXPAREL® arm - the dose of EXPAREL® will be determined by the cohort. Starting at 1mL (13.3mg) for cohort 1, the volume of EXPAREL® will be increased by 1 mL in each subsequent cohort for a maximum of 4mL (53.2mg).
干预措施: EXPAREL (Drug)
Bupivacaine
In each cohort, subjects randomized to the bupivacaine arm will receive 15mg of plain bupivacaine HCL (the equivalent of 13.3mg bupivacaine base) providing a 1:1 reference to the starting dose level chosen for EXPAREL®.
干预措施: Bupivacaine Hydrochloride (Drug)
Placebo
Subjects in the placebo arm will receive normal saline intrathecal injection
干预措施: Placebo (Other)
结局指标
主要结局
Area under the plasma concentration-versus-time curve
时间窗: 6-8 weeks
Pharmacokinetic endpoint
Maximum plasma concentration (Cmax) and time of Cmax (Tmax).
时间窗: 6-8 weeks
Pharmacokinetic endpoint
The apparent terminal elimination half-life (t1/2el)
时间窗: 6-8 weeks
Pharmacokinetic endpoint
Apparent clearance (CL/F)
时间窗: 6-8 weeks
Pharmacokinetic endpoint
Apparent volume of distribution (Vd)
时间窗: 6-8 weeks
Pharmacokinetic endpoint
次要结局
- Incidence of treatment-emergent AEs (TEAEs) through Day 9(6-8 weeks)
- Proportion of subjects who have any of neurological events(6-8 weeks)