A Phase 1, Double-Blind, Active- and Placebo-Controlled Dose Escalation Study to Evaluate the Safety, Pharmacokinetics and Pharmacodynamics of Liposomal Bupivacaine 13.3 Administered Via a Single Intrathecal Injection to Healthy Volunteers
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 54
- 试验地点
- 1
- 主要终点
- Area under the plasma concentration-versus-time curve (AUC0-last and AUC0- ∞)
研究概览
简要总结
Primary Objective: To assess the safety and tolerability of Liposomal Bupivacaine 13.3 administered as a single intrathecal injection in healthy volunteers.
Secondary Objective: To characterize the pharmacokinetic (PK) and pharmacodynamic (PD) profile of Liposomal Bupivacaine 13.3 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 54 adult healthy subjects (Cohort 1, Cohort 2, and Cohort 3). Eighteen subjects will be enrolled in each of the 3 cohorts.
Subjects in Cohort 1, Cohort 2, and Cohort 3 will be randomized 1:1:1 with 6 subjects receiving Liposomal Bupivacaine 13.3 intrathecal (IT), 6 subjects receiving bupivacaine IT, and 6 subjects receiving placebo IT in each cohort.
The dose of Liposomal Bupivacaine 13.3 (and volume of injectate across all three treatment arms) will be determined by the cohort. Cohort 1 subjects randomized to the Liposomal Bupivacaine 13.3 arm will be dosed 2 mL (26.6 mg) of Liposomal Bupivacaine 13.3, Cohort 2 subjects randomized to the Liposomal Bupivacaine 13.3 arm will be dosed 3 mL (39.9 mg) of Liposomal Bupivacaine 13.3, and Cohort 3 subjects randomized to the Liposomal Bupivacaine 13.3 arm will be dosed 4 mL (53.2 mg) of Liposomal Bupivacaine 13.3.
The dose of bupivacaine IT administered in all cohorts will be 15 mg. Cohort 1 subjects randomized to the bupivacaine arm will be dosed 2 mL (7.5 mg/ 1 mL) of 0.75% bupivacaine. Cohort 2 subjects randomized to the bupivacaine arm will be dosed 2 mL (7.5 mg/ 1 mL) of 0.75% bupivacaine mixed with 1 mL of preservative free normal saline to create a total volume of solution administered of 3 mL. Cohort 3 subjects randomized to the bupivacaine arm will be dosed 2 mL (7.5 mg / 1 mL) of 0.75% bupivacaine mixed with 2 mL of preservative free normal saline to create a total volume of solution administered of 4 mL.
Cohort 1 subjects randomized to the placebo arm will be dosed 2 mL of preservative free normal saline. Cohort 2 subjects randomized to the placebo arm will be dosed 3 mL of preservative free normal saline. Cohort 3 subjects randomized to the placebo arm will be dosed 4 mL of preservative free normal saline.
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 physical status 1
- •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 (e.g., amide-type local anesthetics, opioids, bupivacaine, NSAIDs, spinal anesthesia).
- •Impaired renal or hepatic function (e.g., serum creatinine level >2 mg/dL [176.8 µmol/L], blood urea nitrogen level >50 mg/dL [17.9 mmol/L], serum aspartate aminotransferase level >1.5 times the upper limit of normal [ULN], or serum alanine aminotransferase 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).
- •Subjects with a history of a difficult airway or a potential difficult airway based on exam by an anesthesiologist.
- •Subjects with a history of migraine, cluster, or tension headache (diagnosed by a healthcare provider) at any time over the life-course.
- •Subjects without a formal headache diagnosis, but currently experiencing frequent headaches (of any severity), defined as headache occurring > or = 1 time per week for the last 3 months. Subjects who report hormonal headaches occurring during their monthly menstrual cycle that are not diagnosed by a healthcare provider (e.g., pure menstrual migraine without aura, menstrually-related migraine without aura, pure menstrual migraine with aura, menstrually-related migraine with aura) will be excluded if there is a reported pattern of headaches that occur consistently or most of the time during or before their monthly menstrual period. Note: if a subject reports hormonal headaches that are not diagnosed by a healthcare provider, the subject may be included in the study if the headache episodes are infrequent (e.g., one episode in the past 3 months), at the discretion of the Principal Investigator.
- •Subjects with a history of a lower back condition (e.g., ankylosing spondylitis, scoliosis, dysraphism, prior back surgery) or a history of chronic low back pain.
- •Subjects with BMIs less than 20 kg/m
- •Comorbidity impacting current physical function that, in the opinion of the investigator, may confound the post dosing assessments
- •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 test confirming menopause at screening.
- •Currently pregnant, nursing, or planning to become pregnant during the study.
- •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 sponsored study.
- •Use of systemic corticosteroids up to 3 days prior to study drug administration.
- •Initiation of treatment with neuromodulating agents (e.g., gabapentin, pregabalin [Lyrica], duloxetine [Cymbalta] etc.) within 1 month prior to Screening or ongoing concomitant use if use is for pain control. a. Subject will be excluded if on neuromodulating agents for chronic pain management. Note: if a subject is on a neuromodulating agent for a reason other than pain control (e.g., a depressive disorder), he or she must be on a stable dose for at least 1 month prior to Screening to be included in the study
- •Opioid medications and NSAIDs are not permitted up to 3 days prior to study drug administration.
- •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
Liposomal Bupivacaine 13.3
Cohort 1 subjects will be dosed 2 mL (26.6 mg) of Liposomal Bupivacaine 13.3.
Cohort 2 subjects randomized to the Liposomal Bupivacaine 13.3 arm will be dosed 3 mL (39.9 mg) of Liposomal Bupivacaine 13.3.
Cohort 3 subjects randomized to the Liposomal Bupivacaine 13.3 arm will be dosed 4 mL (53.2 mg) of Liposomal Bupivacaine 13.3.
干预措施: Liposomal Bupivacaine 13.3 (Drug)
Bupivacaine IT
Cohort 1 subjects randomized to the bupivacaine arm will be dosed 2 mL (7.5 mg/ 1 mL) of 0.75% bupivacaine.
Cohort 2 subjects randomized to the bupivacaine arm will be dosed 2 mL (7.5 mg/ 1 mL) of 0.75% bupivacaine mixed with 1 mL of preservative free normal saline to create a total volume of solution administered of 3 mL.
Cohort 3 subjects randomized to the bupivacaine arm will be dosed 2 mL (7.5 mg / 1 mL) of 0.75% bupivacaine mixed with 2 mL of preservative free normal saline to create a total volume of solution administered of 4 mL.
干预措施: Bupivacaine (Drug)
Placebo
Cohort 1 subjects randomized to the placebo arm will be dosed 2 mL of preservative free normal saline.
Cohort 2 subjects randomized to the placebo arm will be dosed 3 mL of preservative free normal saline.
Cohort 3 subjects randomized to the placebo arm will be dosed 4 mL of preservative free normal saline.
干预措施: Placebo (Other)
结局指标
主要结局
Area under the plasma concentration-versus-time curve (AUC0-last and AUC0- ∞)
时间窗: 7-8 weeks
Pharmacokinetic Endpoint
Maximum plasma concentration (Cmax)
时间窗: 7-8 weeks
Pharmacokinetic Endpoint
Time of Cmax (Tmax)
时间窗: 7-8 weeks
Pharmacokinetic Endpoint
The apparent terminal elimination half-life (t1/2el)
时间窗: 7-8 weeks
Pharmacokinetic Endpoint
Apparent clearance (CL/F)
时间窗: 7-8 weeks
Pharmacokinetic Endpoint
Apparent volume of distribution (Vd)
时间窗: 7-8 weeks
Pharmacokinetic Endpoint
次要结局
- Average time to onset of sensory block and motor block(7-8 weeks)
- Average duration of sensory block and motor block(7-8 weeks)