Neosaxitoxin (NeoSTX) Alone and in Combination With Bupivacaine as Prolonged Duration Local Anesthetics: A Phase I Investigator-initiated Dose Escalation Study
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- 入组人数
- 105
- 试验地点
- 1
- 主要终点
- Presence or absence of Adverse Events as a function of NeoSTX dose
研究概览
简要总结
The primary aim of this Phase 1 study is to evaluate the systemic safety of a novel prolonged-duration local anesthetic, Neosaxitoxin (NeoSTX), given by subcutaneous injection in combination with the commonly used local anesthetic, bupivacaine, and epinephrine.
The investigators hypothesize that a "minimal adverse effect threshold" NeoSTX dose for subcutaneous administration in combination with bupivacaine 0.2% and epinephrine 5mcg/ml respectively, can be defined for awake, young adult healthy volunteer subjects. At the same time, the pharmacokinetics of NeoSTX when delivered subcutaneously will be determined.
详细描述
Currently available amino amide local anesthetics (e.g. bupivacaine, levobupivacaine, ropivacaine) do not reliably provide analgesia beyond roughly 8 hours following subcutaneous infiltration. In addition, they can cause systemic toxicities such as seizures, arrhythmias, and cardiac arrest, as well as local tissue toxicities to muscle, cartilage and nerve. Therefore, there is a need for safe local anesthetics that can provide longer duration analgesia with low systemic and local tissue toxicities.
The investigator team previously reported that tetrodotoxin, saxitoxin, and NeoSTX could produce prolonged sensory blockade (numbness) and motor blockade (weakness) following injection near the sciatic nerves in rats. In these studies, combining the site 1 toxin with either bupivacaine or epinephrine dramatically improved efficacy (duration of sensory blockade) and reduced systemic toxicity.
NeoSTX is the most potent member of the STX series identified to date. In preliminary studies, investigators at the University of Chile, Santiago, and with a small biotech company, Proteus S.A, developed a bioreactor process to produce clinical grade NeoSTX efficiently, with excellent purity, stability, sterility and non-pyrogenicity. A series of preclinical safety and toxicologic studies in mice, rats, and sheep were performed at CHB and Toxikon, Inc.
In this proposal, the investigators plan to conduct a Phase I study to be performed under an Investigator-Initiated FDA IND to further establish the systemic and local safety of escalating doses of NeoSTX via sub-cutaneous infiltration in healthy and awake young adult male human volunteer subjects.
The primary aim of this Phase 1 study is to evaluate the systemic safety of a novel prolonged-duration local anesthetic, neosaxitoxin (NeoSTX), given by subcutaneous injection, either alone or in combination with the commonly used local anesthetic, bupivacaine, and epinephrine. The hypothesis is that, using adverse events as endpoints, a "minimal adverse effect threshold" NeoSTX dose for subcutaneous administration in combination with bupivacaine 0.2% and epinephrine 5mcg/ml respectively, can be defined for awake, young adult healthy volunteer subjects.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 35 Years（Adult）
- 性别
- Male
- 接受健康志愿者
- 是
入选标准
- •Healthy adult males ages 18-35
- •ASA physical status 1 or 2
- •English or Spanish speakers
- •Must be able to come to Boston Children's Hospital for a 24-hour stay and able and willing to attend 5-10 study visits
- •Must be able to provide informed consent
- •Must be able to understand and perform all the procedures of the study including self-reporting of symptom scores
排除标准
- •ASA physical status 3 or greater
- •Cognitively challenged or other inability to understand the self-report measures or to give informed consent
- •Significant cardiovascular, respiratory, neuromuscular disease or other systemic illness(es)
- •No known or suspected allergies to neosaxitoxin, bupivacaine, or other local anesthetics
- •Subjects may not be on any pain controlling medications, or any medications that would alter pain tolerance
- •Subjects may not be on any medication that would alter cognition
- •Subjects may not have any acute or chronic pain conditions requiring ongoing treatment or limiting daily activities
- •No alcohol or illicit drug abuse
- •No current smokers
研究组 & 干预措施
Neosaxitoxin in saline
Subjects receive only one injection of NeoSTX in saline on the back of one calf (test side). Subjects receive NeoSTX in saline in subsequent dose escalation levels: 5mcg, 10mcg, 15mcg, 20mcg, 30mcg, and 40mcg NeoSTX.
干预措施: Neosaxitoxin in saline (Drug)
Neosaxitoxin + bupivacaine 0.2%
Subjects receive only one injection of NeoSTX in combination with 0.2% bupivacaine on the back of one calf (test side). Subjects receive NeoSTX in bupivacaine in subsequent dose escalation levels: 5 mcg, 10 mcg, 15 mcg, 20 mcg, 30 mcg, and 40 mcg NeoSTX.
干预措施: NeoSTX + bupivacaine 0.2% (Drug)
Neosaxitoxin + bupivacaine 0.2% + epinephrine 5mcg/ml
Subjects receive one injection of NeoSTX in bupivacaine 0.2% with epinephrine 5 mcg/ml on the back of one calf (test side). Subjects receive NeoSTX in bupivacaine 0.2% with epinephrine 5 mcg/ml in doses of 10 mcg or 30 mcg of NeoSTX.
干预措施: NeoSTX + bupivacaine 0.2% + epinephrine 5mcg/ml (Drug)
Saline placebo
Subjects receive one injection of saline on the back of one calf (test side).
干预措施: Saline placebo (Other)
结局指标
主要结局
Presence or absence of Adverse Events as a function of NeoSTX dose
时间窗: Within 14 days of injection
次要结局
- Cutaneous sensory blockade (numbness)(Within 14 days of injection)
- Local skin reactions (edema, paresthesias and urticaria)(Within 14 days of injection)
- Pharmacokinetic parameters characterizing uptake and distribution of NeoSTX (content in serum and urine samples)(Within 24 hours of injection)
研究者
Charles Berde
Chief, Division of Pain Medicine (Department of Anesthesiology, Perioperative, and Pain Medicine)
Boston Children's Hospital