Safety Study of Long-Acting Local Anesthetic

Phase 1

Completed

• Conditions: Safety of Neosaxitoxin in Healthy Volunteers
• Interventions: Drug: NeoSTX + bupivacaine 0.2%; Drug: Neosaxitoxin in saline; Drug: NeoSTX + bupivacaine 0.2% + epinephrine 5mcg/ml; Other: Saline placebo

• Registration Number: NCT01786655
• Lead Sponsor: Charles Berde

Brief Summary

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.

Detailed Description

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.

In double blind fashion, each subject will receive two injections simultaneously in a 3 cm x 3cm square area on skin of the posterior aspect of the lower leg (calf), one on each side. Each subject receives one injection with bupivacaine 0.2% alone on one side. On other side, they will receive one of 4 possible solutions: (1) saline placebo, (2) NeoSTX in saline or (3) NeoSTX in combination with bupivacaine or (4) NeoSTX in combination with bupivacaine 0.2% and epinephrine 5mcg/ml.

In each dose group, only one of the injections involves placebo. Prior to each dose increase, there is a safety review and confirmation that no stopping rule has been reached.

Specific Aims

1. Measure the dose dependence of FDA-AEs and SD-AEs from NeoSTX in saline;

2. Measure the dose dependence of FDA-AEs and SD-AEs from NeoSTX in bupivacaine 0.2%;

3. Measure the dose dependence of FDA-AEs and SD-AEs from NeoSTX in bupivacaine 0.2% with epinephrine 5mcg/ml;

4. Measure the serum and urine concentrations of NeoSTX following injections of NeoSTX alone or with bupivacaine 0.2% with and without epinephrine; and correlate the serum concentrations with the "Systemic Effects";

5. Evaluate skin integrity and other potential local reactions (edema, numbness, and paresthesia, erythema) in treated limbs receiving NeoSTX-saline, NeoSTX-bupivacaine, NeoSTX-bupivacaine-epinephrine or plain bupivacaine.

6. Using QST, establish the dependence of sensory blockade intensity and duration on NeoSTX dose and on presence or absence of bupivacaine and epinephrine;

Study Timeline

• Study First Submitted: 2013-02-06
• Study First Submitted QC: 2013-02-06
• Study First Posted: 2013-02-08
• Study Start: 2013-05
• Primary Completion: 2014-03
• Study Completion: 2014-04
• Status Verified: 2016-02
• Last Update Submitted: 2016-02-16
• Last Update Posted: 2016-02-17

Recruitment & Eligibility

• Status: COMPLETED
• Sex: Male
• Target Recruitment: 105

Inclusion Criteria

1. Healthy adult males ages 18-35
2. ASA physical status 1 or 2
3. English or Spanish speakers
4. 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
5. Must be able to provide informed consent
6. Must be able to understand and perform all the procedures of the study including self-reporting of symptom scores

Exclusion Criteria

1. ASA physical status 3 or greater
2. Cognitively challenged or other inability to understand the self-report measures or to give informed consent
3. Significant cardiovascular, respiratory, neuromuscular disease or other systemic illness(es)
4. No known or suspected allergies to neosaxitoxin, bupivacaine, or other local anesthetics
5. Subjects may not be on any pain controlling medications, or any medications that would alter pain tolerance
6. Subjects may not be on any medication that would alter cognition
7. Subjects may not have any acute or chronic pain conditions requiring ongoing treatment or limiting daily activities
8. No alcohol or illicit drug abuse
9. No current smokers

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Neosaxitoxin + bupivacaine 0.2%	NeoSTX + 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.
Neosaxitoxin in saline	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.
Neosaxitoxin + bupivacaine 0.2% + epinephrine 5mcg/ml	NeoSTX + 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.
Saline placebo	Saline placebo	Subjects receive one injection of saline on the back of one calf (test side).

Primary Outcome Measures

Name	Time	Method
Presence or absence of Adverse Events as a function of NeoSTX dose	Within 14 days of injection

Secondary Outcome Measures

Name	Time	Method
Cutaneous sensory blockade (numbness)	Within 14 days of injection	measured by noninvasive quantitative sensory testing (QST)
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

Trial Locations

Locations (1)

Boston Children's Hospital; 🇺🇸 Boston, Massachusetts, United States