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Safety Study of Long-Acting Local Anesthetic

This study is currently recruiting participants. (see Contacts and Locations)
Verified May 2013 by Children's Hospital Boston
Sponsor:
Information provided by (Responsible Party):
Children's Hospital Boston
ClinicalTrials.gov Identifier:
NCT01786655
First received: February 6, 2013
Last updated: May 21, 2013
Last verified: May 2013
  Purpose

The primary aim of this Phase 1 study is to evaluate the safety of a new prolonged-duration local anesthetic (numbing agent), neosaxitoxin (NeoSTX). The investigators hypothesize that a "minimal adverse effect threshold" NeoSTX dose for subcutaneous administration, in saline and in bupivacaine 0.2% respectively, can be defined for awake, young adult healthy volunteer subjects. At the same time, the pharmacokinetics of the NeoSTX when delivered subcutaneously will be determined.


Condition Intervention Phase
Safety of Neosaxitoxin in Healthy Adult Male Volunteers
Drug: Neosaxitoxin (NeoSTX) in saline
Drug: NeoSTX with 0.2% bupivacaine
Other: Placebo
Phase 1

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Official Title: Neosaxitoxin (NeoSTX) Alone and in Combination With Bupivacaine as Prolonged Duration Local Anesthetics: A Phase I Investigator-initiated Dose Escalation Study

Resource links provided by NLM:


Further study details as provided by Children's Hospital Boston:

Primary Outcome Measures:
  • Presence or absence of Adverse Events as a function of NeoSTX dose [ Time Frame: Within 14 days of injection ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Pharmacokinetic parameters characterizing uptake and distribution of NeoSTX (content in serum and urine samples) [ Time Frame: Within 24 hours of injection ] [ Designated as safety issue: Yes ]
  • Cutaneous sensory blockade (numbness) [ Time Frame: Within 14 days of injection ] [ Designated as safety issue: Yes ]
    measured by noninvasive quantitative sensory testing (QST)

  • Local skin reactions (edema, paresthesias and urticaria) [ Time Frame: Within 14 days of injection ] [ Designated as safety issue: Yes ]

Estimated Enrollment: 77
Study Start Date: May 2013
Estimated Study Completion Date: October 2013
Estimated Primary Completion Date: October 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Neosaxitoxin in saline
Subjects receive one injection of NeoSTX in saline on the back of one calf (test side). Subjects receive NeoSTX in saline in subsequent dose escalation levels: 5 mcg, 15 mcg, 30 mcg, 45 mcg, 60 mcg, 70 mcg of NeoSTX.
Drug: Neosaxitoxin (NeoSTX) in saline
NeoSTX will be administered in sequential dose cohorts. Each subject receives one injection with bupivacaine 0.2% alone on one side. On the other side they receive NeoSTX in saline. Subjects receive NeoSTX in saline in subsequent dose escalation levels: 5 mcg, 15 mcg, 30 mcg, 45 mcg, 60 mcg, 70 mcg of NeoSTX.
Experimental: Neosaxitoxin + bupivacaine 0.2%
Subjects receive one injection of NeoSTX in combination with 0.2% bupivacaine on the back of one calf (test side). Subjects receive NeoSTX with 0.2% bupivacaine in subsequent dose escalation levels: 5 mcg, 15 mcg, 30 mcg, 45 mcg, 60 mcg, 70 mcg of NeoSTX.
Drug: NeoSTX with 0.2% bupivacaine
NeoSTX will be administered in sequential dose cohorts. Each subject receives one injection with bupivacaine 0.2% alone on one side. On the other side they receive NeoSTX with 0.2% bupivacaine. Subjects receive NeoSTX with 0.2% bupivacaine in subsequent dose escalation levels: 5 mcg, 15 mcg, 30 mcg, 45 mcg, 60 mcg, 70 mcg of NeoSTX.
Placebo Comparator: Saline placebo
Subjects receive one injection of saline on the back of one calf (test side).
Other: Placebo
Each subject receives one injection with bupivacaine 0.2% alone on one side. On the other side they receive saline placebo.

  Hide Detailed Description

Detailed Description:

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. The hypothesis is that, using adverse events as endpoints, a "minimal adverse effect threshold" NeoSTX dose for subcutaneous administration, in saline and in bupivacaine 0.2% respectively, can be defined for awake, young adult healthy volunteer subjects.

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.

A sequential dose escalation design will be used with groups of either 7, 11, or 15 subjects in each dose step. 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, in a randomized block design as outlined in Table 1. Each subject receives one injection with bupivacaine 0.2% alone on one side. On other side, they will receive one of 3 possible solutions: (1) saline placebo, (2) NeoSTX in saline or (3) NeoSTX in combination with bupivacaine. The dose of NeoSTX will escalate in subsequent cohorts as follows: 5 mcg; 15 mcg; 30 mcg; 45 mcg; 60 mcg; 70 mcg

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.

The first cohort begins with 7 subjects (3 receiving NeoSTX in saline, 3 receiving NeoSTX in bupivacaine, 1 receiving saline placebo).

The size of successive cohorts remains at 7 subjects as long as there are:

  1. 0 Grade 2, 3 or 4 FDA-AEs
  2. 0 Grade 2, 3 or 4 SD-AEs

If there is one Grade 2 FDA-AEs or one Grade 2 SD-AEs, but no stopping rule is triggered, then the size of subsequent cohorts is increased to 11 subjects.

If a stopping rule is triggered, then the dose is reduced to the previous step, defined as the "Maximum Tolerated Dose" and additional subjects are enrolled to reach a total of 15 subjects at that dose. Thus, for example, if 11 subjects had been enrolled at a dose of 30 mcg, dosing was escalated to 45 mcg and then a stopping rule was triggered, then dosing of 45 mcg would stop and 4 additional subjects would be enrolled at the 30 mcg dose.

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 serum and urine concentrations of NeoSTX following injections of NeoSTX alone or with bupivacaine 0.2%; and correlate the serum concentrations with the "Systemic Effects";
  4. Evaluate skin integrity and other potential local reactions (edema, numbness, and paresthesia, erythema) in treated limbs receiving NeoSTX-saline, NeoSTX-bupivacaine, or plain bupivacaine.
  5. Using QST, establish the dependence of sensory blockade intensity and duration on NeoSTX dose and on presence or absence of bupivacaine;

Hypotheses

  1. Using FDA-AEs and SD-AEs as endpoints, a "minimal adverse effect threshold" NeoSTX dose for subcutaneous administration, in saline and in bupivacaine 0.2% respectively, can be defined for awake, young adult healthy volunteer subjects.
  2. PK-PD analysis will define serum concentrations associated with onset of "Systemic Effects" induced by NeoSTX.
  3. NeoSTX will have a low frequency of adverse skin reactions.
  4. The intensity and duration of sensory blockade from NeoSTX in saline or NeoSTX in bupivacaine will vary with NeoSTX dose and with presence or absence of bupivacaine.
  Eligibility

Ages Eligible for Study:   18 Years to 35 Years
Genders Eligible for Study:   Male
Accepts Healthy Volunteers:   Yes
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01786655

Contacts
Contact: Joseph Cravero, MD 617-355-7737
Contact: Kimberly Lobo, MPH 857-218-3556 kimberly.lobo@childrens.harvard.edu

Locations
United States, Massachusetts
Boston Children's Hospital Recruiting
Boston, Massachusetts, United States, 02115
Principal Investigator: Joseph Cravero, MD         
Sponsors and Collaborators
Children's Hospital Boston
Investigators
Principal Investigator: Joseph Cravero, MD Children's Hospital Boston
  More Information

No publications provided

Responsible Party: Children's Hospital Boston
ClinicalTrials.gov Identifier: NCT01786655     History of Changes
Other Study ID Numbers: IRB-P00003344
Study First Received: February 6, 2013
Last Updated: May 21, 2013
Health Authority: United States: Food and Drug Administration

Keywords provided by Children's Hospital Boston:
local anesthetic
neosaxitoxin
neoSTX
bupivacaine
safety
phase 1
pharmacokinetic

Additional relevant MeSH terms:
Anesthetics
Anesthetics, Local
Bupivacaine
Neosaxitoxin
Central Nervous System Agents
Central Nervous System Depressants
Neuromuscular Agents
Neuromuscular Blocking Agents
Peripheral Nervous System Agents
Pharmacologic Actions
Physiological Effects of Drugs
Sensory System Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on November 20, 2014