Safety Study of Long-Acting Local Anesthetic
Condition: Safety of Neosaxitoxin in Healthy Volunteers
Study type: Interventional
Phase: Phase 1

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;
    

Intervention name(s): Neosaxitoxin in saline; NeoSTX + bupivacaine 0.2%; NeoSTX + bupivacaine 0.2% + epinephrine 5mcg/ml; Saline placebo
Intervention type(s): Drug; Drug; Drug; Other
Intervention description(s): NeoSTX will be administered in sequential dose cohorts. Each subject receives one injection with bupivacaine 0.2% alone on one side (control). On the other side they receive NeoSTX in saline (test). Subjects receive NeoSTX in saline in subsequent dose escalation levels: 5 mcg, 10 mcg, 15 mcg, 20 mcg, 30 mcg, and 40 mcg of NeoSTX.; NeoSTX will be administered in sequential dose cohorts. Each subject receives one injection with bupivacaine 0.2% on one side (control). On the other side they receive NeoSTX with 0.2% bupivacaine. Subjects receive NeoSTX in 0.2% bupivacaine in subsequent dose escalation levels: 5 mcg, 10 mcg, 15 mcg, 20 mcg, 30 mcg, and 40 mcg of NeoSTX.; Each subject receives one injection with bupivacaine 0.2% on one side (control). On the other side they receive NeoSTX in 0.2% bupivacaine with epinephrine 5 mcg/ml. Subjects receive NeoSTX in 0.2% bupivacaine with epinephrine 5 mcg/ml in doses of 10 mcg or 30 mcg of NeoSTX.; Each subject receives one injection with bupivacaine 0.2% alone on one side. On the other side they receive saline placebo.
Intervention MeSH terms: Epinephrine; Bupivacaine; Neosaxitoxin
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Keywords: local anesthetic; neosaxitoxin; neoSTX; bupivacaine; safety; phase 1; pharmacokinetic