A Study in Healthy Male Volunteers to Investigate the Safety and Tolerability of a Single Dose of Neosaxitoxin Alone and in Combination With Bupivacaine (With and Without Epinephrine) for Brachial Plexus Blockade

NCT03399435 | Terminated Phase 1

• 3 other identifiers: HP7020-022016-003958-33U1111-1189-1950
• Study Type: interventional
• Target: 242
• Locations: 1 country
• Sites: 1

Brief Summary

Neosaxitoxin is a new compound that is in clinical development as local anesthetic for surgical anesthesia and postoperative analgesia. The primary objective of this study is to evaluate the systemic and local safety and tolerability of ascending doses of neosaxitoxin alone and in combination with fixed doses of bupivacaine (with and without epinephrine), following brachial plexus blockade in healthy male subjects. Secondary objectives:

• Evaluate the pharmacodynamics (PD) of ascending doses of neosaxitoxin, alone and in combination with fixed doses of bupivacaine (with and without epinephrine), following brachial plexus blockade.
• Characterize the pharmacokinetics (PK) of neosaxitoxin and bupivacaine after brachial plexus blockade with neosaxitoxin alone or different drug combinations: neosaxitoxin and epinephrine, neosaxitoxin and bupivacaine, or neosaxitoxin and bupivacaine and epinephrine.

Conditions

Anesthesia; Anesthesia, Local; Analgesia

Keywords

Regional anesthesia; Brachial plexus blockade; Sensory and motor function testing

Outcome Measures

Primary Outcomes (2)

• Occurrence of dose limiting events (DLEs) in all parts of the trial.

  up to 15 days after IMP (investigational medicinal product, i.e. study drug administration)

• Occurrence of other adverse events (AEs) leading to premature termination of dose escalation in Part A and Part B.

  up to 15 days after IMP administration

Secondary Outcomes (14)

• Cold detection threshold (CDT).

  Baseline, 24 and 48 hours after IMP administration

• Warm detection threshold (WDT)

  Baseline, 24 and 48 hours after IMP administration

• Mechanical detection threshold (MDT)

  Baseline, 24 and 48 hours after IMP administration

• Cold pain threshold (CPT)

  Baseline, 24 and 48 hours after IMP administration

• Heat pain threshold (HPT)

  Baseline, 24 and 48 hours after IMP administration

Study Arms (3)

Part A

EXPERIMENTAL

8 cohorts are planned to be treated.

Combination Product: Neosaxitoxin combined with bupivacaine low and epinephrine (T1); Combination Product: Bupivacaine low combined with epinephrine (C1); Combination Product: Bupivacaine high combined with epinephrine (C2)

Part B

EXPERIMENTAL

Part B will start at the earliest after 4 cohorts of Part A have been treated. Up to 8 cohorts are planned to be treated.

Combination Product: Neosaxitoxin combined with bupivacaine low (T2); Drug: Bupivacaine low (C3); Drug: Bupivacaine high (C4)

Part C

EXPERIMENTAL

Part C will comprise 4 treatment groups. The neosaxitoxin dose will be the same in all 4 treatment groups.

Drug: Neosaxitoxin (T3); Combination Product: Neosaxitoxin combined with epinephrine (T4); Combination Product: Neosaxitoxin combined with bupivacaine low and epinephrine; Combination Product: Neosaxitoxin combined with bupivacaine low

Interventions

Neosaxitoxin combined with bupivacaine low and epinephrine (T1) COMBINATION_PRODUCT

A single injection: Neosaxitoxin from 1.25 to 60 µg. Bupivacaine 40 mg. Epinephrine 100 µg.

Part A

Bupivacaine low combined with epinephrine (C1) COMBINATION_PRODUCT

A single injection: Bupivacaine 40 mg. Epinephrine dose 100 µg.

Part A

Bupivacaine high combined with epinephrine (C2) COMBINATION_PRODUCT

A single injection: Bupivacaine 100 mg. Epinephrine 100 µg.

Part A

Neosaxitoxin combined with bupivacaine low (T2) COMBINATION_PRODUCT

A single injection: Neosaxitoxin from 1.25 to 60 μg. Bupivacaine from 10 to 80 mg.

Part B

Bupivacaine low (C3) DRUG

A single injection: Bupivacaine from 10 to 80 mg.

Part B

Bupivacaine high (C4) DRUG

A single injection: Bupivacaine 100 mg.

Part B

Neosaxitoxin (T3) DRUG

A single injection: Neosaxitoxin will be between 1.25 and 60 µg.

Part C

Neosaxitoxin combined with epinephrine (T4) COMBINATION_PRODUCT

A single injection: Neosaxitoxin will be between 1.25 and 60 μg. Epinephrine 100 µg.

Part C

Neosaxitoxin combined with bupivacaine low and epinephrine COMBINATION_PRODUCT

A single injection: Neosaxitoxin will be between 1.25 to 60 µg. Bupivacaine dose based on results from Part B (10 to 80 mg). Epinephrine 100 µg.

Part C

Neosaxitoxin combined with bupivacaine low COMBINATION_PRODUCT

A single injection: Neosaxitoxin will be between 1.25 to 60 μg. Bupivacaine dose based on results from Part B (10 to 80 mg).

Part C

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: male
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Subject has given written informed consent to participate.
• Male subject, aged 18 years to 55 years, inclusive.
• Body mass index between 20.0 kg/m2 and 30.0 kg/m2 inclusive, with a minimal body weight of 60.0 kg.
• Subject must be in good health as determined by the prior/concomitant diseases, physical and laboratory examinations.
• Subject must be willing not to donate sperm and to use barrier contraception (condom) during sexual intercourse with women from the administration of IMP until Day 90 since IMP administration. The subject must be willing to ensure that the female sexual partner of childbearing potential uses at least 1 additional method of contraception with a low failure rate defined as \<1% per year (e.g., oral contraceptives) during this time frame. A single barrier method alone is not acceptable.

You may not qualify if:

• At enrollment:
• Resting pulse rate \<50 beats or \>90 beats per minute.
• Resting systolic blood pressure \<90 mmHg or \>140 mmHg. Resting diastolic blood pressure \>90 mmHg.
• Prolongation of QTcF at enrollment, i.e., QTcF \>450 ms, or presence of any other of risk factors for torsade de pointes or other disturbances of cardiac de- and repolarization.
• Any out-of-reference range value for the following safety laboratory parameters: GGT, serum creatinine, PT, and INR.
• Any out-of-reference range value for any other safety laboratory parameter that is judged as clinically relevant by the investigator.
• Positive or missing virus serology test for HIV Type 1 or Type 2 antibodies and antigen, hepatitis B surface antigen, hepatitis B core antibodies, or hepatitis C virus antibodies.
• Subject received IMP in another clinical trial within 1 month before the Enrollment Visit. Depending on the nature of the previous IMP, a longer washout may be needed.
• Diseases or conditions known to interfere with the distribution, metabolism, or excretion of drugs.
• History of orthostatic hypotension.
• History of, or at risk of seizures.
• Significant cardiovascular, respiratory, neuromuscular diseases, or other systemic illness.
• Subject with an oxygen saturation of less than 95%, as measured by pulse oximetry, or subject with known or suspected respiratory difficulty or any condition that may compromise a subject's breathing or ability to maintain adequate oxygen saturation.
• Known vocal chord palsy.
• Any relevant symptom of neurological dysfunction of the motor and sensory system based on sensory and motor function testing. History or presence of symptoms of depression or anxiety disorders.

Sponsors & Collaborators

• Grünenthal GmbH: lead

Study Sites (1)

NL001

Groningen, 9728 NZ, Netherlands

Location

MeSH Terms

Conditions

Agnosia

Interventions

Epinephrine; neosaxitoxin; Triiodothyronine

Condition Hierarchy (Ancestors)

Perceptual Disorders; Neurobehavioral Manifestations; Neurologic Manifestations; Nervous System Diseases; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Ethanolamines; Amino Alcohols; Alcohols; Organic Chemicals; Amines; Biogenic Monoamines; Biogenic Amines; Catecholamines; Catechols; Phenols; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Thyronines; Thyroid Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Thyroxine; Amino Acids, Aromatic; Amino Acids, Cyclic; Amino Acids; Amino Acids, Peptides, and Proteins

Study Officials

• Study Director

  Grünenthal GmbH

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Sponsor, personnel of the central research pharmacy at the site, the pharmacy CRA and the bioanalytical lab are not blinded.
• Purpose: OTHER
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: Part A: 8 cohorts (equivalent to 40 subjects) are planned to be treated with ascending doses of neosaxitoxin combined with fixed doses of bupivacaine and epinephrine. Part B: Part B will start at the earliest after 4 cohorts of Part A have been treated. Ascending doses of neosaxitoxin combined with fixed doses of bupivacaine. Part C: Part C will comprise 4 treatment groups in which all participants will receive the same neosaxitoxin dose alone, or neosaxitoxin combined with epinephrine, or neosaxitoxin combined with bupivacaine with or without epinephrine.

Study Record Dates

• First Submitted: January 8, 2018
• First Posted: January 16, 2018
• Study Start: January 30, 2018
• Primary Completion: September 21, 2018
• Study Completion: September 21, 2018
• Last Updated: October 11, 2018

Record last verified: 2018-10

Data Sharing

• IPD Sharing: Will share

Locations

NL (1)