Phase 1 Evaluation of (2R,6R)-Hydroxynorketamine

NCT04711005 | Completed Phase 1 Results FDA Drug

• 2 other identifiers: HNK-378227-0118-01
• Study Type: interventional
• Target: 74
• Locations: 1 country
• Sites: 1

Brief Summary

A 6-cohort single ascending dose (SAD) study will be conducted in healthy volunteers utilizing a slow-infusion intravenous (IV) route of administration. Standard safety, pharmacokinetics (PK) and qEEG monitoring will be evaluated at all dose levels. Subsequently, a 2-cohort multiple ascending dose (MAD) study will be conducted. Doses will be administered on days 1, 4, 8, and 11. Standard safety parameters will be monitored, and PK will be evaluated at all dose levels. Finally, a single-cohort group with received a single dose by slow-infusion IV and have PK samples collected from both blood and cerebrospinal fluid (CSF).

Conditions

Major Depressive Disorder

Keywords

Healthy Volunteers; Depression; Antidepressant

Outcome Measures

Primary Outcomes (6)

• Number of Subjects With Adverse Events as a Measure of Safety and Tolerability of (2R,6R)-Hydroxynorketamine

  Investigational product-related adverse events and serious adverse events

  8 days post dosing (SAD)

• Number of Subjects With Adverse Events as a Measure of Safety and Tolerability of (2R,6R)-Hydroxynorketamine

  Investigational product-related adverse events and serious adverse events

  19 days post dosing (MAD)

• Pharmacokinetics of (2R,6R)-Hydroxynorketamine, Maximum Plasma Concentration (Cmax)

  This parameter will be calculated as appropriate and if possible for (2R,6R)-Hydroxynorketamine, depending on actual samples collected.

  3 days post dosing (SAD), 11 days post dosing (MAD)

• Pharmacokinetics of (2R,6R)-Hydroxynorketamine, Time Taken to Reach Maximum Plasma Concentration (Tmax)

  This parameter will be calculated as appropriate and if possible for (2R,6R)-Hydroxynorketamine, depending on actual samples collected.

  3 days post dosing (SAD), 11 days post dosing (MAD)

• Pharmacokinetics of (2R,6R)-Hydroxynorketamine, Area Under the Curve Concentration (AUC)

  This parameter will be calculated as appropriate and if possible for (2R,6R)-Hydroxynorketamine, depending on actual samples collected.

  3 days post dosing (SAD), 11 days post dosing (MAD)

• Pharmacokinetics of (2R,6R)-Hydroxynorketamine, Half-life (t1/2)

  This parameter will be calculated as appropriate and if possible for (2R,6R)-Hydroxynorketamine, depending on actual samples collected.

  3 days post dosing (SAD), 11 days post dosing (MAD)

Study Arms (10)

SAD Cohort 1

EXPERIMENTAL

(2R,6R)-Hydroxynorketamine @ 0.1 mg/kg via slow IV infusion (40 minutes)

Drug: (2R,6R)-Hydroxynorketamine hydrochloride

SAD Cohort 2

EXPERIMENTAL

(2R,6R)-Hydroxynorketamine @ 0.25 mg/kg via slow IV infusion (40 minutes)

Drug: (2R,6R)-Hydroxynorketamine hydrochloride

SAD Cohort 3

EXPERIMENTAL

(2R,6R)-Hydroxynorketamine @ 0.5 mg/kg via slow IV infusion (40 minutes)

Drug: (2R,6R)-Hydroxynorketamine hydrochloride

SAD Cohort 4

EXPERIMENTAL

(2R,6R)-Hydroxynorketamine @ 1.0 mg/kg via slow IV infusion (40 minutes)

Drug: (2R,6R)-Hydroxynorketamine hydrochloride

SAD Cohort 5

EXPERIMENTAL

(2R,6R)-Hydroxynorketamine @ 2.0 mg/kg via slow IV infusion (40 minutes)

Drug: (2R,6R)-Hydroxynorketamine hydrochloride

SAD Cohort 6

EXPERIMENTAL

(2R,6R)-Hydroxynorketamine @ 4.0 mg/kg via slow IV infusion (40 minutes)

Drug: (2R,6R)-Hydroxynorketamine hydrochloride

MAD Cohort 1

EXPERIMENTAL

(2R,6R)-Hydroxynorketamine @ 1.0 mg/kg via slow IV infusion (40 minutes) on days 1, 4, 7, 10

Drug: (2R,6R)-Hydroxynorketamine hydrochloride

MAD Cohort 2

EXPERIMENTAL

(2R,6R)-Hydroxynorketamine @ 2.0 mg/kg via slow IV infusion (40 minutes) on days 1, 4, 7, 10

Drug: (2R,6R)-Hydroxynorketamine hydrochloride

Placebo

PLACEBO COMPARATOR

Control product (placebo) will be sterile saline also administered via slow IV infusion (40 minutes).

Drug: Placebo

CSF Capture Cohort 1

EXPERIMENTAL

(2R,6R)-Hydroxynorketamine @ 0.25 mg/kg via slow IV infusion (40 minutes)

Drug: (2R,6R)-Hydroxynorketamine hydrochloride

Interventions

(2R,6R)-Hydroxynorketamine hydrochloride DRUG

(2R,6R)-Hydroxynorketamine is a metabolite of the drug ketamine. (2R,6R)-Hydroxynorketamine hydrochloride will be administered intravenously over a 40-minute period as a solution in a 25 mM sodium phosphate 0.9% w/v saline solution. The investigational drug product will be diluted into a 53 mL total volume of formulant.

CSF Capture Cohort 1; MAD Cohort 1; MAD Cohort 2; SAD Cohort 1; SAD Cohort 2; SAD Cohort 3; SAD Cohort 4; SAD Cohort 5; SAD Cohort 6

Placebo DRUG

Placebo will be made up of a 0.9% w/v saline solution (53 mL total volume) administered via slow IV infusion over a 40-minute period.

Placebo

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Be a healthy male or female between 18 and 65 years of age (inclusive).
• Voluntarily consents to participate in the study and provides written informed consent before the start of any study-specific procedures.
• Be willing and able to remain in the study unit for the entire duration of the confinement period and return for outpatient visits.
• Agree to comply with prohibitions and restrictions (section 8.5).
• Females must have a negative serum β-human chorionic gonadotropin (hCG) pregnancy test at screening and a negative urine pregnancy test on Day -1 prior to study initiation.
• Females must be of nonchildbearing potential or agree to use appropriate birth control, as defined in section 8.4 Contraception Requirements.
• Males must be surgically sterile for at least 90 days before screening or agree to use a condom with spermicide when sexually active with a female partner who is not using an acceptable form of birth control during the study and for 90 days after study administration. Males must also agree to not donate sperm starting at enrollment and for 90 days after last study drug administration.
• BMI (weight \[kg\]/\[m2\]) between 18 and 35 kg/m2 (inclusive) and weighs between 50 and 120 kg (110 - 264 pounds), inclusive.
• Blood pressure (after Subject is in a supine position for approximately 5 minutes) between 90 and 145 mmHg systolic (inclusive) and no higher than 90 mmHg diastolic at Screening and Day -1.
• A 12-lead ECG with no clinically significant abnormality as judged by the Investigator and QTc interval ≤ 450 milliseconds at Screening and Day -1.
• Resting pulse rate between 45 and 100 beats per minute at Screening and Day -1.
• Clinical laboratory findings and VS within normal range, or if outside of the normal ranges, deemed not clinically significant in the opinion of the Investigator.
• Agree to comply with the rules regarding consumption of alcohol, caffeinated beverages, and tobacco/nicotine products during the study.

You may not qualify if:

• History or presence of clinically significant medical illness including (but not limited to) hepatic, cardiovascular, pulmonary, renal, hematologic, endocrine, gastrointestinal, immunologic, dermatologic, neurologic, oncologic, or psychiatric disease that in the opinion of the Investigator would endanger the safety of the Subject or the validity of the study results.
• Clinically significant acute illness in the 2 weeks prior to dosing.
• Previous or current participation in any clinical study with an investigational drug, device, or biologic within 30 days or five half-lives of the investigational product to dosing.
• Preplanned surgery or procedures that would interfere with the conduct of the study.
• History of severe drug or excipient allergy, or hypersensitivity to be judged at the discretion of the Investigator.
• Donation or loss of greater than 0.5 L of blood within 90 days before screening or study start. Donation of platelets within 40 days before screening or study start. Donation of plasma within 14 days before screening or study start. Receipt of blood products within 60 days before screening or study start.
• Recent history (2 years) of alcohol or drug abuse at the discretion of the Investigator or a positive screen for alcohol or drugs of abuse (including marijuana) at screening and upon check-in.
• Testing positive for hepatitis B, hepatitis C, or HIV, or a history of any of these diseases. Subjects whose results are compatible with prior immunization may be included at the discretion of the Investigator.
• History of unexplained loss of consciousness, epilepsy, or other seizure disorders, or cerebrovascular disease.
• Malignancy within 5 years of screening visit (except basal cell or squamous cell skin carcinoma).
• Inability to adhere to the study unit diet.
• Use of any prescription or nonprescription medication (including vitamins, herbal preparations, and nutritional supplements) within the 14 days prior to dosing except for common analgesics (acetaminophen, ibuprofen), hormonal contraceptives or hormonal replacement therapy or nonsedating antihistamines. Topical medications may be allowed at the discretion of the Investigator.
• History or current diagnosis of mental illness including (but not limited to) psychotic disorder, bipolar disorder, schizophrenia, borderline personality disorder, and antisocial personality disorder, generalized anxiety disorder, obsessive compulsive disorder, posttraumatic stress disorder, and eating disorders.
• History of suicidal or homicidal ideation.
• Significant primary sleep disorder.

Sponsors & Collaborators

• National Institute of Mental Health (NIMH): lead

Study Sites (1)

Duke Early Phase Clinical Research

Durham, North Carolina, 27710, United States

Location

MeSH Terms

Conditions

Depressive Disorder, Major; Depression

Condition Hierarchy (Ancestors)

Depressive Disorder; Mood Disorders; Mental Disorders; Behavioral Symptoms; Behavior

Results Point of Contact

• Title: Michelle Mack
• Organization: Duke University School of Medicine

michelle.mack@duke.edu

919 613 1107

Study Officials

• Shruti Raja, MD, MHS

  Duke University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Model Details: A 6-cohort single ascending dose (SAD) study will be conducted in healthy volunteers followed by a 2-cohort multiple ascending dose (MAD) study in healthy volunteers, followed by a 1-cohort single ascending dose study with collection of cerebrospinal fluid (CSF) and plasma for pharmacokinetics.

Study Record Dates

• First Submitted: January 8, 2021
• First Posted: January 15, 2021
• Study Start: January 11, 2021
• Primary Completion: April 30, 2023
• Study Completion: May 31, 2023
• Last Updated: June 6, 2024
• Results First Posted: June 6, 2024

Record last verified: 2023-02

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)