Clinical TrialHealthy VolunteersKetamineKetamineKetaminePlaceboCompleted

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

Phase I randomised, double-blind IV infusion study in healthy volunteers (n=74): SAD (6 cohorts, 0.1–4.0 mg/kg single 40-min infusions), MAD (2 cohorts, 1.0–2.0 mg/kg on Days 1,4,7,10), plus CSF cohort; PK, qEEG and safety-focused assessments.

Target Enrollment
74 participants
Study Type
Phase I interventional
Design
Randomized, double Blind

Detailed Description

This Phase I study evaluates (2R,6R)-hydroxynorketamine hydrochloride in healthy adult volunteers using a slow 40-minute intravenous infusion across single ascending dose (SAD) cohorts, multiple ascending dose (MAD) cohorts, and a CSF capture cohort. Primary objectives are safety, tolerability, and pharmacokinetics including plasma and CSF sampling.

Safety assessments include AEs/SAEs, vitals, ECGs, clinical labs, ophthalmologic exams, C-SSRS, POMS, CADSS and MOAA/S. Pharmacodynamic measures include qEEG and serial PK sampling at multiple timepoints.

Study design incorporates sentinel dosing, placebo controls in each cohort, and predefined halting rules for dose escalation; MAD dosing occurs over four administrations with intensive safety monitoring.

Study Protocol

Preparation

sessions

Dosing

4 sessions
40 min each

Integration

sessions

Study Arms & Interventions

SAD cohorts

experimental

Six SAD cohorts with single IV slow-infusion (40 min) doses across 0.1–4.0 mg/kg; sentinel dosing and placebo in each cohort.

Interventions

  • Ketamine0.1 - 4 mg/kg
    via IV• single dose

    SAD cohorts 0.1–4.0 mg/kg by 40-min IV infusion; 6 cohorts; sentinel dosing; placebo 2 per cohort.

MAD cohorts

experimental

Two MAD cohorts receiving 4 IV infusions (days 1,4,7,10) of 1.0 or 2.0 mg/kg.

Interventions

  • Ketamine1 - 2 mg/kg
    via IV• four doses• 4 doses total

    MAD cohorts: 1.0 mg/kg and 2.0 mg/kg given on Days 1, 4, 7, 10 (40-min infusion).

CSF cohort

experimental

Single-cohort CSF capture with IV slow-infusion and paired plasma/CSF sampling.

Interventions

  • Ketamine0.25 - 2 mg/kg
    via IV• single dose

    CSF cohort doses include 0.25 mg/kg and 2.0 mg/kg; CSF sampled preinfusion, ~1h and ~8h post-infusion; 40-min infusion.

Placebo

inactive

Sterile saline placebo administered via slow IV infusion (40 minutes).

Interventions

  • Placebo
    via IV• single dose

    0.9% saline, 53 mL, 40-min slow IV infusion; placebo arms across SAD, MAD and CSF cohorts.

Participants

Ages
18 – 65
Sexes
Male & Female

Inclusion Criteria

  • Inclusion Criteria:
  • 1. Be a healthy male or female between 18 and 65 years of age (inclusive).
  • 2. Voluntarily consents to participate in the study and provides written informed consent before the start of any study-specific procedures.
  • 3. Be willing and able to remain in the study unit for the entire duration of the confinement period and return for outpatient visits.
  • 4. Agree to comply with prohibitions and restrictions (section 8.5).
  • 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.
  • 6. Females must be of nonchildbearing potential or agree to use appropriate birth control, as defined in section 8.4 Contraception Requirements.
  • 7. 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.
  • 8. BMI (weight [kg]/[m2]) between 18 and 35 kg/m2 (inclusive) and weighs between 50 and 120 kg (110 - 264 pounds), inclusive.
  • 9. 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.
  • 10. A 12-lead ECG with no clinically significant abnormality as judged by the Investigator and QTc interval ≤ 450 milliseconds at Screening and Day -1.
  • 11. Resting pulse rate between 45 and 100 beats per minute at Screening and Day -1.
  • 12. 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.
  • 13. Agree to comply with the rules regarding consumption of alcohol, caffeinated beverages, and tobacco/nicotine products during the study.

Exclusion Criteria

  • Exclusion Criteria:
  • 1. 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.
  • 2. Clinically significant acute illness in the 2 weeks prior to dosing.
  • 3. 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.
  • 4. Preplanned surgery or procedures that would interfere with the conduct of the study.
  • 5. History of severe drug or excipient allergy, or hypersensitivity to be judged at the discretion of the Investigator.
  • 6. 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.
  • 7. 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.
  • 8. 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.
  • 9. History of unexplained loss of consciousness, epilepsy, or other seizure disorders, or cerebrovascular disease.
  • 10. Malignancy within 5 years of screening visit (except basal cell or squamous cell skin carcinoma).
  • 11. Inability to adhere to the study unit diet.
  • 12. 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.
  • 13. 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.
  • 14. History of suicidal or homicidal ideation.
  • 15. Significant primary sleep disorder.
  • 16. Known allergy to ketamine, heparin, or any of the IDP components.
  • 17. Any strenuous exercise in the 2 days prior to study drug administration.
  • 18. Consumption of beverages or food that contain alcohol, grapefruit, poppy seeds, Brussel sprouts, pomegranate, broccoli, char-grilled meat within 2 days prior to drug administration.
  • 19. Use of tobacco or nicotine-containing products within 4 weeks prior to drug administration.
  • 20. Employee of the PI or study center with direct involvement in the proposed study or other studies under the direction of the study PI.
  • 21. Poor peripheral venous access.
  • 22. Close relative (parent, sibling, child) of clinical site employee.
  • 23. Subjects who, in the opinion of the PI or designee, should not participate in this study.

Study Details

Locations

Duke Early Phase Clinical Research — Durham, North Carolina, United States

Your Library