Phase 1 Evaluation of (2R,6R)-Hydroxynorketamine
Condition: Major Depressive Disorder
MeSH terms: Depressive Disorder; Depressive Disorder, Major
Study type: Interventional
Phase: Phase 1

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).
    

Detailed description: 
      A total of 48 Subjects are planned to be enrolled in a 6-cohort SAD study (36 in the
      treatment groups and 12 in the control groups). All SAD cohorts will have 6 Subjects in the
      treatment group and 2 Subjects in placebo group. All cohorts in the SAD study will
      incorporate sentinel dosing which will include 1 active and 1 placebo Subject. All remaining
      Subjects will be dosed at least 24 hours after the sentinel cohort participants. A total of
      16 Subjects are planned to be enrolled in a 2 cohort MAD study (12 in the treatment groups
      and 4 in the control groups). All MAD cohorts will have 6 Subjects in the treatment group and
      2 Subjects in placebo group. A total of 6 subjects are planned to be enrolled in a single
      cohort CSF capture study. The CSF cohort will have 4 in the treatment group and 2 in the
      placebo group.

      (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 SAD doses will
      range from 0.1 mg/kg to 4.0 mg/kg and the investigational drug product will be diluted into a
      53 mL total volume of formulant. Placebo will be made up of a 0.9% w/v saline solution (53 mL
      total volume) also administered via slow IV infusion over a 40-minute period. The MAD doses
      will range from 1.0 mg/kg to 2.0 mg/kg administered as a 40 minute infusion period in a
      solution of 25 mM sodium phosphate 0.9% w/v saline solution on days 1, 4, 8 and 11. The CSF
      capture doses will be 0.25 mg/mk and 2.0 mg/kg administered via slow infusion over a 40
      minute period in 0.9% w/v saline solution.

      Serial PK blood samples will be collected during the SAD portion for each Subject receiving
      drug and placebo at 9 timepoints (preinfusion, end-of-infusion [approximately 40 minutes], 1,
      2, 4, 8, 12, 24, and approximately 48 hr after the start of the infusion). Pharmacokinetic
      urine samples will be collected during the SAD study for each Subject receiving drug and
      placebo at set intervals following the initiation-of-infusion (0-4, >4-8, >8-12, >12-24 hr).
      Serial PK blood samples will be collected for for each Subject receiving drug and placebo.
      Blood PK samples will be obtained at 8 timepoints for teh first and forth (last) dosing in
      the MAD study (preinfusion, end-of-infusion [approximately 40 minutes], 1, 2, 4, 8, 12, and
      approximately 24 hrs after the start of the infusion). Two PK blood samples will be collected
      for the second and third dosing in the MAD study for each subject receiving drug and placebo
      at approximately 10 minutes predose and at the end of the infusion. Serial PK blood samples
      will be collected for the single dose CSF capture study for each Subject receiving drug and
      placebo. Blood PK samples will be obtained at 8 timepoints (preinfusion, end-of-infusion
      [approximately 40 minutes], 1, 2, 4, 8, 12, and approximately 24hr after the start of the
      infusion). CSF samples will be obtained preinfusion, and at 2 timepoints (1h and 8 hours)
      post infusion.

      Safety will be assessed throughout the study. Baseline and follow-up safety assessments will
      include height, body mass index (BMI), weight, temperature, medical, visual and ocular
      history, physical examinations, ocular examinations, visual acuity, color vision tests,
      electrocardiograms (ECGs), vital signs (VS), clinical laboratory tests (hematology, serum
      chemistry, and urinalysis), the Profile of Mood States (POMS), the Columbia-Suicide Severity
      Rating Scale (C-SSRS), the Clinician Administered Dissociative States Scale (CADSS), and
      adverse events (AEs). Safety assessments will include AEs, ECGs, VS, clinical laboratory
      results, and physical observations. Assessment of each Subject's level of alertness/sedation
      will be accomplished using the Modified Observer's Assessment of Alertness/Sedation (MOAA/S).
      Evaluation of safety in the MAD study will utilize the same safety assessments used in the
      SAD study. Evaluation of safety in the CSF capture study will utilize the same safety
      assessments used in the SAD and MAD study with the exception of the POMS and CADSS
      assessments. Monitoring of AEs will be governed by change from baselines established during
      prescreening and Day -1 examinations and clinical laboratory tests. Dose escalation in the
      SAD study or continued dosing in the MAD study may be stopped according to the predefined
      halting rules or if a Subject's scores demonstrate acute suicidality on the C-SSRS assessment
      or at the discretion of the study Principal Investigator and/or sponsor. Determination of
      whether to escalate to the next dose level in the SAD study or continue dosing in the MAD
      will be made by the Principal Investigator in consultation with the Medical Monitor and Study
      Sponsor.
    

Intervention name(s): (2R,6R)-Hydroxynorketamine hydrochloride; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): (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.; 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.
Allocation: Randomized
Intervention model: Sequential Assignment
Intervention model description: 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.
Masking: Double (Participant, Investigator)
Primary purpose: Treatment
Keywords: Healthy Volunteers; Depression; Antidepressant