Safety, Tolerability, and Pharmacokinetics of Multiple Ascending Doses of REL-1017 (d-Methadone)
Condition: Neuropathic Pain
MeSH terms: Neuralgia
Study type: Interventional
Phase: Phase 1

Summary: 
      This study evaluated the safety, tolerance, and pharmacokinetics (PK) of d-methadone in a
      limited dose range, in multiple administrations in humans.
    

Detailed description: 
      This was a phase 1, single-center study carried out in healthy male and female subjects to
      investigate the safety, tolerability, and PK of multiple doses (25mg, 50mg, and 75mg once
      daily) of d-methadone for 10 days. It was a double-blind, randomized, placebo-controlled
      study in sequential cohorts of healthy subjects. Subjects participated in the study for
      approximately 7 weeks. Eligible subjects were randomized within 30 days of screening. Of the
      8 subjects in each cohort, 2 subjects received placebo and 6 subjects received d-methadone.
      The duration of dosing ensured that steady-state plasma concentrations were achieved.

      A single ascending dose study previously conducted by Relmada Therapeutics, Inc. demonstrated
      that the maximum tolerated single dose for oral d-methadone in healthy opiate-naive subjects
      was 150 mg. The single doses of d-methadone appeared to be safe, with no indication of
      respiratory depression or clinically significant QTc prolongation, and minimal subjective
      pharmacodynamic (PD) effects.

      The following assessments and procedures ensured the safety of the subjects during the study:

        -  continuous cardiac telemetry for 8 hours post-dose to detect any potential cardiac
           issues

        -  continuous pulse oximetry monitoring for 8 hours post-dose to detect any potential
           respiratory distress

        -  presence of a safety catheter to administer rescue medication (naloxone), if needed

      The following signs of opioid toxicity were deemed to be of special interest:

        -  sustained respiratory depression that results in oxygen saturation below 92%

        -  QTc prolongation (>500 ms or >70 ms above the baseline)

        -  protracted nausea and vomiting

        -  any AE deemed by the investigator to be dose-limiting Safety Analysis Safety and
           tolerability parameters were listed by treatment and subject and displayed in summary
           tables using descriptive statistics. Original terms used to identify AEs were coded
           using the Medical Dictionary for Regulatory Activities (MedDRA), version 17.1. The
           number and percentage of subjects with treatment emergent AEs (TEAEs) were summarized by
           system organ class, preferred term, and treatment and for each treatment by maximum
           intensity and maximum relationship to study treatment.

      Descriptive statistics for vital signs were calculated and presented for each time point by
      treatment group (absolute values and change from baseline). Safety ECG results were
      summarized using descriptive statistics; frequencies (numbers and percentages) were
      calculated for the overall evaluation by scheduled time and treatment group. Laboratory data
      were summarized by the type of test and scheduled visit. Descriptive statistics and number of
      subjects with laboratory test results below, within, and above normal ranges were tabulated
      by scheduled time. Abnormal findings in laboratory data were listed with a flag for clinical
      significance. Medical history abnormalities were coded to MedDRA terms and listed. Physical
      examination abnormalities were also listed. Data collected from the C-SSRS were classified
      into the Columbia Classification Algorithm of Suicide Assessment (C-CASA) categories and were
      listed. Frequency tables were used to summarize the total score from the COWS questionnaire,
      by treatment group. The original verbatim terms for concomitant medications were coded into
      drug class and preferred term. These data were listed.

      Pharmacokinetic Analysis The PK parameters for d-methadone determined by non-compartmental
      analysis were summarized by dose. Graphs of concentration (linear and log-linear) vs time
      were generated. Descriptive statistics were calculated by dose and time point for all
      d-methadone concentrations. Concentrations below the limit of quantification (BLQ) were
      analyzed as outlined in the statistical analysis plan (SAP). Concentrations of l-methadone
      were analyzed only if the majority of values were not BLQ.

      For the calculation of the PK parameters, concentration-time data were treated as follows:
      BLQ concentrations prior to the first quantifiable concentration were set to zero; BLQ
      concentrations after the first quantifiable concentration were treated as missing; pre-dose
      sampling times relative to dosing were set to zero. Descriptive statistics were calculated by
      dose. The dose proportionality of Cmax and AUC was assessed by the Hummel method. Tmax and t½
      for different doses were compared using the Kruskal-Wallis test.

      Pharmacodynamic Analysis The PD data at each time point were summarized by descriptive
      statistics and presented graphically (as appropriate). Derived endpoints were summarized
      using descriptive statistics. Pupillometry constriction was listed and grouped by treatment
      group and subject with descriptive statistics for changes from baseline for different time
      points.

      Holter ECG Analysis (Cardiodynamic Analysis) The analysis of the Holter ECG data was
      performed using SAS®. The average of the 3 pre-dose time points on Day 1 was used as baseline
      for all post-dose time points. Heart rate and the PR, QRS, QT, and QTcF intervals collected
      from all randomized subjects were presented in data listings with the same precision as in
      the database. Data listings were sorted by treatment, subject number, day, and time point.
      Both absolute and change from baseline values for each subject were provided.
    

Intervention name(s): REL-1017; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): The investigational product, REL-1017 is prepared as a solution with Ocean Spray® Diet Cranberry Juice on site to obtain a final volume of 100 mL for dosing. The study drug will be administered as a solution of 25 mg, 50 or 75 mg REL-1017 for 10 days, based on randomization prepared in Ocean Spray® Diet Cranberry Juice with a final volume of 100 mL.
Other intervention name(s): (d-Methadone)
Intervention MeSH terms: Methadone; D-methadone
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Basic Science