Ignite Creation Date:
2024-05-06 @ 11:55 AM
Last Modification Date:
2024-10-26 @ 12:52 PM
Study NCT ID:
NCT03637361
Status:
COMPLETED
Last Update Posted:
2019-08-01
First Post:
2018-08-10
Brief Title:
Safety Tolerability and Pharmacokinetics of Single Ascending Doses of REL-1017 d-Methadone
Sponsor:
Relmada Therapeutics Inc
Organization:
Relmada Therapeutics Inc
Study Overview
Official Title:
A Phase 1 Study to Investigate the Safety Tolerability and Pharmacokinetic Profile of Single Ascending Doses of REL-1017 d-Methadone in Healthy Subjects
Status:
COMPLETED
Status Verified Date:
2018-08
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
This study evaluated the safety tolerance and pharmacokinetics PK of d-methadone in a limited dose range in single 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 d-methadone This was a double-blind randomized placebo-controlled study in 6 sequential cohorts of healthy subjects Single oral doses of d-methadone were investigated in sequential cohorts The proposed doses were 5 mg 20 mg 60 mg 100 mg 200 mg 300 mg and 400 mg The decision to enroll the sequential cohort at the next dose level was based on the safety data and available PK data from previous doses Dose escalation depended on the emergence of dose-limiting AEs and review of the safety data Progression to the next higher dose only occurred if the previous dose level was deemed to be safe and well tolerated by the investigator safety review team and sponsor Of the 8 subjects in each cohort 2 subjects received placebo and 6 subjects received d-methadone
Subjects were admitted the day prior to receiving the study drug and remained in the clinical research unit CRU under clinical supervision for at least 72 hours post-dose At the discretion of the investigator or designee the confinement time could have been extended to ensure the safety of each subject Visits 3 and 4 were follow-up visits approximately 62 days and 102 days respectively after drug administration
Based on the blinded safety data from Cohorts 1 to 4 single doses of 5 mg 20 mg 60 mg and 100 mg of d-methadone or placebo were well tolerated and there were no dose-limiting AEs
During all cohorts subjects were evaluated for safety AEs vital signs electrocardiograms ECGs cardiac telemetry pulse oximetry clinical laboratory tests tolerability and PK 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 171 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 absolute values and change from baseline ECG results absolute values and change from baseline average of triplicate assessments where applicable were summarized using descriptive statistics frequencies numbers and percentages were calculated for the overall evaluation by scheduled time and treatment 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 Physical examination abnormalities were also listed 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 set to zero for the generation of summary statistics and mean concentration-time plots
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 Kruskall-Wallis test to determine whether there was any difference among the treatment groups and the Wilcoxon rank-sum test for contrasts
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
Outliers were listed by measure and parameter Pupillometry constriction was listed and grouped by dose and subject with descriptive statistics for changes from baseline for different time points
Subjects were admitted the day prior to receiving the study drug and remained in the clinical research unit CRU under clinical supervision for at least 72 hours post-dose At the discretion of the investigator or designee the confinement time could have been extended to ensure the safety of each subject Visits 3 and 4 were follow-up visits approximately 62 days and 102 days respectively after drug administration
Based on the blinded safety data from Cohorts 1 to 4 single doses of 5 mg 20 mg 60 mg and 100 mg of d-methadone or placebo were well tolerated and there were no dose-limiting AEs
During all cohorts subjects were evaluated for safety AEs vital signs electrocardiograms ECGs cardiac telemetry pulse oximetry clinical laboratory tests tolerability and PK 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 171 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 absolute values and change from baseline ECG results absolute values and change from baseline average of triplicate assessments where applicable were summarized using descriptive statistics frequencies numbers and percentages were calculated for the overall evaluation by scheduled time and treatment 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 Physical examination abnormalities were also listed 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 set to zero for the generation of summary statistics and mean concentration-time plots
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 Kruskall-Wallis test to determine whether there was any difference among the treatment groups and the Wilcoxon rank-sum test for contrasts
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
Outliers were listed by measure and parameter Pupillometry constriction was listed and grouped by dose and subject with descriptive statistics for changes from baseline for different time points
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None