Ignite Creation Date:
2024-05-06 @ 11:56 AM
Last Modification Date:
2024-10-26 @ 12:52 PM
Study NCT ID:
NCT03638869
Status:
COMPLETED
Last Update Posted:
2018-08-20
First Post:
2018-08-10
Brief Title:
Safety Tolerability and Pharmacokinetics of Multiple 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 Multiple 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 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 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 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
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 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 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
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