MDMA in Subjects With Moderate Hepatic Impairment and Subjects With Normal Hepatic Function

A Phase I, Open Label, Study of 3,4-Methylenedioxymethamphetamine (MDMA) Tolerability and Pharmacokinetics in Subjects With Moderate Hepatic Impairment Compared to Matched Control Subjects With Normal Hepatic Function

This study is an open-label, single dose study evaluating the effect of moderate hepatic impairment in the pharmacokinetics of MDMA and its active metabolite, 3,4-methylene-dioxyamphetamine (MDA) in order to decide whether an adjustment to the dosage would be need for individuals with moderate hepatic function in comparison to individuals with normal liver function. Eight participants with moderate hepatic impairment and eight matched participants with normal hepatic function will take part in this study. All patients will be evaluated to see if they meet criteria for study participation, with screening including a physical examination including a 12-lead electrocardiogram (ECG) and questions about mental and physical health. Participants who meet study criteria will stay at the study site for three days. On Day 1, they will receive a single dose of 80 mg MDMA. For the next seven to eight hours, participants will have blood collected and will rate their mood and other experiences. They will stay at the study sight for two more days. Blood will be drawn twice on the second day and once on the third day, and they will have their heart function measured with ECG. Blood will be collected periodically during a 12-hour interval on the day of drug administration. Blood will also be drawn 24, 36, 48, 72 and 96 hours after MDMA administration. Participant mood and feelings or experiences on-drug (subjective effects) will be measured a half-hour, one, two, four, six, and seven hours after receiving MDMA. ECG will be performed every day at the same time upon enrollment (Day -4 or -3) and from the Day 1 (day of drug administration) to Day 5. Blood pressure, heart rate and body temperature on Day 1 through 5. Blood samples will be used to compute the peak or maximum amount of MDMA and MDA in blood (Cmax), the time until reaching peak MDMA or MDA (Tmax) and the area under curve (AUC), or actual degree of exposure to drug. The primary outcome measure will be AUC for MDMA. Finding out if there are differences in drug metabolism between people with normally functioning livers and people whose livers do not function normally will help researchers performing MDMA-assisted psychotherapy.

Study Overview

• Status: Not yet recruiting
• Conditions: Pharmacokinetics; Hepatic Impairment
• Intervention / Treatment: Drug: Midomafetamine

Detailed Description

PTSD is a serious debilitating disorder that negatively impacts a person's daily life. 3,4-methylenedioxymethamphetamine (MDMA) is a ring-substituted phenylisopropylamine derivative that releases serotonin, norepinephrine and dopamine. MDMA has been shown to reduce defenses and fear of emotional injury, enhance communication, and increase empathy, creating productive psychological state that enhances the therapeutic process for the treatment of PTSD and other anxiety disorders. This is supported by data from an international series of Phase 2 pilot studies of MDMA-assisted psychotherapy conducted by the sponsor that provide preliminary evidence that chronic PTSD, independent of cause, is treatable with two to three sessions of MDMA-assisted psychotherapy and associated non-drug preparatory and integrative psychotherapy. The results from multiple independent studies in Phase 2 efficacy analyses demonstrate superiority of MDMA-assisted psychotherapy over psychotherapy with placebo and low dose MDMA.

This protocol is for a Phase 1, open-label study with a primary purpose of evaluating the effect of moderate hepatic impairment in the pharmacokinetics of MDMA and its active metabolite, 3,4-methylene-dioxyamphetamine (MDA), and determining whether an adjustment to the dosage would be indicated in this group of patients in comparison to patients with normal liver function. Because people with moderate hepatic impairment may experience greater exposure to drug than people without it, the secondary purpose of this study is to evaluate the effect of moderate hepatic impairment on the safety and tolerability of oral MDMA, with special attention to ECG data. The study will enroll eight participants, ages 18 to 65 years old, with moderate hepatic impairment, and eight healthy controls with normal hepatic function who are matched with participants with moderate impaired hepatic function on the basis of age, weight and gender.

Participants who give their written informed consent will be screened for study participation that will include a physical examination, assessing current and prior medical and physical health, and a baseline electrocardiogram (ECG) reading. If applicable, they may begin tapering off any contraindicated psychiatric medication. Participants who meet study criteria will receive a single dose of 80 mg MDMA on the first day of a three-day stay at the study site. Blood will be collected periodically in order to calculate pharmacokinetics of MDMA and its active metabolite methylenedioxyamphetamine (MDA). Blood will be collected ten times on Day 1 (-5 min, 0 hours (drug administration), 0.5 h, 1, 2, 4, 6, 7, 10 and 12 hours), starting five minutes before drug administration. Subjective effects of MDMA will be assessed through 15 visual analog scales at similar time points to blood collection, at 0.5, 1, 2, 4, 6 and 7 hours post-drug. There will be six 12-lead ECG measurements on Day 1. Participants will remain at the study site for two more days. Drug safety will be assessed by measuring blood pressure, heart rate and body temperature after MDMA administrations, collecting adverse events throughout the study and measuring suicidal thoughts or behaviors with the Columbia Suicide Severity Rating Scale (C-SSRS). Blood will be collected 24 and 36 hours after drug administration, and ECG will be performed on Day 2, and a single ECG and blood draw will occur on Day 3, 4 and 5. Participants will return for eight and 15 days after drug administration. They will have a single blood draw on each day. The study ends 15 days after drug administration, approximately one month after screening.

The primary outcome measure will be area under the curve from dosing to last dose (AUC) of MDMA and MDA. AUC will be computed from plasma collected multiple times after a single dose of MDMA, twice on the day following the day of drug administration, and once daily for three more days. Other pharmacokinetic measures will be maximal values of MDMA and MDA (Cmax), and time to reach maximum MDMA and MDA levels (Tmax). Safety measures will also include a comparison of subjective effects across groups, ECG readings, number of adverse events, and suicidal ideation or behavior as measured via C-SSRS during the study.

• Study Type: Interventional
• Enrollment (Estimated): 16
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Recruitment Officer; Phone Number: (215) 645-2466; Email: recruitment@mapsbcorp.com

Study Locations

• United States
  • Tennessee
    • Knoxville, Tennessee, United States, 37920
      • Alliance for Multispecialty Research, LLC.
      • Contact: Study Coordinator

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 63 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Participants with moderate hepatic impairment (class B according to Child- Pugh's criteria).
• Participants with normal hepatic function: no clinically significant findings from medical history, physical examination, laboratory values within protocol defined parameters.
• Age 18 to 65 years.
• Weight > 45 kg
• Negative Carbohydrate Deficient Transferrin blood test at Screening and negative breathalyzer alcohol test prior to trial drug administration.
• Negative urine test for drugs of abuse at Screening and prior to trial drug administration.
• Able to comprehend and willing to sign an informed consent form.

Exclusion Criteria:

• Have a current psychiatric diagnosis.
• Are pregnant or nursing, or are women of child bearing potential who are not practicing an effective means of birth control.
• Have acute or exacerbating hepatitis, fluctuating or rapidly deteriorating hepatic function as indicated by widely varying or worsening of clinical and/or laboratory signs of hepatic impairment within 2 weeks.
• Have autoimmune liver disease; esophageal variceal bleeding within 6 months prior to screening, unless successfully treated with banding, or gastric varices.
• Have spontaneous bacterial peritonitis within 3 months prior to screening.
• Have a portosystemic shunt, organ transplant, Wilson's disease, cholestatic liver disease (e g, primary biliary cirrhosis or primary sclerosing cholangitis)
• Evidence or history of significant hematological, endocrine, cerebrovascular, cardiovascular (including controlled hyper-tension), coronary, pulmonary, renal, gastrointestinal, immunocompromising, or neurological disease, including seizure disorder, or any other medical disorder judged by the investigator to significantly increase the risk of MDMA administration.
• For moderate hepatic impairment participants: have clinically significant laboratory findings except as related to hepatic impairment.
• For control participants only: have clinically significant laboratory results outside the normal limits, including AST >48 U/L, ALT > 55 U/L, GGT > 48 U/L, bilirubin > 1.2 mg/dL or hemoglobin < 12 g/dL.
• Have a history of any illness that, in the opinion of the Investigator, might confound the results of the trial or pose risk in administering the trial drug to the subject.
• Have any positive test for drugs of abuse and /or alcohol at screening.
• Have a history or presence of clinically significant abnormal 12-lead ECG or an ECG with QTc by Bazett's correction of > 450 ms in men, > 470 ms in women on the screening ECG.
• Have a PR interval > 240 ms, QRS > 110 ms or a history of prolongation of QT interval.
• Have mental incapacity, unwillingness or language barriers precluding adequate understanding or subject co-operation.
• Are unwilling to stay in the clinical unit for the required duration as per the protocol.
• Have a history of multiple and/or severe allergies to drugs or foods or a history of severe anaphylactic reaction.
• Have a known or suspected allergy to trial product or related products.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Moderate hepatic impairment; Eight participants with moderate hepatic impairment receive a single dose of 80 mg MDMA.	Drug: Midomafetamine; 80 mg MDMA; Other Names: MDMA; 3,4-methylenedioxymethamphetamine
Experimental: Normal hepatic function; Eight participants, each matched on age, weight and gender to a participant with moderate hepatic impairment, receive a single dose of 80 mg MDMA.	Drug: Midomafetamine; 80 mg MDMA; Other Names: MDMA; 3,4-methylenedioxymethamphetamine

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Area under curve from dosing time to last measurement (AUC(0-t)) - MDMA	Computed exposure to MDMA using blood collected periodically at 1, 2, 4, 6, 7, 10, 12, 24, 36, 48, 72 and 96 h post drug	0 to 5 days after drug administration
Area under curve from dosing time to last measurement (AUC(0-t) MDA	Computed exposure to MDA using blood collected periodically at 1, 2, 4, 6, 7, 10, 12, 24, 36, 48, 72 and 96 h post-MDMA administration	0 to 5 days after drug administration

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Peak MDMA (Cmax)	Maximum value of plasma MDMA in nglml	0 to 5 days after drug administration
Peak MDA (Cmax)	Maximum value of plasma MDA in ng/lml	0 to 5 days after drug administration
Time to maximum (Tmax) MDMA	Time to reach maximum plasma values of MDMA	0 to 5 days after drug administration
Time to maximum (Tmax) MDA	Time to reach maximum plasma values of MDA	0 to 5 days after drug administration
Area under curve from dosing time to infinity (AUC(0-infinity)) - MDMA	Computed exposure to MDMA using blood collected periodically at 1, 2, 4, 6, 7, 10, 12, 24, 36, 48, 72 and 96 h post drug	0 to 5 days after drug administration
Area under curve from dosing time to infinity (AUC(0-infinity)) - MDA	Computed exposure to MDA using blood collected periodically at 1, 2, 4, 6, 7, 10, 12, 24, 36, 48, 72 and 96 h post drug	0 to 5 days after drug administration
90% CL between hepatic impaired and no hepatic impairment groups for AUC (0-t)	90% confidence interval (CI) for the ratio of population geometric means between moderate hepatic impairment and normal hepatic function for AUC (0-t)	0 to 5 days after drug administration
90% CL between hepatic impaired and no hepatic impairment groups for AUC (0-infinity)	90% confidence interval (CI) for the ratio of population geometric means between moderate hepatic impairment and normal hepatic function for AUC(0-infinity)	0 to 5 days after drug administration
90% CL between hepatic impaired and no hepatic impairment groups for Cmax	90% confidence interval (CI) for the ratio of population geometric means between moderate hepatic impairment and normal hepatic function for Cmax	0 to 5 days after drug administration
Change in QTcI - Baseline to 0.5 h post drug	Change in ECG QTcl from Baseline compared to 0.5 h post MDMA	0 days after drug administration
Change in QTcI - Baseline to 2 h post-drug	Change in ECG QTcl from Baseline compared to 2 h post MDMA	0 days after drug administration
Change in QTcI Baseline to 4 h post-drug	Change in ECG QTcl from Baseline compared to 4 h post MDMA	0 days after drug administration
Change in QTcI Baseline to 6 h post-drug	Change in ECG QTcl from Baseline compared to 6 h post MDMA	0 days after drug administration
Change in QTcI Baseline to 7 h post-drug	Change in ECG QTcl from Baseline compared to 7 h post MDMA	0 days after drug administration
Change in QTcI Baseline to 1 d post-drug	Change in ECG QTcl from Baseline compared to 1 d post MDMA	1 day after drug administration
Change in QTcI Baseline to 2 d post-drug	Change in ECG QTcl from Baseline compared to 2 d post MDMA	2 days after drug administration
Change in QTcI Baseline to 3 d post-drug	Change in ECG QTcl from Baseline compared to 3 d post MDMA	3 days after drug administration
Change in QTcI Baseline to 4 d post-drug	Change in ECG QTcl from Baseline compared to 4 d post MDMA	4 days after drug administration
Pre-drug Systolic blood pressure (SBP)	First SBP measurement, prior to drug administration, on day of drug administration	0 days after drug administration
Peak Systolic blood pressure (SBP)	Maximum value of SBP measured during day of drug administration	0 days after drug administration
Final systolic blood pressure (SBP)	Last SBP measurement taken on day of drug administration	0 days after drug administration
Pre-drug Diastolic blood pressure (DBP)	First DBP measurement, prior to drug administration, on day of drug administration	0 days after drug administration
Peak Diastolic blood pressure (DBP)	Maximum value of DBP measured during day of drug administration	0 days after drug administration
Final Diastolic blood pressure (DBP)	Last DBP measurement taken on day of drug administration	0 days after drug administration
Pre-drug heart rate (HR)	First HR measurement, prior to drug administration, on day of drug administration	0 days after drug administration
Peak heart rate (HR)	Maximum value of HR measured during day of drug administration	0 days after drug administration
Final heart rate (HR)	Last HR measurement taken on day of drug administration	0 days after drug administration
Pre-drug body temperature (BT)	First body temperature measurement, prior to drug administration, on day of drug administration	0 days after drug administration
Peak body temperature (BT)	Maximum BT value measured during day of drug administration	0 days after drug administration
Final body temperature (BT)	Last BT measurement taken on day of drug administration	0 days after drug administration
Number of AEs reported	Number of AEs reported in each group from enrollment to study end	-4 days to 15 days post drug administration

Collaborators and Investigators

• Sponsor: Lykos Therapeutics
• Investigators: Study Director: Corine de Boer, MD, MAPS Public Benefit Corp.

Study record dates

Study Major Dates

• Study Start (Estimated): March 29, 2024
• Primary Completion (Estimated): December 1, 2024
• Study Completion (Estimated): December 1, 2024

Study Registration Dates

• First Submitted: July 20, 2018
• First Submitted That Met QC Criteria: July 20, 2018
• First Posted (Actual): July 31, 2018

Study Record Updates

• Last Update Posted (Actual): January 24, 2024
• Last Update Submitted That Met QC Criteria: January 22, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: MDMA; metabolism; methylenedioxymethamphetamine
• Additional Relevant MeSH Terms: Digestive System Diseases; Liver Diseases; Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Psychotropic Drugs; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Serotonin Agents; Hallucinogens; Adrenergic Uptake Inhibitors; N-Methyl-3,4-methylenedioxyamphetamine
• Other Study ID Numbers: MPKH

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: We will share outcome data appearing in any published reports upon request.
• IPD Sharing Time Frame: Data and study-related documents will be available when all participants have completed the study
• IPD Sharing Access Criteria: nterested persons should correspond with the central contact for the multisite study.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No