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

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ClinicalTrials.gov Identifier: NCT03606538
Recruitment Status : Not yet recruiting
First Posted : July 31, 2018
Last Update Posted : December 9, 2019
Sponsor:
Information provided by (Responsible Party):
Multidisciplinary Association for Psychedelic Studies

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Pharmacokinetics Hepatic Impairment Drug: MDMA Phase 1

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 16 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Matched group comparison of pharmacokinetics and metabolism of single dose of 80 mg MDMA in participants with moderate hepatic impairment and participants with normal hepatic function and matched on age, weight and gender.
Masking: None (Open Label)
Masking Description: No masking; open-label
Primary Purpose: Basic Science
Official Title: 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
Estimated Study Start Date : January 2020
Estimated Primary Completion Date : May 2020
Estimated Study Completion Date : July 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Club Drugs

Arm Intervention/treatment
Experimental: Moderate hepatic impairment
Eight participants with moderate hepatic impairment receive a single dose of 80 mg MDMA.
Drug: MDMA
80 mg MDMA
Other Name: 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: MDMA
80 mg MDMA
Other Name: methylenedioxymethamphetamine




Primary Outcome Measures :
  1. Area under curve from dosing time to last measurement (AUC(0-t)) - MDMA [ Time Frame: 0 to 5 days after drug administration ]
    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

  2. Area under curve from dosing time to last measurement (AUC(0-t) MDA [ Time Frame: 0 to 5 days after drug administration ]
    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


Secondary Outcome Measures :
  1. Peak MDMA (Cmax) [ Time Frame: 0 to 5 days after drug administration ]
    Maximum value of plasma MDMA in nglml

  2. Peak MDA (Cmax) [ Time Frame: 0 to 5 days after drug administration ]
    Maximum value of plasma MDA in ng/lml

  3. Time to maximum (Tmax) MDMA [ Time Frame: 0 to 5 days after drug administration ]
    Time to reach maximum plasma values of MDMA

  4. Time to maximum (Tmax) MDA [ Time Frame: 0 to 5 days after drug administration ]
    Time to reach maximum plasma values of MDA

  5. Area under curve from dosing time to infinity (AUC(0-infinity)) - MDMA [ Time Frame: 0 to 5 days after drug administration ]
    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

  6. Area under curve from dosing time to infinity (AUC(0-infinity)) - MDA [ Time Frame: 0 to 5 days after drug administration ]
    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

  7. 90% CL between hepatic impaired and no hepatic impairment groups for AUC (0-t) [ Time Frame: 0 to 5 days after drug administration ]
    90% confidence interval (CI) for the ratio of population geometric means between moderate hepatic impairment and normal hepatic function for AUC (0-t)

  8. 90% CL between hepatic impaired and no hepatic impairment groups for AUC (0-infinity) [ Time Frame: 0 to 5 days after drug administration ]
    90% confidence interval (CI) for the ratio of population geometric means between moderate hepatic impairment and normal hepatic function for AUC(0-infinity)

  9. 90% CL between hepatic impaired and no hepatic impairment groups for Cmax [ Time Frame: 0 to 5 days after drug administration ]
    90% confidence interval (CI) for the ratio of population geometric means between moderate hepatic impairment and normal hepatic function for Cmax

  10. Change in QTcI - Baseline to 0.5 h post drug [ Time Frame: 0 days after drug administration ]
    Change in ECG QTcl from Baseline compared to 0.5 h post MDMA

  11. Change in QTcI - Baseline to 2 h post-drug [ Time Frame: 0 days after drug administration ]
    Change in ECG QTcl from Baseline compared to 2 h post MDMA

  12. Change in QTcI Baseline to 4 h post-drug [ Time Frame: 0 days after drug administration ]
    Change in ECG QTcl from Baseline compared to 4 h post MDMA

  13. Change in QTcI Baseline to 6 h post-drug [ Time Frame: 0 days after drug administration ]
    Change in ECG QTcl from Baseline compared to 6 h post MDMA

  14. Change in QTcI Baseline to 7 h post-drug [ Time Frame: 0 days after drug administration ]
    Change in ECG QTcl from Baseline compared to 7 h post MDMA

  15. Change in QTcI Baseline to 1 d post-drug [ Time Frame: 1 day after drug administration ]
    Change in ECG QTcl from Baseline compared to 1 d post MDMA

  16. Change in QTcI Baseline to 2 d post-drug [ Time Frame: 2 days after drug administration ]
    Change in ECG QTcl from Baseline compared to 2 d post MDMA

  17. Change in QTcI Baseline to 3 d post-drug [ Time Frame: 3 days after drug administration ]
    Change in ECG QTcl from Baseline compared to 3 d post MDMA

  18. Change in QTcI Baseline to 4 d post-drug [ Time Frame: 4 days after drug administration ]
    Change in ECG QTcl from Baseline compared to 4 d post MDMA

  19. Pre-drug Systolic blood pressure (SBP) [ Time Frame: 0 days after drug administration ]
    First SBP measurement, prior to drug administration, on day of drug administration

  20. Peak Systolic blood pressure (SBP) [ Time Frame: 0 days after drug administration ]
    Maximum value of SBP measured during day of drug administration

  21. Final systolic blood pressure (SBP) [ Time Frame: 0 days after drug administration ]
    Last SBP measurement taken on day of drug administration

  22. Pre-drug Diastolic blood pressure (DBP) [ Time Frame: 0 days after drug administration ]
    First DBP measurement, prior to drug administration, on day of drug administration

  23. Peak Diastolic blood pressure (DBP) [ Time Frame: 0 days after drug administration ]
    Maximum value of DBP measured during day of drug administration

  24. Final Diastolic blood pressure (DBP) [ Time Frame: 0 days after drug administration ]
    Last DBP measurement taken on day of drug administration

  25. Pre-drug heart rate (HR) [ Time Frame: 0 days after drug administration ]
    First HR measurement, prior to drug administration, on day of drug administration

  26. Peak heart rate (HR) [ Time Frame: 0 days after drug administration ]
    Maximum value of HR measured during day of drug administration

  27. Final heart rate (HR) [ Time Frame: 0 days after drug administration ]
    Last HR measurement taken on day of drug administration

  28. Pre-drug body temperature (BT) [ Time Frame: 0 days after drug administration ]
    First body temperature measurement, prior to drug administration, on day of drug administration

  29. Peak body temperature (BT) [ Time Frame: 0 days after drug administration ]
    Maximum BT value measured during day of drug administration

  30. Final body temperature (BT) [ Time Frame: 0 days after drug administration ]
    Last BT measurement taken on day of drug administration

  31. Number of AEs reported [ Time Frame: -4 days to 15 days post drug administration ]
    Number of AEs reported in each group from enrollment to study end



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03606538


Contacts
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Contact: Study coordinator ClinPharmPKStudy@ucsf.edu

Locations
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United States, California
University of California San Francisco Not yet recruiting
San Francisco, California, United States, 94143
Contact: Study coordinator       ClinPharmPKStudy@ucsf.edu   
Sponsors and Collaborators
Multidisciplinary Association for Psychedelic Studies
Investigators
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Principal Investigator: Janel Long-Boyle, PharmD, PhD University of California San Francisco, Mission Bay

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Responsible Party: Multidisciplinary Association for Psychedelic Studies
ClinicalTrials.gov Identifier: NCT03606538     History of Changes
Other Study ID Numbers: MPKH
First Posted: July 31, 2018    Key Record Dates
Last Update Posted: December 9, 2019
Last Verified: December 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: We will share outcome data appearing in any published reports upon request.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Time Frame: Data and study-related documents will be available when all participants have completed the study
Access Criteria: nterested persons should correspond with the central contact for the multisite study.

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Multidisciplinary Association for Psychedelic Studies:
MDMA
metabolism
methylenedioxymethamphetamine
Additional relevant MeSH terms:
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Liver Diseases
Digestive System Diseases
N-Methyl-3,4-methylenedioxyamphetamine
Hallucinogens
Physiological Effects of Drugs
Psychotropic Drugs
Serotonin Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Adrenergic Uptake Inhibitors
Neurotransmitter Uptake Inhibitors
Membrane Transport Modulators
Adrenergic Agents