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

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 midomafetamine HCl 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.

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 known or suspected allergy to trial product or related products.