A Randomized, Delayed-Treatment Controlled, Phase 2 Pilot Study of Manualized MDMA-Assisted Therapy for Young Adults with Chronic Treatment-Resistant Major Depressive Disorder

Prior treatment

• Have a history of any medical condition that could make receiving a sympathomimetic drug harmful because of increases in blood pressure and heart rate. This includes, but is not limited to, a history of myocardial infarction, cerebrovascular accident, or aneurysm. Participants with other mild, stable chronic medical problems may be enrolled if the site physician and CI agree the condition would not significantly increase the risk of MDMA administration or be likely to produce significant symptoms during the study that could interfere with study participation or be confused with side effects of the IMP. Any medical disorder judged by the investigator to significantly increase the risk of MDMA administration by any mechanism would require exclusion.
• Have a history of arrhythmia, other than occasional premature atrial contractions (PACs) or PVCs in the absence of ischemic heart disease, within 12 months of screening. Participants with a history of atrial fibrillation, atrial tachycardia, atrial flutter or paroxysmal supraventricular tachycardia or any other arrhythmia associated with a bypass tract may be enrolled only if they have been successfully treated with ablation and have not had recurrent arrhythmia for at least one year off all antiarrhythmic drugs and confirmed by a cardiologist.
• History of Hepatitis C virus (HCV), unless it is asymptomatic and has previously undergone evaluation and treatment as needed
• Hypothyroidism, unless if taking adequate and stable thyroid replacement medication
• Have a current moderate (not in early remission in the 3 months prior to enrollment; meets 5 of 11 diagnostic criteria per DSM-5) or severe alcohol or cannabis use disorder within the 12 months prior to enrollment (meets at least 6 of 11 diagnostic criteria per DSM-5).
• Have an active illicit (other than cannabis) or prescription drug substance use disorder at any severity within 12 months prior to enrollment.
• Require ongoing concomitant therapy with a psychiatric medication with exceptions described in Protocol Section 6.9.
• Use of monoamine oxidase inhibitors (MAOIs).
• Have used MDMA/ecstasy previously
• Previous treatment with Electroconvulsive Therapy (ECT) or ketamine
• Previous experience with psychedelic-assisted therapy

Other illness

• Have a history of or a current primary psychotic disorder, or bipolar disorder 1 assessed via MINI and clinical interview
• Autism spectrum disorder
• Have a current eating disorder with active purging assessed via MINI (at screening) and clinical interview.
• Have essential hypertension using the standard criteria of the American Heart Association (values of 140/90 milligrams of Mercury [mmHg] or higher assessed on three separate occasions).
• Have a history of ventricular arrhythmia at any time, other than occasional premature ventricular contractions (PVCs) in the absence of ischemic heart disease.
• Have Wolff-Parkinson-White syndrome or any other accessory pathway that has not been successfully eliminated by ablation
• Have current major depressive disorder with psychotic features assessed via MINI (at screening)
• Epilepsy
• Diabetes Mellitus Type 1. Type 2 may be considered, but only if additional screening measures rule out underlying cardiovascular disease, if the condition is judged to be stable on effective management, and with approval by the Site physician.
• Have current Personality Disorders Cluster A (paranoid, schizoid, schizotypal), Cluster B (antisocial, borderline, histrionic, narcissistic), or Cluster C (avoidant, dependent, obsessive-compulsive) assessed via SCID-5-PD (at screening).
• Any participant presenting current serious suicide risk, as determined through psychiatric interview, responses to C-SSRS, and clinical judgment of the investigator will be excluded; however, history of suicide attempts is not an exclusion. Any participant who is likely to require hospitalization related to suicidal ideation and behavior, in the judgment of the investigator, will not be enrolled. Any participant presenting with the following on the Baseline/Screening C-SSRS will be excluded: 1. Suicidal ideation score of 4 or greater within the last 6 months of the assessment at a frequency of once a week or more 2. Suicidal ideation score of 5 within the last 6 months of the assessment 3. Any suicidal behavior, including suicide attempts or preparatory acts, within the last 6 months of the assessment. Participants with non-suicidal self-injurious behavior may be included if approved by the Site physician.
• Are currently engaged in compensation litigation whereby financial gain would be achieved from prolonged symptoms of MDD or any other psychiatric disorders

Lab values

• Have a marked Baseline prolongation of QT/QTc interval e.g., repeated demonstration of a QTc interval >450 milliseconds [ms] in males and >460 ms in females corrected by Fridericia’s formula). For transgender or non-binary participants, QTc interval will be evaluated based on sex assigned at birth, unless the participant has been on hormonal treatment for five or more years.
• Have a history of additional risk factors for Torsade de pointes (e.g., heart failure, hypokalemia, family history of Long QT Syndrome).
• Require use of concomitant medications that prolong the QT/QTc interval during Dosing Sessions. Refer to Protocol Section 6.9
• History of, or current diagnosis of, glaucoma—unless clearance for participation is provided by an ophthalmologist
• Have symptomatic liver disease or have significant liver enzyme elevations (defined as 2x the upper limit of the laboratory’s reference ranges for ASAT or ALAT).
• Have history of clinically significant hyponatremia (defined as outside of the normal range of 135 to 145 mmol/L on repeated assessments) or hyperthermia.
• Have hypersensitivity to midomafetamine or any listed excipients of MDMA (mannitol and magnesium stearate)

Other

• Are not able to give adequate informed consent
• Clinically significant dissociative symptomatology
• Weigh less than 48 kilograms (kg).
• Pregnancy and breastfeeding
• CYP2D6 poor metabolizer
• Would present a serious risk to others as established through clinical interview and contact with treating psychiatrist.
• Are likely, in the investigator’s opinion and via observation during screening and preparatory period to lack sufficient internal and/or external resources and/or an ability to form a therapeutic alliance. This includes, but is not limited to, an understanding of and willingness to allow and explore inner states, enough social support and a reasonable stable living situation.
• Have any current problem which, in the opinion of the investigator or Site physician, might interfere with participation

• Are 18 – 25 years old
• Are fluent in speaking and reading Norwegian. This criterion is based on the need to ensure effective communication and the development of a strong therapeutic alliance. Limited language proficiency may hinder the therapist’s ability to provide adequate support during and after the MDMA-assisted sessions.
• Are able to swallow pills
• Must provide a contact (relative, spouse, close friend or other support person) who is willing and able to be reached by the investigators in the event of a participant becoming suicidal or unreachable.
• Must agree to inform the investigators within 48 hours of any medical conditions and procedures.
• Women of childbearing potential (WOCBP) as defined in Section 10.4.1 must have a negative pregnancy test at study entry and prior to each Dosing Session and must agree to use adequate birth control through 30 days after the last Dosing Session. Only highly effective contraception methods are permitted in this trial. See section 10.4.2 for a list of these methods.
• Agree to the following lifestyle modifications (described in more detail in Section 5.3 Lifestyle Modifications): comply with requirements for fasting and refraining from certain medications prior to Dosing Sessions, not participate in any other interventional clinical trials during the duration of the study, and be driven home after the Dosing sessions, and commit to medication dosing, therapy, and study procedures. Must provide a contact (relative, spouse, close friend or other support person) who is willing to fill out relevant questionnaires.
• At Screening, meet DSM-5 criteria for moderate to severe MDD without psychotic features (MADRS ≥ 20) that presents as chronic depression (persistent symptoms for ≥ 2 years). The participant must have experienced failure of at least two distinct therapeutic interventions for depression over their lifetime, including both pharmacological treatments (antidepressant medications) and psychotherapy. At least one of the failed treatments must have been a course of psychotherapy. Additionally, at least one treatment failure must be related to the current depressive episode. Only treatments administered at an adequate dose, frequency, and duration—provided they were tolerable—will be considered valid. Notably, a psychotherapy course lasting 2 years or longer will be counted as two separate therapeutic approaches.