A 14-week, multicentre, double-blind, randomised, placebo-controlled phase II study with an 8-week treatment period to assess the efficacy and tolerability of a fixed dose of BH-200 (250 mg BID) in outpatients with Major Depressive Disorder (MDD)

Prior treatment

• Patients with known but untreated conditions causing hyperthyroidism or hypothyroidism with the following exceptions: Patients with a pre-existing history of hypothyroidism who are treated with thyroid hormones must be on a stable dosage for 6 weeks before baseline, are allowed into the study. Patient must have thyroid stimulating hormone (TSH) and free thyroxine (fT4) within normal range at screening. If there is a low TSH or high fT4 in a patient on levothyroxine, the patient could be re-screened after re-adjustment of levothyroxine dose and in-range levels of TSH and fT4 are attained. Patients on thyroid suppressant medication (carbimazole, methimazole, etc.).
• Patients with a history of moderate to severe alcohol use and/or substance use disorder, e.g., including benzodiazepines, opiates, hallucinogens, stimulants (e.g., ketamine, phencyclidine [PCP], lysergic acid diethylamide [LSD], psilocybin, 3,4-methylenedioxymethamphetamine [MDMA], dextromethorphan, amphetamines, cocaine) and cannabis (ICD -10-CM code F10, F12, F16, F18, F11, F13, F14, F15, F19), except nicotine and caffeine, within 6 months before the start of the screening phase, with the following exceptions: Low-risk alcohol drinking, as defined by the Estonian nutrition and exercise recommendations 2015 (i.e., maximum daily amount of alcohol: 40 g for men and 20 g for women; three days per week alcohol-free), is allowed. However, intake of alcohol is disallowed for 24 hours before symptom ratings, assessments of vital parameters and blood withdrawals.
• Prior intermittent use of cannabinoids prior to screening is not exclusionary if the patient does not meet the criteria for substance use disorder.
• A urinary drug screening test using a multi-drug dipstick will be performed at screening. Patients tested positive of any drug of abuse (e.g., MDMA, (meth-)amphetamine, opiates, barbiturates, cocaine, benzodiazepines, cannabis) will be excluded from the study with the following exceptions: a) Patients tested positive for cannabis must be counselled to abstain from cannabis use during the study. They can be included, if, in the judgement of the investigator, the patient will comply. b) Intake of cannabis during the study is prohibited unless the patient has a valid prescription where local legislation permits. c) Intake of benzodiazepines during the study is prohibited unless the patient has a valid prescription (restrictions are further specified in Appendix 1).
• Patients that received fluoxetine treatment within 10 weeks prior to screening
• Patients who donated or lost whole blood ≥500 mL within 2 weeks prior to first dosing. Blood donation during the 8 weeks of drug intake is prohibited.
• Patients with known or suspected lifetime history of surgical procedures involving the brain or meninges, encephalitis, meningitis, degenerative central nervous system (CNS) disorder, epilepsy, or any other disease/procedure/accident/intervention which, according to the screening clinician, is deemed associated with significant injury to or malfunction of the CNS, or history of significant head trauma within the past 2 years prior to screening, with the exception of uncomplicated childhood febrile seizures with no sequelae.

Other illness

• Patients with a history of Hepatitis B or C.
• Patients with Cushing’s Syndrome.
• Patients with Addison’s Disease.
• In addition to the above defined criteria, patients with any significant disease or disorder (e.g., cardiovascular, haematological, pulmonary/respiratory, gastrointestinal, hepatic, renal, neurological, musculoskeletal, endocrine, metabolic, malignant, psychiatric, major physical impairment) which, in the opinion of the investigator, may either put the patient at risk because of participation in the study, or may influence the results of the study, or the patient’s ability to participate in the study.
• Patients with schizophrenia spectrum and other psychotic disorders (ICD-10-CM codes F21, F22, F23, F20.81, F20.9, F25.0, F25.1, F06, F28 and F29) and bipolar disorders (F31, F34, F06).
• Patients with paranoid, schizoid, and schizotypal personality disorder (ICD-10-CM codes F60.0, F.60.1, F21).
• Patients with antisocial, borderline (emotionally unstable personality disorder, borderline type), histrionic and narcissistic personality disorder (ICD-10-CM codes F60.2, F60.3, F60.4, F60.81).
• Patients with intellectual disability / mental retardation, e.g., due to neurodevelopmental disorders, neurocognitive or neurodegenerative disorders, and autism spectrum disorder (ICD-10-CM code F84.0).

Lab values

• Patients with known or suspected cardiovascular or cerebrovascular disease (e.g., unstable angina, congestive heart failure, tachyarrhythmia, myocardial infarction, stroke, prolonged ischaemic neurologic deficit and transient ischaemic attack), as well as patients who have: Abnormal ECG at screening, including a corrected QT (QTc) using Fridericia’s formula (QTcF, QTcF = QT/RR0.33; RR can be manually calculated as RR=60,000/Heart Rate (bpm)) ≥470 msec in females or ≥450 msec in males (can be repeated for a maximum of3 ECGs at screening to obtain the average QTcF), PR interval >220 msec, 2nd degree or higher atrioventricular (AV) block, complete left bundle branch block, complete right bundle branch block with a QRS duration over 150 msec, bifascicular block (right bundle branch block with left atrial hypertrophy or left posterior hemiblock), sick sinus syndrome or chronic or paroxysmal atrial fibrillation. Evidence of acute or sub-acute myocardial infarction, ischaemia or other ECG findings that, in the investigator’s opinion, would preclude participation in the study. Patients can be referred to another physician who is able to evaluate the ECG, if necessary. Heart rate <50 or >110 beats per minute at screening or baseline. History of sudden cardiac death in a first degree relative. Patients with untreated hypertension and a systolic blood pressure (BP) at rest >160 mmHg and/or diastolic BP at rest >100 mmHg.
• Patients with a history of, or symptoms and signs suggestive of, impaired hepatic function or cirrhosis, including an alanine aminotransferase (ALT) or aspartate aminotransferase (AST) value >2 × the upper limit of normal (ULN) or total bilirubin (TBL) >1.5 × the ULN, unless in patients with Gilbert’s Syndrome, at screening. Repeat of screening test for abnormal ALT and AST and bilirubin is permitted once during the screening period per investigator discretion.
• Renal insufficiency (estimated glomerular filtration rate (eGFR) <30 mL/min) as estimated by any of the following criteria: (i.) eGFR according to the Modification of Diet in Renal Disease Study equation, calculated as follows: eGFR (mL/min/1.73m2) = 175 × (serum creatinine in μmol/L) – 1.154 × (Age), or (ii.) Creatinine ≥200 μmol/L or (iii.) undergoing dialysis or with kidney transplants.
• Patients with uncontrolled diabetes (glycated haemoglobin [HbA1c] >8.0% at screening). Diabetes treatment must have been ongoing for 3 months prior to the start of screening.

Other

• Inability to obtain written informed consent from the patient or to comply with the protocol and follow written and verbal instructions.
• Pregnant, lactating females.
• Patients who have participated in 2 or more clinical interventional studies within 1 year before screening.
• Patients who are currently enrolled in a clinical interventional study.
• Patients with PTSD (ICD-10-CM code F43.9).
• Significant risk of suicide, defined as (1) suicidal ideation endorsed by a response of ‘YES’ on items 4 or 5 of the Columbia-Suicide Severity Rating Scale within the past year, at screening, or at baseline, or, (2) suicidal behaviours within the past year, or, (3) clinical identification of a significant suicidal risk during the interview.

• Male or female patients.
• Duration of current episode no longer than 12 months, prior to screening.
• Symptoms of depression present for at least 2 weeks, prior to screening.
• Willingness to stop current antidepressive medication or other prohibited psychotropic medication, after confirmation of eligibility, at least 7 days or 5 half-lives, whichever is longer, before baseline (day 0) (with the exception of benzodiazepines and non-benzodiazepines when needed as sleeping and anti-anxiety medication, permitted dosing is specified in Appendix 1).
• Psychotherapy that has been ongoing for a minimum of 6 weeks prior to screening can continue, but new psychotherapy may not be initiated from 6 weeks prior to screening until 8 weeks after start of treatment (i.e., until last day of treatment). Planned discontinuation of ongoing psychotherapy during the study is not allowed until after the first 8 weeks of treatment.
• Physical activity programmes that have been ongoing for a minimum of 6 weeks prior to screening can continue but should be kept on the same level (i.e., type and frequency), but new physical activity programmes may not be initiated from 6 weeks prior to screening until 8 weeks after start of treatment (i.e., until last day of treatment). Planned discontinuation of ongoing physical activity programmes during the study is not allowed until after the first 8 weeks of treatment.
• Ongoing hormone substitution therapy for post-menopausal women, insulin treatment for diabetes and thyroid disorders is allowed as long as these conditions are well controlled (exclusion criteria below). Only hormonal agents prescribed by healthcare providers are allowed.
• Women of childbearing potential will be required to use highly effective contraceptive measures from the time of informed consent until 28 days after last intake of the investigational drug. A woman is considered of childbearing potential (WOCBP), i.e., fertile, following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilisation methods which are acceptable are: hysterectomy, bilateral salpingectomy or bilateral oophorectomy. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a postmenopausal state in women not using hormonal contraception or hormonal replacement therapy. In the absence of 12 months of amenorrhea, a single FSH measurement is insufficient. Methods that can achieve a failure rate of less than 1% per year when used consistently and correctly are considered as highly effective birth control methods. Such methods include: combined (oestrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation. This method must be supplemented with a barrier method (preferably male condom); oral; intravaginal; transdermal; progestogen-only hormonal contraception associated with inhibition of ovulation. This method must be supplemented with a barrier method (preferably male condom); oral injectable; implantable intrauterine device; intrauterine hormone-releasing system. This method must be supplemented with a barrier method (preferably male condom); bilateral tubal occlusion; vasectomised partner; sexual abstinence. According to CTFG guidance “Recommendations related to contraception and pregnancy testing in clinical trials”, sexual abstinence is considered a highly effective contraception method only if defined as refraining from heterosexual intercourse during the entire trial period. Therefore, the Investigators should assess the reliability of sexual abstinence in relation to the duration of the study and the preferred and usual lifestyle of the trial subject.
• Male patients will be required to use highly effective contraceptive measures (barrier method) or practice abstinence during this study and for 28 days after last intake of investigational drug. Note: these requirements also apply for male patients who have had a vasectomy.
• Between 18 and 75 years of age at the date of informed consent. Serbia only: Between 18 and 65 years of age at the date of informed consent.
• Body mass index between 18 and 35 kg/m2.
• Outpatients.
• Ability of the participant to understand the purpose and risks of the study and provide signed and dated initial informed consent and authorization to use confidential health information in accordance with national and local participant privacy regulations.
• Provide written informed consent.
• Bulgaria only: Availability of a caregiver for the duration of the study. Caregiver has to provide separate written informed consent.
• Primary diagnosis of MDD, moderate or severe, single or recurrent episode, with or without psychotic features (International Classification of Diseases [ICD]-10-CM codes F32.1, F32.2, F32.3, F33.1, F33.2, F33.3), as defined by Diagnostic and Statistical Manual of Mental Disorders 5 (DSM-5) and confirmed by the Mini International Neuropsychiatric Interview (MINI). However, patients with the following co-morbid conditions can be included (secondary diagnosis): a) Patients with anxiety disorders, (excluding post-traumatic stress disorder [PTSD]), can be included as long as the primary diagnosis is MDD. b) Patients with obsessive-compulsive disorder can be included, as long as the primary diagnosis is MDD and the current condition is not impairing/disabling or interfering with the patient’s adherence to study drug intake and study protocol. c) Patients with eating disorders can be included, as long as the primary diagnosis is MDD and the condition does not impact the efficacy of the study drug or raise safety concerns in the investigator’s opinion.
• MADRS score ≥20 at screening and baseline.