| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated | | Major Depressive Disorder | |
| E.1.1.1 | Medical condition in easily understood language | |
| E.1.1.2 | Therapeutic area | Psychiatry and Psychology [F] - Psychological processes [F02] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 | | E.1.2 | Level | PT | | E.1.2 | Classification code | 10057840 | | E.1.2 | Term | Major depression | | E.1.2 | System Organ Class | 10037175 - Psychiatric disorders | |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial | | To assess the efficacy of BH-200 (250 mg BID) versus placebo in improving depressive symptoms in V1b polygenic score-high (V1b-high) patients. | |
| E.2.2 | Secondary objectives of the trial | - To compare the improvement of depressive symptoms in V1b-high versus V1b-low patients treated with BH-200 (250 mg BID).
- To test whether efficacy of BH-200 versus placebo differs in different V1b-classifications (V1b-treatment interaction).
- To explore the efficacy of BH-200 (250 mg BID) on response rate, remission rate, and quality of life and compare these outcomes across all three V1b-classifcations as well as treatment arms.
- To compare the outcome in placebo-treated V1b-high versus V1b-low patients.
- To assess the efficacy of BH-200 (250 mg BID) in improving anxiety symptoms in V1b-high versus V1b-low patients.
- To explore the tolerability and safety of BH-200 (250 mg BID).
- To explore plasma concentrations of BH-200.
- To explore the association of demography, depression and treatment effects. | |
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria | 1. Male or female patients.
2. Between 18 and 75 years of age at the date of informed consent.
3. Body mass index between 18 and 35 kg/m2.
4. Outpatients.
5. 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.
6. Provide written informed consent.
7. Primary diagnosis of MDD, moderate or severe, single or recurrent episode, with or without psychotic features 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 as long as the primary diagnosis is MDD.
b) Patients with obsessive-compulsive disorder 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 and protocol.
c) Patients with eating disorders 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.
8. MADRS score ≥20 at screening and baseline.
9. Duration of current episode no longer than 12 months, prior to screening.
10. Symptoms of depression present for at least 2 weeks, prior to screening.
11. Willingness to stop current antidepressive medication or other prohibited psychotropic medication, at least 7 days or 5 half-lives, whichever is longer, before baseline (day 0).
12. 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.
13. 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.
14. 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
15. 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.
16. 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. | |
| E.4 | Principal exclusion criteria | 1. Inability to obtain written informed consent from the patient or to comply with the protocol and follow written and verbal instructions.
2. Pregnant, lactating females.
3. Patients with schizophrenia spectrum and other psychotic disorders and bipolar disorders.
4. Patients with paranoid, schizoid, and schizotypal personality disorder.
5. Patients with antisocial, borderline (emotionally unstable personality disorder, borderline type), histrionic and narcissistic personality disorder.
6. Patients with intellectual disability / mental retardation, e.g., due to neurodevelopmental disorders, neurocognitive or neurodegenerative disorders, and autism spectrum disorder.
7. Patients with PTSD.
8. Significant risk of suicide.
9. 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.
10. 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
-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.
11. Patients with a history of, or symptoms and signs suggestive of, impaired hepatic function or cirrhosis.
12. Patients with a history of Hepatitis B or C.
13. Patients with Cushing’s Syndrome.
14. Patients with Addison’s Disease.
15. Renal insufficiency.
16. Patients with uncontrolled diabetes (glycated haemoglobin [HbA1c] >8.0% at screening).
17. 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.
18. 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.
19. Patients with a history of moderate to severe alcohol use and/or substance use disorder.
20. Prior intermittent use of cannabinoids prior to screening is not exclusionary if the patient does not meet the criteria for substance use disorder.
21. 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, 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.
c) Intake of benzodiazepines during the study is prohibited unless the patient has a valid prescription.
22. Patients that received fluoxetine treatment within 10 weeks prior to screening
23. Patients who donated or lost whole blood ≥500 mL within 2 weeks prior to first dosing.
24. Patients who have participated in 2 or more clinical interventional studies within 1 year before screening.
25. Patients who are currently enrolled in a clinical interventional study. | |
| E.5 End points |
| E.5.1 | Primary end point(s) | | Change in the 17-item Hamilton Depression Rating Scale (HAMD-17) total score. | |
| E.5.1.1 | Timepoint(s) of evaluation of this end point | | From baseline to visit 7. | |
| E.5.2 | Secondary end point(s) | -Change in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score.
-Response rate.
-Remission rate.
-Change in the HAMD-17 total score.
-Change in the Clinical Global Impression-Severity of Illness rating scale (CGI-S).
-Change in the Hospital Anxiety and Depression Scale (HADS) total score, depressive sub-score, and anxiety sub-score.
-Change in the 36-item Short Form Health Survey (SF-36, one-week recall version).
-Change in the Sheehan Disability Scale (SDS).
-Change in suicidality, assessed by Columbia-Suicide Severity Rating Scale (C-SSRS).
-Number of reported adverse events (AEs), serious AEs (SAEs), number of reported clinical safety abnormalities (safety laboratory, electrocardiogram [ECG]).
-Pharmacokinetic (PK) assessments. | |
| E.5.2.1 | Timepoint(s) of evaluation of this end point | -MADRS - from baseline to each planned post-baseline visit, where the MADRS is assessed (visit 5, visit 7 and visit 8 [follow-up visit]).
-Response rate, Remission rate, HAMD-17, CGI-S and HADS – at each post-baseline visit.
-SF-36, one-week recall version - from baseline to each planned post-baseline visit, where the SF-36 is assessed (visit 5, visit 7 and visit 8 [follow-up visit]).
-SDS and C-SSRS - from baseline to each planned post-baseline visit.
| |
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 | The trial involves single site in the Member State concerned | No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 14 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 45 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned | | Bulgaria | | Estonia | | Germany | | Lithuania | | Poland | | Serbia | | Slovakia | | Spain | |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 | Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial | |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 5 |
