| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Treatment-Resistant Depression (TRD) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Depression that has not improved with other treatments. |
|
| E.1.1.2 | Therapeutic area | Psychiatry and Psychology [F] - Mental Disorders [F03] |
| 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 |
CORE study:
To determine the efficacy of 12 mg of BPL-003 given with psychological support to participants with treatment--resistant depression (TRD)
Open label extension (OLE):
To determine the safety of a second dose of BPL-003 given with psychological support to participants with TRD |
|
| E.2.2 | Secondary objectives of the trial |
CORE:
- To determine the efficacy, including early onset, of BPL-003 given with psychological support to participants with TRD
- To determine the safety of 0.3 mg, 8 mg, or 12 mg of BPL-003 given with psychological support to participants with TRD
- To evaluate the pharmacokinetics (PK) of 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) and its metabolites (including bufotenine) in participants with TRD after nasal administration of BPL-003
- To determine the effects on depression and disability of 0.3 mg, 8 mg, or 12 mg of BPL-003 given with psychological support to participants with TRD
OLE:
- To determine the efficacy of a second dose of BPL-003 given with psychological support to participants with TRD
- To evaluate the PK of 5-MeO-DMT and its metabolites (including bufotenine) in participants with TRD after nasal administration of BPL-003
- To determine the effects of a second dose of BPL-003 on depression and disability, given with psychological support to participants with TRD |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
CORE:
1. Willing and able to give informed consent, with written informed consent available before any study assessments.
2. Male and female participants, age 18 to 75 years at the time of informed consent.
3. At least moderate major depressive disorder (MDD), (single or recurrent episode as informed by Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition [DSM-5] criteria; if single episode, duration of ≥3 months and ≤ 2 years) based on medical records, clinical assessment, and documented completion of the version 7.0.2 Mini International Neuropsychiatric Interview (MINI).
4. Diagnosed with TRD defined as failure to respond to an adequate dose and duration of at least 2 pharmacological treatments, in the current episode, based on the MGH ATRQ assessment. Augmentation with an add-on treatment counts as a second treatment. Participants must not have failed more than 5 prior pharmacological treatments current episode (psychotherapy is not counted towards treatment failure).
5. Hamilton Depression Rating Scale (HDRS) (17 item) score ≥19 at Screening (Visit 1) and baseline (Day -3).
6. CGI-S ≥4 at Screening and baseline (Day -3).
7. If currently taking antidepressant medications, willing and able to
discontinue current antidepressants including selective serotonin reuptake inhibitor, serotonin and norepinephrine reuptake inhibitors, tricyclic antidepressants, monoamine oxidase inhibitors, and any augmentation medication such as antipsychotics or lithium. Withdrawal will follow local treatment guidelines and should aim to avoid withdrawal symptoms by gradually reducing the antidepressant
treatment dose.
8. Able (in the investigator’s opinion) and willing to undertake and comply with all study requirements, including ability to complete all protocol required assessment tools and to comply with all study visits in language used by study site.
9. Willing to abstain from alcohol for 48 hours before Day 1.
10. Willing to abstain from recreational drugs from Screening until the end of the study.
• Intermittent use of cannabinoids prior to Screening is not exclusionary as long as the participant does not meet the criteria for substance use disorder, as assessed using the DSM-5.
11. Willing to allow their own general practitioner, and consultant if appropriate, to be informed of study participation.
OLE:
1. Participants who complete the CORE study.
2. Willing and able to give informed consent for the OLE.
3. Willing to abstain from alcohol for 48 hours before OLE Day 1.
4. Willing to abstain from recreational drugs throughout the duration of the study. |
|
| E.4 | Principal exclusion criteria |
CORE:
1. Positive test for cannabinoids pre-dose on Day 1. Use of cannabinoids is not allowed for the duration of the study.
2. Current or past history of schizophrenia, post-traumatic stress disorder, psychotic disorder including psychotic depression, bipolar disorder, delusional disorder, schizoaffective disorder, or any other severe psychiatric disorder as assessed by medical history and a structured clinical interview (MINI).
3. Current personality disorders: Cluster A (paranoid, schizoid, schizotypal), Cluster B (antisocial, borderline, histrionic, narcissistic), or Cluster C (avoidant, dependent, -obsessive compulsive) assessed via McLean Screening Instrument for Borderline Personality Disorder (MSI-BPD), MINI, and clinical judgement.
4. First-degree family history of schizophrenia, bipolar disorder, delusional disorder, or schizoaffective disorder.
5. Current (within the last year) alcohol or substance use disorder (other than caffeine or nicotine) according to DSM-5 and assessed by the MINI at Screening that in the opinion of the investigator will be a safety concern for enrollment in the study or that could interfere with the therapeutic process or with other aspects of study participation. Any participant who is not able to agree or adhere to a plan to reduce and manage use will be excluded.
6. A participant who at any time has been unresponsive to ketamine or esketamine, unresponsive to an adequate course of treatment with electroconvulsive therapy (ECT) defined as at least 7 treatments with unilateral/bilateral ECT, or has received vagal nerve stimulation or has received deep brain stimulation.
7. Currently receiving prohibited medications or therapy.
8. Suicidal ideation with some intent to act within 12 months prior to the start of Screening, per the investigator’s clinical judgement or based on the C-SSRS, corresponding to a response of “Yes” on Item 4 (active suicidal ideation with some intent to act, without specific plan) or Item 5 (active suicidal ideation with specific plan and intent) for suicidal ideation on the C-SSRS, or any suicidal behavior within the 12 months prior to the start of Screening. Participants reporting suicidal ideation with intent to act or suicidal behavior as assessed on Day 1 should be excluded.
9. Suicide attempt and/or self-injurious behavior within the last 12 months prior to Screening.
10. Depression is secondary to other severe medical conditions according to the investigator’s opinion.
11. Other personal circumstances and behavior judged to be incompatible with establishment of rapport or safe exposure to the study medication.
12. Any other clinically significant psychiatric condition that, in the opinion of the investigator, may interfere with the interpretation of the study results or constitute a health risk for the participant if he/she takes part in the study.
Further medical exclusion criteria are listed in the protocol.
OLE:
1. Currently taking antidepressant medication.
2. Currently taking any other prohibited medication.
3. Participants who, in the opinion of the investigator, are not suitable to participate in the OLE.
4. Participants who met the Subject Dosing Stopping Criteria in the CORE.
5. Participants with controlled hypertension on antihypertensive therapy are excluded if repeated clinic seated or semi-recumbent systolic blood
pressure ≥130 mmHg or diastolic blood pressure ≥ 80 mmHg. Participants without a diagnosis of hypertension are excluded if repeated
clinic seated or semi-recumbent systolic blood pressure ≥ 140 mmHg or diastolic blood pressure ≥ 90 mmHg. Blood pressure eligibility should be assessed during Screening and predose on Day 1.
6. Participants where the CORE dose was not well tolerated. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
CORE:
Change from baseline in Montgomery-Asberg Depression Rating Scale (MADRS) for 12 mg compared to 0.3 mg of BPL-003
OLE:
• Number of events and percentage of participants with TEAEs
• Percentage of participants with clinically significant abnormal laboratory tests compared to OLE and CORE baseline
• Percentage of participants with clinically significant abnormal vital sign measurements (heart rate, blood pressure, and body temperature) compared to OLE and CORE baseline
• Percentage of participants with clinically significant ECG parameters compared to OLE and CORE baseline
• Incidence of suicidal ideation or behavior, as assessed by the C-SSRS compared to OLE and CORE baseline |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
CORE:
At Day 29
OLE:
Up to 9 weeks following CORE period completion |
|
| E.5.2 | Secondary end point(s) |
CORE:
1. Change from baseline in MADRS for 12 mg compared to 0.3 mg of BPL-003
2. Change from baseline in MADRS for 8 mg compared to 0.3 mg of BPL-003
3. Change from baseline in MADRS for 8 mg compared to 0.3 mg of BPL-003
4. Number of events and percentage of participants with treatment -emergent adverse events (TEAEs)
5. Percentage of participants with clinically significant abnormal laboratory tests compared to baseline
6. Percentage of participants with clinically significant abnormal vital sign measurements (heart rate, blood pressure, and body temperature) compared to baseline
7. Percentage of participants with clinically significant electrocardiogram (ECG) parameters compared to baseline
8. Incidence of suicidal ideation or behavior, as assessed by the Columbia-Suicide Severity Rating Scale (C-SSRS) compared to baseline
9. Impairment in cognitive performance, assessed by Cognitive Test Battery compared to baseline
10. Plasma levels of 5-MeO-DMT and it metabolites (including bufotenine) after nasal administration of BPL-003
11. Change from baseline in MADRS for 8 mg and 12 mg of BPL-003 compared to 0.3 mg of BPL-003
12. Percentage of responders (defined as 50% reduction in MADRS total score) by dose group compared to baseline
13. Percentage of participants in remission (defined as MADRS total score ≤ 10) by dose group
14. Change in 16-item Quick Inventory of Depressive Symptomatology-Self-Report (QIDS-SR-16) score by dose group compared to baseline, by dose group
15. Change in Quality of Life in Depression Scale (QLDS) score by dose group compared to baseline, by dose group
16. Change in Sheehan Disability Scale (SDS) total score by dose group compared to baseline, by dose group
17. Change in Clinical Global Impression-Severity (CGI-S) score by dose group compared to baseline, by dose group
OLE:
1. Change in MADRS compared to OLE and CORE baseline
2. Percentage of responders (defined as 50% reduction in MADRS total score) compared to OLE and CORE baseline
3. Percentage of participants in remission (defined as MADRS total score ≤ 10) compared to OLE and CORE baseline
4. Plasma levels of 5-MeO-DMT and its metabolites (including bufotenine) after nasal administration of BPL-003
5. Change in QIDS-SR-16 score compared to OLE and CORE baseline
6. Change in QLDS score compared to OLE and CORE baseline
7. Change in SDS total score compared to OLE and CORE baseline
8. Change in CGI-S score compared to OLE and CORE baseline |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
CORE:
1. at Day 8
2. at Day 29
3. at Day 8
8. at Days 2, 8, 29, 43, and 57
9. at Days 8 and 29
10. up to 60 minutes after administration
11. at Days 2 and 57
12. at Days 2, 8, 29, and 57
13. at Days 2, 8, 29, and 57
14. at Days 2, 8, 29, and 57
15. at Days 2, 8, 29, and 57
16. at Days 29, and 57
17. at Days 2, 8, 29, and 57
OLE:
4. up to 60 minutes after administration
For additional details on remaining endpoints please refer to Schedule of Events
|
|
| 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 | Yes |
| 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 | Yes |
| 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 | Yes |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
|
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 16 |
| 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 |
| Australia |
| United Kingdom |
| United States |
| Germany |
| Poland |
| Spain |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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 | 4 |
| E.8.9.1 | In the Member State concerned days | 18 |
| 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 | 6 |
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