Study to Evaluate the Efficacy and Safety of Intranasal BPL-003 in Patients with Treatment Resistant Depression

Prior treatment

• Use of cannabinoids is not allowed for the duration of the study. Participants should not be administered the study drug if they have a positive urine drug screen result for cannabinoids pre-dose on [CCI] (retesting is allowed if there is a suspected false positive test).
• Other personal circumstances and behavior judged to be incompatible with establishment of rapport or safe exposure to the study medication.
• 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.
  • OLE: 1. Currently taking antidepressant medication.
  • OLE: 2. Currently taking any other prohibited medication.
  • OLE: 3. Participants who, in the opinion of the investigator, are not suitable to participate in the OLE.
  • OLE: 4. Participants who met the Subject Dosing Stopping Criteria in the CORE
  • OLE: 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 [CCI].
  • OLE: 6. Participants where the CORE dose was not well tolerated.
• 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.
• Currently receiving prohibited medications or therapy.
• 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 [CCI] should be excluded.
• Suicide attempt and/or self-injurious behavior within the last 12 months prior to Screening.

Other illness

• Depression is secondary to other severe medical conditions according to the investigator's opinion.
• 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).
• 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 (MSIBPD), MINI, and clinical judgement.
• First-degree family history of schizophrenia, bipolar disorder, delusional disorder, or schizoaffective disorder.
• 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.

• Willing and able to give informed consent, with written informed consent available before any study assessments.
• 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.
• 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.
  • OLE: 2. Willing and able to give informed consent for the OLE.
  • OLE: 3. Willing to abstain from alcohol for 48 hours before OLE [CCI].
  • OLE: 4. Willing to abstain from recreational drugs throughout the duration of the study.
• Male and female participants, age 18 to 75 years at the time of informed consent.
• 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). For clarification, if recurrent MDD, there is no limit on episode duration.
• 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). For clarification, pharmacological treatments initially effective but subsequently ineffective (tachyphylaxis) will be considered treatment failures if they fulfil the ATRQ criteria for dose and duration of failure.
• Hamilton Depression Rating Scale (HDRS) (17 item) score ≥19 at Screening (Visit 1) and baseline (Day -3).
• CGI-S ≥4 at Screening and baseline (Day -3).
• 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.
• 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.
• Willing to abstain from alcohol for 48 hours before [CCI].