Adjunctive Oral KET-AD Capsules in Treatment Resistant Bipolar Depression

Inclusion Criteria:

1. Male or female aged 18 to 65 years (inclusive) at the time of informed consent, with first major depressive episode (MDE) before the age of 50 years.
2. Body mass index (BMI) between 18 and 40 kg/m2, inclusive.
3. Meet the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) diagnostic criteria for BD (any type) currently experiencing a depressive episode, without psychotic features, based upon clinical assessment and confirmed by the Mini International Neuropsychiatric Interview (MINI).
4. Current MDE must be moderate to severe, as determined by the Hamilton Depression Rating Scale (HDRS-17) score > 20 with inadequate response (lack of clinically meaningful improvement of clinical symptoms) to 2 or more adequate evidence based treatment trials for bipolar depression, as per the 2018 Canadian Network for Mood and Anxiety Treatments (CANMAT) Bipolar Disorder Guidelines (25) as assessed using the Massachusetts General Hospital - Antidepressant Treatment Response Questionnaire (MGH-ATRQ) and documented by records (eg, medical/pharmacy/prescription records or a letter from treating physician etc.), for the current episode of depression.
5. Participant is taking a stable dose of a guideline concordant treatment for the bipolar depression on the MGH-ATRQ for at least 6 weeks at or above the minimum therapeutic dose.
6. Any psychotherapeutic treatment has been stable for at least 6 weeks prior to Screening, with no anticipated changes in frequency or therapist anticipated until after the EOS visit.
7. Willing to abstain from recreational/illicit drugs from Screening until the end of the study.
8. Willing to allow their own GP and/or other mental health professional, to be informed of study participation and agree to the participant withdrawing from their current medication as required.
9. Participant has stable, euthyroid thyroid function at Screening, as confirmed by laboratory results. Participants with a history of thyroid disease may be included if they are clinically euthyroid and have been on a stable thyroid treatment regimen for at least 2 months prior to the Screening visit.
10. Woman of childbearing potential (WOCBP) or fertile man agrees to use an acceptable method of contraception from at least 1 month prior to the Screening visit (WOCBP) or the start of Screening (fertile man) until 90 days after the last dose of IP. WOCBP must agree to not donate eggs and males must agree to not donate sperm from the first dose of IP until at least 90 days after the last dose of IP.
11. Not pregnant or breastfeeding, or willing to cease breastfeeding.
12. Any form of exercise, including but not limited to, sporting activities, gym, yoga or Pilates attendance, has been stable for at least 6 weeks prior to Screening, with the participant agreeable to not making changes to their type or frequency of exercise/s until after the EOS visit.
13. Able and willing to attend the necessary visits to the study site.
14. Able and willing to provide written informed consent after the nature of the study has been explained and prior to the commencement of any study procedures.

Exclusion Criteria:

1. In the Investigator's opinion, participant has chronic, refractory treatment resistant depression characterised by a lifetime history of > 4 adequate therapeutic trials of guideline concordant medications for bipolar depression (with or without adjuvants and/or electroconvulsive therapy [ECT]) without response, as confirmed by the MGH-ATRQ.
2. Current MDE for longer than 12 months prior to the Screening visit.
3. Current symptoms of mania, hypomania, or mixed features, as determined by the YMRS score > 12.
4. Has a history or current diagnosis of rapid cycling BD.
5. History of mania or hypomania in the past 6 months as determined by psychiatric history.
6. Has a current substance use disorder or history of any substance use disorder per DSM-5 criteria within 6 months prior to Screening, except for tobacco use disorder.
7. Has a history or current diagnosis of schizophrenia, schizoaffective disorders, or any psychotic disorder. Has posttraumatic stress disorder, obsessive compulsive disorder, autism spectrum disorder, borderline personality disorder, antisocial personality disorder, narcissistic personality disorder or histrionic personality disorder, or any other mental disorder with psychotic features.

8. Has past suicidal behaviour and/or suicidal thoughts with an intention defined by:

   1. suicidal ideation as endorsed on items 4 or 5 on the C-SSRS within the past year, during the Screening period, or at Baseline; or
   2. suicidal behaviours within the past year; or
   3. clinical assessment of significant suicidal risk during clinical interview; or
   4. non-suicidal self-injury within the past year.
9. Has dementia, delirium, amnesia, or any other significant cognitive disorder.
10. Has any known aneurysmal disease, recent myocardial infarction (MI) (within past 12 months), or medical condition for which an increase in blood pressure or intracranial pressure poses a serious risk. Has clinically significant cardiovascular disorders such as uncontrolled atrial fibrillation, heart failure, or ischaemic heart disease.
11. Recent hospitalisation (within 6 months of Screening) for procedures, such as percutaneous coronary intervention or coronary artery bypass surgery.
12. Has prolonged QTcF interval at Screening (QTcF > 450 msec for men and > 470 msec for women).
13. Has uncontrolled hypertension (≥ 140 mm Hg systolic or ≥ 90 mm Hg diastolic).
14. Participants who have taken phencyclidine (PCP)/ketamine within 12 months prior to the Screening visit.
15. Has had vagal nerve stimulation, deep brain stimulation, ECT, or transcranial magnetic stimulation during the current MDE episode.
16. Has current or history of seizures. Note: uncomplicated childhood febrile seizures with no sequelae are not exclusionary.
17. Has medically unstable condition such as clinically significant neurological, hepatic, renal, metabolic, haematological, immunological, cardiovascular, pulmonary, gastrointestinal, or psychiatric disorders.
18. Has unstable diabetes mellitus (insulin dependent diabetes mellitus [IDDM] and non IDDM) of HbA1C > 7.0 or above or fasting blood sugars >125 mg/dL.

19. Participant has a history of, or symptoms and signs suggestive of, liver cirrhosis (eg, oesophageal varices, ascites, and increased prothrombin time) OR alanine aminotransferase (ALT) or aspartate aminotransferase (AST) values > 2× the upper limit of normal (ULN) or total bilirubin >1.5× the ULN during Screening.

    For elevations in bilirubin if, in the opinion of the Investigator and agreed upon by the Sponsor's medical officer, the elevation in bilirubin is consistent with Gilbert's disease, the participant may be enrolled in the study.

20. Participants with known history of, or a positive test for, HIV.
21. Participants with an active hepatitis B and/or hepatitis C infection.
22. Poor pill swallowing ability.
23. History of severe allergic or anaphylactic reactions, or sensitivity to the IP or its constituents.
24. Positive toxicology screening panel (urine test including qualitative identification of barbiturates, tetrahydrocannabinol [THC], amphetamines, benzodiazepines, opiates, methadone, methamphetamine, ecstasy [MDMA], phencyclidine, and cocaine), or alcohol breath test.
25. Clinical laboratory values outside the normal range as specified by the testing laboratory, unless deemed not clinically significant by the Investigator or designee.
26. Unwilling to abstain from alcohol from 24 hours before to 24 hours after each IP administration.
27. Use of rifampicin, St John's wort, diazepam or secobarbital, clarithromycin, or moderate to strong CYP3A4 inhibitors within 30 days or 5 half-lives of the medication (whichever is longer) prior to first IP administration.
28. Use of any investigational medical device or investigational drug within 30 days or 5 half lives of the investigational drug (whichever is longer) prior to the first administration of the IP.
29. Anything that the Investigator considers would jeopardise the safety of the participant, prevent complete participation in the study, or compromise interpretation of study data.