Adjunctive Oral KET-AD Capsules in Treatment Resistant Bipolar Depression

Abuse-deterrent Immediate Release Oral Ketamine Capsules for Treatment Resistant Bipolar Depression: A Phase 2A, Randomised, Double-blind, Placebo-controlled Study

This study is testing a new oral ketamine treatment called KET-AD in adults with treatment-resistant bipolar depression (TRBD). The study will look at how safe and tolerable the treatment is, and whether it may help improve symptoms of depression when used together with a participant's usual treatment.

About 160 people will take part in the study. Participants will be randomly assigned (like flipping a coin) to receive either KET-AD or a placebo (a treatment with no active medicine). Neither the participant nor the study team will know which treatment the participant is receiving during the study.

The study treatment will be taken by mouth 3 times a week for up to 7 weeks. Participants will continue taking their usual standard treatment throughout the study.

The study has several parts:

Screening Period (up to 28 days)

Before joining the study, participants will complete tests and assessments to confirm whether they are eligible to take part.

Titration Phase (Weeks 1-3)

The first 3 weeks are used to find the highest dose of study treatment that each participant can comfortably tolerate.

All doses during this phase are given at the study clinic. Participants will start on a lower dose. Depending on how well the treatment is tolerated, the dose may be increased, kept the same, or reduced. The study doctor will carefully monitor participants for side effects after each dose.

Participants who cannot tolerate the treatment, or who cannot reach the required dose level by the end of Week 3, will stop study treatment and complete an early finish visit.

Maintenance Phase (Weeks 4-7)

Participants who tolerate the treatment during the Titration Phase may continue into the 4-week Maintenance Phase.

Participants will stay on the same dose throughout this phase. Some doses will still be given at the study clinic. Other doses may be taken at home if approved by the study doctor. Home doses will be supervised remotely by a mental health professional using a secure telehealth app.

Participants will use an electronic app during the study. The app will be used to complete questionnaires and other study assessments both at the clinic and at home. Participants may use their own device or be provided with one by the study team. Training will be provided before participants begin using the app independently.

Safety Monitoring

Participant safety will be closely monitored throughout the study by the study doctors and by an independent safety committee called a Data Safety Monitoring Board (DSMB).

Follow-up Visits

After treatment ends, participants will attend:

a follow-up clinic visit on Day 50, and an end-of-study visit on Day 64, which may be completed remotely.

Participants can leave the study at any time if they choose.

This is a Phase 2a, double-blind, randomised, placebo-controlled, parallel-group comparison of flexible-dose KET-AD (140 mg to 280 mg) administered orally 3 times a week, over a period of 7 weeks, as adjunctive to standard of care (SOC) in adults with TRBD. The primary endpoint will evaluate the safety and tolerability of KET-AD administered 3 times a week for up to 7 weeks. Secondary and exploratory endpoints will assess participant- and Investigator-reported symptoms of TRBD via validated questionnaires, the PK of KET-AD and its metabolites, and the use of a telehealth platform during at-home dosing of a novel formulation of oral ketamine.

Up to approximately 160 participants who meet all eligibility criteria will be randomised in a 1:1 ratio to receive KET-AD 3 times a week for up to 7 weeks, or placebo dosing to match. An initial 3-week Titration Phase will be completed to find each participant's highest individualised maximum dose (210 mg or 280 mg), which will be used in the 4-week Maintenance Phase. Only participants receiving 210 mg or 280 mg KET-AD or matched placebo on Day 19 or participants tolerating 140 mg KET-AD and suitable to increase to 210 mg KET-AD or matched placebo on Day 22 will progress to the Maintenance Phase. Participants are to continue their SOC treatment during the study.

A Data Safety Monitoring Board (DSMB) will provide safety oversight. The Screening period will be up to 28 days. A participant who meets all inclusion and none of the exclusion criteria is eligible to be randomised into the study. An interactive response technology (IRT) will be used for randomisation. Participant randomisation will be stratified based on site and on each participant's current SOC treatment.

During the study, participants will use an electronic platform (app). Participants will either use their own device or will be provided with a handheld device on Day 1. This electronic platform will be used to collect all PD data, including assessments completed at the study site and at home. Participants who meet all eligibility criteria will receive training on the electronic platform prior to independent use of the app during the Maintenance Phase.

The duration of treatment will be up to 7 weeks. Any participant who receives at least 1 dose of investigational product (IP) but does not complete 7 weeks of dosing will complete the Early Termination (ET) visit. Participants will be followed through Day 64, unless the participant withdraws consent.

Titration Phase The Titration Phase is a 3-week period and is designed to identify each participant's highest tolerated dose. All doses of IP are administered at the study site, 3 times per week. Participants are to continue their SOC treatment during the Titration Phase.

After each dose of IP, the Investigator will record their determination on whether the participant tolerated the dose and is suitable for continued dosing. Dose level decisions will be managed through the IRT. If the Investigator determines that a participant is not tolerating the dose of IP, the IRT may decrease the dose (to the lowest allowable dose of 140 mg).

Participants who are unable to be titrated to at least 210 mg KET-AD on Day 22 (start of the Maintenance Phase) will discontinue the IP, continue their SOC treatment, and complete the ET visit. A participant who does not tolerate 140 mg KET-AD at any time during the Titration Phase may discontinue IP and progress to the ET visit.

Week 1 On Day 1, participants are randomised 1:1 to receive KET-AD or placebo. Participants will receive a single oral dose of IP (KET-AD 140 mg or placebo). The participant will receive 2 further doses of IP on Day 3 and then on Day 5, provided that the Investigator has not identified any clinically significant AEs arising since the most recent IP dose administration (ie, the participant has tolerated the dose).

If the Investigator identifies any clinically significant AEs arising after IP administration on Day 1 only, the participant will be discontinued from further dosing and will progress to the ET visit, and a new participant will be enrolled to the study.

Week 2 Participants will continue to receive the IP they were randomised to in Week 1. Based on the Investigator's assessment of dose tolerability and suitability for continued dosing, the IRT may increase the dose by 70 mg (to a maximum of 210 mg in Week 2), maintain the current dose, and/or reduce the dose by 70 mg (to a minimum dose of 140 mg) at any time during Week 2. Participants will be maintained on a minimum of 140 mg KET-AD during Week 2 unless, in the opinion of the Investigator, the participant should be withdrawn from further dosing. In this case, the participant will progress to the ET visit.

Week 3 Participants will continue to receive the IP they were randomised to in Week 1. Based on the Investigator's assessment of dose tolerability and suitability for continued dosing, the IRT may increase the dose by 70 mg (to a maximum dose of 280 mg), maintain the current dose, and/or reduce the dose by 70 mg (to a minimum dose of 140 mg) at any time during Week 3. Participants will be maintained on a minimum of 140 mg KET-AD during Week 3 unless, in the opinion of the Investigator, the participant should be withdrawn from further dosing. In this case, the participant will progress to the ET visit. Only participants receiving 210 mg or 280 mg KET-AD or matched placebo on Day 19, or participants tolerating 140 mg KET-AD and suitable to increase to 210 mg KET-AD or matched placebo on Day 22, will progress to the Maintenance Phase.

Maintenance Phase During the Maintenance Phase, the Investigator will continue to assess and record IP tolerability assessments. Participants who are increasing to 210 mg KET-AD on Day 22 or who tolerated the 210 mg or 280 mg doses of IP during the Titration Phase are assumed to be at the highest individualised dose level (ie, either 210 mg or 280 mg) and will remain on the same dose during the 4 week Maintenance Phase. Participants not tolerating the IP during the Maintenance Phase will discontinue the IP and progress to the ET visit. The dose level cannot be increased or decreased at any time for any participant during the Maintenance Phase. Participants are to continue their SOC treatment during the Maintenance Phase.

IP doses on Days 22, 29, 36, and 43 (ie, the first doses of Weeks 4, 5, 6, and 7, respectively) will be administered at the study site as per the Titration Phase. At the discretion of the Investigator, all other doses may be administered at home. For at-home dosing, up to 2 doses of IP will be provided to the participant. During at-home dosing, participants will administer the IP in the presence of a mental health professional via an electronic telehealth platform (app).

Participants who discontinue the IP during the Maintenance Phase will continue their SOC treatment and will complete the ET visit.

Follow-up and End of Study Visits Participants will return to the study site for a Follow-up visit on Day 50. The End of Study (EOS) visit on Day 64 may be conducted remotely.

Oversight will be provided by a DSMB.

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.