A Clinical Trial of Add-on Oral Slow-release Ketamine Treatment in Major Depression

Prior treatment

• Known psychiatric and neurological concomitant condition of:
  • MDD, single episode, severe, with psychotic features (ICD-10-CM: F32.3), MDD, recurrent, severe, with psychotic features (ICD-10-CM: F33.3), Schizophrenia spectrum and other psychotic disorders (ICD-10-CM: F21, F22, F23, F20.81, F20.9, F25.0, F25.1, F06.0, F06.1, F06.2, F28 and F29) or bipolar disorder (ICD-10-CM: F31), other mental disorder due to known physiological condition (ICD-10-CM: F06). Participants with first-degree relatives (parents, brothers, sisters or children) with psychotic or bipolar disorders are also not considered eligible. Paranoid or schizoid personality disorder (ICD-10-CM: F60.0, F60.1). Antisocial, borderline, histrionic or narcissistic personality disorder (ICD-10-CM: F60.2, F60.3, F60.4, F60.81). Neurodevelopmental disorders, e.g. moderate to profound intellectual developmental disorders (ICD-10-CM: F71, F72, F73), or autism spectrum disorders (ICD-10-CM: F84).
• History of significant head trauma within the past 2 years prior to Visit 1.
• Uncontrolled hypothyroidism i.e. not at stable treatment with thyroid hormones (triiodothyronine/thyroxine \[T3/T4\]) within the 6 weeks before Visit 1 or abnormal thyroid stimulating hormone (TSH) and free thyroxine (fT4) values at Visit 1.
• Previous administration of ketamine (with exception of known or suspected ketamine-anaesthesia) or esketamine.
• Prohibited prior and concomitant therapies and medication (see 7.3 Concomitant use of other medicinal products and treatments).
• History of moderate to severe alcohol use disorder or substance use disorder, including e.g. benzodiazepines, opiates, ketamine, hallucinogens and related drugs, stimulants (e.g. phencyclidine \[PCP\]), lysergic acid diethylamide \[LSD\], 3,4-methylenedioxymethamphetamine \[MDMA\], dextromethorphan, amphetamines, cocaine) or cannabis, except nicotine and caffeine, within 6 months before Visit 1 or a positive drug abuse test except for allowed medication prescribed for a medical condition.

Other illness

• Known hypersensitivity or intolerance to ketamine or any of the excipients.
• Known or suspected lifetime history of surgical procedures involving the brain or meninges, encephalitis, meningitis, degenerative central nervous system (CNS) disorder, epilepsy (excluding uncomplicated childhood febrile seizures with no sequelae) or any other disease/procedure/accident/intervention which, according to the investigator is deemed associated with significant injury to or malfunction of the CNS.
• History of cerebrovascular event (e.g. stroke, prolonged ischaemic neurologic deficit \[PRIND\], transient ischaemic attack).
• Known or suspected ongoing cardiac disease (e.g. unstable angina, congestive heart failure, tachyarrhythmia or myocardial infarction).
• Untreated or uncontrolled hypertension (after 5 minutes of rest, systolic blood pressure ≥ 180 mmHg or diastolic blood pressure ≥ 120 mmHg confirmed by three sequential measurements with at least 5 minutes between the single measurements).
• Known hepatitis B or C.
• History (within 5 years before Visit 1) of complicated cystitis (defined as cystitis in males; due to anatomical abnormalities; due to immunocompromised state, in pregnant women; recurrent infections despite adequate treatment; infections occurring after instrumentation such as nephrostomy).
• Any other significant disease or disorder which, in the opinion of the investigator, may either put the participant at risk because of participation in the trial, or jeopardise the conduct of the trial according to the protocol.
• Ongoing compulsory psychiatric care.

Lab values

• Laboratory findings suggesting impaired hepatic function or liver cirrhosis i.e. gamma-glutamyl transferase (GGT), alkaline phosphatase (ALP), alanine aminotransferase (ALT) or aspartate aminotransferase (AST) values \> 2x times the upper limit of normal (ULN) or total bilirubin \> 1.5 times the ULN at Visit 1. Participants with an isolated increase of indirect bilirubin not previously documented as a diagnosis of Gilbert's syndrome must be discussed with the medical monitor.
• eGFR \< 60 mL/min/1.73 m2 or creatinine \> 200 μmol/L at Visit 1 or ongoing dialysis or kidney transplants.
• Diabetes mellitus with a haemoglobin A1c (HbA1c) value \> 64 mmol/mol at the screening visit.

Other

• Pregnancy, breastfeeding or planned pregnancy (if female).
• High suicide risk according to the overall assessment of the research physician.
• Clinically significant abnormal electrocardiogram findings at Visit 1 which may jeopardize participant's safety according to the investigator.
• Hyperthyroidism.
• Participation in other treatment studies.
• Ongoing electroconvulsive treatment (ECT) or repetitive transcranial magnetic stimulation (rTMS).
• Other reason, as assessed by the investigator, that prevents the research subject's participation such as risk that the subject is unable to complete the trial (non-compliance).
• Recently started psychotherapy (within 6 weeks) or planning to start such treatment during participation in the trial.

• The subject has given their written consent to participate in the trial.
• BMI ≥ 18 and ≤ 35 kg/m2.
• Primary diagnosis of MDD meeting DSM-5-TR criteria and one of the following episode characteristics: (a)MDD, single episode, moderate (ICD-10-CM: F32.1); (b) MDD, single episode, severe, without psychotic features (ICD-10-CM: F32.2); (c) MDD, recurrent, moderate (ICD-10-CM: F33.1); (d) MDD, recurrent, severe, without psychotic features (ICD-10-CM: F33.2)
• Duration of current depressive episode no longer than 12 months prior to screening.
• MADRS score ≥ 22 at screening
• Willingness to start a new, conventional antidepressant treatment which is chosen by the treating physician with regards to side effect profile and previous treatments, together with KET01, dosed according to the prescribed schedule.
• Willingness to terminate any ongoing antidepressant treatment if deemed ineffective by study physician in accordance with clinical practice (tapering or immediate stop), followed by a wash-out phase of at least 7 days without medication before treatment with the new antidepressant is initiated together with KET01.
• For females of childbearing potential: Must be willing to undergo pregnancy tests and will be required to use highly effective contraceptive measures from the time of informed consent until 28 days after last IMP intake. Methods that can achieve a failure rate of less than 1% per year when used consistently and correctly are considered as highly effective birth control methods. Such methods include combined (oestrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal or transdermal); progestogen-only hormonal contraception associated with inhibition of ovulation (oral or injectable); implantable intrauterine device (IUD); intrauterine hormone-releasing system (IUS), bilateral tubal occlusion or practicing sexual abstinence (if this is in line with the preferred and usual lifestyle of the participant).
• For male participants with a partner of childbearing potential: Must be willing to use adequate contraceptive measures (barrier method) or practice sexual abstinence (if this is in line with the preferred and usual lifestyle of the participant) from the time of informed consent until 28 days after last IMP intake. Note: These requirements also apply for male participants who have had a vasectomy.