Phase II Open-label Study of Adjunctive Ketamine Hydrochloride Prolonged-Release Tablets During Antidepressant Initiation in Patients with Major Depressive Disorder
- Trial ID
- 2025-524841-28-00
- Sponsor
- Region Skane
Trial statistics
Diseases & Conditions
Objectives
The primary objective is to evaluate the preliminary antidepressant efficacy of ketamine hydrochloride prolonged-release tablets as an adjunctive therapy to a standard antidepressant agent in patients with major depressive disorder after one week of treatment. 5
Secondary objectives include:
- Assessment of anxiety, depression, and clinical global impression.
- Evaluation of safety and tolerability. 4
- Investigation of changes in suicidal ideation.
- Analysis of inflammatory markers and their association with symptom improvement.
- Examination of the relationship between epigenetic markers and resilience.
- Monitoring changes in physical activity and sleep patterns.
- Investigation of the lived experience regarding mood changes during treatment.
Participants
The sponsor did not provide information regarding the total number of participants. The study population consists of male and female patients diagnosed with major depressive disorder. Eligible participants are aged between 18 and 75 years with a body mass index between 18 and 35 kg/m2. Inclusion requires a Montgomery-Åsberg Depression Rating Scale score of 22 or higher at screening and a current depressive episode lasting no more than 12 months. The diagnosis must meet DSM-5-TR criteria for moderate or severe single or recurrent episodes without psychotic features. Participants must be willing to initiate a standard antidepressant agent as an adjunctive treatment and adhere to specific contraception requirements for women of childbearing potential and male participants with a partner of childbearing potential.
Plans and Procedures
This is an open-label, Phase II trial designed to evaluate the antidepressant efficacy of ketamine hydrochloride prolonged-release tablets as an adjunctive treatment for major depressive disorder during the initiation of standard antidepressant therapy. The study methodology involves the administration of 240 mg of the test product orally alongside a physician-selected antidepressant. Following a screening visit to assess eligibility via DSM-5-TR criteria and a Montgomery-Åsberg Depression Rating Scale (MADRS) score, participants undergo a wash-out period of at least 7 days if required by clinical practice. The trial includes a baseline visit on day 1, followed by multiple assessment points on days 3, 5, 8, 15, and 29. The primary objective is to measure the change in the MADRS total score at day 8 compared to baseline. Secondary endpoints include assessments of clinical severity, efficacy, anxiety, and biological markers such as inflammatory biomarkers and DNA methylation patterns. The total duration of participant involvement extends to 29 days from the start of treatment.
Treatment
The experimental medication consists of ketamine hydrochloride in the form of prolonged release tablets. The prescribed dosage is 240 mg administered via the oral route.
The study involves the administration of the test product as an adjunctive treatment to complement the initiation of a standard antidepressant agent for the management of major depressive disorder.
Efficacy
The primary efficacy endpoint is the change in the total Montgomery-Åsberg Depression Rating Scale (MADRS) score from baseline on day 1 to day 8. Secondary endpoints include the change in total MADRS score at days 3, 5, 15, and 29, as well as the response rate, defined as a reduction of $\ge$ 50% from baseline, and the remission rate, defined as a MADRS score of $\le$ 10, at days 3, 5, 8, 15, and 29.
Additional clinical assessments involve the Clinical Global Impression – Severity (CGI-S) and Clinical Global Impression – Efficacy Index (CGI-E) scales at days 3, 5, 8, 15, and 29. Changes in the Patient Health Questionnaire-9 (PHQ-9) and the generalized anxiety disorder-7 (GAD-7) are measured at days 15 and 29. A composite inflammatory depressive symptom score (InfDep score), comprising specific PHQ-9 items, is also evaluated at days 15 and 29. The Columbia Suicide Severity Rating Scale (C-SSRS) is assessed at days 8, 15, and 29.
Efficacy is further evaluated through the following parameters:
- Changes in sedentary behaviour, low-intensity physical activity, moderate- to vigorous physical activity, and step counts at days 3, 5, 8, 15, and 29.
- Variations in sleep patterns, including total sleep time, sleep efficiency, wake after sleep onset, and the number of awakenings at days 3, 5, 8, 15, and 29.
- Changes in blood plasma levels of high-sensitive C-reactive protein, interleukin-6, tumor necrosis factor alpha, and white blood cell count at days 8, 15, and 29.
- Alterations in DNA methylation patterns at days 8 and 29.
- Changes in the Connor-Davidsson Resilience Scale (CD-RISC-25) at days 8 and 29.
- Qualitative assessment of the personal experience regarding mood effects through an interview at day 29.
Inclusion and Exclusion Criteria
Inclusion Criteria
- The subject has given their written consent to participate in the trial.
- Age ≥ 18 and ≤ 75 years.
- Body mass index (BMI) ≥ 18 and ≤ 35 kg/m2.
- Primary diagnosis of MDD meeting Diagnostic and Statistical Manual of Mental Disorders, 5th edition, Text Revision (DSM-5-TR) criteria and one of the following episode characteristics: (1) MDD, single episode, moderate (ICD-10-CM: F32.1); (2) MDD, single episode, severe, without psychotic features (ICD-10-CM: F32.2); (3) MDD, recurrent, moderate (ICD-10-CM: F33.1); (4) 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 women of childbearing potential (WOCBP; definition: A WOCBP is defined as any female who has experienced menarche and who has not undergone surgical sterilisation (hysterectomy or bilateral oophorectomy) or is not postmenopausal. Menopause is defined clinically as 12 months of amenorrhea in a woman over age 45 in the absence of other biological or physiological causes.): 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 (see definition of WOCBP above): 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.
Exclusion Criteria
- Known hypersensitivity or intolerance to ketamine or any of the excipients.
- Pregnancy, breastfeeding or planned pregnancy (if female).
- High suicide risk according to the overall assessment of the research physician.
- 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).
- 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 significant head trauma within the past 2 years prior to Visit 1.
- 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).
- Clinically significant abnormal electrocardiogram findings at Visit 1 which may jeopardize participant’s safety according to the investigator.
- 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).
- 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.
- Known hepatitis B or C.
- Estimated Glomerular Filtration Rate (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.
- Hyperthyroidism.
- 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.
- 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.
- 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 in Study Protocol).
- 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.
- Participation in other treatment studies.
- Ongoing electroconvulsive treatment (ECT) or repetitive transcranial magnetic stimulation (rTMS).
- Ongoing compulsory psychiatric care.
- 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.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Sweden | Not Recruiting | 01 Mar 2026 | 12 |
Sites & Investigators
Research sites
Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Ketamine hydrochloride prolonged release tablets | Test | PROLONGED RELEASE TABLETS | ORAL | 240 | 8 | PRD10278228 |