Comparative Efficacy of Oral Esketamine Versus Electroconvulsive Therapy in Non-Psychotic Treatment-Resistant Unipolar Depression
- Trial ID
- 2024-517485-42-00
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate whether **oral esketamine** is non-inferior to electroconvulsive therapy (ECT) in terms of the percentage of patients with a treatment response after eight weeks of individually optimized treatment in patients with non-psychotic therapy-resistant unipolar depression. Additionally, the study aims to compare the efficacy of maintenance oral esketamine treatment versus ECT in preventing relapse at a one-year follow-up in participants who responded to the initial treatment phase. This is clinically relevant as it may offer an alternative treatment option for patients with treatment-resistant depression, potentially improving patient outcomes and quality of life.
Secondary objectives include: - Investigating whether esketamine remains non-inferior to ECT, defining treatment response as a ≥50% reduction on the Montgomery-Åsberg Depression Rating Scale (MADRS). - Comparing the efficacy of maintenance oral esketamine and ECT in preventing relapse, with treatment response defined as a ≥50% reduction on the MADRS. - Evaluating whether oral esketamine is non-inferior to ECT in patients with non-psychotic therapy-resistant depression in terms of depressive symptom severity, suicidal ideation, clinical impression, functionality, and quality of life. - Assessing whether oral esketamine is more patient-friendly than ECT regarding treatment burden, side effects, and tolerability. - Investigating the cost-effectiveness of oral esketamine compared to ECT. - Exploring predictors and mechanisms of successful oral esketamine and ECT treatment. - Exploring participants' subjective experiences with treatment using oral esketamine or ECT.
Participants
The clinical trial involves participants diagnosed with **non-psychotic therapy resistant unipolar depression**. The study population includes both male and female subjects aged 18 years and older. Participants are required to have a sufficient level of spoken and written Dutch and must be able to provide written informed consent. The trial does not include a vulnerable population. Participants must have a current DSM-5 diagnosis of major depressive disorder (MDD) without psychotic symptoms, confirmed by the Mini International Neuropsychiatry Interview (MINI-S). They should exhibit at least moderate to severe depression, as indicated by a Montgomery-Åsberg Depression Rating Scale (MADRS) total score of 20 or higher, and have an indication for electroconvulsive therapy (ECT) for the current depressive episode. The trial targets individuals with treatment-resistant depression (TRD), defined by non-response or intolerance to at least two different antidepressants plus an augmentation step such as lithium, mirtazapine, or quetiapine, all prescribed in adequate doses for a minimum of four weeks. Participants must agree to initial clinical admission followed by daycare or outpatient treatment. The sponsor has not provided information regarding the total number of participants in the study.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy of **oral esketamine** compared to electroconvulsive therapy (ECT) in patients with non-psychotic therapy-resistant unipolar depression. This is a randomized, controlled, and double-blind trial, structured in two phases. The primary objective of Phase 1 is to assess whether oral esketamine is non-inferior to ECT in terms of treatment response after eight weeks. Phase 2 aims to compare the efficacy of maintenance oral esketamine treatment versus ECT in preventing relapse over a one-year follow-up period for participants who responded to initial treatment in Phase 1. The trial is expected to conclude by November 2026, with recruitment having commenced in July 2022.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, language proficiency, and a current DSM-5 diagnosis of major depressive disorder (MDD) without psychotic symptoms. The inclusion visit will also involve the Mini International Neuropsychiatry Interview (MINI-S) and assessment of depression severity using the Montgomery-Åsberg Depression Rating Scale (MADRS). Following randomization, participants will attend regular follow-up visits to monitor treatment response and safety, with the primary endpoint being a ≥30% reduction in MADRS score after eight weeks. The end-of-study visit will evaluate long-term outcomes, including relapse rates after 12 months of maintenance treatment.
Participant involvement is anticipated to last up to 60 weeks, depending on individual response and continuation into the maintenance phase. Conditions that may lead to early termination from the study include withdrawal of consent, adverse events, or non-compliance with study protocols. The trial is conducted under strict ethical guidelines, ensuring that all participants provide informed consent and that their safety and well-being are prioritized throughout the study duration.
Treatment
The clinical trial involves the administration of **esketamine**, marketed under the name Ketanest-S 25 Multi-dose, oplossing voor injectie 25 mg/ml. This experimental medication is provided in the form of a **solution for injection**. However, for the purposes of this study, it is administered orally. The maximum daily dose is 3.0 mg/kg, with the same amount being the maximum total dose per administration. The treatment period is limited to a maximum of 60 days. The formulation has been modified by the addition of citric acid and sirupus simplex to facilitate oral administration. The active substance, esketamine, is of chemical origin and is classified under the ATC code N01AX14. The pharmaceutical product is manufactured by Pfizer B.V. in the Netherlands.
In this trial, the experimental treatment with oral esketamine is compared to **electroconvulsive therapy (ECT)**, which serves as the comparator treatment. ECT is a standard-of-care therapy for patients with treatment-resistant depression. The trial aims to evaluate the non-inferiority of oral esketamine compared to ECT in terms of treatment response after eight weeks and to assess the efficacy of maintenance oral esketamine treatment versus ECT in preventing relapse at one-year follow-up. Participant compliance with the dosing schedule will be monitored throughout the study to ensure adherence to the treatment protocol.
Efficacy
The efficacy of oral **esketamine** compared to Electroconvulsive Therapy (ECT) in patients with Treatment Resistant Depression (TRD) will be assessed through a randomized clinical trial. The primary endpoint for evaluating short-term efficacy is the percentage of treatment response, defined as a ≥30% reduction in the Montgomery-Åsberg Depression Rating Scale (MADRS) score after eight weeks of treatment. Non-inferiority of esketamine is established if it achieves at least 70% of the efficacy of ECT. Additionally, the trial will assess the percentage of relapse, defined as a <30% reduction in MADRS score, after 12 months of maintenance treatment.
Inclusion and Exclusion Criteria
Inclusion Criteria
- To be eligible to participate in this study, a participant must meet the following criteria: • 18 years or older of age at screening; • Sufficient level of spoken and written Dutch; • Ability to freely provide written informed consent prior to study participation; • Current DSM-5 diagnosis of MDD without psychotic symptoms, ascertained by the Mini International Neuropsychiatry Interview (MINI-S); • At least moderate to severe depression, defined by a MADRS total score ≥ 20; • Indication for ECT treatment for the treatment of the current depressive episode. • TRD, defined as non-response to (or established non-tolerability of) treatment with at least two different antidepressants plus an augmentation step such as lithium, mirtazapine or quetiapine during lifetime, all prescribed in an adequate dose (i.e. defined daily dose) for at least four weeks; • Patients agree with initial clinical admission and subsequent daycare/outpatient treatment.
Exclusion Criteria
- A potential participant who meets any of the following criteria is excluded from participation in this study: • Prior or current bipolar disorder, schizophrenia spectrum, other psychotic disorders, current MDD with psychotic features (previous MDD with psychotic features is allowed if the current episode is non-psychotic). All diagnoses according to DSM-5, assessed with MINI-S interview at screening; • The presence of current moderate or severe dependence of alcohol or drugs 6 months within screening according to the DSM-5, not including tobacco-related and caffeinerelated disorders, ascertained by the MINI-S interview at screening; • Current use of a MAOI in excess of a daily dose of 60 mg
- Recent (within the last four weeks of screening) or current use of cannabis or any other non-prescribed psychoactive compounds, including Saint John’s wort, assessed at screening; • Relevant neurological disorders, such as dementia or epilepsy; • Recent (within the last four weeks of screening) change of treatment with antidepressants; • Planned changes in antidepressant treatment during phase 1 of the study, not being part of the standard practice of ECT treatment like change in lithium or anti-epileptics; • Active suicidal plans, defined by a score higher than 5 (explicit plans for suicide when there is an opportunity or active preparations for suicide) on the MADRS’s item for suicidal ideation; • (Suspected) pregnancy, lactation, or insufficient contraception. In fertile women, a urine pregnancy test will be performed prior to Phase 1 (screening) and prior to Phase 2 (month 1) of the study. • Current use of benzodiazepine and benzodiazepine-like agents (zolpidem, zopiclone) in excess of 3 mg lorazepam or an equivalent per day; • Recent (within the last four weeks of screening) start or change in the use of somatic medication that commonly affects mood, like corticosteroids; • Previous treatment with ECT or esketamine during the current depressive episode
- Presence of any absolute contra-indication for esketamine use (according to the Summaries of Product Characteristics) or ECT (according to Dutch ECT guidelines, Appendix A), namely pheochromocytoma, increased intracranial pressure, intracranial surgery (< 6 months), a recent cerebrovascular accident / cerebral trauma, glaucoma, recent myocardial infarction (<6 months), unstable angina pectoris or myocardial disease (New York Heart Association (NYHA) class IV), aneurysmal vascular disease, severe hypertension, severe hyperthyroidism, severe liver problems (Child-Pugh class C), severe kidney problems, acute intermittent porphyria, severe upper airway infection, the use of medication that esketamine interacts with on a major level, such as xanthine derivates (aminophylline, theophylline) or previous hypersensitivity to esketamine or its components; • Presence of any of the following relative contra-indications for esketamine use (according to the Summaries of Product Characteristics) or ECT (according to Dutch ECT guidelines, Appendix A), namely stable angina pectoris, hypertension, myocardial infarction (> 6 months ago), intracranial process, unstable cervical spine, carcinoid, severe COPD, severe obesity, pseudocholinesterase deficiency, malignant hyperthermia and congenital muscle diseases. Cardiovascular relative contra-indications will lead to consultation with a colleague from the cardiology department. This will be performed after screening by the researcher who screened the patient. After cardiological clearance it may still be possible to enrol. Presence of an intracranial process will be discussed after screening with a colleague from neurosurgery department and an anaesthesiologist. Remaining relative contra-indications will lead to discussion with the anaesthesiology department. This will be performed after screening by the researcher who screened the patient. After anaesthesiologic clearance it may still be possible to enrol. • Mental incompetence to fully understand the informed consent of this study, based on the judgment of the general practitioner or treating psychiatrist of the participant; • Inability to understand or comply with study requirements, as judged by the investigator(s); • Use of other investigational drugs within 4 weeks of screening.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 The Netherlands | Not Yet Recruiting | 01 Jul 2022 | — |
| Netherlands | — | — | 172 |
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 |
|---|---|---|---|---|---|---|
Ketanest-S 25 Multi-dose, oplossing voor injectie 25 mg/ml | Test | OPLOSSING VOOR INJECTIE | ORAL | 3.0 | 60 | PRD6796182 |