RESET-TRD; a Randomised trial on oral ESketamine compared to Electroconvulsive Therapy for patients with Treatment Resistant Depression

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Universitair Medisch Centrum Groningen

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Psychiatry and Psychology [F] - Mental Disorders [F03]

Decision date (initial)

2024-11-12

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

No

External identifiers

EU CT number

2024-517485-42-00

EudraCT number

2022-000383-21

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy

Phase 1: To investigate whether oral esketamine is non-inferior to ECT in terms of the percentage of patients with a treatment response after eight weeks of individually optimized treamtent in patients with non-psychotic therapy resistant depression.
Phase 2: To compare the efficacy of maintenance oral esketamine treatment versus ECT to prevent relapse, at one year follow-up, in participants who responded to initial treatment in phase 1.

Secondary objectives 1

1. 1. To investigate whether esketamine remains non-inferior to ECT while defining treatment response as a ≥50% reduction on the MADRS. 2. To compare the efficacy of maintenance oral esketamine and ECT to prevent relapse in terms of loss off response while defining treatment response as a ≥50% reduction on the MADRS. 3. To investigate whether oral esketamine is non-inferior to ECT in patients with NTRD on the short-term in relation to depressive symptom severity, suicidal ideation, clinical impression, functionality, and quality of life; 4. To investigate whether oral esketamine is more patient friendly than ECT with respect to treatment burden, side effects, and tolerability; 5. To investigate whether oral esketamine is more cost-effective compared to ECT; 6. To explore predictors and working mechanisms of successful oral esketamine and ECT treatment 7. To explore participants’ subjective experiences with treatment with oral esketamine or ECT

Conditions and MedDRA coding

Non-psychotic therapy resistant unipolar depression

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 1

1. 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 3

1. 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
2. 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
3. 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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. The primary objective of this trial is to compare the shortterm efficacy of oral esketamine versus ECT in patients with NTRD. In this regard, the percentage of treatment response, defined as a ≥30% reduction on the MADRS, in the esketamine relative to the ECT condition after eight weeks of treatment will be determined. Non-inferiority is defined as the esketamine arm having no less than 70% of the efficacy of ECT.
2. In this regard, the percentage of relapse, defined as a <30% reduction, in the esketamine relative to the ECT condition after 12 months of maintenance treatment will be determined.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Universitair Medisch Centrum Groningen

Sponsor organisation

Universitair Medisch Centrum Groningen

Address

Hanzeplein 1

City

Groningen

Postcode

9713 GZ

Country

Netherlands

Scientific contact point

Organisation

Universitair Medisch Centrum Groningen

Contact name

Martijn Godschalk

Public contact point

Organisation

Universitair Medisch Centrum Groningen

Contact name

Martijn Godschalk

Locations

1 EU/EEA country · 8 investigational sites

By country

Investigational sites

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 3 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

1 submissions — initial application plus substantial / non-substantial modifications