The Effect of a Six Week Intensified Pharmacological Treatment for Major Depressive Disorder Compared to Treatment as Usual in Subjects Who Had a First-time Treatment Failure on Their First-line Treatment.

NCT05973851 | Recruiting Phase 3 DMC

• 1 other identifier: 2023-506617-21-00 (EU CT#)
• Study Type: interventional
• Target: 418
• Locations: 6 countries
• Sites: 12

Brief Summary

Over 28 million people suffer from current depressive disorder in the European Union. Major depressive disorder (MDD) is one of the most common psychiatric illnesses. The symptoms cause clinically significant distress or impairment in social, occupational, and other important areas of functioning. To treat MDD, there are several antidepressants available and prescribing medication is a process of trial-and-error. Guidelines do not explicitly advise on the order in which antidepressant medication should be prescribed. The choice of antidepressant should be tailored to the patient, while involving the patient in the decision-making process. In general, the choice for the first- and second-line treatment will be a second-generation antidepressant. Recently, esketamine nasal spray (intranasal (IN) administration) was approved for patients with treatment-resistant MDD (TRD). A patient is diagnosed with TRD when having used two antidepressants in sufficient duration and adequate dose without sufficient effect. TRD is associated with a negative impact on quality of life, higher risk for hospitalisations and suicide, comorbidities, poorer social and occupational functioning and a high carer burden. The efficacy of intranasal use of esketamine has been demonstrated in MDD subjects with treatment-resistant symptoms but also in subjects with non-treatment resistant depression, and is approved by the FDA and EMA as a third-line treatment. Besides the registered esketamine nasal spray, which is not available in all countries to all patients because of the high costs, off-label utilization of (es)ketamine infusions (IV) is growing extensively over time to treat TRD. Research conducted so far indicates an unequivocal initial substantial response to (es)ketamine IV in MDD populations, regardless of whether or not patients suffer from treatment resistant MDD. However, until now, there has not been a study investigating this in a sufficiently large population. This may be a unique opportunity to potentially prevent patients progressing into a treatment resistant illness stage. The potential implications of the results of the current study are the prevention of unnecessary trials of ineffective treatments, reducing subject burden substantially, as well as a reduction of healthcare and societal costs.

Conditions

Major Depressive Disorder; Treatment Resistant Depression

Keywords

Major Depressive Disorder; Treatment as usual; Early treatment-resistance

Outcome Measures

Primary Outcomes (1)

• Comparing the change in symptom severity on Montgomery Asberg Depression Rating Scale

  Change in symptom severity (EIPT vs. TAU) total score from baseline (visit 2) to end of treatment (visit 4). This is measured using the Montgomery Asberg Depression Rating Scale. Minimum score is 0, maximum score 60. A bigger mean change means a better outcome

  6 weeks

Secondary Outcomes (16)

• Compare proportion of participants that is in symptomatic remission

  6 weeks

• Compare the change in the severity and improvement CGI-S sub-scores

  6 weeks

• Compare the change in the severity and improvement CGI-I sub-scores

  6 weeks

• Compare the changes in the levels of depression and anxiety

  6 weeks

• To compare changes in cognitive performance as measured through the Trail Making Test

  6 weeks

Study Arms (2)

Major Depressive Disorder EIPT: second-line antidepressant + esketamine nasal spray

EXPERIMENTAL

Major depressive disorder randomized to EIPT: Switch to second-line antidepressant + esketamine nasal spray or (es)ketamine infusion. Antidepressant: Compound, brand, dosage, frequency and duration up to the investigator's discretion (in accordance with SmPC). Esketamine nasal spray: 2 times per week for 4 weeks. Initial dose 28 mg, after that increases can be made with 28 mg per increase (up to 84 mg per week). This decision is up to the investigator's discretion (in accordance with SmPC). (Es)ketamine infusion: performed twice weekly for 4 weeks. Compound, brand up to the investigator's discretion (in accordance with SmPC).

Drug: Esketamine Nasal Product; Drug: Ketamine Hydrochloride; Drug: Esketamine hydrochloride

Major Depressive Disorder TAU: second-line antidepressant

ACTIVE COMPARATOR

Subject with major depressive disorder, randomized to TAU: switch to second-line antidepressant. When randomized to second-line anti-depressants, this means participants will receive treatment as usual. The physician has the choice to administer any second-line anti-depressant. More specification is not possible, as this is a choice the physician makes with the participant based on the characteristic and preference of the participant (in line with standard clinical practice).

Drug: Second-line Antidepressants

Interventions

Esketamine Nasal Product DRUG

See arm description

Also known as: ATC code: N06AB10

Major Depressive Disorder EIPT: second-line antidepressant + esketamine nasal spray

Ketamine Hydrochloride DRUG

See arm description

Also known as: N01AX03

Major Depressive Disorder EIPT: second-line antidepressant + esketamine nasal spray

Esketamine hydrochloride DRUG

See arm description

Also known as: N015X14

Major Depressive Disorder EIPT: second-line antidepressant + esketamine nasal spray

Second-line Antidepressants DRUG

See arm description

Major Depressive Disorder TAU: second-line antidepressant

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• In- or outpatients, at least 18 years of age up until 65.
• Being willing and able to provide written informed consent. Having a legal guardian to cosign is allowed. Informed consent will be signed at visit 1, before any study procedure.
• Female subjects of child bearing potential must use effective contraception during the trial as per the requirements of the applicable SmPCs and should have a negative pregnancy test at visit 1 or 2 (before randomisation).
• Meeting diagnostic criteria for a primary diagnosis of major depressive disorder (without psychotic features), according to DSM-5. The primary diagnosis will be confirmed by the Mini International Neuropsychiatric Interview (MINI v7.0.2).
• Subject experiences a treatment failure due to lack of efficacy in the current episode, as confirmed by a CGI-I ≥3; perferably, this treatment is a first-line pharmacotherapeutic agent for the primary DSM-5 diagnosis, and was prescribed for at least 4 weeks within an effective dose range as specified in the Summary of Product Characteristics (SmPCs).
• Subject and clinician intend to change pharmacotherapeutic treatment. However, other lines of treatment are allowed as well.
• A minimum symptom severity threshold needs to be present (moderate level; see below) and subject needs to experience functional impairment.
• The minimum symptom severity threshold is a score of ≥20 on the Montgomery Åsberg Depression Rating Scale (MADRS)
• Functional impairment is defined as a score of 5 or higher on any of the three scales of the Sheehan Disability Scale (SDS).

You may not qualify if:

• Being pregnant or breastfeeding.
• Subject has used (es)ketamine previously for the treatment of depressive symptoms.
• Subject has a known intolerance to (es)ketamine or to all TAU medication.
• Meeting any of the contraindications for (es)ketamine, or to all TAU medication options, as specified within the applicable SmPC, supported by clinically significant abnormal values on local laboratory tests, electrocardiogram (ECG) or physical examinations.
• Subject has participated in another clinical trial in which the subject received an experimental or investigational drug or agent within 30 days before visit 1.
• Subject experiences any other significant disease or disorder which, in the opinion of the investigator, may either put the subjects at risk because of participation in the trial, or may influence the result of the trial, or the subject's ability to participate in the trial.
• Subjects with active suicidal ideation with some intent to act, without specific plan ("Yes" to question 4 of the Columbia-Suicide Severity Rating Scale (C-SSRS)) or active suicidal ideation with specific plan and intent ("Yes" to question 5 of the C-SSRS), followed by an assessment by the treating clinician who determines it is not safe for the subject to participate in the study
• Subject meets criteria for current substance use disorder, as confirmed by the Mini International Neuropsychiatric Interview (MINI v7.0.2). Nicotine dependency is allowed, as well as mild and moderate alcohol and/or cannabis use disorder (as defined by MINI v7.0.2). Severe alcohol and/or cannabis use disorder are not allowed.
• Subjects have not been committed to an institution by virtue of an order issued either by the judicial or the administrative authorities.
• Subjects dependent on the sponsor, investigator or trial site must be excluded from participation in advance.

Sponsors & Collaborators

• Dr. Inge Winter: lead
• Universität Münster: collaborator

Study Sites (12)

Medical University Innsbruck

Innsbruck, Austria

RECRUITING

Universitätsklinik für Psychiatrie und Psychotherapie Bielefeld

Bielefeld, Germany

RECRUITING

LWL-Klinik Dortmund, Bereich Forschung & Wissenschaft

Dortmund, 44287, Germany

RECRUITING

University Hospital Frankfurt am Main - Goethe University

Frankfurt am Main, Germany

RECRUITING

Westfälische Wilhelms-Universität Münster

Münster, Germany

RECRUITING

Eginition Hospital, department of psychiatry

Athens, 11528, Greece

NOT YET RECRUITING

Universita degli Studi di Brescia

Brescia, Italy

NOT YET RECRUITING

University of Cagliari

Cagliari, Italy

RECRUITING

Università degli studi della Campania Luigi Vanvitelli

Naples, 80138, Italy

RECRUITING

Azienda Ospedaliero-Universitaria "Città della Salute e della Scienza di Torino"

Turin, Italy

NOT YET RECRUITING

Fundació Clínic per a la Recerca Biomèdica

Barcelona, Spain

RECRUITING

King's College London, Psychiatry & Cognitive Neuroscience

London, SE5 8AF, United Kingdom

NOT YET RECRUITING

MeSH Terms

Conditions

Depressive Disorder, Major; Depressive Disorder, Treatment-Resistant

Interventions

Ketamine

Condition Hierarchy (Ancestors)

Depressive Disorder; Mood Disorders; Mental Disorders

Intervention Hierarchy (Ancestors)

Cyclohexanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals

Central Study Contacts

Inge Winter, Dr.

CONTACT

+31875553227; i.winter@umcutrecht.nl

Cynthia Okhuijsen-Pfeifer, Dr.

CONTACT

+31875553227; c.pfeifer@umcutrecht.nl

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Masking Details: Open label, except for the assessors of the primary outcome
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Principal Investigator

Model Details: Parallel randomization to the 2 arms, treatment as usual (TAU) or early-intensified pharmacological treatment (EIPT).

Study Record Dates

• First Submitted: July 25, 2023
• First Posted: August 3, 2023
• Study Start: August 31, 2024
• Primary Completion (Estimated): June 30, 2028
• Study Completion (Estimated): June 30, 2028
• Last Updated: September 26, 2025

Record last verified: 2025-09

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, CSR

Locations

DE (4); AU (1); ES (1); GB (1); IT (4); GR (1)