Early efficacy of ketamine compared to placebo, in add-on therapy of venlafaxine for inpatients with severe unipolar major depressive episodes: a double blind randomized controlled trial

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Assistance Publique Hopitaux De Paris

Participant type

Patients

Age range

18-64 years

Gender

Male and Female

Therapeutic area

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

Trial duration

20 Nov 2024 → ongoing

Decision date (initial)

2024-06-27

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

DGOS ET ANR

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Therapy

Objective For the main Study
to compare early efficacy at day 7 on depressive symptoms of intravenous ketamine versus placebo on add on to venlafaxine in patients hospitalized for severe major depressive episode
Objectives for ancillary study
1) To compare synaptic density changes assessed by PET-MRI before (d0) and after (d14) early add on treatment of ketamine or placebo in patients hospitalized for severe major depressive episode.
2) To assess whether clinical improvement after ketamine correlates with synaptic density changes

Secondary objectives 7

1. To compare efficacy of add on ketamine at d14, d28, and d48 ( after the acute treatment phase) and placebo
2. To assess whether add on ketamine decrease hospitalisation duration as compared to placebo
3. To assess whether add on ketamine early decrease suicide ideations as compared to placebo
4. To assess whether very early clinical improvement (d1 or d4) predict clinical improvement at d14, d28, d42 in ketamine group as compared to placebo
5. To compare side effects in ketamine and placebo groups
6. To compare anxiolytic consumption in ketamine and placebo groups
7. To identify predictive or associate biomarker of venlafaxine+ketamine efficacy

Conditions and MedDRA coding

Major depressive disorder with current severe major depressive episode

Study design 1 period

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 5

1. Current MDE in the context of Major Depressive Disorder (DSM-5 criteria), hospitalized (open care) for this episode, with a minimum HDRS score of 24 and in the context of an indication for the introduction of venlafaxine treatment.
2. Patient aged between 18 and 65
3. Signed free and informed consent
4. Membership of a social security scheme
5. For women of childbearing age, effective contraception throughout study participation

Exclusion criteria 11

1. Criteria relating to associated pathologies entailing particular risks: pharmaco-resistant MDE (failure of at least two properly conducted treatments with two different antidepressant treatment classes), MDE with psychotic features, psychotic disorder, bipolar disorder, current (<1 month) substance use disorder (excluding tobacco
2. Liver impairment (AST and/or ALT > 3 ULN, PAL and/or GGT and/or bilirubin > 2 ULN)
3. Severe renal insufficiency (GFR <30ml/min with Cockcroft's formula)
4. Contraindication to ketamine : Hypersensitivity to active substance or excipients, comatose state, central nervous system (CNS) depression, Parkinson's disease, Lewy body dementia, progressive supranuclear palsy, known prolongation of the QTc interval (>450ms for men and >470ms for women) or congenital long QT syndrome, recent acute myocardial infarction, uncompensated heart failure, history of ventricular arrhythmias or torsades de pointes, uncorrected hypokalemia (K+ < 3. 5 mmol/l), epilepsy, uncontrolled hypertension, porphyria.
5. Contraindication to venlafaxine (hypersensitivity to venlafaxine or excipients, unstable hypertension, no indication for venlafaxine treatment in clinician's opinion due to ineffectiveness or tolerability of previous venlafaxine treatment).
6. Current or previous treatment with venlafaxine or ketamine in the month prior to study inclusion
7. Need to maintain another antidepressant, MAOI, Millepertuis or benzodiazepines (cyamemazine is permitted)
8. Pregnant or breast-feeding patients (women of childbearing potential must have a negative urine or blood test for human chorionic gonadotropin prior to trial entry). Planned pregnancy within three months of enrolment
9. Adult under guardianship, curatorship, or safeguard of justice
10. Participating in other interventional research involving the human body or within the exclusion period following previous research involving the human body, if applicable
11. Social insurance

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Total score change of the Hamilton Depression Rating Scale (HDRS 17 items: scale items are rated from 0 to 2 or from 0 to 4 and the score ranges from 0 to 52) after 7 days of treatment

Secondary endpoints 6

1. 1 et 4) Efficacy: assessed by 5 complementary criteria a) main criteria : Total score change of the Hamilton Depression Rating Scale (HDRS 17) b) response rate : ≥50% HDRS total score improvement c) remission : (HDRS 17 items ≤ 7) d) Beck Depression Inventory (BDI) change e) Clinical Global Impression rating scale (CGI)
2. 2) hospital stay length ( the number of days spent in hospital, including re-hospitalization, during the fallow up 42 days). The end of the hospital stay is decided by the clinician blinded to treatment.
3. 3) Total scores change on the Columbia Suicide Risk Scale (C-SSRS)
4. 5) The safety assessed with Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0. The occurrence of adverse effects in the ketamine and placebo groups will be assessed by monitoring during the infusion of treatment or placebo and up to 40 minutes afterwards blood pressure, heart rate, respiratory rate, nausea/vomiting, dissociation, headache.
5. 6) cumulative consumption in mg of cyamemazine over the entire study period
6. 7) biomarkers predictive or associated with the efficacy of ketamine on add on to venlafaxine

Investigational products

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

Test 1

Comparator 1

Auxiliary 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Assistance Publique Hopitaux De Paris

Sponsor organisation

Assistance Publique Hopitaux De Paris

Address

Porte 23, 1 Avenue Claude Vellefaux 1 Avenue Claude Vellefaux

City

Paris Cedex 10

Postcode

75475

Country

France

Scientific contact point

Organisation

Assistance Publique Hopitaux De Paris

Contact name

Dr Romain COLLE

Public contact point

Organisation

Assistance Publique Hopitaux De Paris

Contact name

Mme Wafa FETHALLAH

Locations

1 EU/EEA country · 4 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

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

Documents 8 files

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

Application history

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