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

NCT05973786 | Recruiting Phase 3 DMC

• 1 other identifier: 2023-506605-19-00 (EU CT#)
• Study Type: interventional
• Target: 418
• Locations: 6 countries
• Sites: 13

Brief Summary

Bipolar disorders affect approximately 4.5 million people across the European Union (EU) and are associated with high annual healthcare and societal costs. Bipolar disorder I and II represent disorders that cause extreme fluctuation in a person's mood, energy, and ability to function, in which symptoms of (hypo)mania and depression alternate. The depressive episodes of bipolar disorders are often referred to as bipolar depression (BD). In other words: it is a phase/state of the disorder. For many patients with BD, the depressive polarity is often more pervasive and more debilitating than manic states, with estimates that depressed mood accounts for up to two-thirds of the time spent unwell, even with treatment. The burden of not received an effective treatment for BD is high: more severe psychopathology, higher rates of unemployment, more hospitalisations, lower quality of life, lower cognitive functioning, risk of suicide, comorbidities and poorer social and occupational functioning and thus more carer burden. For BD, the treatment guidelines are very heterogeneous, amongst other reasons because the disease is heterogeneous and treatments should be tailored to the patients. There is no clear treatment algorithm and it cannot yet be predicted which treatment will be effective. Especially the place of adjunctive antidepressants is under debate. Usually, for psychiatric disorders (including bipolar disorder), a patient is considered to be treatment-resistant is two medicinal treatments have been tried (in sufficient duration and dosage) without sufficient success. For BD, there is no consensus on when to consider a patient as treatment-resistant, but the most common definition is after one prior treatment failure. This raises the research question whether adjunctive antidepressants to treat BD should be introduced earlier in the treatment. Additionally, The INTENSIFY trial is part of the larger Horizon 2021 project, with the central goal of paving the way for a shift towards a treatment decision-making process tailored for the individual at risk for treatment resistance. To that end, we aim to establish evidence-based criteria to make decisions of early intense treatment in individuals at risk for treatment resistance across the major psychiatric disorders of schizophrenia, bipolar disorder and major depression.

Conditions

Bipolar Depression

Outcome Measures

Primary Outcomes (1)

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

  Mean 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 is 60. A bigger mean change means a better outcome

  6 weeks

Secondary Outcomes (17)

• 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)

Bipolar Depression EIPT: Switch to one of the following combinations:

EXPERIMENTAL

Bipolar Depression randomized to EIPT: Switch to 1. one of the following: escitalopram, sertraline, bupropion or venlafaxine plus 2. two of the following: lithium, valproate acid or quetiapine

Drug: Escitalopram; Drug: Sertraline; Drug: Venlafaxine; Drug: Lithium; Drug: Valproate acid; Drug: Quetiapine; Drug: Bupropion

Bipolar Depression TAU: Switch to quetiapine plus lithium or valproate acid

ACTIVE COMPARATOR

Bipolar Depression randomized to TAU: Switch to quetiapine plus lithium or valproate acid Compound, brand, dosage, frequency and duration up to the investigator's discretion (in accordance with SmPC).

Drug: Lithium; Drug: Valproate acid; Drug: Quetiapine

Interventions

Escitalopram DRUG

See arm description

Also known as: ATC code: N06AB10

Bipolar Depression EIPT: Switch to one of the following combinations:

Sertraline DRUG

See arm description

Also known as: ATC code: N06AB06

Bipolar Depression EIPT: Switch to one of the following combinations:

Venlafaxine DRUG

See arm description

Also known as: ATC code: N06AX16

Bipolar Depression EIPT: Switch to one of the following combinations:

Lithium DRUG

See arm description

Also known as: ATC code: N05AN01

Bipolar Depression EIPT: Switch to one of the following combinations:; Bipolar Depression TAU: Switch to quetiapine plus lithium or valproate acid

Valproate acid DRUG

See arm description

Also known as: ATC code: N03AG01

Bipolar Depression EIPT: Switch to one of the following combinations:; Bipolar Depression TAU: Switch to quetiapine plus lithium or valproate acid

Quetiapine DRUG

See arm description

Also known as: ATC code: N05AH04

Bipolar Depression EIPT: Switch to one of the following combinations:; Bipolar Depression TAU: Switch to quetiapine plus lithium or valproate acid

Bupropion DRUG

See arm description

Also known as: ATC cose: N06AX12

Bipolar Depression EIPT: Switch to one of the following combinations:

Eligibility Criteria

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

You may qualify if:

• In- or out patients, at least 18 years of age.
• 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). Male subjects that will use valproate acid during the trial must use effective contraceptive measures during the trial (see section 8.2.1).
• Meeting diagnostic criteria for a primary diagnosis of bipolar depression (bipolar disorder type I and II currently in a depressive episode), 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; preferably, 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). However, other lines of treatment are accepted as well.
• Subject and clinician intend to change pharmacotherapeutic treatment.
• A minimum symptom severity threshold needs to be present (moderate leve) 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 a known intolerance to quetiapine or to all EIPT medication or to all TAU medication.
• Meeting any of the contraindications for quetiapine, or to all EIPT medication 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.
• A score of 12 or higher on the Young Mania Rating Scale (YMRS) in order to exclude subjects with predominant manic symptoms or mixed symptoms.
• Subjects dependent on the sponsor, investigator or trial site must be excluded from participation in advance.
• Subjects with pre-existing severe liver damage (as tested within the local laboratory test at visit 1).
• Subjects with a history of antidepressant-induced mania or hypomania or recent rapid cycling (based on the medical file of the potential participant or the clinical judgment of the clinician).

Sponsors & Collaborators

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

Study Sites (13)

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

Klinik für Psychiatrie und Psychotherapie der Universitätsmedizin Mainz

Mainz, 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

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

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

Bipolar Disorder

Interventions

Escitalopram; Sertraline; Venlafaxine Hydrochloride; Lithium; Quetiapine Fumarate; Bupropion

Condition Hierarchy (Ancestors)

Bipolar and Related Disorders; Mood Disorders; Mental Disorders

Intervention Hierarchy (Ancestors)

Propylamines; Amines; Organic Chemicals; Nitriles; Benzofurans; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; 1-Naphthylamine; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Polycyclic Compounds; Cyclohexanols; Hexanols; Fatty Alcohols; Alcohols; Phenethylamines; Ethylamines; Cyclohexanes; Cycloparaffins; Hydrocarbons, Alicyclic; Lipids; Metals, Alkali; Elements; Inorganic Chemicals; Metals, Light; Metals; Dibenzothiazepines; Thiazepines; Thiepins; Sulfur Compounds; Heterocyclic Compounds, 3-Ring; Propiophenones; Ketones

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: February 11, 2025
• 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

IT (4); AU (1); DE (5); GR (1); ES (1); GB (1)