A randomised, controlled trial to investigate 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.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Universitair Medisch Centrum Utrecht

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

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

Trial duration

11 Feb 2025 → ongoing

Decision date (initial)

2024-01-15

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

European Commission

External identifiers

EU CT number

2023-506605-19-00

ClinicalTrials.gov

NCT05973786

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy

The primary objective is to compare the treatment response, expressed as mean change in symptom severity from baseline to end of treatment, as measured through the Montgomery-Åsberg Depression Rating Scale (MADRS) under an early-intensified pharmacological treatment to that under treatment as usual.

Secondary objectives 10

1. To compare changes in severity and improvement in global functioning assessed by the Clinical Global Impression Scale (CGI) between the two treatment arms.
2. To compare changes in the levels of depression and anxiety between treatment arms.
3. To compare changes in quality of life and functioning measures between treatment arms.
4. To compare changes in cognitive performance between treatment arms.
5. To compare the proportion of participants (EIPT vs. TAU) that is in symptomatic remission at visit 4.
6. To compare presence of adverse events (related and unrelated) between treatment arms.
7. To compare use of concomitant medication between treatment arms.
8. To compare premature discontinuation (timing and reason) between treatment arms.
9. To compare changes in suicidal ideation between treatment arms.
10. To compare occurrence of (hypo)manic episode during the study between the treatment arms

Conditions and MedDRA coding

Bipolar depression

Study design 1 period

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 7

1. In- or out patients, at least 18 years of age.
2. 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.
3. Female participants 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; section 8.2.1). Male subjects that will use valproate acid during the trial must use effective contraceptive measures during the trial (see section 8.2.1).
4. 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).
5. Participant experiences a current treatment failure due to lack of efficacy, 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 treatments are accepted as long as they are in line with clinical guidelines and protocols for BD.
6. Participant and clinician intend to change pharmacotherapeutic treatment.
7. A minimum symptom severity threshold needs to be present (moderate level; see below) and participant 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).

Exclusion criteria 12

1. Being pregnant or breastfeeding.
2. Participant has a known intolerance to quetiapine or to all EIPT medication or to all TAU medication.
3. 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.
4. Participant has participated in another clinical trial in which the subject received an experimental or investigational drug or agent within 30 days before visit 1.
5. Participant experiences any other significant disease or disorder which, in the opinion of the investigator, may either put the participants at risk because of participation in the trial, or may influence the result of the trial, or the participant’s ability to participate in the trial.
6. Participants 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.
7. Participant 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.
8. Participants dependent on the sponsor, investigator or trial site must be excluded from participation in advance.
9. Participants with pre-existing severe liver damage (as tested within the local laboratory test at visit 1).
10. Participants 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).
11. Participants have not been committed to an institution by virtue of an order issued either by the judicial or the administrative authorities.
12. A score of 12 or higher on the Young Mania Rating Scale (YMRS) in order to exclude participants with predominant manic symptoms or mixed symptoms.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Mean change from baseline (visit 2) in symptom severity as measured by the MADRS total score at six weeks (visit 4) will be compared between the two treatment arms (EIPT vs. TAU) for the lines of treatment separately (subgroup analysis wherein the focus will be on participants who had a first time treatment failure on their first-line treatment) and for the group as a whole (irrespective of line of treatment).

Secondary endpoints 10

1. 1.a. Change from baseline (visit 2) in the severity sub-score of the Clinical Global Impression Scale (CGI) at visit 4; EIPT vs TAU. 1.b. Improvement sub-score of the Clinical Global Impression Scale (CGI) at visit 4; EIPT vs TAU.
2. Changes from baseline (visit 2) in total Hospital Anxiety and Depression Scale (HADS) total score and anxiety and depression subscales at visit 4; EIPT vs TAU.
3. Change from baseline (visit 2) in quality of life and functioning measures (Q-LES-Q-SF, LAPS, QLS-100 and SDS ) at visit 4; EIPT vs TAU.
4. Changes from baseline (visit 2) on Trail Making Test, Digit Symbol Substitution Test, Rey Auditory Verbal Learning Test as well as the Perceived Deficits Questionnaire at visit 4; EIPT vs TAU.
5. Presence of symptomatic remission at visit 4; EIPT vs TAU. Remission is defined as a MADRS score ≤ 12.
6. Presence of reported adverse events (related and unrelated to treatment) as measured through General Assessment of Side Effects Scale (GASE) and reported spontaneously at visit 4; EIPT vs TAU.
7. Concomitant medication use throughout the study; EIPT vs TAU.
8. Premature treatment discontinuation before visit 4 and time to treatment discontinuation and reported reason of discontinuation; EIPT vs TAU.
9. Changes on the Columbia-Suicide Severity Rating Scale (C-SSRS) throughout the study; EIPT vs TAU.
10. Occurrence of (hypo)manic episodes throughout the study (including V5); EIPT vs TAU. Scores of 12 or higher means that a participant is in a (hypo)manic episode of bipolar disorder.

Investigational products

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

Test 4

Comparator 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Universitair Medisch Centrum Utrecht

Sponsor organisation

Universitair Medisch Centrum Utrecht

Address

Heidelberglaan 100

City

Utrecht

Postcode

3584 CX

Country

Netherlands

Scientific contact point

Organisation

Universitair Medisch Centrum Utrecht

Contact name

Dr. Inge Winter

Public contact point

Organisation

Universitair Medisch Centrum Utrecht

Contact name

Dr. Inge Winter

Third parties 4

Locations

5 EU/EEA countries · 12 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 67 files

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

Application history

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