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.

Study Overview
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Brief Summary
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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.

Detailed Description
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Rationale 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. Objective The primary objective is to compare the treatment response, expressed as mean change in symptom severity as measured through the Montgomery-Åsberg Depression Rating Scale (MADRS) under an early-intensified pharmacological treatment to that under treatment as usual, in subjects who had a first-time treatment failure on their first-line treatment. Main trial endpoints Change in symptom severity total score from baseline (visit 2) to end of treatment (visit 4). This is measured using MADRS. Secondary trial endpoints Comparison of the proportion of participants (EIPT vs. TAU) that is in symptomatic remission at visit 4. Remission is defined as a MADRS score ≤ 12. To compare mean changes in the severity and improvement sub-scores of the Clinical Global Impression Scale (CGI) between the two treatment arms (EIPT/TAU) over the six week treatment period (visit 2 versus visit 4). To compare mean changes in the levels of depression and anxiety as assessed with the Hospital Anxiety and Depression Scale (HADS) between the two treatment arms (EIPT/TAU) over the six week treatment period (visit 2 versus visit 4). To compare mean changes in cognitive performance as measured through the Trail Making Test, Digit Symbol Substitution Test, Rey Auditory Verbal Learning Test as well as the Perceived Deficits Questionnaire between the two treatment arms (EIPT/TAU) over the six week treatment period (visit 2 versus visit 4). To compare mean changes in quality of life and functioning measures (Q-LES-Q-SF, LAPS, QLS-100 and SDS between the two treatment arms (EIPT/TAU) over the six week treatment period (visit 2 versus visit 4). To compare presence of side effects as measured through General Assessment of Side Effects Scale (GASE) and reported spontaneously between the two treatment arms (EIPT/TAU) over the six week treatment period (visit 2 versus visit 4). To compare use of concomitant medication between the two treatment arms (EIPT/TAU) over the six week treatment period (visit 2 versus visit 4). To compare premature discontinuation (timing and reason) between the two treatment arms (EIPT/TAU) over the six week treatment period (visit 2 versus visit 4). Trial design The clinical study is an international, multicenter controlled, randomised, open label trial (with blinded raters), with a treatment duration of six weeks. Trial population The aim is to recruit 418 subjects with bipolar disorder type I or II, currently in a depressive episode. Male and female subjects, in- and out-patients, within the age range of 18 to 70 years old are eligible for participation. The main exclusion criteria are defined to protect the wellbeing of subjects, e.g. being pregnant or breastfeeding, subjects with previous failure on quetiapine, meeting any contraindications, or participants with a known intolerance to quetiapine. Interventions Subjects are randomised to treatment as usual (second-line treatment) or to the early-intensified pharmacological treatment (third-line treatment). Treatment per can be found in the table below: Table 1. Overview of treatment randomisation per study sample. BD sample Treatment as Usual (TAU) Switch to quetiapine plus lithium or valproate acid Early-Intensified Pharmacological Treatment (EIPT) Switch to one of the following: escitalopram, sertraline, duloxetine, bupropion or venlafaxine plus two of the following: lithium, valproate acid or quetiapine Ethical considerations relating to the clinical trial including the expected benefit to the individual subject or group of subjects represented by the trial subjects as well as the nature and extent of burden and risks All medications studied in the current trial are widely used (alone or in combination) in clinical practice and the risks for side effects are well established. In the current study, clinical practice is mimicked as much as possible to maximize generalisability and for feasibility purposes. To this end, Summaries of Product Characteristics (SmPCs) are followed with regards to contraindications (implemented as exclusion criterion), safety measures and allowed combinations with other medications. Site visits and assessments are kept to a minimum to keep subject burden at an acceptable level, while meeting the objectives of the study. Blood samples for biomarker analyses are only collected when subjects provide consent; safety measures are performed as part of clinical routine. Overall, the risks are similar to daily clinical practice; the only difference relative to clinical practice is the application of three pharmacological treatments (EIPT) versus two (TAU) earlier in the illness. Still, these additional treatment options are also commonly prescribed by clinicians. There are no indications in existing literature or clinical practice that the earlier introduction of these medications poses a safety risk when used in an earlier illness phase than indicated in the SmPC. A benefit of the study is that if it indeed turns out that the early-intensified treatment is associated with more symptom improvement compared to treatment as usual, future patients have to go through less trial and error, which results in a reduced burden (higher quality of life, less unemployment, less hospitalisations) for patients and carers as well as lower societal and healthcare costs. IMPORTANT: the study was submitted to the European authorities before (see NCT05603104) and they requested to split this study into 3 studies (1 for each diagnostic category). We have done this and created 3 new ClinicalTrials.gov studies as well, from which this is one for schizophrenia. Once we have received the NCT numbers for BD and MDD, we will add them here. The site in the UK (London) followed the advice and will submit 3 separate protocols and are therefore included in the current record. However, Israel already submitted this as one protocol. Therefore, we keep the old clinicaltrials.gov number for Israel (NCT05603104).

Official Title
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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.

Conditions
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Bipolar Depression

Intervention / Treatment
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* Drug: Escitalopram
* Drug: Sertraline
* Drug: Duloxetine
* Drug: Venlafaxine
* Drug: Lithium
* Drug: Lamotrigine
* Drug: Valproate acid
* Drug: Quetiapine


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: In- or out patients, at least 18 years of age up until 70. Being willing and able to provide written informed consent. If unable, having a legal guardian to provide written informed consent is allowed (subject's opinion will also be considered in these cases). Female subjects of child bearing potential must use effective contraception during the trial and as per the requirements in the protocol (section 8.2). 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 experienced (in total) one treatment failure due to lack of efficacy; this treatment is a first-line pharmacotherapeutic agent for the primary DSM-5 diagnosis, and was prescribed for at least 4 weeks within the dose range as specified in the Summary of Product Characteristics (SmPCs). The psychopharmacological treatment failure (inclusion criterion 5) should be confirmed by a CGI-I ≥3. Subject and clinician intend to change pharmacotherapeutic treatment. 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 26) 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 Being pregnant or breastfeeding. Subject has failed previously on quetiapine due to inefficacy (after treatment duration of ≥ 4 weeks within an efficacious dose range according to the SmPC. Subject has a known intolerance to quetiapine or to all TAU medication. Meeting any of the contraindications for quetiapine, or to all TAU medication options, as specified within the applicable SmPC. 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 currently uses more than the allowed psychotropic concomitant medication and needs to stay on this medication during the study. 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. Moderate or high suicidal ideation within the last 2 weeks, defined as a score of 9 or higher on Module B (Suicidality) of the Mini International Neuropsychiatric Interview (MINI v7.0.2) 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 alcohol and/or cannabis use disorder (as defined by MINI v7.0.2). Moderate and severe alcohol and/or cannabis use disorder are not allowed. Subjects who are admitted in the (psychiatric) clinic due to a court or administrative order are not allowed to participate in the study. A score of 8 or higher on the Young Mania Rating Scale (YMRS) in order to exclude subjects with predominant manic symptoms or mixed symptoms.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Parallel randomization to the 2 arms, treatment as usual (TAU) or early-intensified pharmacological treatment (EIPT).
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Bipolar Depression EIPT: Switch to one of the following combinations:<br>Bipolar Depression randomized to EIPT: Switch to 1. one of the following: escitalopram, sertraline, duloxetine or venlafaxine plus 2. two of the following: lithium, lamotrigine, valproate acid or quetiapine | Drug: Escitalopram<br>* ATC code: N06AB10<br>* Other names: ATC code: N06AB10;Drug: Sertraline<br>* See arm description<br>* Other names: ATC code: N06AB06;Drug: Duloxetine<br>* See arm description<br>* Other names: ATC code: N06AX21;Drug: Venlafaxine<br>* See arm description<br>* Other names: ATC code: N06AX16;Drug: Lithium<br>* See arm description<br>* Other names: ATC code: N05AN01;Drug: Lamotrigine<br>* See arm description<br>* Other names: ATC code: N03AX09;Drug: Valproate acid<br>* See arm description<br>* Other names: ATC code: N03AG01;Drug: Quetiapine<br>* See arm description<br>* Other names: ATC code: N05AH04;|
| Active Comparator: Bipolar Depression TAU: Switch to quetiapine plus lithium or valproate acid or lamotrigine<br>Bipolar Depression randomized to TAU: Switch to quetiapine plus lithium or valproate acid or lamotrigine Compound, brand, dosage, frequency and duration up to the investigator's discretion (in accordance with SmPC). | Drug: Lithium<br>* See arm description<br>* Other names: ATC code: N05AN01;Drug: Lamotrigine<br>* See arm description<br>* Other names: ATC code: N03AX09;Drug: Valproate acid<br>* See arm description<br>* Other names: ATC code: N03AG01;Drug: Quetiapine<br>* See arm description<br>* Other names: ATC code: N05AH04;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Comparing the mean change in symptom severity on Montgomery Asberg Depression Rating Scale | Mean 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 is 60. A bigger mean change means a better outcome | 6 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Compare proportion of participants that is in symptomatic remission | Comparison of the proportion of participants (EIPT vs. TAU) that is in symptomatic remission at visit 4. Remission is defined as a Montgomery Asberg Depression Rating scale score of ≤ 12. | 6 weeks | 
| Compare the mean change in the severity and improvement CGI-S sub-scores | To compare mean changes in the severity sub-score of the Clinical Global Impression Scale (CGI 2) between the two treatment arms (EIPT/TAU) over the six week treatment period (visit 2 versus visit 4). Higher scores indicate higher illness severity. Minimum score: 1, maximum score: 7 | 6 weeks | 
| Compare the mean change in the severity and improvement CGI-I sub-scores | To compare mean changes in the total improvement sub-score of the Clinical Global Impression Scale (CGI 2) between the two treatment arms (EIPT/TAU) over the six week treatment period (visit 2 versus visit 4). A higher score means lower treatment improvement. Minimum score: 1, maximum score: 7 | 6 weeks | 
| Compare the mean changes in the levels of depression and anxiety | To compare changes in the levels of depression and anxiety as assessed with the Hospital Anxiety and Depression Scale between the two treatment arms (EIPT/TAU) over the four week treatment period (visit 2 versus visit 4). Lower scores mean less depression and anxiety. | 6 weeks | 
| To compare mean changes in cognitive performance as measured through the Trail Making Test | To compare changes in cognitive performance as measured through the Trail Making Test between the two treatment arms over the four weeks treatment period (visit 2 versus visit 4). A lower time to complete the test means better cognitive performance. | 6 weeks | 
| To compare the mean changes in cognitive performance as measured through the Rey Auditory Verbal Learning Test | To compare changes in cognitive performance as measured through the Rey Auditory Verbal Learning Test between the two treatment arms over the six weeks treatment period (visit 2 versus visit 4). A higher scores means better cognitive performance. | 6 weeks | 
| To compare the mean changes in subjective cognitive performance as measured through the Perceived Deficits Questionnaire | To compare mean changes in cognitive performance as measured through the Perceived Deficits Questionnaire between the two treatment arms over the six weeks treatment period (visit 2 versus visit 4). A higher scores means worse subjective cognitive performance. | 6 weeks | 
| To compare the mean changes in functioning on the Leuven Affective and Pleasure Scale | To compare mean changes in the functioning measure, Leuven Affective and Pleasure Scale, between the two treatment arms over the six weeks treatment period (visit 2 versus visit 4). A higher scores means worse functioning. Minimum score: 0, Maximum score: 160 | 6 weeks | 
| To compare the mean changes in functioning on the Sheehan Disability Scale | To compare mean changes in the functioning measure,Sheehan Disability Scale, between the two treatment arms over the six weeks treatment period (visit 2 versus visit 4). A higher scores means worse functioning. Minimum score: 0, maximum score 30. | 6 weeks | 
| To compare the mean changes in quality of life measure, Quality of Life Enjoyment and Satisfaction Questionnaire Short Form | To compare mean changes in quality of life measure, Quality of Life Enjoyment and Satisfaction Questionnaire Short Form between the two treatment arms over the four weeks treatment period (visit 2 versus visit 4). A higher scores means better quality of life. Minimum score: 16, maximum score: 80. | 6 weeks | 
| To compare the mean changes in quality of life measure, Quality of Life Scale -100, subscale inner tension | To compare mean changes in quality of life measure, Quality of Life Scale -100, subscale inner tension between the two treatment arms over the four weeks treatment period (visit 2 versus visit 4). This is a dichotomous scale (unsatisfactory or satisfactory). More 'satisfactory' answers means higher quality of life. | 6 weeks | 
| To compare the frequency of occurence of side effects between the two treatment arms. | To compare presence of side effects as measured through General Assessment of Side Effects Scale and reported spontaneously between the two treatment arms (EIPT/TAU) over the six week treatment period (visit 2 versus visit 4). Higher scores means more side effects. Minimum score: 0 side effects, maximum score: 38 side effects. | 6 weeks | 
| To compare the proportion of participants using concomitant medication between the two treatment arms. | To compare use of concomitant medication between the two treatment arms (EIPT/TAU) over the six week treatment period (visit 2 versus visit 4) effects. | 6 weeks | 
| To compare the proportion of participants who prematurely discontinue between the two treatment arms. | To compare premature discontinuation between the two treatment arms (EIPT/TAU) over the six week treatment period (visit 2 versus visit 4). | 6 weeks |