xml: <clinical_study>
    <!-- This xml conforms to an XML Schema at:
      https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
    <required_header>
      <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
      <link_text>Link to the current ClinicalTrials.gov record.</link_text>
      <url>https://clinicaltrials.gov/ct2/show/NCT05973786</url>
    </required_header>
    <id_info>
      <org_study_id>2023-506605-19-00 (EU CT#)</org_study_id>
      <nct_id>NCT05973786</nct_id>
    </id_info>
    <brief_title>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.</brief_title>
    <acronym>INTENSIFY BD</acronym>
    <official_title>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.</official_title>
    <sponsors>
      <lead_sponsor>
        <agency>Dr. Inge Winter</agency>
        <agency_class>Other</agency_class>
      </lead_sponsor>
      <collaborator>
        <agency>Westfälische Wilhelms-Universität Münster</agency>
        <agency_class>Other</agency_class>
      </collaborator>
    </sponsors>
    <source>UMC Utrecht</source>
    <oversight_info>
      <has_dmc>Yes</has_dmc>
      <is_fda_regulated_drug>No</is_fda_regulated_drug>
      <is_fda_regulated_device>No</is_fda_regulated_device>
    </oversight_info>
    <brief_summary>
      <textblock>
        Bipolar disorders affect approximately 4.5 million people across the European Union (EU) and&#xD;
        are associated with high annual healthcare and societal costs. Bipolar disorder I and II&#xD;
        represent disorders that cause extreme fluctuation in a person's mood, energy, and ability to&#xD;
        function, in which symptoms of (hypo)mania and depression alternate. The depressive episodes&#xD;
        of bipolar disorders are often referred to as bipolar depression (BD). In other words: it is&#xD;
        a phase/state of the disorder. For many patients with BD, the depressive polarity is often&#xD;
        more pervasive and more debilitating than manic states, with estimates that depressed mood&#xD;
        accounts for up to two-thirds of the time spent unwell, even with treatment. The burden of&#xD;
        not received an effective treatment for BD is high: more severe psychopathology, higher rates&#xD;
        of unemployment, more hospitalisations, lower quality of life, lower cognitive functioning,&#xD;
        risk of suicide, comorbidities and poorer social and occupational functioning and thus more&#xD;
        carer burden. For BD, the treatment guidelines are very heterogeneous, amongst other reasons&#xD;
        because the disease is heterogeneous and treatments should be tailored to the patients. There&#xD;
        is no clear treatment algorithm and it cannot yet be predicted which treatment will be&#xD;
        effective. Especially the place of adjunctive antidepressants is under debate. Usually, for&#xD;
        psychiatric disorders (including bipolar disorder), a patient is considered to be&#xD;
        treatment-resistant is two medicinal treatments have been tried (in sufficient duration and&#xD;
        dosage) without sufficient success. For BD, there is no consensus on when to consider a&#xD;
        patient as treatment-resistant, but the most common definition is after one prior treatment&#xD;
        failure. This raises the research question whether adjunctive antidepressants to treat BD&#xD;
        should be introduced earlier in the treatment. Additionally, The INTENSIFY trial is part of&#xD;
        the larger Horizon 2021 project, with the central goal of paving the way for a shift towards&#xD;
        a treatment decision-making process tailored for the individual at risk for treatment&#xD;
        resistance. To that end, we aim to establish evidence-based criteria to make decisions of&#xD;
        early intense treatment in individuals at risk for treatment resistance across the major&#xD;
        psychiatric disorders of schizophrenia, bipolar disorder and major depression.&#xD;
      </textblock>
    </brief_summary>
    <detailed_description>
      <textblock>
        Rationale Bipolar disorders affect approximately 4.5 million people across the European Union&#xD;
        (EU) and are associated with high annual healthcare and societal costs. Bipolar disorder I&#xD;
        and II represent disorders that cause extreme fluctuation in a person's mood, energy, and&#xD;
        ability to function, in which symptoms of (hypo)mania and depression alternate. The&#xD;
        depressive episodes of bipolar disorders are often referred to as bipolar depression (BD). In&#xD;
        other words: it is a phase/state of the disorder. For many patients with BD, the depressive&#xD;
        polarity is often more pervasive and more debilitating than manic states, with estimates that&#xD;
        depressed mood accounts for up to two-thirds of the time spent unwell, even with treatment.&#xD;
        The burden of not received an effective treatment for BD is high: more severe&#xD;
        psychopathology, higher rates of unemployment, more hospitalisations, lower quality of life,&#xD;
        lower cognitive functioning, risk of suicide, comorbidities and poorer social and&#xD;
        occupational functioning and thus more carer burden. For BD, the treatment guidelines are&#xD;
        very heterogeneous, amongst other reasons because the disease is heterogeneous and treatments&#xD;
        should be tailored to the patients. There is no clear treatment algorithm and it cannot yet&#xD;
        be predicted which treatment will be effective. Especially the place of adjunctive&#xD;
        antidepressants is under debate. Usually, for psychiatric disorders (including bipolar&#xD;
        disorder), a patient is considered to be treatment-resistant is two medicinal treatments have&#xD;
        been tried (in sufficient duration and dosage) without sufficient success. For BD, there is&#xD;
        no consensus on when to consider a patient as treatment-resistant, but the most common&#xD;
        definition is after one prior treatment failure. This raises the research question whether&#xD;
        adjunctive antidepressants to treat BD should be introduced earlier in the treatment.&#xD;
        Additionally, The INTENSIFY trial is part of the larger Horizon 2021 project, with the&#xD;
        central goal of paving the way for a shift towards a treatment decision-making process&#xD;
        tailored for the individual at risk for treatment resistance. To that end, we aim to&#xD;
        establish evidence-based criteria to make decisions of early intense treatment in individuals&#xD;
        at risk for treatment resistance across the major psychiatric disorders of schizophrenia,&#xD;
        bipolar disorder and major depression.&#xD;
  &#xD;
        Objective The primary objective is to compare the treatment response, expressed as mean&#xD;
        change in symptom severity as measured through the Montgomery-Åsberg Depression Rating Scale&#xD;
        (MADRS) under an early-intensified pharmacological treatment to that under treatment as&#xD;
        usual, in subjects who had a first-time treatment failure on their first-line treatment.&#xD;
  &#xD;
        Main trial endpoints Change in symptom severity total score from baseline (visit 2) to end of&#xD;
        treatment (visit 4). This is measured using MADRS.&#xD;
  &#xD;
        Secondary trial endpoints&#xD;
  &#xD;
          1. Comparison of the proportion of participants (EIPT vs. TAU) that is in symptomatic&#xD;
             remission at visit 4. Remission is defined as a MADRS score ≤ 12.&#xD;
  &#xD;
          2. To compare changes in the severity and improvement sub-scores of the Clinical Global&#xD;
             Impression Scale (CGI) between the two treatment arms (EIPT/TAU) over the six week&#xD;
             treatment period (visit 2 versus visit 4).&#xD;
  &#xD;
          3. To compare changes in the levels of depression and anxiety as assessed with the Hospital&#xD;
             Anxiety and Depression Scale (HADS) between the two treatment arms (EIPT/TAU) over the&#xD;
             six week treatment period (visit 2 versus visit 4).&#xD;
  &#xD;
          4. To compare changes in cognitive performance as measured through the Trail Making Test,&#xD;
             Digit Symbol Substitution Test, Rey Auditory Verbal Learning Test as well as the&#xD;
             Perceived Deficits Questionnaire between the two treatment arms (EIPT/TAU) over the six&#xD;
             week treatment period (visit 2 versus visit 4).&#xD;
  &#xD;
          5. To compare changes in quality of life and functioning measures (Q-LES-Q-SF, LAPS,&#xD;
             QLS-100 and SDS between the two treatment arms (EIPT/TAU) over the six week treatment&#xD;
             period (visit 2 versus visit 4).&#xD;
  &#xD;
          6. To compare presence of side effects as measured through General Assessment of Side&#xD;
             Effects Scale (GASE) and reported spontaneously between the two treatment arms&#xD;
             (EIPT/TAU) over the six week treatment period (visit 2 versus visit 4).&#xD;
  &#xD;
          7. To compare use of concomitant medication between the two treatment arms (EIPT/TAU) over&#xD;
             the six week treatment period (visit 2 versus visit 4).&#xD;
  &#xD;
          8. To compare premature discontinuation (timing and reason) between the two treatment arms&#xD;
             (EIPT/TAU) over the six week treatment period (visit 2 versus visit 4).&#xD;
  &#xD;
        Trial design The clinical study is an international, multicenter controlled, randomised, open&#xD;
        label trial (with blinded raters), with a treatment duration of six weeks.&#xD;
  &#xD;
        Trial population The aim is to recruit 418 subjects with bipolar disorder type I or II,&#xD;
        currently in a depressive episode. Male and female subjects, in- and out-patients, within the&#xD;
        age range of 18 to 70 years old are eligible for participation. The main exclusion criteria&#xD;
        are defined to protect the wellbeing of subjects, e.g. being pregnant or breastfeeding,&#xD;
        subjects with previous failure on quetiapine, meeting any contraindications, or participants&#xD;
        with a known intolerance to quetiapine.&#xD;
  &#xD;
        Interventions&#xD;
  &#xD;
        Subjects are randomised to treatment as usual (second-line treatment) or to the&#xD;
        early-intensified pharmacological treatment (third-line treatment). Treatment per can be&#xD;
        found in the table below:&#xD;
  &#xD;
        Table 1. Overview of treatment randomisation per study sample. BD sample Treatment as Usual&#xD;
        (TAU) Switch to quetiapine plus lithium or valproate acid Early-Intensified Pharmacological&#xD;
        Treatment (EIPT) Switch to&#xD;
  &#xD;
          1. one of the following: escitalopram, sertraline, duloxetine, bupropion or venlafaxine&#xD;
             plus&#xD;
  &#xD;
          2. two of the following: lithium, valproate acid or quetiapine&#xD;
  &#xD;
        Ethical considerations relating to the clinical trial including the expected benefit to the&#xD;
        individual subject or group of subjects represented by the trial subjects as well as the&#xD;
        nature and extent of burden and risks All medications studied in the current trial are widely&#xD;
        used (alone or in combination) in clinical practice and the risks for side effects are well&#xD;
        established. In the current study, clinical practice is mimicked as much as possible to&#xD;
        maximize generalisability and for feasibility purposes. To this end, Summaries of Product&#xD;
        Characteristics (SmPCs) are followed with regards to contraindications (implemented as&#xD;
        exclusion criterion), safety measures and allowed combinations with other medications. Site&#xD;
        visits and assessments are kept to a minimum to keep subject burden at an acceptable level,&#xD;
        while meeting the objectives of the study. Blood samples for biomarker analyses are only&#xD;
        collected when subjects provide consent; safety measures are performed as part of clinical&#xD;
        routine.&#xD;
  &#xD;
        Overall, the risks are similar to daily clinical practice; the only difference relative to&#xD;
        clinical practice is the application of three pharmacological treatments (EIPT) versus two&#xD;
        (TAU) earlier in the illness. Still, these additional treatment options are also commonly&#xD;
        prescribed by clinicians. There are no indications in existing literature or clinical&#xD;
        practice that the earlier introduction of these medications poses a safety risk when used in&#xD;
        an earlier illness phase than indicated in the SmPC.&#xD;
  &#xD;
        A benefit of the study is that if it indeed turns out that the early-intensified treatment is&#xD;
        associated with more symptom improvement compared to treatment as usual, future patients have&#xD;
        to go through less trial and error, which results in a reduced burden (higher quality of&#xD;
        life, less unemployment, less hospitalisations) for patients and carers as well as lower&#xD;
        societal and healthcare costs.&#xD;
  &#xD;
        IMPORTANT: the study was submitted to the European authorities before (see NCT05603104) and&#xD;
        they requested to split this study into 3 studies (1 for each diagnostic category). We have&#xD;
        done this and created 3 new ClinicalTrials.gov studies as well, from which this is one for&#xD;
        schizophrenia. Once we have received the NCT numbers for BD and MDD, we will add them here.&#xD;
        The site in the UK (London) followed the advice and will submit 3 separate protocols and are&#xD;
        therefore included in the current record. However, Israel already submitted this as one&#xD;
        protocol. Therefore, we keep the old clinicaltrials.gov number for Israel (NCT05603104).&#xD;
      </textblock>
    </detailed_description>
    <overall_status>Not yet recruiting</overall_status>
    <start_date type="Anticipated">September 1, 2023</start_date>
    <completion_date type="Anticipated">June 30, 2026</completion_date>
    <primary_completion_date type="Anticipated">June 30, 2026</primary_completion_date>
    <phase>Phase 4</phase>
    <study_type>Interventional</study_type>
    <has_expanded_access>No</has_expanded_access>
    <study_design_info>
      <allocation>Randomized</allocation>
      <intervention_model>Parallel Assignment</intervention_model>
      <intervention_model_description>Parallel randomization to the 2 arms, treatment as usual (TAU) or early-intensified pharmacological treatment (EIPT).</intervention_model_description>
      <primary_purpose>Treatment</primary_purpose>
      <masking>Single (Outcomes Assessor)</masking>
      <masking_description>Open label, except for the assessors of the primary outcome</masking_description>
    </study_design_info>
    <primary_outcome>
      <measure>Comparing the mean change in symptom severity on Montgomery Asberg Depression Rating Scale</measure>
      <time_frame>6 weeks</time_frame>
      <description>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</description>
    </primary_outcome>
    <secondary_outcome>
      <measure>Compare proportion of participants that is in symptomatic remission</measure>
      <time_frame>6 weeks</time_frame>
      <description>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.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Compare the mean change in the severity and improvement CGI-S sub-scores</measure>
      <time_frame>6 weeks</time_frame>
      <description>To compare 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</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Compare the mean change in the severity and improvement CGI-I sub-scores</measure>
      <time_frame>6 weeks</time_frame>
      <description>To compare 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</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Compare the mean changes in the levels of depression and anxiety</measure>
      <time_frame>6 weeks</time_frame>
      <description>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.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>To compare mean changes in cognitive performance as measured through the Trail Making Test</measure>
      <time_frame>6 weeks</time_frame>
      <description>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.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>To compare the mean changes in cognitive performance as measured through the Rey Auditory Verbal Learning Test</measure>
      <time_frame>6 weeks</time_frame>
      <description>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.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>To compare the mean changes in subjective cognitive performance as measured through the Perceived Deficits Questionnaire</measure>
      <time_frame>6 weeks</time_frame>
      <description>To compare 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.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>To compare the mean changes in functioning on the Leuven Affective and Pleasure Scale</measure>
      <time_frame>6 weeks</time_frame>
      <description>To compare 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</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>To compare the mean changes in functioning on the Sheehan Disability Scale</measure>
      <time_frame>6 weeks</time_frame>
      <description>To compare 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.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>To compare the mean changes in quality of life measure, Quality of Life Enjoyment and Satisfaction Questionnaire Short Form</measure>
      <time_frame>6 weeks</time_frame>
      <description>To compare 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.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>To compare the mean changes in quality of life measure, Quality of Life Scale -100, subscale inner tension</measure>
      <time_frame>6 weeks</time_frame>
      <description>To compare 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.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>To compare the frequency of occurence of side effects between the two treatment arms.</measure>
      <time_frame>6 weeks</time_frame>
      <description>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.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>To compare the proportion of participants using concomitant medication between the two treatment arms.</measure>
      <time_frame>6 weeks</time_frame>
      <description>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.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>To compare the proportion of participants who prematurely discontinue between the two treatment arms.</measure>
      <time_frame>6 weeks</time_frame>
      <description>To compare premature discontinuation between the two treatment arms (EIPT/TAU) over the six week treatment period (visit 2 versus visit 4).</description>
    </secondary_outcome>
    <number_of_arms>2</number_of_arms>
    <enrollment type="Anticipated">418</enrollment>
    <condition>Bipolar Depression</condition>
    <arm_group>
      <arm_group_label>Bipolar Depression EIPT: Switch to one of the following combinations:</arm_group_label>
      <arm_group_type>Experimental</arm_group_type>
      <description>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</description>
    </arm_group>
    <arm_group>
      <arm_group_label>Bipolar Depression TAU: Switch to quetiapine plus lithium or valproate acid or lamotrigine</arm_group_label>
      <arm_group_type>Active Comparator</arm_group_type>
      <description>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).</description>
    </arm_group>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>Escitalopram</intervention_name>
      <description>ATC code: N06AB10</description>
      <arm_group_label>Bipolar Depression EIPT: Switch to one of the following combinations:</arm_group_label>
      <other_name>ATC code: N06AB10</other_name>
    </intervention>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>Sertraline</intervention_name>
      <description>See arm description</description>
      <arm_group_label>Bipolar Depression EIPT: Switch to one of the following combinations:</arm_group_label>
      <other_name>ATC code: N06AB06</other_name>
    </intervention>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>Duloxetine</intervention_name>
      <description>See arm description</description>
      <arm_group_label>Bipolar Depression EIPT: Switch to one of the following combinations:</arm_group_label>
      <other_name>ATC code: N06AX21</other_name>
    </intervention>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>Venlafaxine</intervention_name>
      <description>See arm description</description>
      <arm_group_label>Bipolar Depression EIPT: Switch to one of the following combinations:</arm_group_label>
      <other_name>ATC code: N06AX16</other_name>
    </intervention>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>Lithium</intervention_name>
      <description>See arm description</description>
      <arm_group_label>Bipolar Depression EIPT: Switch to one of the following combinations:</arm_group_label>
      <arm_group_label>Bipolar Depression TAU: Switch to quetiapine plus lithium or valproate acid or lamotrigine</arm_group_label>
      <other_name>ATC code: N05AN01</other_name>
    </intervention>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>Lamotrigine</intervention_name>
      <description>See arm description</description>
      <arm_group_label>Bipolar Depression EIPT: Switch to one of the following combinations:</arm_group_label>
      <arm_group_label>Bipolar Depression TAU: Switch to quetiapine plus lithium or valproate acid or lamotrigine</arm_group_label>
      <other_name>ATC code: N03AX09</other_name>
    </intervention>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>Valproate acid</intervention_name>
      <description>See arm description</description>
      <arm_group_label>Bipolar Depression EIPT: Switch to one of the following combinations:</arm_group_label>
      <arm_group_label>Bipolar Depression TAU: Switch to quetiapine plus lithium or valproate acid or lamotrigine</arm_group_label>
      <other_name>ATC code: N03AG01</other_name>
    </intervention>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>Quetiapine</intervention_name>
      <description>See arm description</description>
      <arm_group_label>Bipolar Depression EIPT: Switch to one of the following combinations:</arm_group_label>
      <arm_group_label>Bipolar Depression TAU: Switch to quetiapine plus lithium or valproate acid or lamotrigine</arm_group_label>
      <other_name>ATC code: N05AH04</other_name>
    </intervention>
    <eligibility>
      <criteria>
        <textblock>
          Inclusion criteria:&#xD;
  &#xD;
            1. In- or out patients, at least 18 years of age up until 70.&#xD;
  &#xD;
            2. Being willing and able to provide written informed consent. If unable, having a legal&#xD;
               guardian to provide written informed consent is allowed (subject's opinion will also&#xD;
               be considered in these cases).&#xD;
  &#xD;
            3. Female subjects of child bearing potential must use effective contraception during the&#xD;
               trial and as per the requirements in the protocol (section 8.2).&#xD;
  &#xD;
            4. Meeting diagnostic criteria for a primary diagnosis of bipolar depression (bipolar&#xD;
               disorder type I and II currently in a depressive episode), according to DSM-5. The&#xD;
               primary diagnosis will be confirmed by the Mini International Neuropsychiatric&#xD;
               Interview (MINI v7.0.2).&#xD;
  &#xD;
            5. Subject experienced (in total) one treatment failure due to lack of efficacy; this&#xD;
               treatment is a first-line pharmacotherapeutic agent for the primary DSM-5 diagnosis,&#xD;
               and was prescribed for at least 4 weeks within the dose range as specified in the&#xD;
               Summary of Product Characteristics (SmPCs).&#xD;
  &#xD;
            6. The psychopharmacological treatment failure (inclusion criterion 5) should be&#xD;
               confirmed by a CGI-I ≥3.&#xD;
  &#xD;
            7. Subject and clinician intend to change pharmacotherapeutic treatment.&#xD;
  &#xD;
            8. A minimum symptom severity threshold needs to be present (moderate level; see below)&#xD;
               and subject needs to experience functional impairment.&#xD;
  &#xD;
                 -  The minimum symptom severity threshold is a score of ≥20 on the Montgomery Åsberg&#xD;
                    Depression Rating Scale (MADRS 26)&#xD;
  &#xD;
                 -  Functional impairment is defined as a score of 5 or higher on any of the three&#xD;
                    scales of the Sheehan Disability Scale (SDS).&#xD;
  &#xD;
          Exclusion criteria&#xD;
  &#xD;
            1. Being pregnant or breastfeeding.&#xD;
  &#xD;
            2. Subject has failed previously on quetiapine due to inefficacy (after treatment&#xD;
               duration of ≥ 4 weeks within an efficacious dose range according to the SmPC.&#xD;
  &#xD;
            3. Subject has a known intolerance to quetiapine or to all TAU medication.&#xD;
  &#xD;
            4. Meeting any of the contraindications for quetiapine, or to all TAU medication options,&#xD;
               as specified within the applicable SmPC.&#xD;
  &#xD;
            5. Subject has participated in another clinical trial in which the subject received an&#xD;
               experimental or investigational drug or agent within 30 days before visit 1.&#xD;
  &#xD;
            6. Subject currently uses more than the allowed psychotropic concomitant medication and&#xD;
               needs to stay on this medication during the study.&#xD;
  &#xD;
            7. Subject experiences any other significant disease or disorder which, in the opinion of&#xD;
               the investigator, may either put the subjects at risk because of participation in the&#xD;
               trial, or may influence the result of the trial, or the subject's ability to&#xD;
               participate in the trial.&#xD;
  &#xD;
            8. Moderate or high suicidal ideation within the last 2 weeks, defined as a score of 9 or&#xD;
               higher on Module B (Suicidality) of the Mini International Neuropsychiatric Interview&#xD;
               (MINI v7.0.2)&#xD;
  &#xD;
            9. Subject meets criteria for current substance use disorder, as confirmed by the Mini&#xD;
               International Neuropsychiatric Interview (MINI v7.0.2). Nicotine dependency is&#xD;
               allowed, as well as mild alcohol and/or cannabis use disorder (as defined by MINI&#xD;
               v7.0.2). Moderate and severe alcohol and/or cannabis use disorder are not allowed.&#xD;
  &#xD;
           10. Subjects who are admitted in the (psychiatric) clinic due to a court or administrative&#xD;
               order are not allowed to participate in the study.&#xD;
  &#xD;
           11. A score of 8 or higher on the Young Mania Rating Scale (YMRS) in order to exclude&#xD;
               subjects with predominant manic symptoms or mixed symptoms.&#xD;
        </textblock>
      </criteria>
      <gender>All</gender>
      <minimum_age>18 Years</minimum_age>
      <maximum_age>70 Years</maximum_age>
      <healthy_volunteers>No</healthy_volunteers>
    </eligibility>
    <overall_contact>
      <last_name>Inge Winter, Dr.</last_name>
      <phone>+31875553227</phone>
      <email>i.winter@umcutrecht.nl</email>
    </overall_contact>
    <overall_contact_backup>
      <last_name>Cynthia Okhuijsen-Pfeifer, Dr.</last_name>
      <phone>+31875553227</phone>
      <email>c.pfeifer@umcutrecht.nl</email>
    </overall_contact_backup>
    <location>
      <facility>
        <name>Medical University Innsbruck</name>
        <address>
          <city>Innsbruck</city>
          <country>Austria</country>
        </address>
      </facility>
    </location>
    <location>
      <facility>
        <name>University Augsburg, BKH Augsburg, Department of Psychiatry, Psychotherapy and Psychosomatics</name>
        <address>
          <city>Augsburg</city>
          <country>Germany</country>
        </address>
      </facility>
    </location>
    <location>
      <facility>
        <name>Universitätsklinik für Psychiatrie und Psychotherapie Bielefeld</name>
        <address>
          <city>Bielefeld</city>
          <country>Germany</country>
        </address>
      </facility>
    </location>
    <location>
      <facility>
        <name>Technische Universität Dresden</name>
        <address>
          <city>Dresden</city>
          <country>Germany</country>
        </address>
      </facility>
    </location>
    <location>
      <facility>
        <name>University Hospital Frankfurt am Main - Goethe University</name>
        <address>
          <city>Frankfurt am Main</city>
          <country>Germany</country>
        </address>
      </facility>
      <contact>
        <last_name>Andreas Reif, MD, PhD</last_name>
        <email>andreas.reif@kgu.de</email>
      </contact>
    </location>
    <location>
      <facility>
        <name>Klinik für Psychiatrie und Psychotherapie der Universitätsmedizin Mainz</name>
        <address>
          <city>Mainz</city>
          <country>Germany</country>
        </address>
      </facility>
    </location>
    <location>
      <facility>
        <name>Westfälische Wilhelms-Universität Münster</name>
        <address>
          <city>Münster</city>
          <country>Germany</country>
        </address>
      </facility>
    </location>
    <location>
      <facility>
        <name>Universita degli Studi di Brescia</name>
        <address>
          <city>Brescia</city>
          <country>Italy</country>
        </address>
      </facility>
    </location>
    <location>
      <facility>
        <name>University of Cagliari</name>
        <address>
          <city>Cagliari</city>
          <country>Italy</country>
        </address>
      </facility>
    </location>
    <location>
      <facility>
        <name>Università degli studi della Campania Luigi Vanvitelli</name>
        <address>
          <city>Naples</city>
          <zip>80138</zip>
          <country>Italy</country>
        </address>
      </facility>
    </location>
    <location>
      <facility>
        <name>Azienda Ospedaliero-Universitaria &quot;Città della Salute e della Scienza di Torino&quot;</name>
        <address>
          <city>Turin</city>
          <country>Italy</country>
        </address>
      </facility>
    </location>
    <location>
      <facility>
        <name>Fundació Clínic per a la Recerca Biomèdica</name>
        <address>
          <city>Barcelona</city>
          <country>Spain</country>
        </address>
      </facility>
    </location>
    <location>
      <facility>
        <name>King's College London, Psychiatry &amp; Cognitive Neuroscience</name>
        <address>
          <city>London</city>
          <zip>SE5 8AF</zip>
          <country>United Kingdom</country>
        </address>
      </facility>
    </location>
    <location_countries>
      <country>Austria</country>
      <country>Germany</country>
      <country>Italy</country>
      <country>Spain</country>
      <country>United Kingdom</country>
    </location_countries>
    <verification_date>August 2023</verification_date>
    <study_first_submitted>July 25, 2023</study_first_submitted>
    <study_first_submitted_qc>July 25, 2023</study_first_submitted_qc>
    <study_first_posted type="Actual">August 3, 2023</study_first_posted>
    <last_update_submitted>August 22, 2023</last_update_submitted>
    <last_update_submitted_qc>August 22, 2023</last_update_submitted_qc>
    <last_update_posted type="Actual">August 24, 2023</last_update_posted>
    <responsible_party>
      <responsible_party_type>Sponsor-Investigator</responsible_party_type>
      <investigator_affiliation>UMC Utrecht</investigator_affiliation>
      <investigator_full_name>Dr. Inge Winter</investigator_full_name>
      <investigator_title>Principal Investigator</investigator_title>
    </responsible_party>
    <condition_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Depression</mesh_term>
      <mesh_term>Depressive Disorder</mesh_term>
      <mesh_term>Bipolar Disorder</mesh_term>
    </condition_browse>
    <intervention_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Lamotrigine</mesh_term>
      <mesh_term>Duloxetine Hydrochloride</mesh_term>
      <mesh_term>Valproic Acid</mesh_term>
      <mesh_term>Quetiapine Fumarate</mesh_term>
      <mesh_term>Venlafaxine Hydrochloride</mesh_term>
      <mesh_term>Sertraline</mesh_term>
      <mesh_term>Escitalopram</mesh_term>
    </intervention_browse>
    <patient_data>
      <sharing_ipd>Yes</sharing_ipd>
      <ipd_info_type>Study Protocol</ipd_info_type>
      <ipd_info_type>Clinical Study Report (CSR)</ipd_info_type>
    </patient_data>
    <!-- Results have not yet been posted for this study                                          -->
  </clinical_study>
  
  
text: download date: ClinicalTrials.gov processed this data on September 20, 2023
  link text: Link to the current ClinicalTrials.gov record.
  url: https://clinicaltrials.gov/ct2/show/NCT05973786
  org study id: 2023-506605-19-00 (EU CT#)
  nct id: NCT05973786
  lead sponsor: 
  collaborator: 
  has dmc: Yes
  is fda regulated drug: No
  is fda regulated device: No
  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.
  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
  
          1. 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.
  
          2. To compare 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).
  
          3. To compare 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).
  
          4. To compare 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).
  
          5. To compare 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).
  
          6. 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).
  
          7. To compare use of concomitant medication between the two treatment arms (EIPT/TAU) over
             the six week treatment period (visit 2 versus visit 4).
  
          8. 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
  
          1. one of the following: escitalopram, sertraline, duloxetine, bupropion or venlafaxine
             plus
  
          2. 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).
  allocation: Randomized
  intervention model: Parallel Assignment
  intervention model description: Parallel randomization to the 2 arms, treatment as usual (TAU) or early-intensified pharmacological treatment (EIPT).
  primary purpose: Treatment
  masking: Single (Outcomes Assessor)
  masking description: Open label, except for the assessors of the primary outcome
  measure: Comparing the mean change in symptom severity on Montgomery Asberg Depression Rating Scale
  time frame: 6 weeks
  description: 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
  measure: Compare proportion of participants that is in symptomatic remission
  time frame: 6 weeks
  description: 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.
  measure: Compare the mean change in the severity and improvement CGI-S sub-scores
  time frame: 6 weeks
  description: To compare 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
  measure: Compare the mean change in the severity and improvement CGI-I sub-scores
  time frame: 6 weeks
  description: To compare 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
  measure: Compare the mean changes in the levels of depression and anxiety
  time frame: 6 weeks
  description: 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.
  measure: To compare mean changes in cognitive performance as measured through the Trail Making Test
  time frame: 6 weeks
  description: 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.
  measure: To compare the mean changes in cognitive performance as measured through the Rey Auditory Verbal Learning Test
  time frame: 6 weeks
  description: 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.
  measure: To compare the mean changes in subjective cognitive performance as measured through the Perceived Deficits Questionnaire
  time frame: 6 weeks
  description: To compare 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.
  measure: To compare the mean changes in functioning on the Leuven Affective and Pleasure Scale
  time frame: 6 weeks
  description: To compare 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
  measure: To compare the mean changes in functioning on the Sheehan Disability Scale
  time frame: 6 weeks
  description: To compare 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.
  measure: To compare the mean changes in quality of life measure, Quality of Life Enjoyment and Satisfaction Questionnaire Short Form
  time frame: 6 weeks
  description: To compare 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.
  measure: To compare the mean changes in quality of life measure, Quality of Life Scale -100, subscale inner tension
  time frame: 6 weeks
  description: To compare 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.
  measure: To compare the frequency of occurence of side effects between the two treatment arms.
  time frame: 6 weeks
  description: 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.
  measure: To compare the proportion of participants using concomitant medication between the two treatment arms.
  time frame: 6 weeks
  description: 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.
  measure: To compare the proportion of participants who prematurely discontinue between the two treatment arms.
  time frame: 6 weeks
  description: To compare premature discontinuation between the two treatment arms (EIPT/TAU) over the six week treatment period (visit 2 versus visit 4).
  arm group label: Bipolar Depression EIPT: Switch to one of the following combinations:
  arm group type: Experimental
  description: 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
  arm group label: Bipolar Depression TAU: Switch to quetiapine plus lithium or valproate acid or lamotrigine
  arm group type: Active Comparator
  description: 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).
  intervention type: Drug
  intervention name: Escitalopram
  description: ATC code: N06AB10
  arm group label: Bipolar Depression EIPT: Switch to one of the following combinations:
  other name: ATC code: N06AB10
  intervention type: Drug
  intervention name: Sertraline
  description: See arm description
  arm group label: Bipolar Depression EIPT: Switch to one of the following combinations:
  other name: ATC code: N06AB06
  intervention type: Drug
  intervention name: Duloxetine
  description: See arm description
  arm group label: Bipolar Depression EIPT: Switch to one of the following combinations:
  other name: ATC code: N06AX21
  intervention type: Drug
  intervention name: Venlafaxine
  description: See arm description
  arm group label: Bipolar Depression EIPT: Switch to one of the following combinations:
  other name: ATC code: N06AX16
  intervention type: Drug
  intervention name: Lithium
  description: See arm description
  arm group label: Bipolar Depression EIPT: Switch to one of the following combinations:
  arm group label: Bipolar Depression TAU: Switch to quetiapine plus lithium or valproate acid or lamotrigine
  other name: ATC code: N05AN01
  intervention type: Drug
  intervention name: Lamotrigine
  description: See arm description
  arm group label: Bipolar Depression EIPT: Switch to one of the following combinations:
  arm group label: Bipolar Depression TAU: Switch to quetiapine plus lithium or valproate acid or lamotrigine
  other name: ATC code: N03AX09
  intervention type: Drug
  intervention name: Valproate acid
  description: See arm description
  arm group label: Bipolar Depression EIPT: Switch to one of the following combinations:
  arm group label: Bipolar Depression TAU: Switch to quetiapine plus lithium or valproate acid or lamotrigine
  other name: ATC code: N03AG01
  intervention type: Drug
  intervention name: Quetiapine
  description: See arm description
  arm group label: Bipolar Depression EIPT: Switch to one of the following combinations:
  arm group label: Bipolar Depression TAU: Switch to quetiapine plus lithium or valproate acid or lamotrigine
  other name: ATC code: N05AH04
  criteria: 
  gender: All
  minimum age: 18 Years
  maximum age: 70 Years
  healthy volunteers: No
  last name: Inge Winter, Dr.
  phone: +31875553227
  email: i.winter@umcutrecht.nl
  last name: Cynthia Okhuijsen-Pfeifer, Dr.
  phone: +31875553227
  email: c.pfeifer@umcutrecht.nl
  facility: 
  facility: 
  facility: 
  facility: 
  facility: 
  contact: 
  facility: 
  facility: 
  facility: 
  facility: 
  facility: 
  facility: 
  facility: 
  facility: 
  country: Austria
  country: Germany
  country: Italy
  country: Spain
  country: United Kingdom
  responsible party type: Sponsor-Investigator
  investigator affiliation: UMC Utrecht
  investigator full name: Dr. Inge Winter
  investigator title: Principal Investigator
  mesh term: Depression
  mesh term: Depressive Disorder
  mesh term: Bipolar Disorder
  mesh term: Lamotrigine
  mesh term: Duloxetine Hydrochloride
  mesh term: Valproic Acid
  mesh term: Quetiapine Fumarate
  mesh term: Venlafaxine Hydrochloride
  mesh term: Sertraline
  mesh term: Escitalopram
  sharing ipd: Yes
  ipd info type: Study Protocol
  ipd info type: Clinical Study Report (CSR)