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/NCT05973851</url>
    </required_header>
    <id_info>
      <org_study_id>2023-506617-21-00 (EU CT#)</org_study_id>
      <nct_id>NCT05973851</nct_id>
    </id_info>
    <brief_title>The Effect of a Four Week Intensified Pharmacological Treatment for Major Depressive Disorder Compared to Treatment as Usual in Subjects Who Had a First-time Treatment Failure on Their First-line Treatment.</brief_title>
    <acronym>INTENSIFY MDD</acronym>
    <official_title>A Randomised, Controlled Trial to Investigate the Effect of a Four Week Intensified Pharmacological Treatment for Major Depressive Disorder 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>
        Over 28 million people suffer from current depressive disorder in the European Union. Major&#xD;
        depressive disorder (MDD) is one of the most common psychiatric illnesses. The symptoms cause&#xD;
        clinically significant distress or impairment in social, occupational, and other important&#xD;
        areas of functioning. To treat MDD, there are several antidepressants available and&#xD;
        prescribing medication is a process of trial-and-error. Guidelines do not explicitly advise&#xD;
        on the order in which antidepressant medication should be prescribed. The choice of&#xD;
        antidepressant should be tailored to the patient, while involving the patient in the&#xD;
        decision-making process. In general, the choice for the first- and second-line treatment will&#xD;
        be a second-generation antidepressant. Recently, esketamine nasal spray (intranasal (IN)&#xD;
        administration) was approved for patients with treatment-resistant MDD (TRD). A patient is&#xD;
        diagnosed with TRD when having used two antidepressants in sufficient duration and adequate&#xD;
        dose without sufficient effect. TRD is associated with a negative impact on quality of life,&#xD;
        higher risk for hospitalisations and suicide, comorbidities, poorer social and occupational&#xD;
        functioning and a high carer burden. The efficacy of intranasal use of esketamine has been&#xD;
        demonstrated in MDD subjects with treatment-resistant symptoms but also in subjects with&#xD;
        non-treatment resistant depression, and is approved by the FDA and EMA as a third-line&#xD;
        treatment. Besides the registered esketamine nasal spray, which is not available in all&#xD;
        countries to all patients because of the high costs, off-label utilization of (es)ketamine&#xD;
        infusions (IV) is growing extensively over time to treat TRD. Research conducted so far&#xD;
        indicates an unequivocal initial substantial response to (es)ketamine IV in MDD populations,&#xD;
        regardless of whether or not patients suffer from treatment resistant MDD. However, until&#xD;
        now, there has not been a study investigating this in a sufficiently large population. This&#xD;
        may be a unique opportunity to potentially prevent patients progressing into a treatment&#xD;
        resistant illness stage. The potential implications of the results of the current study are&#xD;
        the prevention of unnecessary trials of ineffective treatments, reducing subject burden&#xD;
        substantially, as well as a reduction of healthcare and societal costs.&#xD;
      </textblock>
    </brief_summary>
    <detailed_description>
      <textblock>
        Rationale Over 28 million people suffer from current depressive disorder in the European&#xD;
        Union. Major depressive disorder (MDD) is one of the most common psychiatric illnesses. The&#xD;
        symptoms cause clinically significant distress or impairment in social, occupational, and&#xD;
        other important areas of functioning. To treat MDD, there are several antidepressants&#xD;
        available and prescribing medication is a process of trial-and-error. Guidelines do not&#xD;
        explicitly advise on the order in which antidepressant medication should be prescribed. The&#xD;
        choice of antidepressant should be tailored to the patient, while involving the patient in&#xD;
        the decision-making process. In general, the choice for the first- and second-line treatment&#xD;
        will be a second-generation antidepressant. Recently, esketamine nasal spray (intranasal (IN)&#xD;
        administration) was approved for patients with treatment-resistant MDD (TRD). A patient is&#xD;
        diagnosed with TRD when having used two antidepressants in sufficient duration and adequate&#xD;
        dose without sufficient effect. TRD is associated with a negative impact on quality of life,&#xD;
        higher risk for hospitalisations and suicide, comorbidities, poorer social and occupational&#xD;
        functioning and a high carer burden. The efficacy of intranasal use of esketamine has been&#xD;
        demonstrated in MDD subjects with treatment-resistant symptoms but also in subjects with&#xD;
        non-treatment resistant depression, and is approved by the FDA and EMA as a third-line&#xD;
        treatment. Besides the registered esketamine nasal spray, which is not available in all&#xD;
        countries to all patients because of the high costs, off-label utilization of (es)ketamine&#xD;
        infusions (IV) is growing extensively over time to treat TRD. Research conducted so far&#xD;
        indicates an unequivocal initial substantial response to (es)ketamine IV in MDD populations,&#xD;
        regardless of whether or not patients suffer from treatment resistant MDD. However, until&#xD;
        now, there has not been a study investigating this in a sufficiently large population. This&#xD;
        may be a unique opportunity to potentially prevent patients progressing into a treatment&#xD;
        resistant illness stage. The potential implications of the results of the current study are&#xD;
        the prevention of unnecessary trials of ineffective treatments, reducing subject burden&#xD;
        substantially, as well as a reduction of healthcare and societal costs.&#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 1) 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 2) 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 3,&#xD;
             Digit Symbol Substitution Test 4, Rey Auditory Verbal Learning Test 5 as well as the&#xD;
             Perceived Deficits Questionnaire 6 between the two treatment arms (EIPT/TAU) over the&#xD;
             six 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 7, LAPS 8,&#xD;
             QLS-100 9 and SDS 10 between the two treatment arms (EIPT/TAU) over the six week&#xD;
             treatment 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 four weeks.&#xD;
  &#xD;
        Trial population The aim is to recruit 418 subjects with major depressive disorder, without&#xD;
        psychotic features. Male and female subjects, in- and out-patients, within the age range of&#xD;
        18 to 70 years old are eligible for participation. The main exclusion criteria are defined to&#xD;
        protect the wellbeing of subjects, e.g. being pregnant or breastfeeding, subjects with&#xD;
        previous failure on (es)ketamine, meeting any contraindications, or participants with a known&#xD;
        intolerance to (es)ketamine.&#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. MDD sample Treatment as Usual&#xD;
        (TAU) Switch to second-line antidepressant Early-Intensified Pharmacological Treatment (EIPT)&#xD;
        Oral antidepressant plus esketamine nasal spray or esketamine IV or ketamine IV&#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 In the current study, clinical practice is mimicked as&#xD;
        much as possible to maximize generalizability and for feasibility purposes. To this end,&#xD;
        Summaries of Product Characteristics (SmPCs) are followed with regards to contraindications&#xD;
        (implemented as exclusion criterion), safety measures and allowed combinations with other&#xD;
        medications. Site visits and assessments are kept to a minimum to keep subject burden at an&#xD;
        acceptable level, while meeting the objectives of the study. Blood samples for biomarker&#xD;
        analyses are only collected when subjects provide consent; safety measures are performed as&#xD;
        part of clinical routine.&#xD;
  &#xD;
        Use of both EIPT and TAU medications implies that there is a risk of side effects. For TAU,&#xD;
        these side effects are well-known, and would be no different from regular clinical practice.&#xD;
        For EIPT, there are acute psychotropic effects of (es)ketamine which are considered side&#xD;
        effects for this study, such as anxiety, delusional thoughts, dissociation and hallucinations&#xD;
        (see IMPDs). In addition, increased blood pressure and heart rate, as well as dizziness and&#xD;
        nausea are reported. These acute effect are transient and after 2 hours completely&#xD;
        dissipated. Therefore, an observation period of 2 hours after every administration is&#xD;
        implemented to monitor this closely. The potential side effects of all treatments are&#xD;
        well-known and will be monitored during the study with a standardized side-effect scale&#xD;
        (GASE), spontaneous reporting and the local standard procedure regarding other measures such&#xD;
        as laboratory tests, physical examinations, ECGs. The results will be captured (as data) and&#xD;
        reviewed for tolerability. Most of the tests that will be done as part of standard clinical&#xD;
        care (lab tests, ECG, physical examination) for EIPT are also part of TAU.&#xD;
  &#xD;
        A benefit of the study is that while ensuring that the tolerability and additional burden&#xD;
        remains acceptable, the investigators expect that the larger effect in reducing symptom&#xD;
        severity will justify the increase in burden relative to the TAU group. When participants are&#xD;
        treated with the intense treatment in earlier stage of the illness (less trial and error&#xD;
        before moving on to this treatment option), this is expected to result in a reduced burden of&#xD;
        disease for subjects, expressed as less relapses, lower all-cause mortality, hospitalisations&#xD;
        and job losses and improved quality of life, in addition to lower societal and healthcare&#xD;
        costs as well as preventing patients from turning into a treatment-resistant treatment phase.&#xD;
        Last, an advantage of participation could be that subjects will be more thoroughly followed&#xD;
        and examined, and that therefore effects and side effects are measured and managed better.&#xD;
  &#xD;
        Rationale Schizophrenia (SZ) affects approximately 4.5 million people across the European&#xD;
        Union (EU) and is associated with annual healthcare and societal costs of 29 billion Euros.&#xD;
        The impact on the daily life of patients is huge, ranging from frequent relapses and&#xD;
        hospitalisations, the inability to maintain a job or continue schooling, to a low quality of&#xD;
        life, impaired cognitive functioning, suicidal ideation and an increase morbidity rate, next&#xD;
        to the large burden for carers. When diagnosed with schizophrenia or related disorder,&#xD;
        patients are commonly prescribed antipsychotics. One-third of the schizophrenia patients are&#xD;
        regarded treatment-resistant (TR), meaning that at least two antipsychotic trials have&#xD;
        failed. Typically, clozapine is prescribed for TR patients, which is effective for&#xD;
        approximately 40% of patients. Clozapine is among the most effective treatments, with the&#xD;
        lowest all-cause mortality. Although it is among the most effective antipsychotics, it is&#xD;
        generally not used earlier in the illness course due to a small risk of severe&#xD;
        neutropenia/agranulocytosis, which is why patients treated with clozapine are intensely&#xD;
        monitored. However, this small risk outweighs the burden of not receiving an effective&#xD;
        treatment.&#xD;
  &#xD;
        Since clozapine is among the most effective treatments, this leads to the research question&#xD;
        whether earlier initiation of third-line treatment ('early intensified' pharmacological&#xD;
        treatment; EIPT) would be more beneficial than the current second-line treatments (treatment&#xD;
        as usual; TAU). If this is indeed the case, this could lead to the prevention of unnecessary&#xD;
        trials of ineffective treatments, hospitalisations, and recommendations for adaptations of&#xD;
        worldwide guidelines as well as a reduction of healthcare and societal costs The&#xD;
        INTENSIFY-Schizophrenia trial is part of the larger Horizon 2021 project Psych-STRATA, with&#xD;
        the 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, the investigators&#xD;
        aim to establish evidence-based criteria to make decisions of early intense treatment in&#xD;
        individuals at risk for treatment resistance across the major psychiatric disorders of&#xD;
        schizophrenia, bipolar disorder and major depression. The current protocol focuses on the&#xD;
        sample of schizophrenia patients.&#xD;
  &#xD;
        Objective The primary objective is to compare the treatment response, expressed as mean&#xD;
        change in symptom severity as measured through the Positive And Negative Syndrome Scale&#xD;
        (PANSS) 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 for&#xD;
        schizophrenia, schizoaffective or schizophreniform disorder.&#xD;
  &#xD;
        Main trial endpoints Mean change in symptom severity total score from baseline (visit 2) to&#xD;
        end of treatment (visit 4) between the two treatment arms (EIPT vs. TAU). This is measured&#xD;
        using PANSS.&#xD;
  &#xD;
        Secondary trial objectives&#xD;
  &#xD;
        Comparison of the proportion of participants (EIPT vs. TAU) that is in symptomatic remission&#xD;
        at visit 4. Remission is defined as meeting the PANSS modified Andreasen criteria (Low scores&#xD;
        (≤3) P1. Delusions; P3. Hallucinatory behavior; P2. Conceptual disorganization; N1. Blunted&#xD;
        affect; N4. Passive/apathetic social withdrawal; N6. Lack of spontaneity and flow of&#xD;
        conversation; G5. Mannerisms/posturing; G9. Unusual thought content.&#xD;
  &#xD;
        To compare changes in PANSS subscale scores (positive, negative and general) between the two&#xD;
        treatment arms over the six-week treatment period (visit 2 versus visit 4).&#xD;
  &#xD;
        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 treatment&#xD;
        period (visit 2 versus visit 4).&#xD;
  &#xD;
        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 six&#xD;
        week treatment period (visit 2 versus visit 4).&#xD;
  &#xD;
        To compare changes in cognitive performance as measured through the Trail Making Test, Digit&#xD;
        Symbol Substitution Test, Rey Auditory Verbal Learning Test as well as the Perceived Deficits&#xD;
        Questionnaire between the two treatment arms (EIPT/TAU) over the six week treatment period&#xD;
        (visit 2 versus visit 4).&#xD;
  &#xD;
        To compare changes in quality of life and functioning measures (Q-LES-Q-SF, LAPS, QLS-100 and&#xD;
        SDS between the two treatment arms (EIPT/TAU) over the six week treatment period (visit 2&#xD;
        versus visit 4).&#xD;
  &#xD;
        To compare presence of side effects as measured through General Assessment of Side Effects&#xD;
        Scale (GASE) and reported spontaneously between the two treatment arms (EIPT/TAU) over the&#xD;
        six week treatment period (visit 2 versus visit 4).&#xD;
  &#xD;
        To compare use of concomitant medication between the two treatment arms (EIPT/TAU) over the&#xD;
        six week treatment period (visit 2 versus visit 4).&#xD;
  &#xD;
        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 schizophrenia, schizoaffective&#xD;
        disorder or schizophreniform disorder. Male and female subjects, in- and out-patients, within&#xD;
        the age range of 18 to 70 years old are eligible for participation. The main exclusion&#xD;
        criteria are defined to protect the wellbeing of subjects, e.g. being pregnant or&#xD;
        breastfeeding, subjects with previous failure on clozapine, meeting any contraindications, or&#xD;
        participants with a known intolerance to clozapine.&#xD;
  &#xD;
        Interventions Subjects are randomised to treatment as usual (second-line treatment) or to the&#xD;
        early-intensified pharmacological treatment (third-line treatment; clozapine).&#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 side effect profiles are well&#xD;
        established. In the current study, clinical practice is mimicked as much as possible to&#xD;
        maximize generalizability 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 prohibited comedications. Site visits and&#xD;
        assessments are kept to a minimum to keep subject burden at an acceptable level, while&#xD;
        meeting the objectives of the study. Blood samples for biomarker analyses are only collected&#xD;
        when subjects provide consent; safety measures are performed as part of clinical routine.&#xD;
  &#xD;
        Overall, the risks are similar to daily clinical practice; the only difference relative to&#xD;
        clinical practice is the application of early-intensified pharmacological treatment earlier&#xD;
        in the illness. Still, these intense treatment options are also commonly prescribed by&#xD;
        clinicians. There are no indications in existing literature or clinical practice that the&#xD;
        earlier introduction of these medications poses a safety risk when used in an earlier illness&#xD;
        phase than indicated in the SmPC.&#xD;
  &#xD;
        A benefit of the study is that if it indeed turns out that the clozapine is associated with&#xD;
        more symptom improvement compared to treatment as usual, future patients have to go through&#xD;
        less trial and error, which results in a reduced burden (higher quality of life, less&#xD;
        unemployment, less hospitalisations) for patients and carers as well as lower societal and&#xD;
        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). The&#xD;
        investigators have done this and created 3 new ClinicalTrials.gov studies as well, from which&#xD;
        this is one for major depressive disorder. Once the investigators have received the NCT&#xD;
        numbers for SZ and BD, they will add them here. The site in the UK (London) followed the&#xD;
        advice and will submit 3 separate protocols and are therefore included in the current record.&#xD;
        However, Israel already submitted this as one protocol. Therefore, the investigators keep the&#xD;
        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 3</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>4 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 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>4 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>4 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 four 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>4 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 four 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>4 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>4 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>4 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 four 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>4 weeks</time_frame>
      <description>To compare changes in cognitive performance as measured through the Perceived Deficits Questionnaire between the two treatment arms over the four 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>4 weeks</time_frame>
      <description>To compare changes in the functioning measure, Leuven Affective and Pleasure Scale, between the two treatment arms over the four 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>4 weeks</time_frame>
      <description>To compare changes in the functioning measure,Sheehan Disability Scale, between the two treatment arms over the four 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>4 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 of participants in quality of life measure, Quality of Life Scale -100, subscale inner tension</measure>
      <time_frame>4 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 occurrence of side effects between the two treatment arms.</measure>
      <time_frame>4 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 four 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>4 weeks</time_frame>
      <description>To compare use of concomitant medication between the two treatment arms (EIPT/TAU) over the four 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>4 weeks</time_frame>
      <description>To compare premature discontinuation between the two treatment arms (EIPT/TAU) over the four week treatment period (visit 2 versus visit 4).</description>
    </secondary_outcome>
    <number_of_arms>2</number_of_arms>
    <enrollment type="Anticipated">418</enrollment>
    <condition>Major Depressive Disorder</condition>
    <condition>Treatment Resistant Depression</condition>
    <arm_group>
      <arm_group_label>Major Depressive Disorder EIPT: second-line antidepressant + esketamine nasal spray</arm_group_label>
      <arm_group_type>Experimental</arm_group_type>
      <description>Major depressive disorder randomized to EIPT: Switch to second-line antidepressant + esketamine nasal spray or (es)ketamine infusion. Antidepressant: Compound, brand, dosage, frequency and duration up to the investigator's discretion (in accordance with SmPC).&#xD;
  Esketamine nasal spray: 2 times per week for 4 weeks. Initial dose 28 mg, after that increases can be made with 28 mg per increase (up to 84 mg per week). This decision is up to the investigator's discretion (in accordance with SmPC).&#xD;
  (Es)ketamine infusion: performed twice weekly for 4 weeks. Compound, brand up to the investigator's discretion (in accordance with SmPC).</description>
    </arm_group>
    <arm_group>
      <arm_group_label>Major Depressive Disorder TAU: second-line antidepressant</arm_group_label>
      <arm_group_type>Active Comparator</arm_group_type>
      <description>Subject with major depressive disorder, randomized to TAU: switch to second-line antidepressant. When randomized to second-line anti-depressants, this means participants will receive treatment as usual. The physician has the choice to administer any second-line anti-depressant. More specification is not possible, as this is a choice the physician makes with the participant based on the characteristic and preference of the participant (in line with standard clinical practice).</description>
    </arm_group>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>Esketamine Nasal Product</intervention_name>
      <description>See arm description</description>
      <arm_group_label>Major Depressive Disorder EIPT: second-line antidepressant + esketamine nasal spray</arm_group_label>
      <other_name>ATC code: N06AB10</other_name>
    </intervention>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>Ketamine Hydrochloride</intervention_name>
      <description>See arm description</description>
      <arm_group_label>Major Depressive Disorder EIPT: second-line antidepressant + esketamine nasal spray</arm_group_label>
      <other_name>N01AX03</other_name>
    </intervention>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>Esketamine hydrochloride</intervention_name>
      <description>See arm description</description>
      <arm_group_label>Major Depressive Disorder EIPT: second-line antidepressant + esketamine nasal spray</arm_group_label>
      <other_name>N015X14</other_name>
    </intervention>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>Second-line Antidepressants</intervention_name>
      <description>See arm description</description>
      <arm_group_label>Major Depressive Disorder TAU: second-line antidepressant</arm_group_label>
    </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 major depressive disorder&#xD;
               (without psychotic features), according to DSM-5. The primary diagnosis will be&#xD;
               confirmed by the Mini International Neuropsychiatric 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)&#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 (es)ketamine 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 (es)ketamine or to all TAU medication.&#xD;
  &#xD;
            4. Meeting any of the contraindications for (es)ketamine, or to all TAU medication&#xD;
               options, 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;
        </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>
    <keyword>Major Depressive Disorder</keyword>
    <keyword>Treatment as usual</keyword>
    <keyword>Early treatment-resistance</keyword>
    <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>Depressive Disorder, Major</mesh_term>
      <mesh_term>Depressive Disorder, Treatment-Resistant</mesh_term>
    </condition_browse>
    <intervention_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Ketamine</mesh_term>
      <mesh_term>Antidepressive Agents</mesh_term>
      <mesh_term>Esketamine</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/NCT05973851
  org study id: 2023-506617-21-00 (EU CT#)
  nct id: NCT05973851
  lead sponsor: 
  collaborator: 
  has dmc: Yes
  is fda regulated drug: No
  is fda regulated device: No
  Over 28 million people suffer from current depressive disorder in the European Union. Major
        depressive disorder (MDD) is one of the most common psychiatric illnesses. The symptoms cause
        clinically significant distress or impairment in social, occupational, and other important
        areas of functioning. To treat MDD, there are several antidepressants available and
        prescribing medication is a process of trial-and-error. Guidelines do not explicitly advise
        on the order in which antidepressant medication should be prescribed. The choice of
        antidepressant should be tailored to the patient, while involving the patient in the
        decision-making process. In general, the choice for the first- and second-line treatment will
        be a second-generation antidepressant. Recently, esketamine nasal spray (intranasal (IN)
        administration) was approved for patients with treatment-resistant MDD (TRD). A patient is
        diagnosed with TRD when having used two antidepressants in sufficient duration and adequate
        dose without sufficient effect. TRD is associated with a negative impact on quality of life,
        higher risk for hospitalisations and suicide, comorbidities, poorer social and occupational
        functioning and a high carer burden. The efficacy of intranasal use of esketamine has been
        demonstrated in MDD subjects with treatment-resistant symptoms but also in subjects with
        non-treatment resistant depression, and is approved by the FDA and EMA as a third-line
        treatment. Besides the registered esketamine nasal spray, which is not available in all
        countries to all patients because of the high costs, off-label utilization of (es)ketamine
        infusions (IV) is growing extensively over time to treat TRD. Research conducted so far
        indicates an unequivocal initial substantial response to (es)ketamine IV in MDD populations,
        regardless of whether or not patients suffer from treatment resistant MDD. However, until
        now, there has not been a study investigating this in a sufficiently large population. This
        may be a unique opportunity to potentially prevent patients progressing into a treatment
        resistant illness stage. The potential implications of the results of the current study are
        the prevention of unnecessary trials of ineffective treatments, reducing subject burden
        substantially, as well as a reduction of healthcare and societal costs.
  Rationale Over 28 million people suffer from current depressive disorder in the European
        Union. Major depressive disorder (MDD) is one of the most common psychiatric illnesses. The
        symptoms cause clinically significant distress or impairment in social, occupational, and
        other important areas of functioning. To treat MDD, there are several antidepressants
        available and prescribing medication is a process of trial-and-error. Guidelines do not
        explicitly advise on the order in which antidepressant medication should be prescribed. The
        choice of antidepressant should be tailored to the patient, while involving the patient in
        the decision-making process. In general, the choice for the first- and second-line treatment
        will be a second-generation antidepressant. Recently, esketamine nasal spray (intranasal (IN)
        administration) was approved for patients with treatment-resistant MDD (TRD). A patient is
        diagnosed with TRD when having used two antidepressants in sufficient duration and adequate
        dose without sufficient effect. TRD is associated with a negative impact on quality of life,
        higher risk for hospitalisations and suicide, comorbidities, poorer social and occupational
        functioning and a high carer burden. The efficacy of intranasal use of esketamine has been
        demonstrated in MDD subjects with treatment-resistant symptoms but also in subjects with
        non-treatment resistant depression, and is approved by the FDA and EMA as a third-line
        treatment. Besides the registered esketamine nasal spray, which is not available in all
        countries to all patients because of the high costs, off-label utilization of (es)ketamine
        infusions (IV) is growing extensively over time to treat TRD. Research conducted so far
        indicates an unequivocal initial substantial response to (es)ketamine IV in MDD populations,
        regardless of whether or not patients suffer from treatment resistant MDD. However, until
        now, there has not been a study investigating this in a sufficiently large population. This
        may be a unique opportunity to potentially prevent patients progressing into a treatment
        resistant illness stage. The potential implications of the results of the current study are
        the prevention of unnecessary trials of ineffective treatments, reducing subject burden
        substantially, as well as a reduction of healthcare and societal costs.
  
        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 1) 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 2) 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 3,
             Digit Symbol Substitution Test 4, Rey Auditory Verbal Learning Test 5 as well as the
             Perceived Deficits Questionnaire 6 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 7, LAPS 8,
             QLS-100 9 and SDS 10 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 four weeks.
  
        Trial population The aim is to recruit 418 subjects with major depressive disorder, without
        psychotic features. 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 (es)ketamine, meeting any contraindications, or participants with a known
        intolerance to (es)ketamine.
  
        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. MDD sample Treatment as Usual
        (TAU) Switch to second-line antidepressant Early-Intensified Pharmacological Treatment (EIPT)
        Oral antidepressant plus esketamine nasal spray or esketamine IV or ketamine IV
  
        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 In the current study, clinical practice is mimicked as
        much as possible to maximize generalizability 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.
  
        Use of both EIPT and TAU medications implies that there is a risk of side effects. For TAU,
        these side effects are well-known, and would be no different from regular clinical practice.
        For EIPT, there are acute psychotropic effects of (es)ketamine which are considered side
        effects for this study, such as anxiety, delusional thoughts, dissociation and hallucinations
        (see IMPDs). In addition, increased blood pressure and heart rate, as well as dizziness and
        nausea are reported. These acute effect are transient and after 2 hours completely
        dissipated. Therefore, an observation period of 2 hours after every administration is
        implemented to monitor this closely. The potential side effects of all treatments are
        well-known and will be monitored during the study with a standardized side-effect scale
        (GASE), spontaneous reporting and the local standard procedure regarding other measures such
        as laboratory tests, physical examinations, ECGs. The results will be captured (as data) and
        reviewed for tolerability. Most of the tests that will be done as part of standard clinical
        care (lab tests, ECG, physical examination) for EIPT are also part of TAU.
  
        A benefit of the study is that while ensuring that the tolerability and additional burden
        remains acceptable, the investigators expect that the larger effect in reducing symptom
        severity will justify the increase in burden relative to the TAU group. When participants are
        treated with the intense treatment in earlier stage of the illness (less trial and error
        before moving on to this treatment option), this is expected to result in a reduced burden of
        disease for subjects, expressed as less relapses, lower all-cause mortality, hospitalisations
        and job losses and improved quality of life, in addition to lower societal and healthcare
        costs as well as preventing patients from turning into a treatment-resistant treatment phase.
        Last, an advantage of participation could be that subjects will be more thoroughly followed
        and examined, and that therefore effects and side effects are measured and managed better.
  
        Rationale Schizophrenia (SZ) affects approximately 4.5 million people across the European
        Union (EU) and is associated with annual healthcare and societal costs of 29 billion Euros.
        The impact on the daily life of patients is huge, ranging from frequent relapses and
        hospitalisations, the inability to maintain a job or continue schooling, to a low quality of
        life, impaired cognitive functioning, suicidal ideation and an increase morbidity rate, next
        to the large burden for carers. When diagnosed with schizophrenia or related disorder,
        patients are commonly prescribed antipsychotics. One-third of the schizophrenia patients are
        regarded treatment-resistant (TR), meaning that at least two antipsychotic trials have
        failed. Typically, clozapine is prescribed for TR patients, which is effective for
        approximately 40% of patients. Clozapine is among the most effective treatments, with the
        lowest all-cause mortality. Although it is among the most effective antipsychotics, it is
        generally not used earlier in the illness course due to a small risk of severe
        neutropenia/agranulocytosis, which is why patients treated with clozapine are intensely
        monitored. However, this small risk outweighs the burden of not receiving an effective
        treatment.
  
        Since clozapine is among the most effective treatments, this leads to the research question
        whether earlier initiation of third-line treatment ('early intensified' pharmacological
        treatment; EIPT) would be more beneficial than the current second-line treatments (treatment
        as usual; TAU). If this is indeed the case, this could lead to the prevention of unnecessary
        trials of ineffective treatments, hospitalisations, and recommendations for adaptations of
        worldwide guidelines as well as a reduction of healthcare and societal costs The
        INTENSIFY-Schizophrenia trial is part of the larger Horizon 2021 project Psych-STRATA, 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, the investigators
        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. The current protocol focuses on the
        sample of schizophrenia patients.
  
        Objective The primary objective is to compare the treatment response, expressed as mean
        change in symptom severity as measured through the Positive And Negative Syndrome Scale
        (PANSS) 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 for
        schizophrenia, schizoaffective or schizophreniform disorder.
  
        Main trial endpoints Mean change in symptom severity total score from baseline (visit 2) to
        end of treatment (visit 4) between the two treatment arms (EIPT vs. TAU). This is measured
        using PANSS.
  
        Secondary trial objectives
  
        Comparison of the proportion of participants (EIPT vs. TAU) that is in symptomatic remission
        at visit 4. Remission is defined as meeting the PANSS modified Andreasen criteria (Low scores
        (≤3) P1. Delusions; P3. Hallucinatory behavior; P2. Conceptual disorganization; N1. Blunted
        affect; N4. Passive/apathetic social withdrawal; N6. Lack of spontaneity and flow of
        conversation; G5. Mannerisms/posturing; G9. Unusual thought content.
  
        To compare changes in PANSS subscale scores (positive, negative and general) between the two
        treatment arms over the six-week treatment period (visit 2 versus visit 4).
  
        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).
  
        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).
  
        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).
  
        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).
  
        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 schizophrenia, schizoaffective
        disorder or schizophreniform disorder. 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 clozapine, meeting any contraindications, or
        participants with a known intolerance to clozapine.
  
        Interventions Subjects are randomised to treatment as usual (second-line treatment) or to the
        early-intensified pharmacological treatment (third-line treatment; clozapine).
  
        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 side effect profiles are well
        established. In the current study, clinical practice is mimicked as much as possible to
        maximize generalizability 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 prohibited comedications. 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 early-intensified pharmacological treatment earlier
        in the illness. Still, these intense 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 clozapine 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). The
        investigators have done this and created 3 new ClinicalTrials.gov studies as well, from which
        this is one for major depressive disorder. Once the investigators have received the NCT
        numbers for SZ and BD, they 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, the investigators 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: 4 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 60. A bigger mean change means a better outcome
  measure: Compare proportion of participants that is in symptomatic remission
  time frame: 4 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: 4 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 four 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: 4 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 four 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: 4 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: 4 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: 4 weeks
  description: To compare changes in cognitive performance as measured through the Rey Auditory Verbal Learning Test between the two treatment arms over the four 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: 4 weeks
  description: To compare changes in cognitive performance as measured through the Perceived Deficits Questionnaire between the two treatment arms over the four 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: 4 weeks
  description: To compare changes in the functioning measure, Leuven Affective and Pleasure Scale, between the two treatment arms over the four 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: 4 weeks
  description: To compare changes in the functioning measure,Sheehan Disability Scale, between the two treatment arms over the four 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: 4 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 of participants in quality of life measure, Quality of Life Scale -100, subscale inner tension
  time frame: 4 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 occurrence of side effects between the two treatment arms.
  time frame: 4 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 four 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: 4 weeks
  description: To compare use of concomitant medication between the two treatment arms (EIPT/TAU) over the four 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: 4 weeks
  description: To compare premature discontinuation between the two treatment arms (EIPT/TAU) over the four week treatment period (visit 2 versus visit 4).
  arm group label: Major Depressive Disorder EIPT: second-line antidepressant + esketamine nasal spray
  arm group type: Experimental
  description: Major depressive disorder randomized to EIPT: Switch to second-line antidepressant + esketamine nasal spray or (es)ketamine infusion. Antidepressant: Compound, brand, dosage, frequency and duration up to the investigator's discretion (in accordance with SmPC).
  Esketamine nasal spray: 2 times per week for 4 weeks. Initial dose 28 mg, after that increases can be made with 28 mg per increase (up to 84 mg per week). This decision is up to the investigator's discretion (in accordance with SmPC).
  (Es)ketamine infusion: performed twice weekly for 4 weeks. Compound, brand up to the investigator's discretion (in accordance with SmPC).
  arm group label: Major Depressive Disorder TAU: second-line antidepressant
  arm group type: Active Comparator
  description: Subject with major depressive disorder, randomized to TAU: switch to second-line antidepressant. When randomized to second-line anti-depressants, this means participants will receive treatment as usual. The physician has the choice to administer any second-line anti-depressant. More specification is not possible, as this is a choice the physician makes with the participant based on the characteristic and preference of the participant (in line with standard clinical practice).
  intervention type: Drug
  intervention name: Esketamine Nasal Product
  description: See arm description
  arm group label: Major Depressive Disorder EIPT: second-line antidepressant + esketamine nasal spray
  other name: ATC code: N06AB10
  intervention type: Drug
  intervention name: Ketamine Hydrochloride
  description: See arm description
  arm group label: Major Depressive Disorder EIPT: second-line antidepressant + esketamine nasal spray
  other name: N01AX03
  intervention type: Drug
  intervention name: Esketamine hydrochloride
  description: See arm description
  arm group label: Major Depressive Disorder EIPT: second-line antidepressant + esketamine nasal spray
  other name: N015X14
  intervention type: Drug
  intervention name: Second-line Antidepressants
  description: See arm description
  arm group label: Major Depressive Disorder TAU: second-line antidepressant
  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
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  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: Depressive Disorder, Major
  mesh term: Depressive Disorder, Treatment-Resistant
  mesh term: Ketamine
  mesh term: Antidepressive Agents
  mesh term: Esketamine
  sharing ipd: Yes
  ipd info type: Study Protocol
  ipd info type: Clinical Study Report (CSR)