A Randomised, Controlled Trial to Investigate the Effect of an Intensified Pharmacological Treatment for Schizophrenia, Major Depressive Disorder and Bipolar Depression in Subjects Who Had a First-time Treatment Failure on Their First-line Treatment.
试验速览
- 阶段
- 3 期
- 状态
- 招募中
- 发起方
- 入组人数
- 1,254
- 试验地点
- 1
- 主要终点
- Change in symptom severity
研究概览
简要总结
Schizophrenia, bipolar and major depressive disorders collectively affect over 10 million people across the EU and are associated with annual healthcare and societal costs in excess of 100 billion Euros. When diagnosed with one of these disorders, patients are prescribed psychotropic medication such as antidepressants, mood stabilisers or antipsychotics. It is unknown whether this first-line treatment will be successful. After this first-line treatment fails, usually a second-line treatment is initiated, and when this is not successful either a third-line treatment is initiated. Third-line treatments are quite successful, especially when compared to second-line treatments. The research question is whether the third-line treatments (early-intensified treatments) when used earlier in the disease course for schizophrenia, bipolar and major depressive disorders. If this is indeed the case, this could lead to the prevention of unnecessary trials of ineffective treatments and adaptations of worldwide guidelines as well as a reduction of healthcare and societal costs.
详细描述
Rationale Schizophrenia (SZ), bipolar depression (BD) and major depressive disorders (MDD) collectively affect over 10 million people across the European Union (EU) and are associated with annual healthcare and societal costs in excess of 100 billion Euros. When diagnosed with one of these disorders, patients are prescribed psychotropic medication such as antidepressants, mood stabilisers and/or antipsychotics. The effectiveness of these treatments for individual patients cannot be predicted. After this first-line treatment fails, usually a second-line treatment is initiated; when this is not effective either, a third-line treatment is initiated. Third-line treatments are quite effective, for people not responding to the first two treatments lines. However, they are used late in the disease course and clear evidence from direct comparisons of treatment algorithms is lacking. The research question is whether the third-line treatments would be more efficacious than the current second-line treatments (treatment as usual) for schizophrenia, bipolar and major depressive disorders. Third-line treatment can then be regarded as 'early-intensified'. If this is indeed the case, this could lead to the prevention of unnecessary trials of ineffective treatments and recommendations for adaptations of worldwide guidelines as well as a reduction of healthcare and societal costs. 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 change in symptom severity as measured through the Positive And Negative Syndrome Scale (PANSS; SZ sample), and the Montgomery-Åsberg Depression Rating Scale (MADRS; MDD/BD samples) 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). For SZ, this is measured using PANSS. For MDD and BD, MADRS is applied.
Secondary trial endpoints
- All study samples: to compare changes in the severity and improvement sub-scores of the Clinical Global Impression Scale (CGI) between the two treatment arms over the six week treatment period (visit 2 versus visit 4).
- All study samples: 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 over the six week treatment period (visit 2 versus visit 4).
- All study samples: 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 over the six week treatment period (visit 2 versus visit 4).
- All study samples: to compare changes in quality of life and functioning measures (Q-LES-Q-SF, LAPS, QLS-100 and SDS between the two treatment arms over the six week treatment period (visit 2 versus visit 4).
- All study samples: to compare presence of side effects as measured through General Assessment of Side Effects Scale (GASE) and reported spontaneously between the two treatment arms over the six week treatment period (visit 2 versus visit 4).
- All study samples: to compare use of concomitant medication between the two treatment arms over the six week treatment period (visit 2 versus visit 4).
- All study samples: to compare premature discontinuation (timing and reason)between the two treatment arms over the six week treatment period (visit 2 versus visit 4).
- All study samples: comparison of the proportion of participants (EIPT vs. TAU) that is remission at visit 4. For SZ, 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. For MDD/BD, remission is defined as a MADRS score ≤ 12
- To compare changes in suicidal ideation between treatment arms.
- SZ sample: to compare changes in PANSS subscale scores between the two treatment arms over the six-week treatment period (visit 2 versus visit 4).
- BD study sample: To compare occurrence of (hypo)manic episode during the study between the treatment arms
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Single (Outcomes Assessor)
盲法说明
Open label, except for the assesseors of the primary outcome
入排标准
- 年龄范围
- 18 Years 至 70 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •1. In- or out patients, at least 18 years of age up until 70 (SZ study sample), 65 years (MDD study sample) and no limit for the BD study..
- •Being willing and able to provide written informed consent. Having a legal guardian to cosign is allowed. Informed consent will be signed at visit 1, before any study procedure.
- •3. Female subjects of child bearing potential must be willing to ensure that they use effective contraception during the trial and as per the requirements in the protocol (section 8.2.1).Male subjects that will use valproate acid during the trial must use effective contraceptive measures during the trial.
- •4. Meeting diagnostic criteria for a primary diagnosis of schizophrenia, schizoaffective disorder, schizophreniform disorder, major depressive disorder (without psychotic features) or bipolar depression (bipolar disorder type I and II currently in a depressive episode), according to DSM-
- •The primary diagnosis will be confirmed by the Mini International Neuropsychiatric Interview (MINI v7.0.2).
- •5. Subject experiences a treatment failure due to lack of efficacy in the current episode, as confirmed by a CGI-I ≥3; preferably this treatment is a first-line pharmacotherapeutic agent for the primary DSM-5 diagnosis, and was prescribed for at least 4 weeks within an effective dose range as specified in the Summary of Product Characteristics (SmPCs). However, other lines of treatment are accepted as well.
- •6. Subject and clinician intend to change pharmacotherapeutic treatment.
- •A minimum symptom severity threshold needs to be present (moderate level; see below) and subject needs to experience functional impairment.
- •The minimum symptom severity threshold for SZ subjects is at least 2 PANSS positive or negative items with a score of 4, or at least one PANSS positive or negative item with a score of
- •The minimum symptom severity threshold for MDD is a score of ≥ 20 on the Montgomery Åsberg Depression Rating Scale (MADRS)
- •The minimum symptom severity threshold for BD is a score of ≥20 on the Montgomery Åsberg Depression Rating Scale (MADRS)
- •For all study samples: Functional impairment is defined as a score of 5 or higher on any of the three scales of the Sheehan Disability Scale (SDS).
排除标准
- •Being pregnant or breastfeeding.
- •Subject has failed previously on the EIPT study medication (i.e. SZ: clozapine; MDD: esketamine intranasal/(es)ketamine IV) Treatment duration as ≥ 4 weeks within an efficacious dose range according to the SmPC.
- •Subject has a known intolerance to clozapine (SZ only), esketamine intranasal/ (es)ketamine IV (MDD only) or quetiapine (BD only) or to all medication options for a study sample (related to the TAU treatment arms) or all EIPT medications (BD study sample).
- •Meeting any of the contraindications of clozapine (SZ only), esketamine intranasal/ (es)ketamine IV (MDD only) or quetiapine (BD only), or to all medication options for a study sample (related to the TAU treatment arms), or all EIPT medications (BD study sample), as specified within the applicable SmPC.
- •Subject has participated in another clinical trial in which the subject received an experimental or investigational drug or agent within 30 days before visit
- •Subject experiences any other significant disease or disorder which, in the opinion of the investigator, may either put the subjects at risk because of participation in the trial, or may influence the result of the trial, or the subject's ability to participate in the trial.
- •7. Subjects with active suicidal ideation with some intent to act, without specific plan ("Yes" to question 4 of the Columbia-Suicide Severity Rating Scale (C-SSRS)) or active suicidal ideation with specific plan and intent ("Yes" to question 5 of the C-SSRS), followed by an assessment by the treating clinician who determines it is not safe for the subject to participate in the study
- •Subject meets criteria for current substance use disorder, as confirmed by the Mini International Neuropsychiatric Interview (MINI v7.0.2). Nicotine dependency is allowed, as well as mild and moderate alcohol and/or cannabis use disorder (as defined by MINI v7.0.2). Severe alcohol and/or cannabis use disorder are not allowed.
- •Subjects have not been committed to an institution by virtue of an order issued either by the judicial or the administrative authorities.
- •Subjects dependent on the sponsor, investigator or trial site must be excluded from participation in advance.
- •For the SZ sample only: schizophrenia subjects cannot meet the modified Andreasen criteria for remission.
- •For the SZ sample only: Subjects that have any clinically significant abnormal values on the local laboratory test (especially ANC/WBC and liver values), electrocardiogram (ECG) or physician examinations.
- •For the BD sample only: a score of 12 or higher on the Young Mania Rating Scale (YMRS) in order to exclude subjects with predominant manic symptoms or mixed symptoms.
- •For the BD study sample only: Subjects with a history of antidepressant-induced mania or hypomania or recent rapid cycling (based on the medical file of the potential participant or the clinical judgment of the clinician).
- •For the BD study sample only: Subjects with pre-existing severe liver damage (as tested within the local laboratory test at visit 1).
研究组 & 干预措施
Schizophrenia EIPT: Switch to clozapine
Schizophrenia randomized to EIPT: Switch to clozapine. Brand, dosage, frequency and duration up to the investigator's discretion
干预措施: Clozapine (Drug)
Schizophrenia TAU: second-line antispychotic
Schizophrenia randomized to TAU: switch to second-line antispychotic. Compound, brand, dosage, frequency and duration up to the investigator's discretion (in accordance with SmPC)
干预措施: Second-line Antipsychotics (Drug)
Major Depressive Disorder EIPT: second-line antidepressant + esketamine nasal spray
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).
干预措施: Esketamine Nasal Product (Drug)
Major Depressive Disorder EIPT: second-line antidepressant + esketamine nasal spray
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).
干预措施: Second-line Antidepressants (Drug)
Major Depressive Disorder EIPT: second-line antidepressant + esketamine nasal spray
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).
干预措施: Ketamine Hydrochloride (Drug)
Major Depressive Disorder EIPT: second-line antidepressant + esketamine nasal spray
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).
干预措施: Esketamine hydrochloride (Drug)
Major Depressive Disorder TAU: second-line antidepressant
Major depressive disorder randomized to TAU: Switch to second-line antidepressant + esketamine nasal spray or ketamine IV or esketamine IV . Antidepressant: Compound, brand, dosage, frequency and duration up to the investigator's discretion (in accordance with SmPC).
干预措施: Second-line Antidepressants (Drug)
Bipolar Depression EIPT: Switch to one of the following combinations:
Bipolar Depression randomized to EIPT: Switch to 1. one of the following: escitalopram, sertraline, bupropion or venlafaxine plus 2. two of the following: lithium, valproate acid or quetiapine
干预措施: Escitalopram (Drug)
Bipolar Depression EIPT: Switch to one of the following combinations:
Bipolar Depression randomized to EIPT: Switch to 1. one of the following: escitalopram, sertraline, bupropion or venlafaxine plus 2. two of the following: lithium, valproate acid or quetiapine
干预措施: Sertraline (Drug)
Bipolar Depression EIPT: Switch to one of the following combinations:
Bipolar Depression randomized to EIPT: Switch to 1. one of the following: escitalopram, sertraline, bupropion or venlafaxine plus 2. two of the following: lithium, valproate acid or quetiapine
干预措施: Venlafaxine (Drug)
Bipolar Depression EIPT: Switch to one of the following combinations:
Bipolar Depression randomized to EIPT: Switch to 1. one of the following: escitalopram, sertraline, bupropion or venlafaxine plus 2. two of the following: lithium, valproate acid or quetiapine
干预措施: Lithium (Drug)
Bipolar Depression EIPT: Switch to one of the following combinations:
Bipolar Depression randomized to EIPT: Switch to 1. one of the following: escitalopram, sertraline, bupropion or venlafaxine plus 2. two of the following: lithium, valproate acid or quetiapine
干预措施: Valproate acid (Drug)
Bipolar Depression EIPT: Switch to one of the following combinations:
Bipolar Depression randomized to EIPT: Switch to 1. one of the following: escitalopram, sertraline, bupropion or venlafaxine plus 2. two of the following: lithium, valproate acid or quetiapine
干预措施: Quetiapine (Drug)
Bipolar Depression EIPT: Switch to one of the following combinations:
Bipolar Depression randomized to EIPT: Switch to 1. one of the following: escitalopram, sertraline, bupropion or venlafaxine plus 2. two of the following: lithium, valproate acid or quetiapine
干预措施: Bupropion (Drug)
Bipolar Depression TAU: Switch to quetiapine plus lithium or valproate acid or lamotrigine
Bipolar Depression randomized to TAU: Switch to quetiapine plus lithium or valproate acid Compound, brand, dosage, frequency and duration up to the investigator's discretion (in accordance with SmPC).
干预措施: Lithium (Drug)
Bipolar Depression TAU: Switch to quetiapine plus lithium or valproate acid or lamotrigine
Bipolar Depression randomized to TAU: Switch to quetiapine plus lithium or valproate acid Compound, brand, dosage, frequency and duration up to the investigator's discretion (in accordance with SmPC).
干预措施: Valproate acid (Drug)
Bipolar Depression TAU: Switch to quetiapine plus lithium or valproate acid or lamotrigine
Bipolar Depression randomized to TAU: Switch to quetiapine plus lithium or valproate acid Compound, brand, dosage, frequency and duration up to the investigator's discretion (in accordance with SmPC).
干预措施: Quetiapine (Drug)
结局指标
主要结局
Change in symptom severity
时间窗: 6 weeks
Change in symptom severity total score from baseline (visit 2) to end of treatment (visit 4). For Schizophrenia, this is measured using the Positive And Negative Syndrome Scale. For Major Depressive Disorder and Bipolar Depression, Montgomery Åsberg Depression Rating Scale is applied.
次要结局
- All study samples: to compare changes in the severity and improvement(6 weeks)
- All study samples: to compare changes in the levels of depression and anxiety(6 weeks)
- All study samples: to compare changes in cognitive performance #1(6 weeks)
- All study samples: to compare changes in cognitive performance #2(6 weeks)
- All study samples: to compare changes in cognitive performance #3(6 weeks)
- All study samples: to compare changes in cognitive performance #4(6 weeks)
- All study samples: to compare changes in functioning measure #1(6 weeks)
- All study samples: to compare changes in functioning measure #2(6 weeks)
- All study samples: to compare changes in quality of life #1(6 weeks)
- All study samples: to compare changes in quality of life #2(6 weeks)
- All study samples: to compare presence of side effects(6 weeks)
- All study samples: to compare use of concomitant medication(6 weeks)
- All study samples: to compare premature treatment discontinuation(6 weeks)
- Schizophrenia sample: to compare changes in Positive and Negative syndrome subscale scores(6 weeks)
- All study samples: comparison of the proportion of participants (EIPT vs. TAU) that is remission at visit 4.(6 weeks)
- All study samples: To compare changes in suicidal ideation between treatment arms.(6 weeks)
- BD study sample: To compare occurrence of (hypo)manic episode during the study between the treatment arms using the Young Mania Rating Scale(6 weeks.)
研究者
Dr. Inge Winter
Workpackage leader
UMC Utrecht