A Randomised, Controlled Trial to Investigate the Effect of a Six Week Intensified Pharmacological Treatment for Schizophrenia Compared to Treatment as Usual in Subjects Who Had a First-time Treatment Failure on Their First-line Treatment.
试验速览
- 阶段
- 4 期
- 状态
- 招募中
- 发起方
- 入组人数
- 418
- 试验地点
- 13
- 主要终点
- Change in symptom severity on Positive and Negative Syndrome Scale
研究概览
简要总结
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 scholing, to a low quality of life, impaired cognitive functioning, suicidal ideation and an increase morbidity rate, next to the large burden for carers 1. 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 inestigators 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.
详细描述
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 scholing, 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
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 assessors 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
- •In- or out patients, at least 18 years of age up until
- •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.
- •Female subjects of child bearing potential must use effective contraception during the trial as per the requirements of the applicable SmPCs and should have a negative pregnancy test at visit 1 or 2 (before randomisation; section 8.2).
- •Meeting diagnostic criteria for a primary diagnosis of schizophrenia, schizoaffective disorder, or schizophreniform disorder, according to DSM-
- •The primary diagnosis will be confirmed by the Mini International Neuropsychiatric Interview (MINI v7.0.2).
- •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.
- •Subject and clinician intend to change pharmacotherapeutic treatment.
- •A minimum symptom severity threshold needs to be present (moderate level; see below) and subject needs to experience functional impairment.
- •The minimum symptom severity threshold is 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
- •Functional impairment is defined as a score of 5 or higher on any of the three scales of the Sheehan Disability Scale (SDS).
- •Exclusion criteria:
- •Being pregnant or breastfeeding.
- •Subject has used clozapine in the past.
- •Subject has a known intolerance to clozapine or to all TAU medication options.
- •Meeting any of the contraindications of clozapine or to all TAU medication options, as specified within the applicable SmPC.
- •Subject has participated in another clinical trial in which the subject received an experimental or investigational drug or agent within 30 days before visit
- •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.
- •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 who meet the modified Andreasen criteria for remission.
- •Subjects that have any clinically significant abnormal values on the local laboratory test (especially ANC/WBC and liver values), electrocardiogram (ECG) or physician examinations.
- •Subjects dependent on the sponsor, investigator or trial site must be excluded from participation in advance
排除标准
- 未提供
研究组 & 干预措施
Schizophrenia early intensified treatment (EIPT): Switch to clozapine
Subject with 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 treatment as usual (TAU): second-line antispychotic
Subject with schizophrenia or related disorder 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 (treatment as usual) (Drug)
结局指标
主要结局
Change in symptom severity on Positive and Negative Syndrome Scale
时间窗: 6 weeks
Change in symptom severity (EIPT vs. TAU) total score from baseline (visit 2) to end of treatment (visit 4). This is measured using the Positive And Negative Syndrome Scale. Minimum score is 30, maimum score 210. A bigger mean change means a better outcome.
次要结局
- Compare symptomatic remission.(6 weeks)
- To compare changes in PANSS subscale scores (positive, negative and general) between the two treatment arms.(6 weeks)
- Compare changes in the levels of depression and anxiety(6 weeks)
- To compare changes in cognitive performance as measured through the Trail Making Test(6 weeks)
- To compare changes cognitive performance as measured through the Digit Symbol Substitution Test(6 weeks)
- To compare changes in cognitive performance as measured through the Rey Auditory Verbal Learning Test(6 weeks)
- To compare changes in subjective cognitive performance as measured through the Perceived Deficits Questionnaire(6 weeks)
- To compare changes in functioning on the Leuven Afective and Pleasure Scale(6 weeks)
- To compare changes in functioning on the Sheehan Disability Scale(6 weeks)
- To compare changes in quality of life measure, Quality of Life Enjoyment and Satisfaction Questionnaire Short Form(6 weeks)
- To compare changes in quality of life measure, Quality of Life Scale -100, subscale inner tension(6 weeks)
- To compare presence of adverse events (related and unrelated to treatment) between treatment arms.(6 weeks)
- To compare the use of concomitant medication between the two treatment arms.(6 weeks)
- To compare the difference in number of participants (EIPT vs. TAU) that prematurely discontinuate the study treatment.(6 weeks)
- To compare mean changes in symptom severity on the Clinical Global Impression Scale, Severity(6 weeks.)
- To compare mean changes in symptom severity on the Clinical Global Impression Scale, Improvement(6 weeks.)
- To compare the reasons for premature treatment discontinuation (EIPT vs. TAU) (stopping before visit 4 while started medication at visit 2(6 weeks.)
- To compare changes in suicidal ideation between treatment arms.(6 weeks.)
研究者
Dr. Inge Winter
Principal Investigator
UMC Utrecht