A Randomised, Controlled Trial to Investigate the Effect of a Sixweek 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.
试验速览
- 阶段
- 3 期
- 状态
- 招募中
- 发起方
- 入组人数
- 418
- 试验地点
- 12
- 主要终点
- Comparing the change in symptom severity on Montgomery Asberg Depression Rating Scale
研究概览
简要总结
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.
详细描述
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 (baseline; visit 2 vs. end of treatment; visit 4), expressed as symptom severity at six weeks and changes in symptom severity from baseline, 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 of first-line treatment during the current episode of MDD.
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
- To compare changes in severity and improvement in global functioning assessed by the Clinical Global Impression Scale (CGI) between the two treatment arms.
- To compare changes in the levels of depression and anxiety between treatment arms.
- To compare changes in quality of life and functioning measures between treatment arms.
- To compare changes in cognitive performance between treatment arms.
- To compare the proportion of participants (EIPT vs. TAU) that is in symptomatic remission at visit 4.
- To compare presence of side effects between treatment arms.
- To compare use of concomitant medication between treatment arms.
- To compare premature discontinuation (timing and reason) between treatment arms.
- To compare changes in suicidal ideation between 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 assessors of the primary outcome
入排标准
- 年龄范围
- 18 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •In- or outpatients, 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).
- •Meeting diagnostic criteria for a primary diagnosis of major depressive disorder (without psychotic features), 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; perferably, 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).
- •Subject and clinician intend to change pharmacotherapeutic treatment. However, other lines of treatment are allowed as well.
- •A minimum symptom severity threshold needs to be present (moderate level; see below) and subject needs to experience functional impairment.
- •The minimum symptom severity threshold is a score of ≥20 on the Montgomery Åsberg Depression Rating Scale (MADRS)
- •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 (es)ketamine previously for the treatment of depressive symptoms.
- •Subject has a known intolerance to (es)ketamine or to all TAU medication.
- •Meeting any of the contraindications for (es)ketamine, or to all TAU medication options, as specified within the applicable SmPC, supported by clinically significant abnormal values on local laboratory tests, electrocardiogram (ECG) or physical examinations.
- •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 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
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: 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
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).
干预措施: Second-line Antidepressants (Drug)
结局指标
主要结局
Comparing the change in symptom severity on Montgomery Asberg Depression Rating 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 Montgomery Asberg Depression Rating Scale. Minimum score is 0, maximum score 60. A bigger mean change means a better outcome
次要结局
- Compare proportion of participants that is in symptomatic remission(6 weeks)
- Compare the change in the severity and improvement CGI-S sub-scores(6 weeks)
- Compare the change in the severity and improvement CGI-I sub-scores(6 weeks)
- Compare the 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 the changes in cognitive performance as measured through the Rey Auditory Verbal Learning Test(6 weeks)
- To compare the changes in subjective cognitive performance as measured through the Perceived Deficits Questionnaire(6 weeks)
- To compare the changes in functioning on the Leuven Affective and Pleasure Scale(6 weeks)
- To compare the changes in functioning on the Sheehan Disability Scale(6 weeks)
- To compare the changes in quality of life measure, Quality of Life Enjoyment and Satisfaction Questionnaire Short Form(6 weeks)
- To compare the changes of participants in quality of life measure, Quality of Life Scale -100, subscale inner tension(6 weeks)
- To compare the frequency of occurrence of side effects between the two treatment arms.(6 weeks)
- To compare the proportion of participants using concomitant medication between the two treatment arms.(6 weeks)
- To compare the proportion of participants who prematurely discontinue between the two treatment arms.(6 weeks)
- To compare the reason of participants that prematurely treatment discontinue the study between the two treatment arms.(6 weeks)
- To compare changes in suicidal ideation between treatment arms.(6 weeks.)
研究者
Dr. Inge Winter
Principal Investigator
UMC Utrecht