Esketamine Versus Crisis Response Planning Versus Enhanced Treatment as Usual for Suicide Prevention: A Pragmatic Randomized Trial in a Brazilian Municipality (SAVE)
试验速览
- 阶段
- 4 期
- 状态
- 招募中
- 入组人数
- 478
- 试验地点
- 3
- 主要终点
- Time to first event
研究概览
简要总结
The SAVE study will test whether a single esketamine infusion or a single Crisis Response Planning session, each added to enhanced treatment as usual, reduces future suicide-related events compared with enhanced treatment as usual alone. The study takes place in the public emergency care network of Indaiatuba, São Paulo, Brazil, and includes adolescents and adults aged 14 years or older who have attempted suicide within the previous 30 days or currently have severe suicidal thoughts with intent to act.
The main questions are whether either intervention reduces suicide-related events over 12 months and whether the interventions improve suicidal thoughts, depression, anxiety, sleep, well-being, hopelessness, and quality of life. Researchers will also evaluate acceptability, feasibility, use of health services, and costs.
Anticipated total enrollment is 478 participants: 10 participants in a separate pilot cohort and 468 in the main cohort used to test the study hypotheses. The main cohort will be assigned by chance, in equal numbers of 156 participants, to one of three groups:
- Esketamine plus enhanced treatment as usual: one intravenous infusion of esketamine at 0.375 mg/kg over 40 minutes, with medical supervision and monitoring of heart rhythm, blood pressure, and oxygen levels. Participants remain under clinical observation, with discharge after 24 hours if clinically stable.
- Crisis Response Planning plus enhanced treatment as usual: one 20-to-45-minute session with a trained clinician to develop a personalized plan covering warning signs, coping strategies, reasons for living, support contacts, and emergency resources. Participants receive a printed plan and a digital copy.
- Enhanced treatment as usual alone: early outpatient psychiatric consultation, arranged to take place within seven days of randomization, plus lethal means safety counseling to reduce access to potentially lethal means. Both components are offered to participants in all three groups, alongside routine emergency care. The study records whether each component was delivered; booking a consultation alone does not count as receiving it.
Participants will complete assessments at enrollment, 24 hours, seven days, and weeks 2, 4, 8, 16, 24, 32, 40, and 52. Blood samples will be collected at enrollment for exploratory analyses of biological factors that may be associated with treatment response. Safety monitoring and contact to identify new events will continue throughout follow-up.
Participants will also use a smartphone application to answer brief questions about their mood, thoughts, and experiences during three periods of 30 consecutive days, beginning at enrollment and at calendar months 4 and 8. There will be three prompts each day: two at fixed times, 09:00 and 21:00, and one at a randomly selected time between 10:00 and 20:00, using local time in Indaiatuba. This represents 90 assessment days and 270 scheduled prompts over the study. The study team will contact participants within 24 hours of a safety alert through a dedicated study mobile phone with WhatsApp. Participants will be instructed to seek emergency care immediately when needed rather than wait for a study response.
The main outcome is the time to the first qualifying event: a suicide attempt, including an attempt stopped by the person or interrupted by someone else; a psychiatric admission to prevent suicide; death by suicide; or self-injury requiring emergency department care. An external adjudicator who does not know the assigned treatment will review suspected events and determine whether they meet the study definition. Outcome assessors will also be unaware of treatment allocation.
Participants who experience a qualifying event may be offered rescue treatment combining esketamine and Crisis Response Planning, depending on clinical eligibility and safety. They will remain in follow-up and in analyses according to their original randomized group. The first qualifying event will still count in the main analysis. Pilot data will be described separately and will not be included in confirmatory efficacy analyses.
详细描述
STUDY DESIGN AND OBJECTIVES:
SAVE is a single-municipality, pragmatic, three-arm, parallel-group, superiority randomized controlled trial with 1:1:1 allocation and a Hybrid Type 1 effectiveness-implementation approach. It compares a single intravenous esketamine infusion plus enhanced treatment as usual (eTAU), a single Crisis Response Planning (CRP) session plus eTAU, and eTAU alone.
The primary objective is to determine whether either active intervention reduces the hazard of a first suicide-related event during 12 months of follow-up compared with eTAU alone. The comparison between CRP and esketamine is exploratory. Secondary objectives concern suicidal ideation, associated symptoms, well-being, quality of life, service use, implementation, and costs. The pragmatic design integrates study procedures into municipal emergency care while retaining standardized eligibility, outcome assessment, and safety procedures. An independent Data and Safety Monitoring Board (DSMB) oversees safety.
PILOT COHORT AND CONFIRMATORY COHORT:
Recruitment began in June 2026. Following a temporary suspension for an internal data-quality and process audit, recruitment has resumed and the study is currently recruiting. The first 10 randomized participants constitute a pilot cohort enrolled before the current protocol procedures. The updated protocol has institutional ethics approval under CAAE 89878225.0.0000.0068 and specifies the revised substance-related eligibility criteria, visit windows, esketamine dose, EMA schedule, safety contact procedures, and external blinded endpoint adjudication.
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
Participants and treating clinicians are unblinded. Outcome assessors, an external endpoint adjudicator, and confirmatory data analysts are blinded to allocation. All T1 assessments are conducted by telephone or video by a centralized blinded assessor in every arm, including participants still in the clinical unit. T1 assessors have no access to participants' location, clinical records, or treating team during assessment. The external adjudicator reviews suspected endpoint events using source dossiers with treatment-identifying information removed and determines whether each event meets the endpoint definition, its component, and its date. Clinical care and safety reporting do not wait for adjudication. Analysts receive coded treatment groups until confirmatory analyses are finalized. Accidental disclosures and any emergency unblinding are documented.
入排标准
- 年龄范围
- 14 Years 至 —（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Participants must meet all of the following criteria:
- •Age 14 years or older.
- •Presentation to a participating public emergency service (ED/UEU) in Indaiatuba, São Paulo, Brazil.
- •Either of the following:
- •A suicide attempt within the previous 30 days, including an actual, interrupted, or aborted attempt; OR
- •Current severe suicidal ideation, defined as endorsement of item 4 or 5 of the Columbia-Suicide Severity Rating Scale (C-SSRS) screening version: active suicidal ideation with intent to act, without a specific plan (item 4), or with a specific plan (item 5).
- •Non-suicidal self-injury alone does not satisfy this criterion.
- •Residence within the study catchment area in Indaiatuba, enabling completion of follow-up assessments.
- •Ability to provide written informed consent for participants aged 18 years or older, or written assent with written informed consent from a parent or legal guardian for participants aged 14-17 years.
- •No clinical decision for voluntary or involuntary admission to a psychiatric inpatient unit following the index emergency evaluation.
排除标准
- •Participants meeting any of the following criteria are excluded:
- •A contraindication to esketamine, including aneurysmal vascular disease, arteriovenous malformation, a history of intracerebral hemorrhage, or known hypersensitivity to esketamine or ketamine.
- •Current pregnancy or breastfeeding. Pregnancy testing is performed in the emergency setting for participants with pregnancy potential; breastfeeding status is established by clinical history.
- •Medical instability requiring intensive care unit admission without feasible study follow-up.
- •A primary psychotic disorder, such as schizophrenia or schizoaffective disorder; or current acute psychosis or an acute manic episode that precludes informed participation.
- •Any of the following substance-related conditions:
- •Acute intoxication at assessment that precludes valid informed consent, reliable administration of the C-SSRS, or safe delivery of the assigned intervention, as determined by the attending physician. Re-screening is permitted after clinical recovery if all other eligibility criteria remain satisfied. For participants qualifying on the basis of a recent suicide attempt, that attempt must still fall within the preceding 30 days.
- •High-risk hallucinogen involvement, defined as a WHO ASSIST substance-specific involvement score of 27 or higher for the hallucinogen category, item (h).
- •A documented history of ketamine use disorder identified during baseline psychiatric assessment.
- •Inability to maintain contact for follow-up assessments.
- •Substance-use assessment:
- •The Brazilian Portuguese WHO ASSIST is administered during baseline eligibility assessment. Substance-specific involvement scores are calculated from questions 2 through 7, with question 5 omitted for tobacco. Questions 1 and 8 do not contribute to these scores. High risk is defined as a score of 27 or higher.
- •The ASSIST hallucinogen category does not identify ketamine exposure specifically; relevant substance history is also assessed clinically. Except for the high-risk hallucinogen criterion above, ASSIST scores do not automatically exclude participation. Among eligible participants, high-risk involvement with alcohol or other non-tobacco substances is recorded for exploratory moderation analyses and to inform clinical care.
研究组 & 干预措施
Esketamine plus Enhanced Treatment as Usual (eTAU)
Participants receive a single intravenous esketamine infusion of 0.375 mg/kg over 40 minutes, together with enhanced treatment as usual (eTAU). eTAU comprises early outpatient psychiatric consultation within 7 days of randomization and lethal means safety counseling during the index emergency attendance, alongside routine emergency care. The outpatient consultation is arranged through CAPS or CEEM. Delivery of both eTAU components is documented separately, including completion dates and reasons for non-completion.
干预措施: Enhanced Treatment as Usual (eTAU) (Other)
Crisis Response Planning plus Enhanced Treatment as Usual (eTAU)
Participants receive a single 20-to-45-minute Crisis Response Planning (CRP) session with a trained clinician, together with enhanced treatment as usual (eTAU). eTAU comprises early outpatient psychiatric consultation within 7 days of randomization and lethal means safety counseling during the index emergency attendance, alongside routine emergency care. The outpatient consultation is arranged through CAPS or CEEM. Delivery of both eTAU components is documented separately, including completion dates and reasons for non-completion.
干预措施: Crisis Response Planning (CRP) (Other)
Esketamine plus Enhanced Treatment as Usual (eTAU)
Participants receive a single intravenous esketamine infusion of 0.375 mg/kg over 40 minutes, together with enhanced treatment as usual (eTAU). eTAU comprises early outpatient psychiatric consultation within 7 days of randomization and lethal means safety counseling during the index emergency attendance, alongside routine emergency care. The outpatient consultation is arranged through CAPS or CEEM. Delivery of both eTAU components is documented separately, including completion dates and reasons for non-completion.
干预措施: Intravenous Esketamine (Drug)
Crisis Response Planning plus Enhanced Treatment as Usual (eTAU)
Participants receive a single 20-to-45-minute Crisis Response Planning (CRP) session with a trained clinician, together with enhanced treatment as usual (eTAU). eTAU comprises early outpatient psychiatric consultation within 7 days of randomization and lethal means safety counseling during the index emergency attendance, alongside routine emergency care. The outpatient consultation is arranged through CAPS or CEEM. Delivery of both eTAU components is documented separately, including completion dates and reasons for non-completion.
干预措施: Enhanced Treatment as Usual (eTAU) (Other)
Enhanced Treatment as Usual (eTAU) Alone
Participants receive enhanced treatment as usual (eTAU) alone as their randomized intervention. eTAU comprises early outpatient psychiatric consultation within 7 days of randomization and lethal means safety counseling during the index emergency attendance, alongside routine emergency care. The outpatient consultation is arranged through CAPS or CEEM. Delivery of both components is documented separately, including completion dates and reasons for non-completion. Consultation attendance is verified at the Day 7 assessment (T2) and through municipal service records; appointment booking alone is not counted as consultation delivery.
干预措施: Enhanced Treatment as Usual (eTAU) (Other)
结局指标
主要结局
Time to first event
时间窗: One year from baseline enrollment
Time from randomization to the first occurrence of a composite suicide-related event, defined as any suicide attempt (actual, interrupted, or aborted) assessed via the Columbia-Suicide Severity Rating Scale (C-SSRS), suicide-preventive psychiatric admission, suicide death, or self-injury requiring emergency department care. Events are ascertained through structured C-SSRS interviews at each follow-up visit, medical record linkage, and routine clinical surveillance. Analysis uses Cox proportional-hazards models with Holm-Bonferroni family-wise error control for two co-primary comparisons (esketamine + eTAU vs. eTAU; CRP + eTAU vs. eTAU).
Repeated Suicide-Related Events at One Year
时间窗: One year from baseline enrollment
Composite outcome including repeated suicide attempts (actual, interrupted, aborted), hospitalizations for suicide prevention, deaths by suicide, and non-suicidal self-harm requiring medical attention in emergency settings. Based on validated definitions from the Columbia-Suicide Severity Rating Scale and previous suicide prevention studies. Events assessed through medical records review, participant self-report, and contact with emergency services in both study municipalities.
Time to first event
时间窗: One year from randomization
Time from randomization to the first suicide-related event: an actual, interrupted, or aborted suicide attempt; suicide-preventive psychiatric admission; suicide death; or self-injury requiring emergency department care. Events are identified through structured C-SSRS interviews, medical record linkage, and routine clinical surveillance. An external adjudicator blinded to treatment allocation reviews treatment-redacted source documentation to confirm whether each event meets the endpoint definition, its component and date, and whether multiple reports refer to the same episode. Suicidal intent and event components are recorded separately. The confirmatory analysis uses Cox proportional-hazards models, with Holm family-wise error control for esketamine plus eTAU versus eTAU and CRP plus eTAU versus eTAU. The 10 pilot participants are excluded from confirmatory efficacy analyses and reported descriptively.
次要结局
- Total Suicide-Related Events (Count)(12 months from randomization)
- Suicidal Ideation Severity (Beck Scale for Suicide Ideation)(Baseline, 24 hours, 7 days, 2 weeks, 4 weeks, 8 weeks, 16 weeks, 24 weeks, 32 weeks, 40 weeks, and 1 year)
- Suicidal Ideation and Behavior (Columbia-Suicide Severity Rating Scale)(Baseline, 7 days, 2 weeks, 4 weeks, 8 weeks, 16 weeks, 24 weeks, 32 weeks, 40 weeks, and 1 year)
- Depressive Symptoms - Self-Reported (Patient Health Questionnaire-9)(Baseline, 7 days, 2 weeks, 4 weeks, 8 weeks, 16 weeks, 24 weeks, 32 weeks, 40 weeks, and 1 year)
- Depression Severity - Clinician-Rated (Montgomery-Åsberg Depression Rating Scale)(Baseline, 24 hours, 7 days, 2 weeks, 4 weeks, 8 weeks, 16 weeks, 24 weeks, 32 weeks, 40 weeks, and 1 year)
- Anxiety Symptoms (Generalized Anxiety Disorder-7)(Baseline, 2 weeks, 4 weeks, 8 weeks, 16 weeks, 24 weeks, 40 weeks, and 1 year)
- Anhedonia (Snaith-Hamilton Pleasure Scale - Brazilian Version)(Baseline, 4 weeks, 32 weeks, and 1 year)
- Sleep Quality (Pittsburgh Sleep Quality Index - Abbreviated Version)(Baseline, 4 weeks, 16 weeks, 40 weeks, and 1 year)
- Mental Well-Being (Short Warwick-Edinburgh Mental Well-Being Scale)(Baseline, 4 weeks, 16 weeks, 32 weeks, and 1 year)
- Hopelessness (Beck Hopelessness Scale - 7-Item Version)(Baseline, 4 weeks, 32 weeks, and 1 year)
- Health-Related Quality of Life (12-Item Short Form Health Survey)(Baseline, 4 weeks, 8 weeks, 16 weeks, 24 weeks, 40 weeks, and 1 year)
- Clinical Global Impression - Improvement (CGI-I)(24 hours, 7 days, and 2 weeks)
- Changes in Patient-Reported Quality of Life(Baseline, 1 month, 3 months, 6 months, and 1 year)
- Frequency and Nature of Treatment-Related Adverse Events(Throughout study participation, up to one year)
- Comparative Cost-Effectiveness of Treatment Approaches(One year from baseline enrollment)
- Patients' Treatment Satisfaction and Acceptability Ratings(1 month, 6 months, and 1 year post-treatment)
- Healthcare Providers' Treatment Satisfaction and Acceptability Ratings(1 month, 6 months, and 1 year post-treatment)
- Implementation Science Outcomes for Clinical Integration(Throughout study conduct, analyzed at study completion)
- Changes in Depressive Symptoms and Depression Prevalence(Baseline, 7 days, 1 month, 3 months, 6 months, and 1 year)
- Changes in Depression, Anxiety, and Mood Disorder Severity(Baseline, 7 days, 1 month, 3 months, 6 months, and 1 year)
- Time to Next Suicidal Crisis or Emergency(Up to one year from baseline)
- Demographic Variability in Treatment Response(One year from baseline)
- Post-Treatment Healthcare Service Utilization(Six months and one year post-treatment)
- Healthcare Professional Engagement with Implementation Strategies(Throughout study conduct, up to one year)
- Serum Brain-derived neurotrophic factor (BDNF) Predictor of Treatment Outcome(Baseline biomarker collection with outcome correlation at 6 months and 1 year)
- Monoamine oxidase (MAO) Predictor of Treatment Outcome(Baseline biomarker collection with outcome correlation at 6 months and 1 year)
- Hormones (TSH, T3, Free T3 and Free T4, Total Testosterone, SHBG, S-DHEA, Prolactin) Predictors of Treatment Outcome(Baseline biomarker collection with outcome correlation at 6 months and 1 year)
- Vitamins and Minerals Biomarkers Predictors of Treatment Outcome(Baseline biomarker collection with outcome correlation at 6 months and 1 year)
- Iron Profile (Iron, Ferritin and Transferrin Saturation) Predictors of Treatment Outcome(Baseline biomarker collection with outcome correlation at 6 months and 1 year)
- Homocysteine Predictor of Treatment Outcome(Baseline biomarker collection with outcome correlation at 6 months and 1 year)
- Ultrasensitive C-Reactive Protein Predictor of Treatment Outcome(Baseline biomarker collection with outcome correlation at 6 months and 1 year)
- 25-hydroxy-vitamin D Predictor of Treatment Outcome(Baseline biomarker collection with outcome correlation at 6 months and 1 year)
- Sleep Quality (Short Pittsburgh Sleep Quality Index)(Baseline, 4 weeks, 16 weeks, 40 weeks, and 1 year)
研究者
Rodolfo Furlan Damiano
Post-doc Student
University of Sao Paulo