EMECLO (trial of ECT vs medication in difficult-to-treat psychosis)

In July 2021 we were awarded a "Voorbereidend doelmatigheidsonderzoek" grant by ZonMW to investigate whether ECT (electroconvulsive therapy) or medication works best as add-on to clozapine in patients not fully responsive to clozapine. We have started recruiting participants in 2022 and encourage any potentially interested colleagues to join us in our recruitment endeavor and potentially eligible participants to contact us about possible participation in the trial. Below is a short outline of the study. 

Rationale: Clozapine (CLZ) is a last-resort antipsychotic agent used in thetreatment of schizophrenia- spectrum disorders (SSD). Although benefits of CLZhave been demonstrated in a range of clinical situations approximately60% of patients considered treatment resistant do not fully respond to CLZ,i.e. are CLZ-refractory (CR), meaning they experience important residualpsychiatric and physical symptoms on CLZ, hampering their social functioningand reducing quality of life (QoL). Although CR is common and has asubstantial negative effect on the quality of life of the affected patients andtheir families, current guidelines do not offer clinicians clear advice on thebest treatment in this situation. Increasing evidence suggests addition ofelectroconvulsive therapy (ECT) to clozapine is a safe and effective treatmentin CR patients. On the other hand, meta-analyses suggest that aripiprazole(ARI) addition to CLZ is a promising treatment strategy in CR patients.However, it is unknown how these treatment strategies compare to one another ashead-to-head comparisons for add-on options to CLZ in CR patients are lacking.Such a comparison is relevant not only to assess potential efficacy andcost-effectiveness but also to establish possible differences in AEs burdenbetween strategies as both ECT and medication augmentation with ARI havedifferential EA profiles. ECT is also relatively expensive and time-consumingcompared with medication augmentation. Second, trials of treatment options forCR patients to date have focused on symptom reduction instead of a morecomprehensive set of outcome measures including quality of life (QoL), AEs andrecovery. Together, this emphasises the lack of evidence to assist clinicaldecision-making for CR patients. This knowledge gap is likely a consequence ofinherent difficulties in designing and conducting a randomized trial in which(cost-) effectiveness and safety of treatments are compared in CR patients. Thefirst factor explaining this currently unmet need is lack of knowledge aboutrandomization willingness. Second, it is unknown how many participants can beincluded as well as what the attrition rate in such a trial will be. And third,since no studies have compared ECT with ARI, the magnitude of the effect sizesfor the differences in outcomes between the two arms is unknown. Consideringthe challenges of performing a RCT in this specific, severely affected patientgroup, it is important to first study the feasibility of such a trial in apreparatory study in order to strategically optimize the eventual randomizedtrial.

Objective: The mainobjective of this study is to investigate the feasibility of a largersingle-blind, randomized trial focused on (cost) effectiveness and safety ofECT vs. aripiprazole addition in patients with schizophrenia spectrum disorders(SSD) insufficiently responsive to clozapine. The specific research questionsaddressed are: 1.How many of the patients eligible for inclusion are willing to be randomized?2.How many patients will we be able to recruit?; and how many will we lose tofollow-up at what stage of the trial? 3.What is the magnitude of the effectsizes in both arms that can be expected?

Study design: The current study is a multi-center preparatory,single-blind, randomized, head-to-head clinical feasibility study. Participantsare randomized at 1:1 to i) addition of ECT; ii) addition of ARI. The outcomeof this preparatory study will be used to design a foreseen large-scale single(rater)-blind, randomized trial focused on (cost) effectiveness and safety ofECT vs. aripiprazole addition to clozapine in patients with schizophreniaspectrum disorders (SSD) insufficiently responsive to clozapine. A superioritydesign was chosen given the increased costs and burden on patients involvedwith ECT relative to aripiprazole addition.

Study population: Adult patients (N=20)currently on CLZ with a diagnosis of schizophrenia, psychotic disorder nototherwise specified or schizoaffective disorder, according to the DSM-5criteria, who are CR, meaning they failed to achieve Andreasen remissioncriteria, while on CLZ either for a minimum period of 12 weeks at aconcentration ≥ 350 Ug/L or lower with incomplete tolerance to CLZ.

Intervention (if applicable):Arm 1: ECT addition to clozapine. Bilateral ECT will be started twice weeklyfor 10 weeks and then in responders (i.e. those with either positive or totalsymptom reductions ≥ 20%) tapered to once weekly for an additional 6 weeks(total number of ECT sessions = 26). Non-responders at 10 weeks willdiscontinue ECT but will be followed up. Arm 2: Addition to clozapine of aripiprazole (ARI) for 16weeks (same duration of treatment as ECT). All participants continue CLZ at the blood level they receiveat study entry during the trial.

Main study parameters/endpoints: Themain endpoints of this feasibility study are 1. The proportion of patientswilling to be randomized in this study. To that end, we will record the totalnumber of eligible patients asked to participate in the trial and the number ofeligible patients willing to be randomized who actually are randomized. Then wewill compute the proportion of those willing to participate. 2. The number ofparticipants we are able to recruit in 8 months’ time. 3. the dropout rate ofthe study. In addition, 4. effect sizes of the outcome measures of the foreseentrial will also be assessed. The primary outcome of the foreseen trial is:difference between the two arms in QoL measured using the EQ5D(https://euroqol.org/) from baseline until 10 weeks after treatment inception.Secondary outcome measures include: differencesin PANSS (Positive and Negative Syndrome Scale; positive and negative symptomsanalysed separately as well as total symptoms) from baseline to 10 and to 16weeks between both arms; differences in response (≥20% reduction of total orpositive symptoms on the PANSS), clinical global impression-schizophrenia(CGI-S), recovery (Recovery Assessment Scale, RAS), depressive symptoms(Calgary depression scale for schizophrenia, CDSS), all-cause discontinuation,number of (S)AEs and Cost effectiveness assessed through questionnaires (MedicalConsumption Questionnaire and Productivity Cost Questionnaire, iMCQ and iPCQ)from baseline to 10 and at 16 weeks.

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