The main objective of this study is to investigate the feasibility of a larger single-blind, randomized trial focused on (cost) effectiveness and safety of ECT vs. aripiprazole addition in patients with schizophrenia spectrum disorders (SSD)…
ID
Source
Brief title
Condition
- Schizophrenia and other psychotic disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The main endpoints of this feasibility study are 1. The proportion of patients
willing to be randomized in this study. To that end, we will record the total
number of eligible patients asked to participate in the trial and the number of
eligible patients willing to be randomized who actually are randomized. Then we
will compute the proportion of those willing to participate. 2. The number of
participants we are able to recruit in 8 months* time. 3. the dropout rate of
the study.
Secondary outcome
In addition, 4. effect sizes of the outcome measures of the foreseen trial 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: differences in PANSS (Positive and Negative Syndrome Scale; positive
and negative symptoms analysed separately as well as total symptoms) from
baseline to 10 and to 16 weeks between both arms; differences in response (>=20%
reduction of total or positive symptoms on the PANSS), clinical global
impression-schizophrenia (CGI-S), recovery (Recovery Assessment Scale, RAS),
depressive symptoms (Calgary depression scale for schizophrenia, CDS),
all-cause discontinuation, number of (S)AEs and Cost effectiveness assessed
through questionnaires (Medical Consumption Questionnaire and Productivity Cost
Questionnaire, iMCQ and iPCQ) from baseline to 10 and at 16 weeks.
Background summary
Clozapine (CLZ) is a last-resort antipsychotic agent used in the treatment of
schizophrenia- spectrum disorders (SSD). Although benefits of CLZ have been
demonstrated in a range of clinical situations [1-3] approximately 60% of
patients considered treatment resistant do not fully respond to CLZ, i.e. are
CLZ-refractory (CR), meaning they experience important residual psychiatric and
physical symptoms on CLZ, hampering their social functioning and reducing
quality of life (QoL) [4]. Although CR is common and has a substantial negative
effect on the quality of life of the affected patients and their families,
current guidelines do not offer clinicians clear advice on the best treatment
in this situation. Increasing evidence suggests addition of electroconvulsive
therapy (ECT) to clozapine is a safe and effective treatment in CR patients
[5]. On the other hand, meta-analyses suggest that aripiprazole (ARI) addition
to CLZ[6, 7] is a promising treatment strategy in CR patients. However, it is
unknown how these treatment strategies compare to one another as head-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 and
cost-effectiveness but also to establish possible differences in AEs burden
between strategies as both ECT and medication augmentation with ARI have
differential EA profiles. ECT is also relatively expensive and time-consuming
compared with medication augmentation. Second, trials of treatment options for
CR patients to date have focused on symptom reduction instead of a more
comprehensive set of outcome measures including quality of life (QoL), AEs and
recovery. Together, this emphasises the lack of evidence to assist clinical
decision-making for CR patients. This knowledge gap is likely a consequence of
inherent difficulties in designing and conducting a randomized trial in which
(cost-) effectiveness and safety of treatments are compared in CR patients. The
first factor explaining this currently unmet need is lack of knowledge about
randomization willingness. Second, it is unknown how many participants can be
included 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 sizes
for the differences in outcomes between the two arms is unknown. Considering
the challenges of performing a RCT in this specific, severely affected patient
group, it is important to first study the feasibility of such a trial in a
preparatory study in order to strategically optimize the eventual randomized
trial.
Study objective
The main objective of this study is to investigate the feasibility of a larger
single-blind, randomized trial focused on (cost) effectiveness and safety of
ECT vs. aripiprazole addition in patients with schizophrenia spectrum disorders
(SSD) insufficiently responsive to clozapine. The specific research questions
addressed 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 to follow-up at what stage of the trial? 3.What is the magnitude
of the effect sizes 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. Participants are randomized at 1:1 to
i) addition of ECT; ii) addition of ARI. The outcome of this preparatory study
will be used to design a foreseen large-scale single (rater)-blind, randomized
trial focused on (cost) effectiveness and safety of ECT vs. aripiprazole
addition to clozapine in patients with schizophrenia spectrum disorders (SSD)
insufficiently responsive to clozapine. A superiority design was chosen given
the increased costs and burden on patients involved with ECT relative to
aripiprazole addition.
Intervention
Arm 1: ECT addition to clozapine. Bilateral ECT will be started twice weekly
for 10 weeks and then in responders (i.e. those with either positive or total
symptom reductions >= 20%) tapered to once weekly for an additional 6 weeks
(total number of ECT sessions = 26). Non-responders at 10 weeks will
discontinue ECT but will be followed up.
Arm 2: Addition to clozapine of aripiprazole (ARI) for 16 weeks (same duration
of treatment as ECT).
All participants continue CLZ at the blood level they receive at study entry
during the trial.
Study burden and risks
Participants could have a direct benefit as the studied interventions may lead
to improvement of their symptoms and quality of life. The main risk is that of
adverse effects (AEs) of either ECT or ARI, in which case patients and
clinicians may decide (based on shared decision making) to lower the dose of
ARI, or discontinue the treatment and switch to another agent, which is also in
line with clinical practice. In the ECT arm, non-responders at 10 weeks will
discontinue ECT but will be followed up. If participants do not respond (<20%
response at week 16) with the treatment they are randomized to, they will be
provided the oppertunity to cross-over to the other treatment. Should AEs
arise, clinicians and patients may in the interest of shared decision-making
decide to decrease ECT frequency or switch to right unilateral ECT.
Additionally, there will be a burden in time for patients undergoing ECT, as
they will have to come to the clinic for several hours twice weekly during the
course of this treatment. To limit participant burden related to the data
collection, to reduce the chances of COVID-19 transmission and to facilitate
inclusion, outcomes will be assessed through video calling as much as possible
by a central, blinded rater. Each of the three visits participants will undergo
take about one hour, for which they will be financially compensated. If
non-responders participate in the cross-over, there will be two additional
visits at week 26 and 32 (10 and 16 weeks after cross-over intervention), which
will take about one hour each. The participants will be financially compensated
for these visits. Participants can also give consent for a naturalistic
follow-up a year after randomisation. This visit will also take about one hour
and the participants will be financially compensated for the visit.
*
Meibergdreef 5
Amsterdam 1105 AZ
NL
Meibergdreef 5
Amsterdam 1105 AZ
NL
Listed location countries
Age
Inclusion criteria
In order to be eligible to participate in this study, a subject must meet all
of the following criteria:
• He/she currently uses CLZ or discontinued CLZ and is willing to restart CLZ,
treated in inpatient or outpatient settings with a diagnosis of schizophrenia,
psychotic disorder not otherwise specified or schizoaffective disorder,
according to the DSM5 criteria,
• He/she is CR, meaning they failed to achieve Andreasen remission criteria,
while on CLZ either for a minimum period of 12 weeks at a concentration >= 350
Ug/L or lower with incomplete tolerance to CLZ.
• His/her age must be >= 18 years old
• He/she must be able to speak and read Dutch
• He/she must be mentally competent and have decisional capacity with regard to
a decision to participate in the current study
Exclusion criteria
• prior treatment with ECT or ARI concomitantly with CLZ;
• known intolerance to ECT or ARI; and ARI or ECT-related contra-indications,
i.e. kidney failure (GFR<30ml/min) and conditions predisposing to kidney
failure (e.g. dehydration, infections and hypovolemic shock); recent CVA or
intra cranial surgery; feochromocytome; current instable angina pectoris;
disorders in the use of alcohol defined as > 2 reported consumptions daily
and/or a gGT of over 60U/L and liver failure.
• pregnancy or nursing or being of child-bearing age without appropriate
contraception.
• A history of Parkinson*s disease
• Admission to a psychiatric unit involuntarily in the context of a *crisis
maatregel* or treatment with ECT or aripiprazole is provided as compulsory care
in the context of a *zorgmachtiging* (as described in the care plan (*zorg en
afstemmingsplan*) of the patient) or 'terbeschikkingstelling (TBS)'.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2021-006333-19-NL |
| CCMO | NL79853.018.21 |