Schizophrenia Clinical Trial
Official title:
Amisulpride Augmentation in Clozapine-unresponsive Schizophrenia
Schizophrenia is a mental health problem usually starting in the late teens/early twenties,
and often lasting many years. The standard medication ('antipsychotics') for this problem is
usually helpful, and if taken continually can keep people well, reducing the likelihood of
further episodes. However, in up to one in three people with schizophrenia, the illness does
not show much improvement with antipsychotic medication. For some of these 'resistant'
illnesses, one particular antipsychotic, clozapine, can work well, but one disadvantage is
the risk of a severe blood side effect which means that regular blood testing is necessary.
If the response to clozapine treatment is disappointing, there is some evidence that adding
another antipsychotic can sometimes produce more improvement. However, it seems that the
added antipsychotic may need to be taken by the person for at least 10 weeks in order to
work well. The investigators plan to test carefully the possible benefits and problems when
the antipsychotic amisulpride or a dummy tablet ('placebo') is added to clozapine for 12
weeks in people whose schizophrenia illness has not been helped much by any antipsychotic
medication on its own, and who are now taking clozapine, but again with not much
improvement. The investigators have chosen amisulpride because its pharmacological action
may be complementary to that of clozapine, and also it is less likely than some other
antipsychotics to compound some of the characteristic side effects of clozapine, such as
sedation, weight gain and other metabolic problems.
Adjunctive amisulpride or placebo will be randomly assigned. The investigators expect that
adding amisulpride will be more likely to cause an improvement than adding placebo. But the
investigators should learn more about the risks and side effects of combining these two
medications. Also, the investigators should gain a greater understanding of the possible
benefits of adding another antipsychotic to clozapine in relation to particular problem
symptoms, and a person's ability to live and work in the community.
This 12-week, placebo-controlled RCT will be conducted in secondary care, specifically
mental health services, at UK centres. The health technology to be assessed is the
augmentation of clozapine treatment with another second-generation antipsychotic,
amisulpride, which will be compared with placebo: 400mg amisulpride or 1 matching placebo
capsule for the first 4 weeks, then the option of titrating up to 800mg amisulpride or 2
matching placebo capsules for the remaining 8 weeks. The study will be double-blind, with
medication supplied as identical capsules containing either 400mg amisulpride or placebo.
The optimum dose of clozapine at entry and subsequent augmentation will be achieved through
a flexible dosing regimen whereby treating psychiatrists will be able to flexibly alter dose
regimens to maximise clinical risk-benefit ratios; there will be opportunities for clinical
titration of clozapine dose at two and six weeks. Any direct pharmacokinetic effect on
clozapine levels will be assessed by pre- and post-augmentation plasma levels of clozapine,
samples being taken at baseline and at the end of the 12 weeks. Recommended
pharmacovigilance procedures will be followed. Clinicians will be asked not to prescribe any
additional medication during the course of the study, and will be reminded of the drugs with
potential adverse interactions, as mentioned in the SPCs for clozapine and amisulpride.
Medication adherence will be assessed by 'pill count' and clozapine/norclozapine plasma
level ratio.
Therapeutic improvement will be assessed in terms of overall symptom severity, but also
using broader, clinically-relevant outcome measures of social and occupational function and
target symptoms and/or behaviours as well as overall health status and utility. Side effects
will be systematically assessed. The costs and outcomes for a cost effectiveness
acceptability and net benefit analysis will also be measured. The primary economic measure
will be the incremental cost effectiveness ratio of clozapine augmentation, estimated as the
net cost of clozapine augmentation divided by net QALY of clozapine augmentation.
Twenty-four months will be allowed for recruitment of participants, plus 3 months for the
final follow-up assessments.
;
Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator), Primary Purpose: Treatment
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