Aripiprazole, Olanzapine and Haloperidol in the Long-Term Treatment of Schizophrenia: The Rationale and Development of the GiSAS Pragmatic Randomized Controlled Trial, a Consideration and Empirical Study of Factors Associated With Recruitment (the GiSAS Survey) and the Concept of Endpoints Using a Secondary Analysis of Existing Data and a Preliminary Analysis of GiSAS Trial Data

Parabiaghi, Alberto (2012). Aripiprazole, Olanzapine and Haloperidol in the Long-Term Treatment of Schizophrenia: The Rationale and Development of the GiSAS Pragmatic Randomized Controlled Trial, a Consideration and Empirical Study of Factors Associated With Recruitment (the GiSAS Survey) and the Concept of Endpoints Using a Secondary Analysis of Existing Data and a Preliminary Analysis of GiSAS Trial Data. PhD thesis The Open University.

DOI: https://doi.org/10.21954/ou.ro.0000f189

Abstract

This thesis described the development of a pragmatic, randomized clinical trial evaluating the safety and efficacy of antipsychotic treatment in schizophrenia. In the perspective of highlighting some critical issues of the trial design, the thesis focused on the trial's planning and conduct and on the preliminary analysis of the first followed-up subjects.

Having experienced significant problems in patient recruitment a survey on perceived inclusion barriers and antipsychotic preference was performed. Investigators mainly complained about system-related barriers, and believed in the superiority of second-generation antipsychotics. Taking the cue from these results, strategies were adopted in order to reach the planned target of 800 subjects. Remedial actions included study promotion activities, education initiatives and bursaries, and resulted in a significant improvement of the recruitment rate. Nevertheless, we had to reduce the sample to one third of the original size.

The second part of the thesis focused on the concept of endpoints using a secondary analysis of existing data and a preliminary analysis of GiSAS trial data. The assumption that differences in discontinuation rates reflect differences in effectiveness was reinforced by the results of a pharmaco-epidemiological study comparing the use of reboxetine and SSRIs in a large population sample. The established lack of efficacy of this antidepressant was mirrored by a higher proportion of treatment discontinuations. We explored the baseline characteristics of 114 included subjects and compared the baseline and follow-up variables between those who discontinued study drugs at follow-up and those who did not. Discontinues' worse outcome was mainly attributable to self reported side-effects.

This thesis highlighted some critical issues on the execution of a pragmatic trial in schizophrenia. The feasibility of the trial design and the concept of endpoints were critically analyzed. The trial mechanism is now fully functional and most problems of its implementation have been identified and contained.