Open Access Highly Accessed Study protocol

Rationale and design of an independent randomised controlled trial evaluating the effectiveness of aripiprazole or haloperidol in combination with clozapine for treatment-resistant schizophrenia

Michela Nosè1*, Simone Accordini2, Paola Artioli4, Francesco Barale5, Corrado Barbui1, Rossella Beneduce6, Domenico Berardi7, Gerardo Bertolazzi8, Bruno Biancosino9, Alfredo Bisogno10, Raffaella Bivi9, Filippo Bogetto11, Marianna Boso5, Alberto Bozzani12, Piera Bucolo13, Marcello Casale14, Liliana Cascone10, Luisa Ciammella15, Alessia Cicolini1, Gabriele Cipresso15, Andrea Cipriani1, Paola Colombo16, Barbara Dal Santo4, Michele De Francesco17, Giorgio Di Lorenzo18, Walter Di Munzio10, Giuseppe Ducci19, Arcadio Erlicher20, Eleonora Esposito1, Luigi Ferrannini3, Farida Ferrato21, Antonio Ferro22, Nicoletta Fragomeno23, Vincenzo Fricchione Parise24, Maria Frova20, Francesco Gardellin25, Nicola Garzotto26, Andrea Giambartolomei19, Giancarlo Giupponi17, Luigi Grassi9, Natalia Grazian20, Lorella Grecu23, Gualtiero Guerrini27, Francesco Laddomada12, Ermanna Lazzarin25, Camilla Lintas26, Francesca Malchiodi28, Lara Malvini21, Livio Marchiaro29, Alessandra Marsilio30, Massimo Carlo Mauri31, Antonio Mautone14, Marco Menchetti7, Giuseppe Migliorini32, Marco Mollica3, Daniele Moretti22, Serena Mulè1, Stylianos Nicholau8, Flavio Nosè33, Guglielmo Occhionero13, Anna Maria Pacilli29, Stefania Pecchioli23, Mauro Percudani16, Ennio Piantato34, Carlo Piazza32, Francesco Pontarollo1, Roger Pycha35, Roberto Quartesan36, Luciana Rillosi6, Francesco Risso29, Raffella Rizzo33, Paola Rocca11, Stefania Roma19, Matteo Rossattini31, Giuseppe Rossi6, Giovanni Rossi30, Alessandra Sala25, Claudio Santilli36, Giuseppe Saraò23, Antonio Sarnicola19, Francesca Sartore34, Silvio Scarone4, Tiziana Sciarma36, Alberto Siracusano18, Stefania Strizzolo25, Michele Tansella1, Gino Targa9, Annamarie Tasser35, Rodolfo Tomasi17, Rossana Travaglini23, Antonio Veronese1 and Simona Ziero13

Author Affiliations

1 Department of Medicine and Public Health, Section of Psychiatry and Clinical Psychology, University of Verona, Italy

2 Unit of Epidemiology and Medical Statistics, Department of Medicine and Public Health University of Verona, Italy

3 Dipartimento di Salute Mentale, ASL n. 3 " Genovese", Genova, Italy

4 UOP 51 Psichiatria A.O. San Paolo, Milano, Italy

5 Department of Applied Health and Behavioral Sciences, Section of Psychiatry, University of Pavia, Italy

6 Centro S. Giovanni di Dio IRCCS FBF, Brescia, Italy

7 Institute of Psychiatry, Bologna University, Italy

8 Dipartimento Salute Mentale- Servizio Psichiatrico Area sud-ULSS 22, Verona, Italy

9 Section of Psychiatry, Department of Medical Sciences of Communication and Behaviour, University of Ferrara and Department of Mental Health, Ferrara, Italy

10 DSM ASL Salerno 1, Salerno, Italy

11 Dipartimento di Neuroscienze, Universita' degli Studi di Torino, Italy

12 Dipartimento Salute Mentale, ASL Taranto, Italy

13 DSM, ASL 19, Asti, Italy

14 Unità Operativa Salute Mentale, distretto 112/113, ASL Salerno 3, Salerno, Italy

15 Dipartimento di Salute Mentale, ASL n. 3 " Genovese", Genova, Italy

16 Psychiatric Unit of Bollate, Department of Mental Health, Hospital "G. Salvini", Garbagnate Milanese, Milano, Italy

17 CSM, Azienda Sanitaria di Bolzano, Italy

18 Unità Operativa Complessa di Psichiatria, Dipartimento di Neuroscienze, Facoltà di Medicina e Chirurgia, Università degli Studi di Roma "Tor Vergata", Roma, Italy

19 UOC, SPDC, Ospedale San Filippo Neri, ASL RM E, Roma, Italy

20 Azienda Ospedaliera "Ospedale Niguarda Ca' Granda", Milano, Italy

21 Unità Operativa n42, Rho, Azienda Ospedaliera "G. Salvini", Garbagnate Milanese, Milano, Italy

22 DSM, ASL n2 "Savonese", Savona, Italy

23 ASF-Toscana (Centro Salute Mentale del MOM-SMA Q2), Firenze, Italy

24 U.O.Salute Mentale "Roseto", ASL AV2, Avellino, Italy

25 Centro di Salute Mentale di Vicenza (ULSS 6), Vicenza, Italy

26 First Psychiatric Service, ULSS 20, Ospedale Civile Maggiore, Verona, Italy

27 Centro Salute mentale ASL 5, La Spezia, Italy

28 Servizio Psichiatrico, AO Melegnano, sede Gorgonzola, Italy

29 Struttura Complessa di Psichiatria, A.S.L. CN1, Cuneo, Italy

30 Azienda Ospedaliera "Carlo Poma", Mantova, Italy

31 Clinical Psychiatry, IRCCS Ospedale Maggiore Policlinico, Milano, Italy

32 Fourth Psychiatric Service, ULSS 20, San Bonifacio, Verona, Italy

33 Second Psychiatric Service, ULSS 20, Ospedale Civile Maggiore, Verona, Italy

34 SPDC c/o Azienda Osp. Naz. Ss Antonio E Biagio-Alessandria, Italy

35 Servizio Psichiatrico di Brunico (BZ), Azienda Sanitaria di Bolzano, Italy

36 Sezione di Psichiatria, Psicologia Clinica e Riabilitazione Psichiatrica, Dipartimento di Medicina Clinica e Sperimentale, Università degli Studi di Perugia, Italy

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Trials 2009, 10:31  doi:10.1186/1745-6215-10-31

Published: 15 May 2009

Abstract

Background

One third to two thirds of people with schizophrenia have persistent psychotic symptoms despite clozapine treatment. Under real-world circumstances, the need to provide effective therapeutic interventions to patients who do not have an optimal response to clozapine has been cited as the most common reason for simultaneously prescribing a second antipsychotic drug in combination treatment strategies. In a clinical area where the pressing need of providing therapeutic answers has progressively increased the occurrence of antipsychotic polypharmacy, despite the lack of robust evidence of its efficacy, we sought to implement a pre-planned protocol where two alternative therapeutic answers are systematically provided and evaluated within the context of a pragmatic, multicentre, independent randomised study.

Methods/Design

The principal clinical question to be answered by the present project is the relative efficacy and tolerability of combination treatment with clozapine plus aripiprazole compared with combination treatment with clozapine plus haloperidol in patients with an incomplete response to treatment with clozapine over an appropriate period of time. This project is a prospective, multicentre, randomized, parallel-group, superiority trial that follow patients over a period of 12 months. Withdrawal from allocated treatment within 3 months is the primary outcome.

Discussion

The implementation of the protocol presented here shows that it is possible to create a network of community psychiatric services that accept the idea of using their everyday clinical practice to produce randomised knowledge. The employed pragmatic attitude allowed to randomly allocate more than 100 individuals, which means that this study is the largest antipsychotic combination trial conducted so far in Western countries. We expect that the current project, by generating evidence on whether it is clinically useful to combine clozapine with aripiprazole rather than with haloperidol, provides physicians with a solid evidence base to be directly applied in the routine care of patients with schizophrenia.

Trial Registration

Clincaltrials.gov Identifier: NCT00395915