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The quality of reporting of phase II and III trials for new antipsychotics: a systematic review

Published online by Cambridge University Press:  02 June 2014

M. X. Patel ,
S. Collins ,
J. Hellier ,
G. Bhatia  and
R. M. Murray
M. X. Patel*
Affiliation:
Department of Psychosis Studies, Institute of Psychiatry, King's College London, UK
S. Collins
Affiliation:
Department of Psychosis Studies, Institute of Psychiatry, King's College London, UK
J. Hellier
Affiliation:
Department of Psychosis Studies, Institute of Psychiatry, King's College London, UK
G. Bhatia
Affiliation:
Department of Psychosis Studies, Institute of Psychiatry, King's College London, UK
R. M. Murray
Affiliation:
Department of Psychosis Studies, Institute of Psychiatry, King's College London, UK
*
* Address for correspondence: Dr M. X. Patel, Department of Psychosis Studies, PO Box 68, Institute of Psychiatry, King's College London, 16 De Crespigny Park, London SE5 8AF, UK. (Email: [email protected])
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Abstract

Background

The findings of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study and the Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study (CUtLASS) called previous trials of antipsychotics into question, including pre-licensing trials. Concerns regarding methodological robustness and quality of reporting increased. This systematic review aimed to examine the quality of reporting of phase II and III trials for new antipsychotics in the aftermath of the CATIE and CUtLASS studies.

Method

Electronic searches were conducted in EMBASE, Medline and Cochrane databases and also ClinicalTrials.gov for antipsychotic trials (published between January 2006 and February 2012). Phase II and III randomized controlled trials (RCTs) for iloperidone, asenapine, paliperidone, olanzapine, lurasidone and pomaglumetad methionil were selected for schizophrenia and schizoaffective disorder. The reporting of the methodology was evaluated in accordance with Consolidated Standards of Reporting Trials (CONSORT) guidelines.

Results

Thirty-one articles regarding 32 studies were included. There was insufficient reporting of design in 47% of studies and only 13% explicitly stated a primary hypothesis. Exclusion criteria were poorly reported for diagnosis in 22% of studies. Detail regarding comparators, particularly placebos, was suboptimal for 56% of studies, and permitted concomitant medication was often not reported (19%). Randomization methods were poorly described in 56% of studies and reporting on blinding was insufficient in 84% of studies. Sample size calculations were insufficiently reported in 59% of studies.

Conclusions

The quality of reporting of phase II and III trials for new antipsychotics does not reach the standards outlined in the CONSORT guidelines. Authors often fail to adequately report design and methodological processes, potentially impeding the progress of research on antipsychotic efficacy. Both policymakers and clinicians require high quality reporting before decisions are made regarding licensing and prescribing of new antipsychotics.

Keywords

Antipsychotic agentsclinical trialsCONSORTmethodologyschizophreniasystematic review
Type
Review Articles
Information
Psychological Medicine , Volume 45 , Issue 3 , February 2015 , pp. 467 - 479
Copyright
Copyright © Cambridge University Press 2014 

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References

Agid, O, Siu, CO, Potkin, SG, Kapur, S, Watsky, E, Vanderburg, D, Zipursky, RB, Remington, G (2013). Meta-regression analysis of placebo response in antipsychotic trials, 1970–2010. American Journal of Psychiatry 170, 1335–1344.Google Scholar
Alphs, L, Benedetti, F, Flieschhacker, WW, Kane, JM (2012). Placebo-related effects in clinical trials in schizophrenia: what is driving this phenomenon and what can be done to minimize it? International Journal of Neuropsychopharmacology 15, 1003–1014.CrossRefGoogle Scholar
APA (1994). Diagnostic and Statistical Manual of Mental Disorders, 4th edn. American Psychiatric Association: Washington, DC.Google Scholar
Barnes, TR (1989). A rating scale for drug-induced akathisia. British Journal of Psychiatry 154, 672–676.Google Scholar
Barnes, TRE, Drake, RJ, Dunn, G, Hayhurst, KP, Jones, PB, Lewis, SW (2013). Effect of prior treatment with antipsychotic long-acting injection on randomised clinical trial treatment outcomes. British Journal of Psychiatry 203, 215–220.Google Scholar
Begg, C, Cho, M, Eastwood, S, Horton, R, Moher, D, Olkin, I, Pitkin, R, Rennie, D, Schulz, KF, Simel, D, Stroup, DF (1996). Improving the quality of reporting of randomized controlled trials. The CONSORT statement. Journal of the American Medical Association 276, 637–639.Google Scholar
Borison, RL, Huff, FJ, Griffiths, I (1996). Efficacy of 5 mg/day and 8 mg iloperidone administered to schizophrenic patients for 42 days. Psychopharmacology Bulletin 32, 416.Google Scholar
* Buchanan, RW, Panagides, J, Zhao, J, Phiri, P, den Hollander, W, Ha, X, Kouassi, A, Alphs, L, Schooler, N, Szegedi, A, Cazorla, P (2012). Asenapine versus olanzapine in people with persistent negative symptoms of schizophrenia. Journal of Clinical Psychopharmacology 32, 36–45.CrossRefGoogle ScholarPubMed
* Canuso, CM, Dirks, B, Carothers, J, Kosik-Gonzalez, C, Bossie, CA, Zhu, Y, Damaraju, CV, Kalali, AH, Mahmoud, R (2009). Randomized, double-blind, placebo-controlled study of paliperidone extended-release and quetiapine in inpatients with recently exacerbated schizophrenia. American Journal of Psychiatry 166, 691–701.CrossRefGoogle ScholarPubMed
* Canuso, CM, Lindenmayer, JP, Kosik-Gonzalez, C, Turkoz, I, Carothers, J, Bossie, CA, Schooler, NR (2010 a). A randomized, double-blind, placebo-controlled study of 2 dose ranges of paliperidone extended-release in the treatment of subjects with schizoaffective disorder. Journal of Clinical Psychiatry 71, 587–598.Google Scholar
* Canuso, CM, Schooler, N, Carothers, J, Turkoz, I, Kosik-Gonzalez, C, Bossie, CA, Walling, D, Lindenmayer, JP (2010 b). Paliperidone extended-release in schizoaffective disorder: a randomized, controlled study comparing a flexible dose with placebo in patients treated with and without antidepressants and/or mood stabilizers. Journal of Clinical Psychopharmacology 30, 487–495.Google Scholar
Chouinard, G, Ross-Chouinard, A, Annable, L, Jones, B (1980). The extrapyramidal symptom rating scale. Canadian Journal of Neurological Sciences 7, 233.Google Scholar
Citrome, L, Litman, RE, Wang, Y, Mokliatchouk, O, Németh, G, Laszlovsky, I, Durgam, S (2013). Cariprazine efficacy in acute exacerbation of schizophrenia: analysis of PANSS data from a Phase III, international, randomized, double-blind, placebo-controlled trial. Schizophrenia Bulletin 39, S325.Google Scholar
* ClinicalTrials.gov (2012 a). A Comparison of Study Drug With Placebo and Haloperidol in Patients With Schizophrenia (www.clinicaltrials.gov/ct2/show/NCT00044044?term=NCT00044044&rank=1). Accessed first 27 March 2012, last 28 January 2014.Google Scholar
* ClinicalTrials.gov (2012 b). Lurasidone HCL – A 6-Week Phase 3 Study of Patients With Acute Schizophrenia. (PEARL 3) (www.clinicaltrials.gov/ct2/show/NCT00790192?term=NCT00790192&rank=1). Accessed first 27 March 2012, last 28 January 2014.Google Scholar
Cochrane Bias Methods Group (2013). Assessing risk of bias in included studies (http://bmg.cochrane.org/assessing-risk-bias-included-studies). Accessed 2 December 2013.Google Scholar
* Cutler, AJ, Kalali, AH, Weiden, PJ, Hamilton, J, Wolfgang, CD (2008). Four-week, double-blind, placebo- and ziprasidone-controlled trial of iloperidone in patients with acute exacerbations of schizophrenia. Journal of Clinical Psychopharmacology 28, S20–S28.Google Scholar
* Davidson, M, Emsley, R, Kramer, M, Ford, L, Pan, G, Lim, P, Eerdekens, M (2007). Efficacy, safety and early response of paliperidone extended-release tablets (paliperidone ER): results of a 6-week, randomized, placebo-controlled study. Schizophrenia Research 93, 117–130.CrossRefGoogle ScholarPubMed
Essock, SM, Covell, NH, Davis, SM, Stroup, TS, Rosenheck, RA, Lieberman, JA (2006). Effectiveness of switching antipsychotic medications. American Journal of Psychiatry 163, 2090–2095.Google Scholar
* Fleischhacker, WW, Gopal, S, Lane, R, Gassmann-Mayer, C, Lim, P, Hough, D, Remerie, B, Eerdekens, M (2012). A randomized trial of paliperidone palmitate and risperidone long-acting injectable in schizophrenia. International Journal of Neuropsychopharmacology 15, 107–118.CrossRefGoogle ScholarPubMed
* Gopal, S, Hough, DW, Xu, H, Lull, JM, Gassmann-Meyer, C, Remmerie, BM, Eerdekens, MH, Brown, DW (2010). Efficacy and safety of paliperidone palmitate in adult patients with acutely symptomatic schizophrenia: a randomized, double-blind, placebo-controlled, dose-response study. International Clinical Psychopharmacology 25, 247–256.CrossRefGoogle ScholarPubMed
Guy, W (ed.) (1976 a). The Clinical Global Impressions (CGI) Scale. In ECDEU Assessment Manual for Psychopharmacology, pp. 218–222. U.S. Department of Health, Education, and Welfare: Rockville, MD.Google Scholar
Guy, W (ed.) (1976 b). Abnormal Involuntary Movement Scale (AIMS). In ECDEU Assessment Manual for Psychopharmacology, pp. 534–537. U.S. Department of Health, Education, and Welfare: Rockville, MD.Google Scholar
Heres, S, Davis, J, Maino, K, Jetzinger, E, Kissling, W, Leucht, S (2006). Why olanzapine beats risperidone, risperidone beats quetiapine, and quetiapine beats olanzapine: an exploratory analysis of head-to-head studies of second-generation antipsychotics. American Journal of Psychiatry 163, 185–194.Google Scholar
* Hough, D, Gopal, S, Vijapurkar, U, Lim, P, Morozova, M, Eerdekens, M (2009). Paliperidone palmitate maintenance treatment in delaying the time-to-relapse in patients with schizophrenia: a randomized, double-blind, placebo-controlled study. Schizophrenia Research 116, 107–117.Google Scholar
Ioannidis, JP, Evans, SJ, Gøtzsche, PC, O'Neill, RT, Altman, DG, Schulz, K, Moher, D; CONSORT Group (2004). Better reporting of harms in randomized trials: an extension of the CONSORT statement. Annals of Internal Medicine 141, 781–788.Google Scholar
Isaac, M, Koch, A (2010). The risk of death among adult participants in trials of antipsychotic drugs in schizophrenia. European Neuropsychopharmacology 20, 139–145.Google Scholar
Johnson, E, Jørgensen, HA (2008). Effectiveness of second-generation antipsychotics: a systematic review of randomised trials. BMC Psychiatry 8, 31–44.Google Scholar
Jones, PB, Barnes, TRE, Davies, L, Dunn, G, Lloyd, H, Hayhurst, KP, Murray, RM, Markwick, A, Lewis, SW (2006). Randomized controlled trial of the effect on quality of life of second- vs first-generation antipsychotic drugs in schizophrenia: Cost Utility of the Latest Antisychotic Drugs in Schizophrenia Study (CUtLASS). Archives of General Psychiatry 63, 1079–1087.CrossRefGoogle Scholar
* Kane, J, Canas, F, Kramer, M, Ford, L, Gassmann-Mayer, C, Lim, P, Eerdekens, M (2007). Treatment of schizophrenia with paliperidone extended-release tablets: a 6-week placebo-controlled trial. Schizophrenia Research 90, 147–161.Google Scholar
* Kane, JM, Cohen, M, Zhao, J, Alphs, L, Panagides, J (2010 a). Efficacy and safety of asenapine in a placebo- and haloperidol-controlled trial in patients with acute exacerbation of schizophrenia. Journal of Clinical Psychopharmacology 30, 106–115.Google Scholar
* Kane, JM, Detke, HC, Naber, D, Sethuraman, G, Lin, DY, Bergstrom, RF, McDonnell, D (2010 b). Olanzapine long-acting injection: a 24-week, randomised, double-blind trial of maintenance treatment in patients with schizophrenia. American Journal of Psychiatry 167, 181–189.CrossRefGoogle ScholarPubMed
Kane, JM, Laurellio, J, Laska, E, Di Marino, M, Wolfgang, CD (2008). Long-term efficacy and safety of iloperidone: results from 3 clinical trials for the treatment of schizophrenia. Journal of Clinical Psychopharmacology 28, S29–S35.Google Scholar
* Kane, JM, Mackle, M, Snow-Adami, L, Zhao, J, Szegedi, A, Panagides, J (2011). A randomised placebo-controlled trial of asenapine for the prevention of relapse for schizophrenia after long-term treatment. Journal of Clinical Psychiatry 72, 349–355.Google Scholar
Kay, SR, Fiszbein, A, Opler, LA (1987). The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophrenia Bulletin 13, 261–276.Google Scholar
Kinon, B, Millen, BA, Downing, AC, Zhang, L, Stauffer, VL, Anderson, SW, Gomex, JC (2013). LY2140023 monohydrate in the treatment of patients with schizophrenia: results of 2 clinical trials assessing efficacy in treating acutely ill patients and those with prominent negative symptoms. Schizophrenia Bulletin 39, S338.Google Scholar
* Kinon, BJ, Zhang, L, Millen, BA, Osuntokun, OO, Williams, JE, Kollack-Walker, S, Jackson, K, Kryzhanovskaya, L, Jarkova, N (2011). A multicenter, inpatient, phase 2, double-blind, placebo-controlled dose-ranging study of LY2140023 monohydrate in patients with DSM-IV schizophrenia. Journal of Clinical Psychopharmacology 31, 349–355.Google Scholar
* Kramer, M, Litman, R, Hough, D, Lane, R, Lim, P, Liu, Y, Eerdekens, M (2010). Paliperidone palmitate, a potential long-acting treatment for patients with schizophrenia. Results of a randomized, double-blind, placebo-controlled efficacy and safety study. International Journal of Neuropsychopharmacology 13, 635–647.Google Scholar
* Kramer, M, Simpson, G, Maciulis, V, Kushner, S, Vijapurkar, U, Lim, P, Eerdekens, M (2007). Paliperidone extended-release tablets for prevention of symptom recurrence in patients with schizophrenia: a randomized, double-blind, placebo-controlled study. Journal of Clinical Psychopharmacology 27, 6–14.Google Scholar
Lane, P (2008). Handling drop-out in longitudinal clinical trials: a comparison of the LOCF and MMRM approaches. Pharmaceutical Statistics 7, 93–106.CrossRefGoogle ScholarPubMed
* Lauriello, J, Lambert, T, Andersen, S, Lin, D, Taylor, CC, McDonnell, D (2008). An 8-week, double-blind, randomized, placebo-controlled study of olanzapine long-acting injection in acutely ill patients with schizophrenia. Journal of Clinical Psychiatry 69, 790–799.Google Scholar
Leucht, S, Cipriani, A, Spineli, L, Mavridis, D, Örey, D, Richer, F, Samara, M, Barbui, C, Engel, RR, Geddes, JR, Kissling, W, Stapf, MP, Lässig, B, Salanti, G, Davis, JM (2013). Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis. Lancet 382, 951–962.Google Scholar
Leucht, S, Corves, C, Arbter, D, Engel, RR, Li, C, Davis, JM (2009 a). Second-generation versus first-generation antipsychotic drugs for schizophrenia: a meta-analysis. Lancet 373, 31–41.Google Scholar
Leucht, S, Kissling, W, Davis, JM (2009 b). Second-generation antipsychotics for schizophrenia: can we resolve the conflict? Psychological Medicine 39, 1591–1602.CrossRefGoogle ScholarPubMed
* Li, H, Rui, Q, Ning, X, Xu, H, Gu, N (2011). A comparative study of paliperidone palmitate and risperidone long-acting injectable therapy in schizophrenia. Progress in Neuro-Psychopharmacology and Biological Psychiatry 35, 1002–1008.Google Scholar
Lieberman, JA, Stroup, TS, McEvoy, JP, Swartz, MS, Rosenheck, RA, Perkins, DO, Keefe, RSE, Davis, SM, Davis, CE, Lebowitz, BD, Severe, J, Hsiao, JK (2005). Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. New England Journal of Medicine 353, 1209–1223.Google Scholar
Loebel, A, Cucchiaro, J, Sarma, K, Xu, L, Hsu, C, Kalali, AH, Pikalov, A, Potkin, SG (2013). Efficacy and safety of lurasidone 80 mg/day and 160 mg/day in the treatment of schizophrenia: a randomized, double-blind, placebo- and active-controlled trial. Schizophrenia Research 145, 101–109.CrossRefGoogle ScholarPubMed
* Marder, SR, Kramer, M, Ford, L, Eerdekens, E, Lim, P, Eerdekens, M, Lowy, A (2007). Efficacy and safety of paliperidone extended-release tablets: results of a 6-week, randomized, placebo-controlled study. Biological Psychiatry 62, 1363–1370.Google Scholar
Meltzer, HY, Bobo, WV, Nuamah, IF, Lane, R, Hough, D, Kramer, M, Eerdekens, M (2008). Efficacy and tolerability of oral paliperidone extended-release tablets in the treatment of acute schizophrenia: pooled data from three 6-week, placebo-controlled studies. Journal of Clinical Psychiatry 69, 817–829.Google Scholar
* Meltzer, HY, Cucchiaro, J, Silva, R, Ogasa, M, Phillips, D, Xu, J, Kalali, AH, Scweizer, E, Pikalov, A, Loebel, A (2011). Lurasidone in the treatment of schizophrenia: a randomized, double-blind, placebo- and olanzapine-controlled study. American Journal of Psychiatry 168, 957–967.Google Scholar
Moher, D, Schultz, KF, Altman, DG (2001). The CONSORT statement: revised recommendations for improving the quality of reports of parallel-group randomised trials. Lancet 357, 1191–1194.CrossRefGoogle Scholar
* Nakamura, M, Ogasa, M, Guarino, J, Phillips, D, Severs, J, Cucchiaro, J, Loebel, A (2009). Lurasidone in the treatment of acute schizophrenia: a double-blind, placebo-controlled trial. Journal of Clinical Psychiatry 70, 829–836.Google Scholar
* Nasrallah, HA, Gopal, S, Gassmann-Meyer, C, Quiroz, JA, Lim, P, Eerdekens, M, Yuen, E, Hough, D (2010). A controlled, evidence-based trial of paliperidone palmitate, a long-acting injectable antipsychotic, in schizophrenia. Neuropsychopharmacology 35, 2072–2082.CrossRefGoogle ScholarPubMed
* Pandina, G, Lane, R, Gopal, S, Gassmann-Mayer, C, Hough, D, Remmerie, B, Simpson, G (2011). A double-blind study of paliperidone palmitate and risperidone long-acting injectable in adults with schizophrenia. Progress in Neuro-Psychopharmacology and Biological Psychiatry 35, 218–226.Google Scholar
* Pandina, GJ, Lindenmayer, JP, Lull, J, Lim, P, Gopal, S, Herben, V, Kusumakar, V, Yuen, E, Palumbo, J (2010). A randomized, placebo-controlled study to assess the efficacy and safety of 3 doses of paliperidone palmitate in adults with acutely exacerbated schizophrenia. Journal of Clinical Psychopharmacology 30, 235–244.Google Scholar
Patel, MX, Arista, IA, Taylor, M, Barnes, TRE (2013). How to compare doses of different antipsychotics: a systematic review of methods. Schizophrenia Research 149, 141–148.Google Scholar
* Patil, ST, Zhang, L, Martenyi, F, Lowe, SL, Jackson, KA, Andreev, BV, Avedisova, AS, Bardenstein, LM, Gurovich, IY, Morozova, MA, Mosolov, SN, Neznanov, NG, Reznik, AM, Smulevich, AB, Tochilov, VA, Johnson, BG, Monn, JA, Schoepp, DD (2007). Activation of mGlu2/3 receptors as a new approach to treat schizophrenia: a randomized Phase 2 clinical trial. Nature Medicine 13, 1102–1107.Google Scholar
Piaggio, G, Elbourne, DR, Altman, DG, Pocock, SJ, Evans, JW (2006). Reporting of noninferiority and equivalence randomized trials: an extension of the CONSORT statement. Journal of the American Medical Association 295, 1152–1160.Google Scholar
Piaggio, G, Elbourne, D, Altman, DG, Pocock, SJ, Evans, SJW; CONSORT Group (2012). Reporting of non-inferiority and equivalence randomized trials: an extension of the CONSORT statement. Journal of the American Medical Association 308, 2594–2604.Google Scholar
Pope, A, Adams, C, Paton, C, Weaver, T, Barnes, TRE (2010). Assessment of adverse effects in clinical studies of antipsychotic medication: surveys of methods used. British Journal of Psychiatry 197, 67–72.CrossRefGoogle ScholarPubMed
* Potkin, SG, Cohen, MD, Panagides, J (2007). Efficacy and tolerability of asenapine in acute schizophrenia: a placebo- and risperidone-controlled trial. Journal of Clinical Psychiatry 68, 1492–1500.Google Scholar
* Potkin, SG, Litman, RE, Torres, R, Wolfgang, CD (2008). Efficacy of iloperidone in the treatment of schizophrenia: initial phase 3 studies. Journal of Clinical Psychopharmacology 28, S4–S11.Google Scholar
Rabinowitz, J, Werbeloff, N, Caers, I, Mandel, FS, Jaeger, J, Stauffer, V, Menard, F, Kinon, B, Kapur, S (2014). Combining efficacy and completion rates with no data imputation: a composite approach with greater sensitivity for the statistical evaluation of active comparisons in antipsychotic trials. European Neuropsychopharmacology 24, 357–368.Google Scholar
Rabinowitz, J, Werbeloff, N, Caers, I, Mandel, FS, Stauffer, V, Menard, F, Kinon, B, Kapur, S (2013). Negative symptoms in schizophrenia – the remarkable impact of inclusion definitions in clinical trials and their consequences. Schizophrenia Research 150, 334– 338.Google Scholar
* Schoemaker, J, Naber, D, Vrijland, P, Panagides, J, Emsley, R (2010). Long-term assessment of asenapine vs. olanzapine in patients with schizophrenia or schizoaffective disorder. Pharmacopsychiatry 43, 138–146.Google Scholar
Schulz, KF, Altman, DG, Moher, D (2010). CONSORT 2010 statement: updated guidelines for reporting parallel group randomised trials. British Medical Journal 340, 698–702.Google Scholar
Siddiqui, O, Hung, HM, O'Neill, R (2009). MMRM vs LOCF: a comprehensive comparison based on simulation study and 25 NDA datasets. Journal of Biopharmaceutical Statistics 19, 227–246.Google Scholar
Simpson, GM, Angus, JW (1970). A rating scale for extrapyramidal side effects. Acta Psychiatrica Scandinavica 212, S11–S19.Google Scholar
Umbricht, D, Martin-Facklam, M, Youssef, E, Yoo, K, Dorflinger, E, Bausch, A, Alberati, D, Santarelli, L (2011). Glycine reuptake inhibitor RG1678: results of the proof-of-concept study for the treatment of negative symptoms in schizophrenia. European Neuropsychopharmacology 21, S517–S518.Google Scholar
Vickers, AJ, Altman, DG (2001). Analysing controlled trials with baseline and follow up measurements. British Medical Journal 323, 1123–1124.Google Scholar
* Weiden, PJ, Cutler, AJ, Polymeropoulos, MH, Wolfgang, CD (2008). Safety profile of iloperidone: a pooled analysis of 6-week acute-phase pivotal trials. Journal of Clinical Psychopharmacology 28, S12–S19.Google Scholar