Clementine Nordon1, Thomas Bovagnet2, Mark Belger3, Javier Jimenez4, Robert Olivares5, Helene Chevrou-Severac6, Helene Verdoux7, Josep Maria Haro8, Lucien Abenhaim2, Helene Karcher2. 1. LASER Analytica, 3 rue de l'Arrivée, 75015 Paris. Electronic address: clementine.nordon@la-ser.com. 2. LASER Analytica, 3 rue de l'Arrivée, 75015 Paris. 3. Lilly Research Centre, Eli Lilly and Company Limited, Erl Wood Manor, Sunninghill Road, Windlesham, Surrey GU20 6PH, United Kingdom. 4. Medical Evidence and Observational Research, AstraZeneca, 1 Medimmune way, Gaithersburg, MD, United States. 5. Global HEOR, Sanofi, 1 Avenue Pierre Brossolette, 91380 Chilly-Mazarin, France. 6. Takeda Pharmaceuticals International AG, Thurgauerstrasse 130, 8152 Glattpark-Opfikon, Zurich, Switzerland. 7. Univ. Bordeaux 2 and INSERM U1219, 146 rue Léo Saignat, 33076 Bordeaux, France. 8. Research and Development Unit, Parc Sanitari Sant Joan de Déu, Fundació Sant Joan de Déu, Dr. Antoni Pujadas, 42, Sant Boi de Llobregat, Barcelona, Spain.
Abstract
OBJECTIVES: To explore the impact upon estimation of drug effect as a result of applying exclusion criteria in randomized-controlled trials (RCT) measuring the efficacy of antipsychotics (AP) in schizophrenia. METHODS: Three characteristics which may act as effect-modifiers of AP, while also common exclusion criteria in RCTs, were identified through literature review: schizophrenia duration, substance use disorder and poor adherence. The SOHO cohort was used to estimate the effect of initiating antipsychotic drugs "A", "B" or "C" (pooled) upon symptom evolution at 3months from baseline (CGI-S scale). "Estimated effectiveness" and "estimated efficacy" were drawn from the "SOHO" and "RCT-like" (patients with none of the above-listed exclusion criteria) samples, respectively. Effect-modification and impact of each exclusion criterion on AP effect estimates were explored using non-adjusted statistics. RESULTS: The "SOHO sample" included 8250 patients initiating drug A, B or C at baseline, whose AP "estimated effectiveness" was ΔCGI-S=-0.78 (95% CI=-0.80, -0.76). The "RCT-like" sub-sample included 5348 (65%) patients whose AP "estimated efficacy" was ΔCGI-S=-0.73 (95% CI=-0.75, -0.70). Patients with short illness duration (≤3years since first AP; n=2436) experienced significant symptom improvement (ΔCGI-S=-0.89; 95%CI=-0.93, -0.85) compared to patients with duration >3years (mean ΔCGI-S=-0.73; 95%CI=-0.76, -0.71). Excluding patients with short illness duration led to a change in AP effect estimates but this was not the case for substance use disorder or poor adherence. CONCLUSION: Using certain exclusion criteria in RCTs may impact the drug's effect estimate, particularly when exclusion criteria are AP effect-modifiers representing frequent characteristics among patients with schizophrenia.
OBJECTIVES: To explore the impact upon estimation of drug effect as a result of applying exclusion criteria in randomized-controlled trials (RCT) measuring the efficacy of antipsychotics (AP) in schizophrenia. METHODS: Three characteristics which may act as effect-modifiers of AP, while also common exclusion criteria in RCTs, were identified through literature review: schizophrenia duration, substance use disorder and poor adherence. The SOHO cohort was used to estimate the effect of initiating antipsychotic drugs "A", "B" or "C" (pooled) upon symptom evolution at 3months from baseline (CGI-S scale). "Estimated effectiveness" and "estimated efficacy" were drawn from the "SOHO" and "RCT-like" (patients with none of the above-listed exclusion criteria) samples, respectively. Effect-modification and impact of each exclusion criterion on AP effect estimates were explored using non-adjusted statistics. RESULTS: The "SOHO sample" included 8250 patients initiating drug A, B or C at baseline, whose AP "estimated effectiveness" was ΔCGI-S=-0.78 (95% CI=-0.80, -0.76). The "RCT-like" sub-sample included 5348 (65%) patients whose AP "estimated efficacy" was ΔCGI-S=-0.73 (95% CI=-0.75, -0.70). Patients with short illness duration (≤3years since first AP; n=2436) experienced significant symptom improvement (ΔCGI-S=-0.89; 95%CI=-0.93, -0.85) compared to patients with duration >3years (mean ΔCGI-S=-0.73; 95%CI=-0.76, -0.71). Excluding patients with short illness duration led to a change in AP effect estimates but this was not the case for substance use disorder or poor adherence. CONCLUSION: Using certain exclusion criteria in RCTs may impact the drug's effect estimate, particularly when exclusion criteria are AP effect-modifiers representing frequent characteristics among patients with schizophrenia.
Authors: Clementine Nordon; Constance Battin; Helene Verdoux; Josef Maria Haro; Mark Belger; Lucien Abenhaim; Tjeerd Pieter van Staa Journal: Clin Epidemiol Date: 2017-12-14 Impact factor: 4.790