TY - JOUR
T1 - Can a nonequivalent choice of dosing regimen bias the results of flexible dose double blind trials? The CATIE schizophrenia trial
AU - Rosenheck, Robert A.
AU - Davis, Vicki G.
AU - Davis, Sonia M.
AU - Stroup, Scott
AU - McEvoy, Joseph Patrick
AU - Swartz, Marvin
AU - Lieberman, Jeffrey
N1 - Funding Information:
Dr. Rosenheck reports having received research funding from AstraZeneca Pharmaceuticals LP, Bristol-Myers Squibb, and Eli Lilly and Co.; and consulting fees from Bristol-Myers Squibb, Eli Lilly and Co., and Janssen Pharmaceutica Products. Dr. Lieberman reports having received research funding from AstraZeneca Pharmaceuticals LP, Bristol-Myers Squibb, GlaxoSmithKline, Janssen Pharmaceutica Products, and Pfizer Inc.; and consulting and educational fees from AstraZeneca Pharmaceuticals LP, Bristol-Myers Squibb, Eli Lilly and Co., Forest Pharmaceutical Company, GlaxoSmithKline, Janssen Pharmaceutica Products, Novartis, Pfizer Inc., and Solvay. Dr. Stroup reports having received research funding from Eli Lilly and Co.; and consulting fees from Janssen Pharmaceutica Products, GlaxoSmithKline, and Bristol-Myers Squibb. Dr. McEvoy reports having received research funding from AstraZeneca, Forest Research Institute, Eli Lilly and Co., Janssen Pharmaceutica, and Pfizer Inc.; consulting or advisory board fees from Pfizer Inc. and Bristol-Myers Squibb; and lecture fees from Janssen Pharmaceutica, and Bristol-Myers Squibb. Drs. S David and V Davis report no financial disclosures.
Funding Information:
The first author (RR) had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. This article was based on results from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) project, supported by the National Institute of Mental Health (N01 MH90001). The aim of this project is to examine the comparative effectiveness of antipsychotic drugs in conditions for which their use is clinically indicated, including schizophrenia and Alzheimer's disease. The project was carried out by principal investigators from the University of North Carolina, Duke University, the University of Southern California, the University of Rochester, and Yale University in association with Quintiles, Inc.; the program staff of the Division of Interventions and Services Research of the NIMH; and investigators from 56 sites in the United States (CATIE Study Investigators Group). Medication was provided by AstraZeneca Pharmaceuticals LP, Bristol-Myers Squibb Company, Forest Pharmaceuticals, Inc., Janssen Pharmaceutica Products, L.P., Eli Lilly and Company, Otsuka Pharmaceutical Co., Ltd., Pfizer Inc., and Zenith Goldline Pharmaceuticals, Inc. The Foundation of Hope of Raleigh, NC also supported this work.
PY - 2009/8
Y1 - 2009/8
N2 - Background: One of the major challenges in the design of double-blind flexible-dosing clinical trials comparing active drugs is the selection of dosing regimens that are equivalent across drugs. This study uses data from the CATIE schizophrenia trial to evaluate the hypothesis that drugs that were dosed somewhat higher in the trial than in typical practice would show greater efficacy and more side effects, especially at high capsule levels, than drugs that were dosed at lower relative strengths. Methods: CATIE was a large (N = 1460) randomized trial comparing 5 antipsychotics in patients with chronic schizophrenia. The blind was maintained in CATIE by prescribing identical-looking capsules of each medication. Dosing was flexible, such that PIs could prescribe from one to four capsules per day, and could modify the dose based on a patient's symptoms and side effects. Capsule strengths for olanzapine (7.5 mg) and quetiapine (200 mg) were relatively higher than for risperidone (1.5 mg), perphenazine (8 mg) or ziprasidone (40 mg). Proportional hazards models of time to all cause discontinuation and mixed regression models for continuous measures of symptoms, quality of life and side effects were used to test for interactions between randomly assigned drug and number of capsules prescribed per visit. We hypothesized that if a dosing bias was present, the flex-dosing design would result in a significant interaction such that drugs with higher relative dosing per capsule would be more effective and have more side effects than drugs with lower relative dosing and that this effect would be greatest at the largest prescribed dosing regimen (4 capsules). Results: There were no significant interactions between drug assignment and number of capsules in the proportional hazards analyses of time to all cause discontinuation (p = .77, excluding ziprasidone and .74 in the ziprasidone cohort) or in the mixed model analysis of PANSS symptoms (p = .49), quality of life (p = .45); or measures of tardive dyskinesia (AIMS, p = .47). However a significant interaction was observed on the Barnes akathisia scale (p = .0005), on the Simpson Angus EPS scale (p = .10) and on the analysis of weight (p = 0.014). Paired comparisons did not show the hypothesized pattern of relationships for akathisia or EPS, but such a pattern was suggested for olanzapine in the analysis of weight although it emerged at 2, 3 and 4 capsules indicating a general drug effect rather than a relative dosing difference. Conclusion: Dosing biases do not seem to have affected the results of the CATIE trial.
AB - Background: One of the major challenges in the design of double-blind flexible-dosing clinical trials comparing active drugs is the selection of dosing regimens that are equivalent across drugs. This study uses data from the CATIE schizophrenia trial to evaluate the hypothesis that drugs that were dosed somewhat higher in the trial than in typical practice would show greater efficacy and more side effects, especially at high capsule levels, than drugs that were dosed at lower relative strengths. Methods: CATIE was a large (N = 1460) randomized trial comparing 5 antipsychotics in patients with chronic schizophrenia. The blind was maintained in CATIE by prescribing identical-looking capsules of each medication. Dosing was flexible, such that PIs could prescribe from one to four capsules per day, and could modify the dose based on a patient's symptoms and side effects. Capsule strengths for olanzapine (7.5 mg) and quetiapine (200 mg) were relatively higher than for risperidone (1.5 mg), perphenazine (8 mg) or ziprasidone (40 mg). Proportional hazards models of time to all cause discontinuation and mixed regression models for continuous measures of symptoms, quality of life and side effects were used to test for interactions between randomly assigned drug and number of capsules prescribed per visit. We hypothesized that if a dosing bias was present, the flex-dosing design would result in a significant interaction such that drugs with higher relative dosing per capsule would be more effective and have more side effects than drugs with lower relative dosing and that this effect would be greatest at the largest prescribed dosing regimen (4 capsules). Results: There were no significant interactions between drug assignment and number of capsules in the proportional hazards analyses of time to all cause discontinuation (p = .77, excluding ziprasidone and .74 in the ziprasidone cohort) or in the mixed model analysis of PANSS symptoms (p = .49), quality of life (p = .45); or measures of tardive dyskinesia (AIMS, p = .47). However a significant interaction was observed on the Barnes akathisia scale (p = .0005), on the Simpson Angus EPS scale (p = .10) and on the analysis of weight (p = 0.014). Paired comparisons did not show the hypothesized pattern of relationships for akathisia or EPS, but such a pattern was suggested for olanzapine in the analysis of weight although it emerged at 2, 3 and 4 capsules indicating a general drug effect rather than a relative dosing difference. Conclusion: Dosing biases do not seem to have affected the results of the CATIE trial.
KW - Antipsychotic medications
KW - Clinical trials
KW - Schizophrenia
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U2 - 10.1016/j.schres.2009.06.002
DO - 10.1016/j.schres.2009.06.002
M3 - Article
C2 - 19545976
AN - SCOPUS:67649847888
SN - 0920-9964
VL - 113
SP - 12
EP - 18
JO - Schizophrenia Research
JF - Schizophrenia Research
IS - 1
ER -