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Comparative Study
. 2014 Feb;11(1):114-27.
doi: 10.1177/1740774513512184. Epub 2013 Dec 17.

Clinical and Health Outcomes Initiative in Comparative Effectiveness for Bipolar Disorder (Bipolar CHOICE): a pragmatic trial of complex treatment for a complex disorder

Collaborators, Affiliations
Comparative Study

Clinical and Health Outcomes Initiative in Comparative Effectiveness for Bipolar Disorder (Bipolar CHOICE): a pragmatic trial of complex treatment for a complex disorder

Andrew A Nierenberg et al. Clin Trials. 2014 Feb.

Abstract

Background: Classic and second-generation antipsychotic mood stabilizers are recommended for treatment of bipolar disorder, yet there are no randomized comparative effectiveness studies that have examined the 'real-world' advantages and disadvantages of these medications.

Purpose: We describe the strategic decisions in the design of the Clinical and Health Outcomes Initiative in Comparative Effectiveness for Bipolar Disorder (Bipolar CHOICE). This article outlines the key issues and solutions the investigators faced in designing a clinical trial that would maximize generalizability and inform real-world clinical treatment of bipolar disorder.

Methods: Bipolar CHOICE was a 6-month, multi-site, prospective, randomized clinical trial of outpatients with bipolar disorder. This study compares the effectiveness of quetiapine versus lithium, each with adjunctive personalized treatments (APTs). The co-primary outcomes selected are the overall benefits and harms of the study medications (as measured by the Clinical Global Impression-Efficacy Index) and the Necessary Clinical Adjustments (a measure of the number of medication changes). Secondary outcomes are continuous measures of mood, the Framingham General Cardiovascular Risk Score, and the Longitudinal Interval Follow up Evaluation Range of Impaired Functioning Tool (LIFE-RIFT).

Results: The final study design consisted of a single-blind, randomized comparative effectiveness trial of quetiapine versus lithium, plus APT, across 10 sites. Other important study considerations included limited exclusion criteria to maximize generalizability, flexible dosing of APT medications to mimic real-world treatment, and an intent-to-treat analysis plan. In all, 482 participants were randomized to the study, and 364 completed the study.

Limitations: The potential limitations of the study include the heterogeneity of APT, selection of study medications, lack of a placebo-control group, and participants' ability to pay for study medications.

Conclusion: We expect that this study will inform our understanding of the benefits and harms of lithium, a classic mood stabilizer, compared to quetiapine, a second-generation antipsychotic with broad-spectrum activity in bipolar disorder, and will provide an example of a well-designed and well-conducted randomized comparative effectiveness clinical trial.

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Conflict of interest statement

Conflict of Interest Statement

Dr. Nierenberg is a consultant for Abbott Laboratories, Astra Zeneca, Basilea, BrainCells Inc., Brandeis University, Bristol-Myers Squibb, Cephalon, Corcept, Eli Lilly & Co., Forest, Genaissance, GlaxoSmithKline, Innapharma, Janssen Pharmaceutica, Jazz Pharmaceuticals, Lundbeck, Merck, Novartis, PamLabs, PGx Health, Pfizer, Ridge Diagnostics, Roche, Sepracor, Schering-Plough, Shire, Somerset, Sunovion, Takeda, Targacept, and Teva. He is a stakeholder in Appliance Computing, Inc. (MindSite); Brain Cells, Inc., InfoMed (potential share of income). He receives research support from AHRQ, Bristol-Myers Squibb, Cederroth, Cyberonics, Elan, Forest Pharmaceuticals, GlaxoSmithKline, Janssen Pharmaceutica, Lichtwer Pharma, Eli Lilly, Mylin (formerly Dey Pharmaceuticals), NARSAD, NIMH, Pamlabs, Pfizer, Shire, Stanley Foundation, and Wyeth-Ayerst. Honoraria include MGH Psychiatry Academy in the past 3 years (Prior to 3 years ago, honoraria from Bristol-Myers Squibb, Cyberonics, Forest Pharmaceuticals, GlaxoSmithKline, Eli Lilly, Shire, Wyeth-Ayerst). Dr. Nierenberg receives other income from legal case reviews for CRICO, MBL Publishing for past services as Editor-in-chief of CNS Spectrums, Slack Inc. for services as Associate Editor of Psychiatric Annals, and Editorial Board, Mind Mood Memory, Belvior Publications. He has copyright joint ownership with MGH for Structured Clinical Interview for MADRS and Clinical Positive Affect Scale and additional honoraria from ADURS, American Society for Clinical Psychopharmacology and Zucker Hillside Hospital and Forest and Janssen, Biomedical Development, Boston Center for the Arts, University of Pisa, University of Wisconsin at Madison, University Texas Southwest at Dallas, Health New England and Harold Grinspoon Charitable Foundation and Eli Lilly and AstraZeneca, Brandeis University, International Society for Bipolar Disorder, 2nd East Asian Bipolar Forum, Mid-Atlantic Permanente Research Institute, Up-to-Date.

Dr. Sylvia was a shareholder in Concordant Rater Systems and serves as a consultant for United Biosource Corporation and Clintara.

Dr. Leon served on independent Data and Safety Monitoring Boards for AstraZeneca, Sunovion, and Pfizer. He served as a consultant and advisor to FDA, NIMH, MedAvante, and Roche and had equity in MedAvante.

Dr. Reilly-Harrington receives royalties from Oxford University Press and the American Psychological Association and serves as a consultant for United Biosource Corporation.

Ms. Shesler reports no competing interests.

Dr. McElroy is a consultant to or member of the scientific advisory boards of Alkermes, Corcept, MedAvante, Shire, and Teva. She is a principal or co-investigator on studies sponsored by the Agency for Healthcare Research & Quality (AHRQ), Alkermes, AstraZeneca, Cephalon, Eli Lilly and Company, Marriott Foundation, National Institute of Mental Health, Orexigen Therapeutics, Inc., Shire, Takeda Pharmaceutical Company Ltd., and Transcept Pharmaceutical, Inc. She is also an inventor on United States Patent No. 6,323,236 B2, Use of Sulfamate Derivatives for Treating Impulse Control Disorders, and along with the patient’s assignee, University of Cincinnati, Cincinnati, Ohio, has received payments from Johnson & Johnson, which has exclusive rights under the patent.

Dr. Friedman receives grant support from Novartis, St. Jude Medical, Medtronics, Repligen, Astra-Zeneca, Roche, and Takeda. He receives royalties from Springer.

Dr. Thase reports no conflicts of interest specifically pertaining to this project. During the past three years he has been an advisor/consultant: to Alkermes, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Forest Laboratories, GlaxoSmithKline, Janssen Pharmaceuticals, Lundbeck, MedAvante, Merck, Mylan, Neuronetics, Otsuka, Pamlab, PharmaNeuroboost, Pfizer, Rexahn, Roche, Shire, Sunovion, Supernus, Takeda, and Teva, as well as the US Food and Drug Administration and the National Institute of Mental Health. During the same time frame, Dr. Thase has received honoraria for talks from AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Merck, and Pfizer and he has received research grants from Alkermes, AstraZeneca, Eli Lilly, Forest, GlaxoSmithKline, Otsuka, PharmaNeuroboost, and Roche, as well as the National Institute of Mental Health and the Agency for Healthcare Research and Quality.

Dr. Shelton has been a consultant for Bristol-Myers Squibb Company; Cyberonics, Inc.; Eli Lilly and Company; Janssen Pharmaceutica; Medtronic, Inc.; Pamlab, Inc.; Pfizer, Inc.; Ridge Diagnostics; and Takeda Pharmaceuticals. He has grant support from Bristol-Myers Squibb; Eli Lilly and Company; Elan, Corp.; Euthymics Bioscience; Forest Pharmaceuticals; Janssen Pharmaceutica; Naurex, Inc.; Novartis Pharmaceuticals; Otsuka Pharmaceuticals; Pamlab, Inc.; Pfizer, Inc.; Repligen, Corp.; Ridge Diagnostics; St. Jude Medical, Inc.; Takeda Pharmaceuticals.

Dr. Bowden is a research collaborator with Elan and a consultant with Teva, He has no participation with speaker bureaus, nor does he or his wife hold any equity position in any biomedical or pharmaceutical corporation.

Dr. Tohen was a full time employee at Eli Lilly and Company (up to 2008). He has received honoraria from or consulted for AstraZeneca, Bristol Myers Squibb, Glaxo SmithKline, Eli Lilly and Company, Johnson & Johnson, Sepracor, Otsuka, Merck, Sunovion, Forest, Lundbeck, Wyeth and Wiley Publishing; his spouse is a current employee and minor stockholder at Eli Lilly and Company.

Dr. Singh has received research funding from Astra Zeneca and Novartis. He is on the Speaker Bureau for Merck and Sunovion.

Dr. Deckersbach has received research support from NIMH, NARSAD, TSA, OCF, Tufts University, NIH, NIA, Janssen Pharmaceuticals, the Forest Research Institute, Shire Development Inc., Medtronic, Cyberonics, Northstar. He has received honoraria, consultation fees and/or royalties from the following: Medacorp, MGH Psychiatry Academy, BrainCells Inc., Systems Research and Applications Corporation, Boston University, Tufts University, the Catalan Agency for Health Technology Assessment and Research, the National Association of Social Workers Massachusetts, the Massachusetts Medical Society, and Oxford University Press.

Dr. Ketter receives research support from the Agency for Healthcare Research and Quality, AstraZeneca Pharmaceuticals LP, Cephalon Inc., Eli Lilly and Company, National Institute of Mental Health, Pfizer Inc., and Sunovion Pharmaceuticals. He receives consultant fees from Allergan, Inc., Avanir Pharmaceuticals, Bristol-Myers Squibb Company, Cephalon Inc., Forest Pharmaceuticals, Janssen Pharmaceutica Products, LP, Merck & Co., Inc., Sunovion Pharmaceuticals, and Teva Pharmaceuticals. He has lecture honoraria from Abbott Laboratories, Inc., AstraZeneca Pharmaceuticals LP, GlaxoSmithKline, and Otsuka Pharmaceuticals and receives publication royalties from American Psychiatric Publishing, Inc. In addition, Dr. Ketter’s spouse is an employee of and holds stock in Janssen Pharmaceuticals.

Dr. Kocsis has received research grants and contracts from AHRQ, NIMH, NIDA, Burroughs Wellcome Trust, Pritzker Consortium, Takeda, Forest, Astra Zeneca, Roche. He is on the speaker’s bureau at Pfizer and Merck and on the advisory board at Corcept.

Dr. McInnis has received grants for research support from NIMH, the Heinz C Prechter Research Fund, and the Michigan Institute for Clinical Health Research (MICHR). MM has received consulting income from the Qatar National Research Foundation and Merck Pharmaceuticals.

Dr. Schoenfeld has an ongoing consulting relationship with the following pharmaceutical companies, Biogen, Neuronova, Cytokinetics, Edison Pharmaceuticals, Galaxo Smith Kine, Merck, Agennix, Alexion and Pfizer. He also has a consulting relationship with Aptiv a contract research organization.

Dr. Bobo has received research support from the NIMH, NARSAD and Cephalon, Inc. In the past, he has received honoraria from Janssen Pharmaceutica and Pfizer, Inc.

Dr. Calabrese receives federal funding from the Department of Defense, Health Resources Services Administration, and NIMH; he receives research funding or grants from the following private industries or nonprofit funds: Cleveland Foundation, NARSAD, and Stanley Medical Research Institute; he receives research grants from Abbott, AstraZeneca, Cephalon, GlaxoSmithKline, Janssen, Eli Lilly, and Lundbeck; he serves on the advisory boards of Abbott, AstraZeneca, Bristol-Myers Squibb, Dainippon Sumitomo Pharma, Forest, France Foundation, GlaxoSmithKline, Janssen, NeuroSearch, OrthoMcNeil, Repligen, Schering-Plough, Servier, Solvay/Wyeth, Takeda, and Supernus Pharmaceuticals; and he reports CME activities with AstraZeneca, Bristol-Myers Squibb, France Foundation, GlaxoSmithKline, Janssen, Johnson & Johnson, Schering-Plough, and Solvay/Wyeth.

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