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Does idalopirdine, a selective 5-hydroxytryptamine-6 receptor antagonist, improve cognitive change in patients with mild to moderate Alzheimer disease when added to cholinesterase inhibitors?
In 3 randomized clinical trials that included a total of 2525 patients with Alzheimer disease treated with cholinesterase inhibitors, the added use of idalopirdine compared with placebo did not decrease cognitive loss over 24 weeks.
The findings do not support the use of idalopirdine for the treatment of Alzheimer disease.
New therapeutic approaches for Alzheimer disease (AD) are needed.
To assess whether idalopirdine, a selective 5-hydroxytryptamine-6 receptor antagonist, is effective for symptomatic treatment of mild to moderate AD.
Design, Setting, and Participants
Three randomized clinical trials that included 2525 patients aged 50 years or older with mild to moderate AD (study 1: n = 933 patients at 119 sites; study 2: n = 858 at 158 sites; and study 3: n = 734 at 126 sites). The 24-week studies were conducted from October 2013 to January 2017; final follow-up on January 12, 2017.
Idalopirdine (10, 30, or 60 mg/d) or placebo added to cholinesterase inhibitor treatment (donepezil in studies 1 and 2; donepezil, rivastigmine, or galantamine in study 3).
Main Outcomes and Measures
Primary end point in all 3 studies: change in cognition total score (range, 0-70; a lower score indicates less impairment) from baseline to 24 weeks measured by the 11-item cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-Cog); key secondary end points: Alzheimer’s Disease Cooperative Study–Clinical Global Impression of Change Scale and 23-item Activities of Daily Living Inventory scores. Dose group efficacy required a significant benefit over placebo for the primary end point and 1 or more key secondary end points. Safety data and adverse event profiles were recorded.
Among 2525 patients randomized in the 3 trials (mean age, 74 years; mean baseline ADAS-Cog total score, 26; between 62% and 65% of participants were women), 2254 (89%) completed the studies. In study 1, the mean change in ADAS-Cog total score between baseline and 24 weeks was 0.37 for the 60-mg dose of idalopirdine group, 0.61 for the 30-mg dose group, and 0.41 for the placebo group (adjusted mean difference vs placebo, 0.05 [95% CI, −0.88 to 0.98] for the 60-mg dose group and 0.33 [95% CI, −0.59 to 1.26] for the 30-mg dose group). In study 2, the mean change in ADAS-Cog total score between baseline and 24 weeks was 1.01 for the 30-mg dose of idalopirdine group, 0.53 for the 10-mg dose group, and 0.56 for the placebo group (adjusted mean difference vs placebo, 0.63 [95% CI, −0.38 to 1.65] for the 30-mg dose group; given the gated testing strategy and the null findings at the 30-mg dose, statistical comparison of the 10-mg dose was not performed). In study 3, the mean change in ADAS-Cog total score between baseline and 24 weeks was 0.38 for the 60-mg dose of idalopirdine group and 0.82 for the placebo group (adjusted mean difference vs placebo, −0.55 [95% CI, −1.45 to 0.36]). Treatment-emergent adverse events occurred in between 55.4% and 69.7% of participants in the idalopirdine groups vs between 56.7% and 61.4% of participants in the placebo groups.
Conclusions and Relevance
In patients with mild to moderate AD, the use of idalopirdine compared with placebo did not improve cognition over 24 weeks of treatment. These findings do not support the use of idalopirdine for the treatment of AD.
clinicaltrials.gov Identifiers: NCT01955161, NCT02006641, and NCT02006654
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Corresponding Author: Alireza Atri, MD, PhD, Ray Dolby Brain Health Center, California Pacific Medical Center Davies Campus, 45 Castro St, Ste 220, San Francisco, CA 94114 (email@example.com).
Accepted for Publication: December 5, 2017.
Author Contributions: Dr Atri 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. Drs Atri, Frölich, Ballard, Tariot, Molinuevo, and Cummings served as global, European, or US coordinating principal investigators for the idalopirdine phase 3 STAR clinical trial program.
Concept and design: Atri, Frölich, Ballard, Tariot, Boneva, Windfeld, Cummings.
Acquisition, analysis, or interpretation of data: All authors.
Drafting of the manuscript: Atri, Frölich, Ballard, Molinueovo, Windfeld, Cummings.
Critical revision of the manuscript for important intellectual content: All authors.
Statistical analysis: Atri, Windfeld, Raket.
Administrative, technical, or material support: Raket, Cummings.
Supervision: All authors.
Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Atri reported receiving honoraria for consulting, providing educational lectures, programs, and materials, or serving on advisory boards for Allergan, the Alzheimer’s Association, Axovant, Biogen, Grifols, Harvard Medical School Graduate Continuing Education, Lundbeck, Merck, Sunovion, and Suven; receiving book royalties from Oxford University Press; and having institutional contracts or receiving investigational clinical trial–related funding from the American College of Radiology, AbbVie, Avid, Biogen, Lilly, Lundbeck, Merck, and vTV. Dr Frölich reported receiving honoraria for consulting, providing educational lectures, materials, and programs, or serving on advisory boards for Avid–Eli Lilly & Co, Avraham Pharmaceuticals, Axon Neuroscience, Boehringer Ingelheim, GE Healthcare, H. Lundbeck A/S, Merck Sharpe & Dohme, Novartis, Nutricia, Pfizer, Piramal Imaging, Schwabe Pharma, TAD Pharma, and Takeda. Dr Ballard reported receiving research grants from Acadia and H. Lundbeck A/S; and receiving honoraria from Acadia, Bristol-Myers Squibb, Heptares, Lilly, H. Lundbeck A/S, Novartis, Orion, Otsuka, and Roche. Dr Tariot reported receiving consulting fees from Abbott Laboratories, AbbVie, AC Immune, Auspex, Boehringer Ingelheim, California Pacific Medical Center, Clintara, CME Inc, Corium, GliaCure, INSYS, and T3D; receiving consulting fees and research support from AstraZeneca, Avanir, Cognoptix, Lilly, H. Lundbeck A/S, Merck and Company, and Takeda; receiving research support from Elan, Functional Neuromodulation, Genentech, Novartis, Roche, Targacept, the National Institute on Aging, and the Arizona Department of Health Services; owning stock options in Adamas; and being listed as a contributor to a patent owned by the University of Rochester. Dr Molinuevo reported receiving honoraria for consulting, providing educational lectures, or serving on advisory boards for ABL, Axovant, Boehringer Ingelheim, Eli Lilly & Co, Fujirebio, GE Healthcare, H. Lundbeck A/S, Merck Sharpe & Dohme, Novartis, Pfizer, Piramal Imaging, Roche, and Roche Diagnostics. Drs Boneva and Raket are full-time employees of H. Lundbeck A/S. Dr Windfeld was a full-time employee of H. Lundbeck A/S during the design and implementation of the studies reported herein and through the drafting and submission of the first version of the manuscript. Dr Cummings reported serving as a consultant to AbbVie, Acadia, Actinogen, Adamas, Alzheon, Anavex, Astellas, Avanir, Avid, Axovant, Boehringer Ingelheim, Bracket, Eisai, GE Healthcare, Genentech, Intra-Cellular Therapies, Lilly, H. Lundbeck A/S, MedAvante, Merck, Neurocog, Novartis, Orion, Otsuka, Pfizer, Piramal, QR Pharma, reMYND, Resverlogix, Roche, Suven, Takeda, Toyama, and Transition; receiving research support from Avid and Teva; owning stock options in Prana, Neurokos, Adamas, MedAvante, and QR Pharma; and owning the copyright of the Neuropsychiatric Inventory and all its derivatives. No other disclosures were reported.
Funding/Support: This research was supported by funding from H. Lundbeck A/S.
Role of the Funder/Sponsor: H. Lundbeck A/S was responsible for the design and conduct of the study; for the collection, management, analysis of data; and aided in the interpretation of the data. A medical writer employed by the study sponsor assisted in the preparation of the manuscript. The study sponsor had a role in the review and approval of the manuscript or the decision to submit for publication because 3 of the co-authors were employed by the sponsor at the time of the study.
Meeting Presentation: Presented in part at the Alzheimer’s Association International Conference; July 19, 2017; London, England.
Additional Contributions: We acknowledge the contributions of the principal investigators in these original studies; the Idalopirdine Development Teams; the STAR Program Teams, operational partners, and site staff and investigators; and those individuals serving on the data and safety monitoring board from the respective trials. In addition, we express our gratitude for the commitment of the study participants and their caregivers, without whose generous contributions and dedication this research would not be possible. Brian Odlaug, PhD (H. Lundbeck A/S), provided medical writing support in accordance with good publication practice guidelines.
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