Effect of Idalopirdine as Adjunct to Cholinesterase Inhibitors on Change in Cognition in Patients With Alzheimer Disease: Three Randomized Clinical Trials

Abstract

Importance: New therapeutic approaches for Alzheimer disease (AD) are needed.

Objective: 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.

Interventions: 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.

Results: 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.

Trial registration: clinicaltrials.gov Identifiers: NCT01955161, NCT02006641, and NCT02006654.

Conflict of interest statement

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.

Figures

Figure 1.. Patient Enrollment and Flow in Study 1 (Placebo Compared With 30 mg or 60 mg of Idalopirdine)

All patients were taking stable doses of donepezil.

Figure 2.. Patient Enrollment and Flow in Study 2 (Placebo Compared With 10 mg or 30 mg of Idalopirdine)

All patients were taking stable doses of donepezil.

Figure 3.. Patient Enrollment and Flow in Study 3 (Placebo Compared With 60 mg of Idalopirdine)

All patients were taking stable doses of donepezil, rivastigmine, or galantamine.

Figure 4.. Primary and Key Secondary Efficacy Results in the 3 Studies

Error bars indicate 95% CIs. The primary end point was change in cognition total score (range, 0 to 70; a lower score indicates less impairment) from baseline to 24 weeks as assessed by the 11-item cognitive subscale of the Alzheimer’s Disease Assessment Scale. Key secondary end points were changes in activities of daily living (function) measured by the 23-item Alzheimer’s Disease Cooperative Study Activities of Daily Living Inventory (total score range, 0-78; higher scores indicate less impairment) and overall clinical response (global outcome) measured by the Alzheimer’s Disease Cooperative Study–Clinical Global Impression of Change Scale from baseline to 24 weeks (rated from 1 [normal, not at all ill] to 7 [among the most extremely ill patients] at baseline; at subsequent visits, rated from 1 [very much improved] to 7 [very much worse]; 4 indicates no change). These end points were rated at baseline and at weeks 4, 12, and 24 (completion or withdrawal from the study). The targeted effect sizes for idalopirdine treatment was a difference of −2 points vs placebo for the cognitive subscale of the Alzheimer’s Disease Assessment Scale, a difference of 2 points vs placebo for the 23-item Alzheimer’s Disease Cooperative Study Activities of Daily Living Inventory, and a difference of −0.25 points vs placebo for the Alzheimer’s Disease Cooperative Study–Clinical Global Impression of Change Scale.