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Original Investigation
January 9, 2018

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

Author Affiliations
  • 1Ray Dolby Brain Health Center, California Pacific Medical Center, San Francisco
  • 2Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts
  • 3Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany
  • 4University of Exeter Medical School, Exeter, England
  • 5Banner Alzheimer’s Institute, Phoenix, Arizona
  • 6Alzheimer’s Disease and Other Cognitive Disorders Unit, IDIBAPS, Hospital Clinic i Universitari, Barcelona, Spain
  • 7Barcelonaβeta Brain Research Centre, Pasqual Maragall Foundation, Barcelona, Spain
  • 8H. Lundbeck A/S, Valby, Denmark
  • 9Now with Genmab, Copenhagen, Denmark
  • 10Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas, Nevada
JAMA. 2018;319(2):130-142. doi:10.1001/jama.2017.20373
Key Points

Question  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?

Findings  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.

Meaning  The findings do not support the use of idalopirdine for the treatment of Alzheimer disease.

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

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