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Targeting Prodromal Alzheimer Disease With Avagacestat: A Randomized Clinical Trial


Coric, Vladimir, Salloway, Stephen, van Dyck, Christopher H., Dubois, Bruno, Andreasen, Niels, Brody, Mark, Curtis, Craig, Soininen, Hilkka, Thein, Stephen, Shiovitz, Thomas, Pilcher, Gary, Ferris, Steven, Colby, Susan, Kerselaers, Wendy, Dockens, Randy, Soares, Holly, Kaplita, Stephen, Luo, Feng, Pachai, Chahin, Bracoud, Luc, Mintun, Mark, Grill, Joshua D., Marek, Ken, Seibyl, John, Cedarbaum, Jesse M., Albright, Charles, Feldman, Howard H., Berman, Robert M.


JAMA Neurology, Volume: 72, No.: 11, Pages.: 1324-1333

Year of Publication



Importance: Early identification of Alzheimer disease (AD) is important for clinical management and affords the opportunity to assess potential disease-modifying agents in clinical trials. To our knowledge, this is the first report of a randomized trial to prospectively enrich a study population with prodromal AD (PDAD) defined by cerebrospinal fluid (CSF) biomarker criteria and mild cognitive impairment (MCI) symptoms.; Objectives: To assess the safety of the γ-secretase inhibitor avagacestat in PDAD and to determine whether CSF biomarkers can identify this patient population prior to clinical diagnosis of dementia.; Design, Setting, and Participants: A randomized, placebo-controlled phase 2 clinical trial with a parallel, untreated, nonrandomized observational cohort of CSF biomarker-negative participants was conducted May 26, 2009, to July 9, 2013, in a multicenter global population. Of 1358 outpatients screened, 263 met MCI and CSF biomarker criteria for randomization into the treatment phase. One hundred two observational cohort participants who met MCI criteria but were CSF biomarker-negative were observed during the same study period to evaluate biomarker assay sensitivity.; Interventions: Oral avagacestat or placebo daily.; Main Outcomes and Measure: Safety and tolerability of avagacestat.; Results: Of the 263 participants in the treatment phase, 132 were randomized to avagacestat and 131 to placebo; an additional 102 participants were observed in an untreated observational cohort. Avagacestat was relatively well tolerated with low discontinuation rates (19.6%) at a dose of 50 mg/d, whereas the dose of 125 mg/d had higher discontinuation rates (43%), primarily attributable to gastrointestinal tract adverse events. Increases in nonmelanoma skin cancer and nonprogressive, reversible renal tubule effects were observed with avagacestat. Serious adverse event rates were higher with avagacestat (49 participants [37.1%]) vs placebo (31 [23.7%]), attributable to the higher incidence of nonmelanoma skin cancer. At 2 years, progression to dementia was more frequent in the PDAD cohort (30.7%) vs the observational cohort (6.5%). Brain atrophy rate in PDAD participants was approximately double that of the observational cohort. Concordance between abnormal amyloid burden on positron emission tomography and pathologic CSF was approximately 87% (κ = 0.68; 95% CI, 0.48-0.87). No significant treatment differences were observed in the avagacestat vs placebo arm in key clinical outcome measures.; Conclusions and Relevance: Avagacestat did not demonstrate efficacy and was associated with adverse dose-limiting effects. This PDAD population receiving avagacestat or placebo had higher rates of clinical progression to dementia and greater brain atrophy compared with CSF biomarker-negative participants. The CSF biomarkers and amyloid positron emission tomography imaging were correlated, suggesting that either modality could be used to confirm the presence of cerebral amyloidopathy and identify PDAD.; Trial Registration: Identifier: NCT00890890.;

Bibtex Citation

@article{Coric_2015, doi = {10.1001/jamaneurol.2015.0607}, url = {}, year = 2015, month = {nov}, publisher = {American Medical Association ({AMA})}, volume = {72}, number = {11}, pages = {1324}, author = {Vladimir Coric and Stephen Salloway and Christopher H. van Dyck and Bruno Dubois and Niels Andreasen and Mark Brody and Craig Curtis and Hilkka Soininen and Stephen Thein and Thomas Shiovitz and Gary Pilcher and Steven Ferris and Susan Colby and Wendy Kerselaers and Randy Dockens and Holly Soares and Stephen Kaplita and Feng Luo and Chahin Pachai and Luc Bracoud and Mark Mintun and Joshua D. Grill and Ken Marek and John Seibyl and Jesse M. Cedarbaum and Charles Albright and Howard H. Feldman and Robert M. Berman}, title = {Targeting Prodromal Alzheimer Disease With Avagacestat}, journal = {{JAMA} Neurology} }


administration & dosage, adverse, adverse effects, aged, aged, 80 and over, alzheimer, alzheimer disease, atrophy, avagacestat, cerebrospinal fluid, chemically induced, disease, disease progression, drug therapy, events, female, humans, inhibitor, male, mild cognitive impairment, oxadiazoles, pathology, pharmacology, prevention & control, prodromal, prodromal symptoms, radionuclide imaging, secretase, skin neoplasms, sulfonamides, treatment failure

Countries of Study


Types of Dementia

Mild Cognitive Impairment (MCI)

Types of Study

Cohort Study

Type of Outcomes

Cognition, Other, Risk reduction (of dementia and co-morbidities)

Type of Interventions

Pharmaceutical Interventions, Risk Factor Modification

Risk Factor Modifications

At risk population

Pharmaceutical Interventions