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Original Investigation | Clinical Trial

Targeting Prodromal Alzheimer Disease With Avagacestat A Randomized Clinical Trial

Vladimir Coric, MD1; Stephen Salloway, MD2; Christopher H. van Dyck, MD3; Bruno Dubois, MD4; Niels Andreasen, MD, PhD5; Mark Brody, MD6; Craig Curtis, MD7; Hilkka Soininen, MD8; Stephen Thein, PhD9; Thomas Shiovitz, MD10; Gary Pilcher, PhD1; Steven Ferris, PhD11; Susan Colby, BA1; Wendy Kerselaers, BA1; Randy Dockens, PhD1; Holly Soares, PhD1; Stephen Kaplita, MSc1; Feng Luo, PhD1; Chahin Pachai, PhD12; Luc Bracoud, MSc12; Mark Mintun, MD13; Joshua D. Grill, PhD14; Ken Marek, MD15; John Seibyl, MD15; Jesse M. Cedarbaum, MD1; Charles Albright, PhD1; Howard H. Feldman, MD16; Robert M. Berman, MD1
[+] Author Affiliations
1Global Clinical Research, Bristol-Myers Squibb, Wallingford, Connecticut
2Department of Neurology, Brown Medical School, Butler Hospital, Providence, Rhode Island
3Department of Psychiatry, School of Medicine, Yale University, New Haven, Connecticut
4Dementia Research Center, Department of Neurology, Cognition, Neuro-imagerie et maladies du Cerveau, University Pierre et Marie Curie Paris 6, Hôpital de la Salpétrière, Paris, France
5Department of Neurobiology, Karolinska Institute, Stockholm, Sweden
6Brain Matters Research, Delray Beach, Florida
7Compass Research, Orlando, Florida
8Department of Neurology, University of Eastern Finland, Kuopio, Finland
9Pacific Research Network Inc, San Diego, California
10California Neuroscience Research Medical Group Inc, Sherman Oaks
11Department of Psychiatry, New York University Langone Medical Center, New York
12BioClinica Inc, Newtown, Pennsylvania
13Avid Radiopharmaceuticals, Philadelphia, Pennsylvania
14Mary S. Easton Center for Alzheimer’s Disease Research, University of California at Los Angeles
15Institute for Neurodegenerative Disorders, New Haven, Connecticut
16University of British Columbia, Vancouver, British Columbia, Canada
JAMA Neurol. 2015;72(11):1324-1333. doi:10.1001/jamaneurol.2015.0607.
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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  clinicaltrials.gov Identifier: NCT00890890

Figures in this Article


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Figure 1.
CONSORT Flow Diagram: Patient Disposition

Patient flow in the randomized treatment phase (avagacestat vs placebo) for cerebrospinal fluid (CSF) biomarker–positive participants and the observational cohort for CSF biomarker–negative participants. After all participants in the treatment phase had the opportunity to receive double-blind treatment for at least 1 year, the study was terminated early after an interim analysis suggested a lack of efficacy on key clinical outcome measures. MCI indicates mild cognitive impairment; MRI, magnetic resonance imaging; and PET, positron emission tomography.

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Figure 2.
Cerebrospinal Fluid (CSF) Biomarker Entry Criteria on Time to Adjudicated Progression to Dementia

Number of study participants at risk at each time point who had not progressed to dementia. All participants met clinical criteria for mild cognitive impairment but only those in the randomized arms (avagacestat and placebo) met pathologic CSF biomarker criteria cutoff values of Aβ42 level of less than 200 pg/mL or total tau [T-tau]:Aβ42 ratio of 0.39 or greater. Observational cohort participants did not meet pathologic CSF criteria at study entry. Progression from prodromal AD to dementia was confirmed by an independent adjudication committee. At 2 years, rates of progression to dementia were 30.7% in avagacestat participants, 29.0% in the placebo group, and 6.5% in the observational cohort.

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