title: Targeting Prodromal Alzheimer Disease With Avagacestat: A Randomized Clinical Trial.
abstract: OBJECTIVE
  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.
  
  
  OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  Oral avagacestat or placebo daily.
  
  
  METHODS
  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
  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.
  
  
  BACKGROUND
  clinicaltrials.gov Identifier: NCT00890890.
authors.affiliation: Global Clinical Research, Bristol-Myers Squibb, Wallingford, Connecticut.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Coric
authors.affiliation: Department of Neurology, Brown Medical School, Butler Hospital, Providence, Rhode Island.
authors.forename: Stephen
authors.initials: S
authors.lastname: Salloway
authors.affiliation: Department of Psychiatry, School of Medicine, Yale University, New Haven, Connecticut.
authors.forename: Christopher H
authors.initials: CH
authors.lastname: van Dyck
authors.affiliation: Dementia 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.
authors.forename: Bruno
authors.initials: B
authors.lastname: Dubois
authors.affiliation: Department of Neurobiology, Karolinska Institute, Stockholm, Sweden.
authors.forename: Niels
authors.initials: N
authors.lastname: Andreasen
authors.affiliation: Brain Matters Research, Delray Beach, Florida.
authors.forename: Mark
authors.initials: M
authors.lastname: Brody
authors.affiliation: Compass Research, Orlando, Florida.
authors.forename: Craig
authors.initials: C
authors.lastname: Curtis
authors.affiliation: Department of Neurology, University of Eastern Finland, Kuopio, Finland.
authors.forename: Hilkka
authors.initials: H
authors.lastname: Soininen
authors.affiliation: Pacific Research Network Inc, San Diego, California.
authors.forename: Stephen
authors.initials: S
authors.lastname: Thein
authors.affiliation: California Neuroscience Research Medical Group Inc, Sherman Oaks.
authors.forename: Thomas
authors.initials: T
authors.lastname: Shiovitz
authors.affiliation: Global Clinical Research, Bristol-Myers Squibb, Wallingford, Connecticut.
authors.forename: Gary
authors.initials: G
authors.lastname: Pilcher
authors.affiliation: Department of Psychiatry, New York University Langone Medical Center, New York.
authors.forename: Steven
authors.initials: S
authors.lastname: Ferris
authors.affiliation: Global Clinical Research, Bristol-Myers Squibb, Wallingford, Connecticut.
authors.forename: Susan
authors.initials: S
authors.lastname: Colby
authors.affiliation: Global Clinical Research, Bristol-Myers Squibb, Wallingford, Connecticut.
authors.forename: Wendy
authors.initials: W
authors.lastname: Kerselaers
authors.affiliation: Global Clinical Research, Bristol-Myers Squibb, Wallingford, Connecticut.
authors.forename: Randy
authors.initials: R
authors.lastname: Dockens
authors.affiliation: Global Clinical Research, Bristol-Myers Squibb, Wallingford, Connecticut.
authors.forename: Holly
authors.initials: H
authors.lastname: Soares
authors.affiliation: Global Clinical Research, Bristol-Myers Squibb, Wallingford, Connecticut.
authors.forename: Stephen
authors.initials: S
authors.lastname: Kaplita
authors.affiliation: Global Clinical Research, Bristol-Myers Squibb, Wallingford, Connecticut.
authors.forename: Feng
authors.initials: F
authors.lastname: Luo
authors.affiliation: BioClinica Inc, Newtown, Pennsylvania.
authors.forename: Chahin
authors.initials: C
authors.lastname: Pachai
authors.affiliation: BioClinica Inc, Newtown, Pennsylvania.
authors.forename: Luc
authors.initials: L
authors.lastname: Bracoud
authors.affiliation: Avid Radiopharmaceuticals, Philadelphia, Pennsylvania.
authors.forename: Mark
authors.initials: M
authors.lastname: Mintun
authors.affiliation: Mary S. Easton Center for Alzheimer's Disease Research, University of California at Los Angeles.
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Grill
authors.affiliation: Institute for Neurodegenerative Disorders, New Haven, Connecticut.
authors.forename: Ken
authors.initials: K
authors.lastname: Marek
authors.affiliation: Institute for Neurodegenerative Disorders, New Haven, Connecticut.
authors.forename: John
authors.initials: J
authors.lastname: Seibyl
authors.affiliation: Global Clinical Research, Bristol-Myers Squibb, Wallingford, Connecticut.
authors.forename: Jesse M
authors.initials: JM
authors.lastname: Cedarbaum
authors.affiliation: Global Clinical Research, Bristol-Myers Squibb, Wallingford, Connecticut.
authors.forename: Charles
authors.initials: C
authors.lastname: Albright
authors.affiliation: University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Howard H
authors.initials: HH
authors.lastname: Feldman
authors.affiliation: Global Clinical Research, Bristol-Myers Squibb, Wallingford, Connecticut.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Berman
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D006801:Humans; D008297:Male; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid / Q000000981:diagnostic imaging / Q000473:pathology / Q000517:prevention & control; D001284:Atrophy / Q000473:pathology; D060825:Cognitive Dysfunction / Q000134:cerebrospinal fluid / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000473:pathology; D018450:Disease Progression; D010069:Oxadiazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D062706:Prodromal Symptoms; D011877:Radionuclide Imaging; D012878:Skin Neoplasms / Q000139:chemically induced; D013449:Sulfonamides / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D017211:Treatment Failure
chemical_list: C554092:BMS 708163; D010069:Oxadiazoles; D013449:Sulfonamides