Targeting Prodromal Alzheimer Disease With Avagacestat: A Randomized Clinical Trial.

ImportanceEarly 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.ObjectivesTo 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 participantsA 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.InterventionsOral avagacestat or placebo daily.Main outcomes and measureSafety and tolerability of avagacestat.ResultsOf 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 relevanceAvagacestat 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 registrationclinicaltrials.gov Identifier: NCT00890890

T2 Protect AD: Achieving a rapid recruitment timeline in a multisite clinical trial for individuals with mild to moderate Alzheimer's disease.

IntroductionThe reporting of approaches facilitating the most efficient and timely recruitment of Alzheimer's disease (AD) patients into pharmacologic trials is fundamental to much-needed therapeutic progress.MethodsT2 Protect AD (T2), a phase 2 randomized placebo-controlled trial of troriluzole in mild to moderate AD, used multiple recruitment strategies.ResultsT2 exceeded its recruitment target, enrolling 350 participants between July 2018 and December 2019 (randomization rate: 0.87 randomizations/site/month, or 3-fold greater than recent trials of mild to moderate AD). The vast majority (98%) of participants were enrolled during a 10-month window of intense promotion in news media, TV and radio advertisements, and social media. The distribution of primary recruitment sources included: existing patient lists at participating sites (72.3%), news media (12.3%), physician referral (6.0%), word of mouth (3.1%), and paid advertising (2.9%).DiscussionThe rapid recruitment of participants with mild to moderate AD was achieved through a range of approaches with varying success

T2 Protect AD: Achieving a rapid recruitment timeline in a multisite clinical trial for individuals with mild to moderate Alzheimer's disease

Abstract Introduction The reporting of approaches facilitating the most efficient and timely recruitment of Alzheimer's disease (AD) patients into pharmacologic trials is fundamental to much‐needed therapeutic progress. Methods T2 Protect AD (T2), a phase 2 randomized placebo‐controlled trial of troriluzole in mild to moderate AD, used multiple recruitment strategies. Results T2 exceeded its recruitment target, enrolling 350 participants between July 2018 and December 2019 (randomization rate: 0.87 randomizations/site/month, or 3‐fold greater than recent trials of mild to moderate AD). The vast majority (98%) of participants were enrolled during a 10‐month window of intense promotion in news media, TV and radio advertisements, and social media. The distribution of primary recruitment sources included: existing patient lists at participating sites (72.3%), news media (12.3%), physician referral (6.0%), word of mouth (3.1%), and paid advertising (2.9%). Discussion The rapid recruitment of participants with mild to moderate AD was achieved through a range of approaches with varying success