The crisis in recruitment for clinical trials in Alzheimer's and dementia: An action plan for solutions

Fargo, Keith N.; Carrillo, María C.; Weiner, Michael W.; Potter, William Z.; Khachaturian, Zaven S.

doi:10.1016/j.jalz.2016.10.001

Cited by 100 publications

(101 citation statements)

References 14 publications

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“…Slow recruitment to clinical trials is a consistent barrier to developing improved treatments for Alzheimer’s disease (AD)[1–3]. Few interventions have demonstrated effectiveness for improving AD trial recruitment [4].…”

Section: Introductionmentioning

confidence: 99%

Recruiting to preclinical Alzheimer's disease clinical trials through registries

Grill

2017

A&D Transl Res & Clin Interv

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Participant registries are repositories of individuals who have expressed willingness to learn about studies for which they may be eligible. Registries are increasingly being used to improve recruitment to preclinical Alzheimer's disease (AD) clinical trials, which require large screening efforts to identify adequate numbers of participants who meet enrollment criteria. Recruiting to preclinical AD trials from registries is made more efficient through registry collection of data that permits exclusion of those who will not be eligible and identifies individuals most likely to qualify for trials. Such data could include self-reported disease family history or other risk factors but could also include cognitive, genetic, or biomarker testing outcomes. Few data are available to guide investigators overseeing registries and important ethical questions are likely to arise related to their conduct, especially in registries collecting AD risk information. This article outlines three areas of consideration for registry investigators: informed consent, disclosure, and sponsorship.

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Section: Introductionmentioning

confidence: 99%

Recruiting to preclinical Alzheimer's disease clinical trials through registries

Grill

2017

A&D Transl Res & Clin Interv

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“…The available diagnostic tools are, however, invasive (CSF) or expensive (PET), hampering widespread application for diagnosis (eg, in a primary care setting) and large scale identification of individuals with abnormal amyloid status in the context of recruitment for trials 13. There is an urgent need for low‐invasive and affordable techniques to prescreen for cerebral amyloid pathology, subsequently forwarding fewer individuals toward further invasive and/or expensive testing.…”

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confidence: 99%

Plasma Amyloid as Prescreener for the Earliest Alzheimer Pathological Changes

Verberk

Slot

Verfaillie

et al. 2018

Annals of Neurology

263

243

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ObjectiveWe investigated the association of plasma amyloid beta (Abeta)40, Abeta42, and total tau (tTau) with the presence of Alzheimer pathological changes in cognitively normal individuals with subjective cognitive decline (SCD).MethodsWe included 248 subjects with SCD (61 ± 9 years, 42% female, Mini‐Mental State Examination = 28 ± 2) from the SCIENCe project and Amsterdam Dementia Cohort. Subjects were dichotomized as amyloid abnormal by cerebrospinal fluid (CSF) and positron emission tomography (PET). Baseline plasma Abeta40, Abeta42, and tTau were measured using Simoa technology. Associations between plasma levels and amyloid status were assessed using logistic regression analyses and receiver operating characteristic analyses. Association of plasma levels with risk of clinical progression to mild cognitive impairment (MCI) or dementia was assessed using Cox proportional hazard models.ResultsFifty‐seven (23%) subjects were CSF‐amyloid abnormal. Plasma Abeta42/Abeta40 ratio and plasma Abeta42 alone, but not tTau, identified abnormal CSF‐amyloid status (plasma ratio: area under the curve [AUC] = 77%, 95% confidence interval [CI] = 69–84%; plasma Abeta42: AUC = 66%, 95% CI: 58–74%). Combining plasma ratio with age and apolipoprotein E resulted in AUC = 83% (95% CI = 77–89%). The Youden cutoff of the plasma ratio gave a sensitivity of 76% and specificity of 75%, and applying this as a prescreener would reduce the number of lumbar punctures by 51%. Using PET as outcome, a comparable reduction in number of PET scans would be achieved when applying the plasma ratio as prescreener. In addition, low plasma ratio was associated with clinical progression to MCI or dementia (hazard ratio = 2.0, 95% CI = 1.4–2.3).InterpretationPlasma Abeta42/Abeta40 ratio has potential as a prescreener to identify Alzheimer pathological changes in cognitively normal individuals with SCD. Ann Neurol 2018;84:656–666

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“…21 This is especially true in the current era of trials that require PET scans for amyloid or tau to determine eligibility. Hundreds of diverse sites around the world, each recruiting a handful or two of subjects to achieve sample size, are logistically managed by a complex multivendor infrastructure struggling to maintain a semblance of uniformity of protocol.…”

Section: Introductionmentioning

confidence: 99%

Multicrossover Randomized Controlled Trial Designs in Alzheimer Disease

Arnold

Betensky

2018

Annals of Neurology

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Conventional parallel group randomized controlled clinical trials (RCT) in Alzheimer’s disease (AD) are too large, long, expensive and insensitive to clinical change to meet the urgent need for an effective treatment. While providing good evidence for a treatment’s benefit, parallel group RCTs in AD must have very large samples and broad measures of change to accommodate the marked heterogeneity of demographics, genetics, symptoms, pathophysiologies, comorbidities and rates of progression. Multi-crossover, placebo-controlled, double-blind RCTs, including those with sample sizes as small as a single subject (“N-of-1”), are robust designs wherein subjects serve as their own controls in repeated blocks of randomly sequenced crossover treatments. Heterogeneities are inherently controlled and the sensitivity, specificity and clinical relevance of outcomes can be enhanced further by including personalized outcome measures for each individual. Multi-crossover N-of-1 RCTs enable unbiased estimation of efficacy for single subjects, and joint analysis of multiple N-of-1 trials enables estimation of efficacy for populations with much smaller sample sizes than those needed in conventional parallel group studies. It is important to identify carryover effects and natural history time trends to achieve unbiased estimation and testing of the treatment effect. We assert that in AD, multi-crossover RCTs offer many advantages over standard parallel group trials for drugs or other treatments with suitable mechanisms of action, pharmacokinetics and pharmacodynamics; despite the fact that they are almost never conducted. They may be especially useful for therapies directed at symptomatic improvement of cognitive and neuropsychiatric symptoms, but also can be used in early phase studies of disease modifying treatments with biomarker outcome measures.

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The crisis in recruitment for clinical trials in Alzheimer's and dementia: An action plan for solutions

Cited by 100 publications

References 14 publications

Recruiting to preclinical Alzheimer's disease clinical trials through registries

Recruiting to preclinical Alzheimer's disease clinical trials through registries

Plasma Amyloid as Prescreener for the Earliest Alzheimer Pathological Changes

Multicrossover Randomized Controlled Trial Designs in Alzheimer Disease

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