Background: TOMM40 ‘523 has been associated with cognitive performance and risk for developing Alzheimer’s disease independent of the effect of APOE genotype. Few studies have considered the longitudinal effect of this genotype on change in cognition over time. Objective: Our objective was to evaluate the relationship between TOMM40 genotype status and change in cognitive performance in the TOMMORROW study, which was designed to prospectively evaluate an algorithm that includes TOMM40 ‘523 for genetic risk for conversion to mild cognitive impairment. Methods: We used latent growth curve models to estimate the effect of TOMM40 allele carrier (short, very long) status on the intercept and slope of change in cognitive performance in four broad cognitive domains (attention, memory, executive function, and language) and a combined overall cognitive score over 30 months. Results: TOMM40 very long allele carriers had significantly lower baseline performance for the combined overall cognitive function score (B = –0.088, p = 0.034) and for the executive function domain score (B = –0.143, p = 0.013). Slopes for TOMM40 very long carriers had significantly greater increases over time for the executive function domain score only. In sensitivity analyses, the results for executive function were observed in participants who remained clinically stable, but not in those who progressed clinically over the study duration. Conclusions: Our results add to the growing body of evidence that TOMM40, in the absence of APOE ɛ4, may contribute to cognitive changes with aging and dementia and support the view that mitochondrial function is an important contributor to Alzheimer’s disease risk.

Background The onset of mild cognitive impairment (MCI) is an essential outcome in Alzheimer's disease (AD) prevention trials and a compelling milestone for clinically meaningful change. Determining MCI, however, may be variable and subject to disagreement. Adjudication procedures may improve the reliability of these determinations. We report the performance of an adjudication committee for an AD prevention trial. Methods The TOMMORROW prevention trial selected cognitively normal participants at increased genetic risk for AD and randomized them to low-dose pioglitazone or placebo treatment. When adjudication criteria were triggered, a participant's clinical information was randomly assigned to a three-member panel of a six-member independent adjudication committee. Determination of whether or not a participant reached MCI due to AD or AD dementia proceeded through up to three review stages - independent review, collaborative review, and full committee review - requiring a unanimous decision and ratification by the chair. Results Of 3494 participants randomized, the committee adjudicated on 648 cases from 386 participants, resulting in 96 primary endpoint events. Most participants had cases that were adjudicated once (n = 235, 60.9%); the rest had cases that were adjudicated multiple times. Cases were evenly distributed among the eight possible three-member panels. Most adjudicated cases (485/648, 74.8%) were decided within the independent review (stage 1); 14.0% required broader collaborative review (stage 2), and 11.1% needed full committee discussion (stage 3). The primary endpoint event decision rate was 39/485 (8.0%) for stage 1, 29/91 (31.9%) for stage 2, and 28/72 (38.9%) for stage 3. Agreement between the primary event outcomes supported by investigators' clinical diagnoses and the decisions of the adjudication committee increased from 50% to approximately 93% (after around 100 cases) before settling at 80-90% for the remainder of the study. Conclusions The adjudication process was designed to provide independent, consistent determinations of the trial endpoints. These outcomes demonstrated the extent of uncertainty among trial investigators and agreement between adjudicators when the transition to MCI due to AD was prospectively assessed. These methods may inform clinical endpoint determination in future AD secondary prevention studies. Reliable, accurate assessment of clinical events is critical for prevention trials and may mean the difference between success and failure.

Background The identification of people at risk of cognitive impairment is essential for improving recruitment in secondary prevention trials of Alzheimer's disease. We aimed to test and qualify a biomarker risk assignment algorithm (BRAA) to identify participants at risk of developing mild cognitive impairment due to Alzheimer's disease within 5 years, and to evaluate the safety and efficacy of low-dose pioglitazone to delay onset of mild cognitive impairment in these at-risk participants. Methods In this phase 3, multicentre, randomised, double-blind, placebo-controlled, parallel-group study, we enrolled cognitively healthy, community living participants aged 65-83 years from 57 academic affiliated and private research clinics in Australia, Germany, Switzerland, the UK, and the USA. By use of the BRAA, participants were grouped as high risk or low risk. Participants at high risk were randomly assigned 1:1 to receive oral pioglitazone (0.8 mg/day sustained release) or placebo, and all low-risk participants received placebo. Study investigators, site staff, sponsor personnel, and study participants were masked to genotype, risk assignment, and treatment assignment. The planned study duration was the time to accumulate 202 events of mild cognitive impairment due to Alzheimer's disease in White participants who were at high risk (the population on whom the genetic analyses that informed the BRAA development was done). Primary endpoints were time-to-event comparisons between participants at high risk and low risk given placebo ( for the BRAA objective), and between participants at high risk given pioglitazone or placebo (for the efficacy objective). The primary analysis included all participants who were randomly assigned, received at least one dose of study drug, and had at least one valid post-baseline visit, with significance set at p=0.01. The safety analysis included all participants who were randomly assigned and received at least one dose of study medication. An efficacy futility analysis was planned for when approximately 33% of the anticipated events occurred in the high-risk, White, non-Hispanic or Latino group. This trial is registered with ClinicalTrials.gov, NCT01931566. Findings Between Aug 28, 2013, and Dec 21, 2015, we enrolled 3494 participants (3061 at high risk and 433 at low risk). Of those participants, 1545 were randomly assigned to pioglitazone and 1516 to placebo. 1104 participants discontinued treatment (464 assigned to the pioglitazone group, 501 in the placebo high risk group, and 139 in the placebo low risk group). 3399 participants had at least one dose of study drug or placebo and at least one post-baseline follow-up visit, and were included in the efficacy analysis. 3465 participants were included in the safety analysis (1531 assigned to the pioglitazone group, 1507 in the placebo high risk group, and 427 in the placebo low risk group). In the full analysis set, 46 (3.3%) of 1406 participants at high risk given placebo had mild cognitive impairment due to Alzheimer's disease, versus four (1.0%) of 402 participants at low risk given placebo (hazard ratio 3.26, 99% CI 0.85-12.45; p=0.023). 39 (2.7%) of 1430 participants at high risk given pioglitazone had mild cognitive impairment, versus 46 (3.3%) of 1406 participants at high risk given placebo (hazard ratio 0.80, 99% CI 0.45-1.40; p=0.307). In the safety analysis set, seven (0.5%) of 1531 participants at high risk given pioglitazone died versus 21 (1.4%) of 1507 participants at high risk given placebo. There were no other notable differences in adverse events between groups. The study was terminated in January, 2018, after failing to meet the non-futility threshold. Interpretation Pioglitazone did not delay the onset of mild cognitive impairment. The biomarker algorithm demonstrated a 3 times enrichment of events in the high risk placebo group compared with the low risk placebo group, but did not reach the pre-specified significance threshold. Because we did not complete the study as planned, findings can only be considered exploratory. The conduct of this study could prove useful to future clinical development strategies for Alzheimer's disease prevention studies. Copyright (C) 2021 Elsevier Ltd. All rights reserved.

AbstractBackgroundA challenge with AD prevention is the timely identification of subjects at risk of cognitive symptom onset, mitigating prohibitive costs associated with the trial size and duration. A biomarker risk assignment algorithm (BRAA) consisting of genotypes at the apolipoprotein E (APOE) and translocase of outer mitochondrial membrane 40 homolog (TOMM40) rs10524523 loci (‘523) and current age was developed to enrich the TOMMORROW delay of AD onset clinical study. ‘523 is a poly‐T homopolymer of 14 to 50 residues. For the BRAA, the alleles were categorized by T length as “short” (S: <21), “long” (L: 21‐29), or “very long” (VL: >29).MethodThe TOMMORROW study (NCT 01931566) provided a large dataset to assess APOE‐‘523 haplotypes to improve the performance of the BRAA. The original BRAA used phased genetic information to determine risk categories (developed in 150 individuals, verified in 1018 individuals). Because phased haplotype data were not available from the samples genotyped in the TOMMORROW study, an optimized calibration was performed using APOE 3/3 and 4/4 homozygous individuals (n=1625). By maximizing the genetic congruency between the APOE and ‘523 genotypes, the calibration of the ‘523 categorical boundaries was optimized.ResultFrom these haplotype data, the ’523 categorical assignments were optimized to S: <19; L: 19‐31; and VL: >31. When these optimized categorical assignments were applied retrospectively to the TOMMORROW study cohort (n=1803), the hazard ratio for the time‐to‐event comparison between the high and low risk placebo groups improved from 3.3 (95% confidence interval [CI] 1.2‐9.0, P=0.023) to 4.3 (95%CI 1.3‐13.7, P=0.015). Applying the refined BRAA to a future delay of AD onset clinical trial would reduce enrollment by 26% for a 5‐year interventional study versus an all‐comers enrollment strategy. Furthermore, a streamlined, kit‐based genotyping assay for APOE and TOMM40 ‘523 was evaluated and found to yield congruent results with the sequencing‐based method used for genotyping in the TOMMORROW clinical trial.ConclusionUsing phase 3 clinical trial data, the TOMMORROW BRAA demonstrated the ability to enrich delay of onset/prevention of AD studies for subjects more likely to develop cognitive symptom onset during an acceptable timeframe with significant clinical trial cost savings.

Alzheimer's disease (AD) is a continuum with neuropathologies manifesting years before clinical symptoms; thus, AD research is attempting to identify more disease-modifying approaches to test treatments administered before full disease expression. Designing such trials in cognitively normal elderly individuals poses unique challenges. The TOMMORROW study was a phase 3 double-blind, parallel-group study designed to support qualification of a novel genetic biomarker risk assignment algorithm (BRAA) and to assess efficacy and safety of low-dose pioglitazone to delay onset of mild cognitive impairment due to AD. Eligible participants were stratified based on the BRAA (using TOMM40 rs 10524523 genotype, Apolipoprotein E genotype, and age), with high-risk individuals receiving low-dose pioglitazone or placebo and low-risk individuals receiving placebo. The primary endpoint was time to the event of mild cognitive impairment due to AD. The primary objectives were to compare the primary endpoint between high- and low-risk placebo groups (for BRAA qualification) and between high-risk pioglitazone and high-risk placebo groups (for pioglitazone efficacy). Approximately 300 individuals were also asked to participate in a volumetric magnetic resonance imaging substudy at selected sites. The focus of this paper is on the design of the study; study results will be presented in a separate paper. The design of the TOMMORROW study addressed many key challenges to conducting a dual-objective phase 3 pivotal AD clinical trial in presymptomatic individuals. Experiences from planning and executing the TOMMORROW study may benefit future AD prevention/delay-of-onset trials.

One challenge to interventional trials designed to delay the clinical onset of very early symptoms of Alzheimer's disease (AD) is determining meaningful endpoints to detect decline in putatively healthy individuals. The TOMMORROW study (NCT01931566) assessed the value of a biomarker algorithm to identify cognitively healthy adults at near-term risk of developing MCI-AD. The study used a battery of neuropsychological tests and incorporated a time-to-event design over approximately 4 years to define the time of MCI-AD conversion. We describe baseline (pre-randomization) cognitive performance results, underscoring the utility of the selected battery to enable the exclusion of cognitively impaired individuals and the effects of gender, age, and education on test performance. At the time of last subject in (December 2015) 4565 individuals with a mean age of 74.4 years (SD=5.31; range 65–83) had undergone baseline evaluation. Of these, 306 were baseline failures and were not enrolled in the study, primarily due to presence of a cognitive disorder. Neuropsychological performance was examined for men (n=1945) and women (n=2314) separately on key outcome measures for each of the 9 tests (MMSE, BVMT-R, CVLT-II, Lexical fluency, Semantic fluency, MINT, Clock Drawing, Digit Span, and Trail Making). We also examined the impact of low education (n=1143), defined as less than a high school education, on the above measures. Demographic differences were considered in the normative data used by investigators and adjudicators who confirmed diagnostic status. Approximately 6.7% of individuals were not eligible for randomization, primarily because of baseline cognitive impairment. At pre-randomization baseline, women scored significantly higher than men on verbal learning (CVLT-total p<0.001) and on some tests of executive function (Trails A p<0.0004; Trails B, p<0.001) after controlling for age and education. By contrast, men performed better on visual naming (MINT p<0.001). Low education was significantly associated with poorer performance on all tests in men and women except for Digit Span. The TOMMORROW study employed a neuropsychological battery to ensure the enrollment of only cognitively normal subjects; approximately 300 subjects failed to meet study randomization criteria. Patterns of gender and prior education testing effects were observed that are similar to previous studies.

Alzheimer's disease (AD) therapy approaches have evolved to shift focus from treating symptomatic patients to delaying clinical onset. Intervention at the pre-symptomatic stage of the AD continuum requires the ability to reliably discern when individuals transition from being cognitively normal to having mild cognitive impairment (MCI)-due-to-AD. The TOMMORROW study is a global, multicenter, randomized, double-blind, placebo-controlled clinical trial, with a novel study endpoint event that operationalizes core clinical criteria for MCI-due-to-AD. The MCI event criteria must be met at two consecutive study visits approximately 6 months apart. The study duration is event driven, requiring accrual of 202 MCI-due-to-AD events. Cognitively normal subjects (65-83 years) at baseline are assessed in person every 6 months to measure cognitive and functional status. Neuropsychologists are part of the study team at each site. The study utilizes normative standards to guide diagnostic inferences, investigator's clinical judgment, predefined sensitive cognitive trigger criteria, a prescribed subject flow process, and an independent adjudication committee to decide whether subjects have developed MCI-due-to-AD. The adjudication committee includes individuals with clinical expertise in neurology, psychiatry, and neuropsychology to provide consistent event harmonization across multiple countries and cultures over a multi-year timeframe. Unanimous committee agreement is required to determine an event, and formal mechanisms are in place to resolve differences in opinion. TOMMORROW enrolled a total of 3494 subjects. Currently, approximately 200 subjects are in the pipeline at any point in time as potential cases for review. Approximately 65 of these will meet criteria for adjudication. As of early December 2017, the adjudication committee had reviewed and provided endpoint decisions on over 500 cases. The average cycle time from subjects’ most recent study visit to adjudication outcome for Q4 in 2017 was 39 days: 21 days less than the expected timeframe. This procedural efficiency allows rapid determination of subject disposition. The process for determining the MCI-due-to-AD event is central to the phase 3 registration clinical trial, which targets the earliest transition point to clinically symptomatic AD. As more AD clinical trials move toward early intervention strategies, lessons learned from the TOMMORROW study process will be an invaluable resource.

Interventional approaches to Alzheimer's disease (AD) are broadening to include delay-of-onset and prevention strategies, creating substantial challenges to retain study subjects over typically very long study treatment durations. Studies of this type have a different risk-benefit calculus for cognitively normal subjects. Minimizing dropout is essential to scientific integrity and interpretable results. The TOMMORROW study (NCT01931566) is an interventional trial, designed to evaluate over approximately 4 years: 1) the usefulness of an algorithm to identify individuals at near term risk for MCI-AD and 2) effectiveness of low-dose pioglitazone in delaying onset of MCI-AD. Mindful of sources of dropouts in longitudinal neurocognitive designs, we adopted several diverse approaches to participant retention in this international clinical trial. The TOMMORROW study closely monitors site performance, which includes monthly metrics of early termination (ET). With the aid of a retention-focused vendor company, the study works with the sites to develop approaches to mitigate preventable ETs in a way that is responsive, flexible, and site specific. Methods that focus on both the subjects and their project partners include newsletters, phone calls, transportation facilitation, web site, and others. Additionally, coordinators, raters, site principal investigators, and neuropsychologists are involved in regular group calls, face to face meetings, and encouraged to share best practices to aid retention. All current TOMMORROW subjects have passed the one-year study milestone with many now in years 2 and 3. ET is highest in the first year with overall rates remaining low and on track with initial statistical projections. Reasons for drop-out are consistent across the study interval, with most ET due to voluntary withdrawals (49%), development of medical conditions (28%), loss to follow-up (4%), protocol deviation (4%), and a variety of other reasons (15%). The TOMMORROW study has adopted a multifaceted approach to enhance subject retention that is site-specific, focuses on both the subjects and their project partners, and provides site investigators with tools necessary to keep participants engaged in a long clinical trial. Specifics to be discussed may prove useful to future clinical trials aiming to identify interventions that ameliorate the cognitive decline of AD.

In order to address the unmet burden of Alzheimer’s disease (AD), there is a growing interest in delaying symptom onset by initiating treatment in individuals at risk for disease but without overt evidence of cognitive deficits. To identify asymptomatic individuals at risk for disease, a biomarker risk assignment algorithm (BRAA) that includes the apolipoprotein E (APOE) and translocase of outer mitochondrial membrane 40 (TOMM40) genotypes [polyT homopolymer, rs10524523] and age has been developed. The TOMMORROW study will simultaneously qualify the BRAA for assigning risk of developing mild cognitive impairment (MCI) due to AD and evaluate the efficacy of low-dose pioglitazone (0.8 mg SR) for delaying the onset of MCI due to AD in individuals identified by the BRAA to be high-risk. A global, phase 3, double-blind, placebo-controlled trial was initiated in 2013 and has now been fully enrolled. The time-to-onset study operationalizes the core clinical diagnostic criteria (Albert et al. 2011) for MCI due to AD as the primary endpoint event. The study will be completed when 202 events in the high risk subjects have been reached; the treatment period is anticipated to be approximately 5 years. The TOMMORROW study (NCT01931566 clinicaltrials.gov) completed enrollment in December 2015 with 3494 subjects randomized. Screening was carried out on >24,000 individuals between ages 65–83 years (inclusive) at 59 study sites in five countries. At screening, <3% of the subjects self-identified as cognitively normal primarily failed due to not meeting the cognitive threshold for inclusion (age- and education-adjusted MMSE ≥25). The regional composition was 67% US, 20% UK, 11% AU, and 2% Germany and Switzerland. The gender split was approximately 56% female and 44% male. Genetic data for APOE and TOMM40’523were generated on >22,000 subjects. The demographic description, genetic characteristics (including APOE distribution of genotype status), and screening characteristics for this screening cohort of elderly, cognitively normal subjects will be presented. The experience of recruiting this study cohort provides valuable insights into the characteristics of healthy adults interested in clinical trials to delay symptomatic AD. The results may facilitate recruitment efforts for subsequent studies along the AD continuum.

International trials to delay onset of mild cognitive impairment due to Alzheimer's disease (MCI-AD) are complex in design, requiring careful consideration of: case definition, site characteristics, selection of primary outcome metrics, and methods to ensure appropriate cultural and psychometric validation. We describe the methodological and instrumentation challenges faced in the initiation of an international, phase III randomized, controlled trial of low-dose pioglitazone to delay MCI-AD in a cognitively normal population enriched by a novel genetic marker, TOMM40. A Phase III study to delay onset of MCI-AD is in process with sites in the US, Europe, Australia, Russia, and Israel. A group of international experts was assembled to operationalize the recent NIA/AA core clinical criteria for MCI-AD and to determine an appropriate neuropsychological outcome battery for the global context. A deliberative process spanning 18 months involved systematic reviews of the literature and databases followed by statistical modeling to determine methods with optimal performance characteristics. Also considered were 1) methods to secure normative data essential for diagnostic decisions, and 2) approaches to establish linguistic and cultural validity as well as to measure equivalence across sites. We developed an MCI-AD diagnostic algorithm requiring: 1) a Clinical Dementia Rating Scale score of 0.5 based on structured interview; and 2) a specific profile of impairment on neuropsychological testing with an emphasis on episodic memory impairment and evidence of change from baseline. A clinical diagnosis of MCI-AD requires fulfillment of the criteria on two consecutive examinations, 6 months apart, which is supported by clinical, functional, and medical data and ultimately adjudicated by a panel of clinical experts reviewing all cases. The design of the clinical trial and the development of normative and validation data to support the use of the neuropsychological battery in the international context will be discussed. Operationalization of the new NIA/AA research criteria for MCI-AD rests heavily on empirically sound methods acceptable to the international research community and regulatory bodies. Establishing consistent MCI-AD diagnoses across countries is critical to study conduct and broad data acceptance. This trial will begin enrollment in 2013.