Safety and efficacy of pioglitazone for the delay of cognitive impairment in people at risk of Alzheimer's disease (TOMMORROW): a prognostic biomarker study and a phase 3, randomised, double-blind, placebo-controlled trial.

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. FUNDING: Takeda and Zinfandel.

The TOMMORROW study: Design of an Alzheimer's disease delay-of-onset clinical trial.

INTRODUCTION: 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. METHODS: 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. RESULTS: The focus of this paper is on the design of the study; study results will be presented in a separate paper. DISCUSSION: 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.

TOMMORROW neuropsychological battery: German language validation and normative study.

INTRODUCTION: Assessment of preclinical Alzheimer's disease (AD) requires reliable and validated methods to detect subtle cognitive changes. The battery of standardized cognitive assessments that is used for diagnostic criteria for mild cognitive impairment due to AD in the TOMMORROW study have only been fully validated in English-speaking countries. We conducted a validation and normative study of the German language version of the TOMMORROW neuropsychological test battery, which tests episodic memory, language, visuospatial ability, executive function, and attention. METHODS: German-speaking cognitively healthy controls (NCs) and subjects with AD were recruited from a memory clinic at a Swiss medical center. Construct validity, test-retest, and alternate form reliability were assessed in NCs. Criterion and discriminant validities of the cognitive measures were tested using logistic regression and discriminant analysis. Cross-cultural equivalency of performance of the German language tests was compared with English language tests. RESULTS: A total of 198 NCs and 25 subjects with AD (aged 65-88 years) were analyzed. All German language tests discriminated NCs from persons with AD. Episodic memory tests had the highest potential to discriminate with almost twice the predictive power of any other domain. Test-retest reliability of the test battery was adequate, and alternate form reliability for episodic memory tests was supported. For most tests, age was a significant predictor of group effect sizes; therefore, normative data were stratified by age. Validity and reliability results were similar to those in the published US cognitive testing literature. DISCUSSION: This study establishes the reliability and validity of the German language TOMMORROW test battery, which performed similarly to the English language tests. Some variations in test performance underscore the importance of regional normative values. The German language battery and normative data will improve the precision of measuring cognition and diagnosing incident mild cognitive impairment due to AD in clinical settings in German-speaking countries.