PREliminary development of a Multi-Arm, multi-Stage Trial platfOrm for Dementia and mild cOgNitive impairment due to Alzheimer's Disease (PRE-MASTODON-AD)

1. Full Title: PREliminary development of a Multi-Arm, multi-Stage Trial platfOrm for Dementia and mild cOgNitive impairment due to Alzheimer's Disease (PRE-MASTODON-AD) 2. Summary of Research (Abstract) Research Aim

Using this Application Development Award, we will lay the foundations for a multi-arm, multi-stage (MAMS) platform that will transform our ability to rapidly assess repurposed treatments for symptomatic Alzheimer’s Disease. We will establish dedicated PPIE groups and a systematic drug selection process as well as identifying the first three compounds for inclusion into the platform.

We will also finalise the set of outcome measures for the trial and complete trial design, including carrying out appropriate simulations. Background

950,000 people in the UK have dementia, causing major personal hardship and costing over £30 billion/year. Licensed treatments for Alzheimer's Disease (AD), the most common cause of dementia, have not changed in 20-years and offer only modest benefits. Trials of new disease-modifying treatments show promise but increasingly focus on earlier disease stages and show relatively small benefits that vary by gender, ethnicity, and genetic factors.

Potential side-effects are significant. Current trials for Alzheimer's dementia are frequently inefficient, biased to underpowered studies, or poorly representative of the wider population with clinical AD. Trials often focus on testing newer compounds rather than repurposing existing drugs for which there is compelling proof-of-concept evidence, and which have a well-established safety profile.

Aims and objectives

Our long-term aim is to set up and implement a MAMS platform trial, MASTODON-AD, which will, in its first phase, complete evaluation of three leading drugs with proof-of-concept evidence in Alzheimer's Disease. The aim of this proposal is to carry out the initial preparatory work for this platform. Methods

We will lay the groundwork for establishing this MAMS platform by completing three work packages, each being carried out via a separate group with patient and public representation:

1 Establish a systematic, robust, and sustainable drug prioritisation process and identify three compounds for inclusion in the first phase of MASTODON-AD.

2 Identify and select measures of cognition and behaviour that reflect meaningful changes in quality of life and activity at home.

3 Complete design,including simulations and use of placebo, of the proposed MAMS platform in preparation for a full funding proposal in 2025. Timelines for delivery

Our planned grant start date for the proposed work is August 2024 with an end date of 31 July 2025. We would expect to submit a major funding proposal in September 2025 with the aim of starting the platform in 2026. Anticipated impact and dissemination

Our team's previous platform in prostate cancer (STAMPEDE, commenced 2006) resulted in multiple changes to standard of care, and median increase of 7-years in survival. Our use of this design in Motor Neurone Disease and progressive Multiple Sclerosis has transformed UK clinical research in these fields. We aim to develop a sustainable platform that will provide a new paradigm for PPIE co-production, inclusivity, and drug evaluation as well as harnessing existing and new trials infrastructure to transform the UK clinical dementia research landscape.