Title: Clinical Trials Methods in Neurodegenerative Diseases
Funder: Department of Health (England)

Abstract: The broad aim of this research is to improve clinical trials in neurodegenerative diseases (NDs): in particular, the clinical meaningfulness of the information gained, our understanding of treatments and diseases, and the chances of drawing the correct conclusions about treatment effectiveness. The programme focuses on the two most common NDs: Alzheimer's disease (AD) and Parkinson's disease (PD). BACKGROUND: The large projected increase in the prevalence of NDs, especially AD and PD, presents huge problems to the NHS and Social Services. At present there are no treatments that slow progression of either condition convincingly and considerable controversy surrounds some symptomatic treatments, particularly when assessments take a narrow view of disease progression and impact of treatment. Trials of neurodegeneration in AD and PD are problematic. The slow progression of these conditions (often over years) necessitates long-term studies which tend to be associated with high drop-out and high cost using conventional designs and standard analyses. Moreover, it is likely that multiple pathogenic pathways may lead to the same phenotype of AD or PD. Disease heterogeneity may mean that agents acting through a limited number of pathways may only benefit a sub-group of those affected, not easily identified using conventional statistical analysis. To complicate matters, poorly conceived and developed outcome measures have been used in trials of NDs, often without thought of what they are actually measuring, which has made assessing the clinical relevance of results difficult. To overcome these problems surrogate outcomes have been investigated, but to date none has satisfied criteria to be primary outcome measures in clinical trials. This programme will advance each of the four interlinked themes alluded to above: 1) rating scale measures 2) surrogate outcome measures 3) statistical evaluation and 4) clinical trial design. Advances in each theme will underpin advances in the other three themes. METHODS:Theme 1 Rating scales. This theme aims to make scale selection for clinical trials evidence-based. A systematic review and qualitative methods (patients, significant others, experts) guided by consensus opinion will identify the core variables (aspects of disease impact) for measurement in clinical trials of AD and PD. These will be defined explicitly. Next, we will identify all scales that articulate the definitions of the core variables, and evaluate their published psychometric properties. From this we will produce a short list of potentially suitable scales, highlighting all psychometric evaluations and limitations. We will undertake additional evaluations as required, develop and test strategies to overcome them. Guidelines and recommendations on evidence-based rating scale selection for clinical trials and service evaluation will be developed. Theme 2 Surrogate outcomes. We will conduct a systematic review of all surrogates used in diagnosis and monitoring of AD and PD, listing potential advantages and disadvantages of imaging and biochemical markers from various tissues. We will organise workshops in PD and AD presenting results to achieve consensus over the most potentially useful markers for more widespread collection in the NHS. In parallel with this, we will explore connectivity of electronic data already available on NHS systems that may potentially be useful for management of AD and PD. We will focus on imaging data, and cross-institutional communication to develop an electronic Grid. This would have potential to generate large quantities of data not only for this and future programmes, but also to assist delivery of health and social care, facilitating a more multidimensional evaluation of treatment benefit. We will perform qualitative work to establish which identified surrogates are acceptable for measurement to patients and carers, and at what frequency. Theme 3 Statistical methods. This theme is concerned with new methods of statistical evaluation, modelling disease progression and getting the most from collected data. We will start with a systematic review of available statistical methods, identifying their relative merits. We will identify large longitudinal datasets (e.g. the ADNI dataset in the US) and clinical trial data and use modern Bayesian methods to explore issues of disease heterogeneity, treatment targeting, individual responsiveness, separating symptomatic from disease modifying effects and economic assessment. Theme 4 Trial design. The theme will commence with a systematic review of all available evidence and guidelines for conduct of clinical trials and economic evaluation in NDs, summarising advantages and disadvantages. On the basis of this evidence and the outcomes of research in areas 1) - 3) above, we will refine guidance on clinical trial methodology, seek to demonstrate benefits of such guidance and how it aids translation of research, in this difficult area.


Research activity codes: 8.4 RESEARCH DESIGN AND METHODOLOGIES (HEALTH SERVICES)
Health categories: NEUROLOGICAL