Title: Identifying outcomes that define disease severity in AATD; the design of a patient-centred treatment pathway.
Funder: Health Education England

Abstract: Background:Alpha-1 Antitrypsin Deficiency (AATD) is a genetic condition which predisposes to lung and liver disease(2,3) associated with low levels of Alpha 1 Antitrypsin (AAT). 85% of patients develop emphysema and airflow obstruction, presenting at a younger age than usual chronic obstructive pulmonary disease.Generic treatments for AATD include smoking cessation and conventional inhalers. The only specific therapy is regular infusion of plasma derived AAT (augmentation therapy). Across the EU there is inequitable use of augmentation due to differing health systems and controversy over efficacy. Traditionally, spirometry was the primary endpoint in trials but is increasingly recognised as a poor outcome measure in AATD. CT-densitometry is a direct and sensitive measure of emphysema and its progression in AATD and has been used to show benefit of augmentation treatment. It is a not a widely used outcome measure due to cost, expertise and the risks of exposure to ionizing radiation.The UK AATD Registry has 720 well-phenotyped patients on annual review. AAT augmentation therapy is not currently available in the UK. The case for specialist National Commissioning of services in AATD, which may include augmentation therapy, is under review.There is a pressing need to identify outcome measures that are clinically meaningful, patient centred and minimise risks during repetitive testing that can be adopted in clinical trials and clinical practice to help inform NHS Commissioning. Research QuestionWhat features define disease severity in AATD and predict outcome, and could aid stratification of patients' treatment pathway? Aims and methods The fellowship consists of two phases. Phase 1 will be completed in 18 months and Phase 2 in the following two years. Phase 1 Aim 1.1: To assess the clinical effectiveness of treatments frequently used in AATD. A systematic review of clinical trials of treatment will be undertaken, using standard protocol driven methods. Review protocols will be registered in PROSPERO. Aim 1.2: Relate outcome measures used in AATD trials to health outcomes. Results from Aim 1.1 will identify frequently used outcome measures in clinical trials. These will be explored using the UK national registry by retrospective analysis to determine which outcome measures can be used as surrogate markers of disease. Aim 1.3: Relate patient centred outcomes, such as health status, to health outcomes. Results from multiple questionnaires (SGRQ, CAT, EQ5D and SF36) taken from the longitudinal dataset of the UK national registry will be compared to health outcomes identified from Aim 1.2 to determine if they could be used as surrogate markers of disease. Aim 1.4: Develop a prognostic model to identify AATD patients at high risk of progression. Using results from Aims 1.2 & 1.3 I will build a prognostic algorithm to predict decline in AATD. Phase 2 Phase 2 would use data generated in Phase 1 to feed into either any newly commissioned national service (to aid data collection and service design) or service development of ADAPT as an NHS tertiary service. Aim 2.1: Validate the new prognostic model. Using prospective data from a new national service over 2 years following service implementation, or retrospective data from other AATD cohorts, I will validate the prognostic tool in a new population. Aim 2.2: Assess the implementation of the prognostic tool and associated AATD service. I will perform a mixed methods service evaluation pre and post newly implemented service to determine how effectively it can be delivered. Summary of patient benefits Augmentation therapy is expensive, time consuming and not all patients benefit. I will develop a robust tool to assess disease prognosis and direct treatment in AATD. This will support cost-effective NHS services, judicious use of therapies and improve patient care.

Lay abstract: Alpha-1 Antitrypsin Deficiency (AATD) is an inherited condition associated with lung and liver damage. It is unclear which medical investigations are essential or what treatments help people with AATD. I will review treatments for AATD to determine their effectiveness. I will identify which medical tests are the best at identifying early disease and use these to help predict when patients start to deteriorate and treatments should be started.I will also evaluate how these tests and treatments can be used in specialist AATD clinics, to make sure health care professionals and patients find them useful and practical within the NHS.

Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CONGENITAL DISORDERS