Award Title: Extracorporeal Photophoresis in the treatment of Chronic Lung Allograft Dysfunction: a randomised controlled trial  (E-CLAD UK)
Funder: Medical Research Council

Abstract: Lung transplantation offers hope to people with life-threatening lung disease. Sadly, many transplanted lungs do not maintain normal function after transplant due to damage inflicted by the recipient’s own immune system. This loss of function is known as chronic lung allograft dysfunction  or CLAD for short. CLAD affects half of all recipients within 5 years, meaning average survival after lung transplant is only 6 years. As damage worsens, lung function drops and lungs then fail completely, causing premature death. There is an urgent need for treatments that stop CLAD early to protect lung function, preserve quality of life and prolong survival._x000D_
Extra-corporeal photopheresis (ECP) uses a machine to separate blood outside the body into white (immune) cells and red cells. The white cells are then shut down with light treatment. Both the white and red blood cells are then returned to the patient. The treated white cells reprogram the immune system to stop further damage. ECP is routinely used to treat complications after bone marrow transplant._x000D_
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Our aim is to assess if ECP is effective at treating CLAD. We will test if adding ECP treatment to current care is more effective at stabilising transplant lung function than standard care. We aim to understand how ECP works in CLAD, which patients are most likely to benefit, and ultimately help the NHS decide if ECP should be used to treat CLAD. Some studies using ECP to treat CLAD have shown promise at slowing progression. These studies were done in single hospitals in selected patients and without comparison to those not getting ECP, so there is insufficient evidence that ECP is effective in treating CLAD for the NHS to use it routinely._x000D_
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Our trial, in all 5 UK adult lung transplant centres, allows eligible patients with CLAD, who consent, to be randomly allocated to receive either ECP and standard care or standard care alone for 6 months. We will recruit 90 patients over 3 years, 45 to each group, allowing reliable comparison between the groups. Breathing tests will be used to monitor progress of CLAD. The number whose breathing tests stabilise over the 6 months will then be compared to see if this happens more frequently in the ECP group. We will measure changes in quality of life, exercise capacity, survival and assess the safety of ECP and interview patients. We will collect blood from patients to understand how ECP is working, to help identify differences between those in whom CLAD stabilises with ECP and those in whom it does not; this may help us predict which patients are most likely to benefit from ECP._x000D_
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We have significant public and patient involvement (PPI). Initial ideas were shared with a panel of transplant patients, relatives and the public. Modified plans were then shared at a national PPI event, which recommended we research patient experiences post-transplant, and with a panel of lay members who endorsed the need for this study. A patient with experience of ECP and CLAD, and a member of the public, are co-applicants and involved in writing the lay summary and conducting the research. A larger Patient Advisory Group will collaborate throughout the study._x000D_
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Findings will be shared and key messages discussed at meetings, patient groups and with charities before publishing in freely available medical journals and the lay press. Plans have been shared  with NHS commissioners, who pay for transplant care, to ensure the relevance of the trial to decisions on funding.

Lay Abstract: RESEARCH QUESTION: _x000D_
Does Extracorporeal Photopheresis (ECP) therapy for chronic lung allograft dysfunction (CLAD) after lung transplant halt disease progression and if so by what mechanism?_x000D_
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BACKGROUND: _x000D_
Lung transplantation is often the only treatment option for life-threatening chronic lung disease. However, many recipients develop CLAD due to immune mediated damage of the transplanted lungs. CLAD affects 10% of recipients each year, giving a 50% prevalence by 5yrs. The impact of CLAD, causing respiratory failure and premature death, means median survival from time of lung transplant is only 6yrs. There are no proven therapies so there is an urgent need to identify ways to halt CLAD progression, preserve quality of life and prolong survival. One potential treatment is ECP in which a recipient’s leucocytes are isolated from whole blood, sensitised, irradiated with UV light and reinfused. These irradiated leucocytes exert immunomodulatory actions slowing immune damage. Uncontrolled retrospective studies of ECP have shown promise at slowing CLAD progression, yet robust evidence is needed to determine definitively if it works, how it works and in which recipients._x000D_
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AIMS AND OBJECTIVES: _x000D_
This randomised controlled trial will compare efficacy of ECP plus standard of care (SOC) versus SOC alone in the management of CLAD. Additional objectives are to characterise immune responses occurring in recipients responding to ECP compared to non-responders, and those receiving SOC alone, to identify the mechanism of action; to determine if CLAD phenotype, clinical factors or immunological markers in blood can predict who will benefit from ECP; and, to conduct interviews with patients, to understand experiences of living with CLAD and of receiving ECP therapy._x000D_
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METHODS: _x000D_
A phase II, prospective, 2-arm, randomised, open-label, multicentre trial to evaluate the efficacy of ECP in stabilising lung function in lung transplant recipients with progressive CLAD. Eligible recipients (n=90) will be randomised 1:1 to ECP plus SOC (treatment arm) or SOC (control arm) alone for 6 months. Randomisation will be stratified by CLAD phenotype. The primary outcome is a composite responder endpoint defined by (i) lung function stabilisation, as indicated by FEV1 and FVC declining by less than or equal to 10% at 6 months and (ii) no rapid initial decline, as characterised by FEV1 or FVC declining by greater than 20% at 3 months. Safety will be monitored by serious adverse events and all-cause mortality. Regular blood samples will provide mechanistic insights, and 30 recipients will participate in a qualitative interview sub-study._x000D_
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TIMELINES: _x000D_
Total study duration is 57 months; months 1-9 full protocol development, governance approvals, contracting, and set up of 5 sites. Months 10-45, 36 months recruitment; data collection will close at end of month 51. Months 52-57 data analysis, final report and dissemination._x000D_
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IMPACT AND DISSEMINATION: _x000D_
The study will provide robust evidence on the efficacy of ECP for CLAD informing decisions by clinicians globally and commissioners regarding its place in the management of lung transplant recipients. We have engaged with NHS specialist commissioners who support our proposal and will engage with NICE to conduct a technology appraisal for ECP in CLAD. Study results will be shared widely with patients, charities, and at national and international clinical meetings, and with open access publications in leading medical journals.

Research Activity Codes: 5.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES;6.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES
Health Categories: RESPIRATORY