Extracorporeal Photophoresis in the treatment of Chronic Lung Allograft Dysfunction: a randomised controlled trial (E-CLAD UK)

RESEARCH QUESTION:

Does Extracorporeal Photopheresis (ECP) therapy for chronic lung allograft dysfunction (CLAD) after lung transplant halt disease progression and if so by what mechanism? BACKGROUND:

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. AIMS AND OBJECTIVES:

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.

METHODS:

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. TIMELINES:

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. IMPACT AND DISSEMINATION:

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.