Methods and analysis
Trial methods and analysis are reported as per Standard Protocol Items: Recommendations for Interventional Trials reporting guidelines15
Trial setting
The trial will be performed in a tertiary care setting involving all five of the designated adult lung transplant centres in the UK (The Newcastle upon Tyne Hospitals NHS Foundation Trust, Manchester University NHS Foundation Trust, University Hospitals Birmingham NHS Foundation Trust, Royal Brompton & Harefield Hospitals and Royal Papworth Hospital NHS Foundation Trust). This will allow all adult UK bilateral lung transplant recipients who develop CLAD to learn about the trial and decide if they wish to participate. Two of the centres (Royal Papworth Hospital NHS Foundation Trust and Manchester University NHS Foundation Trust) do not have their own ECP centre and so will be supported by other organisations (Cambridge University Hospitals NHS Foundation Trust and NHS Blood and Transplant, respectively) to provide the study intervention.
Eligibility
The target population for E-CLAD UK is patients aged 16 and over who have received a bilateral (a.k.a. single sequential) lung or heart and (bilateral) lung transplantation that fulfil the International Society for Heart and Lung Transplantation (ISHLT) 2019 diagnostic criteria for CLAD. The specific eligibility criteria are detailed in box 1.
Box 1Eligibility criteria for the E-CLAD UK trial
Inclusion criteria
Adults (≥16 years of age) with body weight ≥30 kg.
Bilateral lung or heart and (bilateral) lung transplant recipients.
Confirmed diagnosis of CLAD stages 1, 2 or 3 as per International Society for Heart and Lung Transplantation 2019 consensus definition.
New CLAD diagnosis or prior diagnosis with evidence of current progressive disease.
Exclusion of non-CLAD causes for decline in lung function by high-resolution computed tomography thorax and bronchoscopy+/-transbronchial biopsy within 12 weeks of first CLAD diagnosis.
Adequate treatment of potential non-CLAD causes of a decline in lung function (eg, acute cellular or acute humoral rejection, infections, airway anastomotic strictures and medical treatment for gastro-oesophageal reflux).
Progressive decline in forced expiratory volume in 1 second (FEV1) (≥10%), while on azithromycin for ≥6 weeks.
Capacity to provide written informed consent.
A minimum of two recorded FEV1 and forced vital capacity (FVC) measurements (including home spirometry) obtained during the 26 weeks preceding consent*. Measurements must be at least 3 weeks apart with the last measurement at least 3 weeks prior to consent.
* FEV1 and FVC values collected as part of routine clinic spirometry and research pulmonary function tests along with historical clinical spirometry data from medical records will be used.
Exclusion criteria
Single lung transplant recipients.
Female patients who are breast feeding, pregnant or planning to become pregnant during the timeframe of study participation.
Current treatment with or history of Total Lymphoid Irradiation completed within the last 12 months.
≤1 month wash-out from any other investigational therapies for CLAD.
Inability to perform lung function tests or adhere to study protocol as judged by supervising clinician.
History of haematopoietic stem cell transplantation (HSCT).
Patients who are on a retransplant waiting list.
Current participation in another interventional clinical trial, or participation in a clinical trial of an investigational agent in the previous 4 weeks from consent.
Patients with inadequate vascular access (peripheral or central) options to perform ECP.
Any contraindication to receiving ECP. These include:
Previous allergic reaction to methoxsalen, another psoralen compound, or any of the other UVADEX ingredients.
Coexisting untreated skin cancer* (melanoma, basal cell or squamous cell cancer).
Any disease which involves sensitivity to light such as porphyria, systemic lupus erythematosus or albinism.
Previous removal of spleen.
Blood clotting disorder or an increased white blood cell count >25×109/L.
Significant heart disease or severe anaemia causing inability to tolerate blood volume shifts associated with ECP.
Aphakia or lens removed from either eye (unless already blind in eye without a lens).
Sexually active men and women of childbearing potential unless adequate contraception is used during treatment.
*Patients with coexisting treated skin cancer should be assessed and counselled on the balance of risks of harm from their skin cancer after exposure to methoxsalen or from their CLAD diagnosis in determining if this constitutes an exclusion criterion.
Intervention
Standard of Care
The standard management of lung transplant recipients both before and after the development of CLAD may vary between centres. However, the underlying principles are well aligned in terms of the approach to maintenance immunosuppression regimen (cell cycle inhibitor, calcineurin inhibitor and corticosteroids) and prophylaxis against common viral, bacterial and fungal infections with attention to blood pressure control, lipid profiles, preservation of renal function and bone protection. Acute cellular rejection of ISHLT grade A2 or higher is treated with short-term augmentation of corticosteroids in all centres.
The diagnostic approach to new-onset CLAD is also well aligned with the 2019 ISHLT criteria4 with a diagnosis made only after a failed response to a trial of azithromycin therapy and exclusion of reversible causes such as cellular or humeral rejection, large airway anastomotic obstruction and infection.
All five centres participating in this trial have agreed clear principles for the SOC for CLAD treatment. The basis remains supportive with supplementary oxygen for hypoxia, prevention and treatment of infective exacerbations, physical rehabilitation and psychosocial support. Participants in the trial will not be treated with any immunomodulatory interventions such as total lymphoid irradiation or ECP as part of the SOC arm. This will be the approach in both arms of the study, with use of ECP in the treatment arm the only difference.
Extracorporeal Photopheresis
ECP therapy is performed using the Therakos Cellex Photopheresis System which is an automated enclosed system that separates a given volume of the patient’s whole blood into plasma, red blood cell and leucocyte fractions. The red cells and some of the plasma are immediately returned to the patient while the leucocytes and remaining plasma are collected in a separate chamber. This collection process is repeated over a number of cycles. The buffy coat suspension of leucocytes is then treated with the photosensitising drug UVADEX (methoxsalen). After the cells have absorbed this drug, they are exposed to UVA light radiation to activate the apoptosis pathway, and then returned to the patient’s circulation.
For this trial, UVADEX solution is an investigational drug. The dose of UVADEX used to inoculate cells will be calculated based on the standard treatment volume formula. Heparin is the standard anticoagulant for use with the Therakos Cellex Photopheresis System, however sites will be able to use other anticoagulants if routinely used as part of their standard local ECP protocol, or if heparin is contraindicated for a patient.
Patients will receive nine cycles of ECP, each cycle consisting of two treatments performed on consecutive days, each taking 2–3 hours to complete. Cycles are performed every 2 weeks for the first 12 weeks and then every 4 weeks for the next 8 weeks meaning that those who complete the study will have received nine cycles of ECP over 20 weeks equating to 18 individual treatments (figure 1).
Figure 1Flowchart of research activity for the E-CLAD UK trial. CLAD, chronic lung allograft dysfunction; ECP, extracorporeal photopheresis.
Outcomes
The primary outcome measure is lung function stabilisation derived from the change in forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) at 12 and 24 weeks compared with baseline at study entry. This is a binary composite responder outcome, defined as both ‘lung function stabilisation’ from baseline to 24 weeks and ‘no early rapid decline’ as measured from baseline to 12 weeks (figure 2). Lung function stabilisation is classed as a less than 10% fall in both FEV1 and FVC at 24 weeks compared with baseline. Early rapid decline is defined as a more than 20% fall in either FEV1 or FVC from baseline to 12 weeks due to progressive CLAD.
Figure 2Summary of E-CLAD UK trial primary outcome measure process. CLAD, chronic lung allograft dysfunction; ECP, extracorporeal photopheresis; FEV1, forced expiratory volume in one second; FVC, forced vital capacity; ISHLT, International Society for Heart and Lung Transplantation; SOC, standard of care.
Secondary outcome measures in the E-CLAD UK trial include other measures of lung function, physical performance, health-related quality of life and physical well-being:
rate of decline in lung allograft function measured using spirometry (FEV1 and FVC) at baseline and 24 weeks;
exercise capacity measured using distance walked in the 6-minute walk test at baseline and 24 weeks;
disease severity measured by CLAD classification as per ISHLT guideline at baseline and 24 weeks;
health-related quality of life measured by the SF-36v2 and EQ-5D-5L questionnaires at baseline and 24 weeks;
survival collected from medical records at 24 weeks and
safety measured by collecting details of adverse events (AEs) and serious adverse events (SAEs) occurring between baseline and 24 weeks.
Mechanistic substudy
A mechanistic evaluation of participants’ immune responses will be undertaken to understand how these change before and after commencing ECP therapy and to identify if there are any molecular or cellular markers which may help predict patient response to ECP treatment. Blood samples will be collected to characterise immune responses occurring in recipients responding to ECP compared with non-responders, and those receiving SOC alone, to identify potential mechanisms of action. Data will be analysed to determine if CLAD phenotype, clinical factors or immunological markers in blood can predict who will benefit from ECP. Samples for the mechanistic substudy will only be collected from participants from The Newcastle upon Tyne Hospitals NHS Foundation Trust randomised to receive ECP and who provide separate informed consent.
Qualitative substudy
A qualitative study will be conducted to critically examine the perceptions and experiences of patients with CLAD and their experiences and understandings of ECP therapy.
Individual semistructured interviews will be carried out with up to 30 patients with CLAD including 20 who have experienced ECP, purposively sampled from those who consented to be approached about the qualitative substudy. Separate informed consent will be collected for participation in the qualitative substudy. Interviews will provide new insights about patient experiences of CLAD as well as providing valuable information about experiences of receiving ECP therapy which will inform future wider implementation. Data will be analysed following the principals of Constructivist Grounded Theory and will employ the constant comparative method.16 17 Fully anonymised excerpts of data from interview transcripts will be shared and discussed with our lay applicants and Patient and Public Involvement and Engagement advisory panel.
Participant timeline
All adult lung transplant recipients remain under life-long follow-up at transplant centres and will be familiar to clinical teams. Patients will be identified in clinical practice and potentially eligible patients will be initially approached by the treating clinician. They will be invited to watch a trial information video (https://research.ncl.ac.uk/e-claduk/) and given a short version patient information sheet (PIS) (see online supplemental material). If after watching the video and reading the short PIS they remain interested, patients will be provided with the full PIS to read (see online supplemental material). Willing participants will then be booked in for a baseline visit, at least 24 hours after provision of the full PIS. Eligibility assessments and baseline assessments will take place after consent is given.
For those randomised to ECP, the first ECP cycle will be scheduled within 14 days of the baseline visit. All other visits will be scheduled based on the first ECP treatment date. ECP therapy will take place every 2 weeks for the first 12 weeks and then every 4 weeks until nine cycles are completed by week 20. Research visits will take place for all participants every 4 weeks after the week 0 visit. For participants randomised to the SOC arm, this will be based on the date of consent. These visits will be scheduled to correspond with routine clinical appointments. A final visit will take place for all participants at 24 weeks where final research assessments will occur.
At the week 12 visit, all participants will be assessed for treatment response. Those identified as ‘non-responders’ due to rapid progression of CLAD will be considered for rescue treatment outside the trial and withdrawn from the trial if necessary. Non-response is defined as a more than 20% drop in FEV1 or FVC compared with baseline at trial entry that is confirmed as being due to progressive CLAD. In the event of trial withdrawal, with consent, week 24 assessments will take place at a participant’s final visit.
Allocation
Participants will be randomised 1:1 to receive either ECP plus SOC or SOC alone using a computer-generated randomisation system (Sealed Envelope) with concealed allocation. A balanced allocation will be achieved within the two trial arms by use of two stratification variables, study site and CLAD phenotype, namely BOS, RAS or mixed.
Biological samples
Blood samples will be collected from all participants at study baseline, 12 and 24 weeks for evaluation of immune response. Samples will undergo immunophenotyping, immune marker and transcriptomic analysis. Any samples remaining at the end of the study will be anonymously biobanked for further related analysis outside of the trial.
AEs and assessment process
AEs will be monitored throughout the study from time of consent to end of trial participation through regular face-to-face visits. All participants in the ECP arm will be followed up for a minimum of 4 weeks after their last ECP treatment. Data from all AEs will be recorded on the trial database. SAEs will be assessed for any relationship to the treatment intervention (causality), by a delegated, medically qualified site doctor. Any events believed by the investigator to be due to the progression of CLAD, or any scheduled hospitalisations, including for ECP treatment, will not be reported as SAEs to the Sponsor. The chief investigator will assess, on behalf of Sponsor, expectedness of any serious adverse reactions against the approved reference safety information for the trial.
Data collection and management
All data will be collected by each PI or their delegated nominees and recorded in the electronic case report form (eCRF) for the study. The study-specific eCRF will be set up using Red Pill, Sealed Envelope’s eCRF system. Participant identification will be through a unique trial identifier.
Access to the trial database will be password-limited, with task-specific restrictions. Only staff formally delegated to do so will have access to the database. Newcastle Clinical Trials Unit (NCTU) staff will monitor trial conduct and data integrity in accordance with the trial monitoring plan.
Statistical methods
Our proposed sample size is 90 patients. Todd et al reported changes in longitudinal lung function in 213 patients with CLAD who did not receive ECP; 27% had a <10% loss in FEV1 within 6 months, equating to stabilisation.18 Therefore, based on best available data, we assume conservatively that in the SOC arm, 30% of patients will be responders. The three largest ECP in CLAD studies11–13 show that 54%–61% patients had <10% decline in FEV1 within 6 months; we therefore assume a 55% stabilisation rate in the ECP arm. With 90 patients randomised 1:1 between SOC and ECP arms, there is 80% power (5% one-sided type I error rate) to detect a difference when the ECP arm has a 55% response rate and the SOC arm a 30% response rate. This calculation assumes Barnard’s exact test is used in the analysis and on the basis of a binary primary endpoint. However, as the primary endpoint is a composite responder endpoint, the primary analysis will use the augmented binary method to examine the difference in response rates.19 It is estimated from previous simulation results that this would increase the power of the trial to >90% without inflation in type I error rate.20
Sensitivity analyses of the primary outcome will be conducted using a logistic regression model for the binary responder primary outcome. Secondary outcomes will be analysed using suitable regression models (eg, linear regression for continuous outcomes and ordinal regression for ordinal data). All primary analyses of the primary and secondary outcome measures will be carried out on an intention to treat basis in the full analysis population. This will contain all patients recruited into the study. Safety analyses will be carried out in a population consisting of all patients recruited into the study.
Management and oversight
A Trial Management Group (TMG), consisting of the chief investigator, key NCTU staff, coapplicants, trial statisticians, local research staff and an NHS Sponsor representative, will meet approximately monthly throughout the duration of the trial. A Trial Steering Committee (TSC), which has an independent chair and four independent members including one patient and public involvement representative, will review study progress and provide advice on all aspects of the trial to the TMG. A Data Monitoring Committee, with an independent chair and two independent members, will monitor data including safety and efficacy as well as the overall conduct of the study, reporting to the TSC. An active risk register has been compiled in consultation with the Sponsor. This will be monitored and updated throughout the trial.
Patient and public involvement (PPI)
Public and patient contributors have been extensively involved throughout the development of the trial; from deciding the research question to discussing the rationale, design and delivery of the study. The original idea for the trial was discussed with the NIHR Blood and Transplant Research Unit in Organ Donation and Transplantation Public and Patient Research Panel who supported the trial, feeling it could improve patients’ quality of life and potentially help them to live longer. The panel emphasised the value of understanding the lung transplant patient journey, resulting in the inclusion of qualitative interviews to explore in-depth the patient experiences of CLAD, its treatment and of ECP.
Current ECP recipients have shared their views on treatment acceptability, providing reassurance that the proposed ECP regimen would not be seen as overly burdensome. Lay coinvestigators are part of the research team, helping embed patient and public perspectives throughout the development of the trial, in particular the qualitative work. Long-term PPI in the trial is facilitated through a Public and Patient Advisory Group; members have improved the clarity, inclusivity and accessibility of participant-facing documentation, including patient consent materials and will help review progress and assist with the dissemination of results.
Trial status
The E-CLAD UK trial was opened to recruitment on the 9 February 2023. Recruitment is due to close on 30 June 2025 with the Last Patient Last Visit expected in December 2025. This manuscript is based on Protocol V.2.0 dated 14 October 2022.
Ethics and dissemination
Ethics
A favourable ethical opinion has been granted from the UK Health Research Authority Research Ethics Committee (East Midlands—Derby; REC reference 22/EM/0218). The trial has also received approval from the UK Medicines and Healthcare products Regulatory Agency (MHRA; trial reference CTA 17136/0302/001-0001). The trial has been included in the National Institute for Health and care Research Clinical Research Network (NIHR CRN) portfolio (NIHR CRN study ID: 53956). The trial Sponsor is the Newcastle upon Tyne Hospitals NHS Foundation Trust (tnu-tr.sponsormanagement@nhs.net). The trial Sponsor has delegated responsibility for trial management to NCTU, including trial design; review and approval of all localised patient-facing documentation prior to implementation at each site; collection, analysis and interpretation of data; writing of the protocol publication and final clinical report manuscripts.
Dissemination policy
A final report of the trial will be provided to the Sponsor, funder and Research Ethics Committee within 12 months of the end of the study. The full trial dataset will be uploaded to the European Union Drug Regulating Authorities Clinical Trials (EudraCT) database within 12 months as per the European Commission’s guidelines on posting and publication of result-related information. The trial is registered on the ISRCTN trial database and trial results will be made publicly available within 12 months of the end of the trial, defined as Last Patient, Last Visit date.
The final clinical trial report will be used for publication and presentation at scientific meetings. Summaries of results will also be made available to investigators for dissemination within their clinical areas where appropriate and according to their discretion.
