Extracorporeal Photopheresis for Medicare Recipients of Lung Allografts

  • STATUS
    Recruiting
  • End date
    Dec 25, 2023
  • participants needed
    979
  • sponsor
    Washington University School of Medicine
Updated on 25 January 2021

Summary

The primary aims of this study is to determine the efficacy and tolerability of Extracorporeal Photopheresis (ECP) for the treatment of either refractory (240) or newly diagnosed (739) Bronchiolitis Obliterans Syndrome (BOS) in patients after lung transplantation.In compliance with the Centers for Medicare and Medicaid Services' (CMS) Coverage with Evidence Development (CED) decision, the study will collect specified demographic, comorbidity, treatment, and outcome data exclusively for Medicare beneficiaries who are treated with Extracorporeal Photopheresis for either refractory or New Bronchiolitis Obliterans Syndrome .

Description

Lung transplantation has become the treatment of choice for selected patients with end-stage lung disease. Long-term survival after transplantation remains disappointing. Chronic rejection bronchiolitis obliterans syndrome has emerged as the leading obstacle to better long-term outcomes, and is the leading cause of death beyond the first year after transplantation. This disorder is a fibroproliferative scarring process that involves the narrowing of the airway lumen and ultimately complete luminal obliteration. Physiologically and clinically, this luminal narrowing results in airflow limitation and breathlessness. Histologic confirmation of Bronchiolitis Obliterans Syndrome is difficult with bronchoscopy obtained lung biopsies because of the patchy distribution of the disorder and inadequate sampling of small airways with transbronchial lung biopsies. As a result Bronchiolitis Obliterans Syndrome is diagnosed and staged by the decline in Forced Expiratory Volume measurement from a pulmonary function test.

In general, bronchiolitis obliterans syndrome is treated by intensifying the immunosuppressive regimen. The specific approach is variable from center to center, but typically includes optimizing the maintenance immunosuppressive regimen to include tacrolimus and mycophenolate mofetil, high-dose steroids, and a course of anti-thymocyte globulin. Despite treatment, most patients continue to show progressive decline in lung function resulting in worsening functional status, quality of life, and ultimately graft failure and death.

Extracorporeal photopheresis has been used at some centers as a salvage treatment for progressive bronchiolitis obliterans syndrome. Extracorporeal photopheresis involves separating the patient's blood into a leukocyte-enriched component (buffy coat) and a leukocyte-depleted component. The buffy coat is then photosensitized with 8-methoxypsoralen and treated with ultraviolet light within a photosensitization chamber, resulting in leukocyte apoptosis. Although the exact mechanism of action of extracorporeal photopheresisis unclear, re-infusion of this apoptotic leukocyte population into the patient's circulation is thought to result in alterations in antigen presenting cells, cytokine profiles, and the expansion of regulatory T cells.

On May 2, 2012, Centers for Medicare & Medicaid Services issued a Decision Memo stating that Extracorporeal photopheresis is covered for Medicare beneficiaries for the treatment of bronchiolitis obliterans syndrome following lung allograft transplantation only when the procedure is provided under a clinical research study.

This study looks at (1) Early detection of bronchiolitis obliterans or refractory bronchiolitis obliterans syndrome using a standardized, more frequent spirometry monitoring approach (i.e., defined as using either more frequent laboratory based spirometry every 4-8 weeks) and (2) Early implementation of Extracorporeal photopheresis in both participants with early stage refractory bronchiolitis obliterans syndrome and also as first line therapy in a subset of participants at the initial diagnosis of bronchiolitis obliterans syndrome, in the context of a new randomized controlled trial.

The study will look at whether certain coexisting disease states or patient-related demographic, functional, treatment-related or diagnostic variables (e.g. extent or statistical significance of the rate of pre-Extracorporeal Photopheresis - Forced Expiratory Volume decline) might prove to have predictive value in identifying subsets of bronchiolitis obliterans syndrome patients that are likely, or unlikely, to experience reduced rate of decline or stabilization in Forced Expiratory Volume following extracorporeal photopheresis treatment. Therefore this study will look to enroll a large series of patients from multiple United States centers to confirm that Extracorporeal Photopheresis significantly reduces the rate of Forced Expiratory Volume decline in bronchiolitis obliterans syndrome patients refractory to standard immunosuppressive drug therapy, and to capture and assess specified patient demographic, treatment-related, diagnostic, functional and co-morbidity-related variables that may predict outcomes after Extracorporeal Photopheresis therapy.

This study includes a randomized controlled trial that will compare outcomes in patients with an initial diagnosis of bronchiolitis obliterans syndrome or New bronchiolitis obliterans syndrome who receive either conventional (i.e., that involves the standard of care at the respective enrolling center) or Extracorporeal Photopheresis for first line management of New bronchiolitis obliterans syndrome. The randomized controlled trial component of the study will enable evaluation of potential survival and quality of life benefits of early treatment of bronchiolitis obliterans syndrome with first-line Extracorporeal Photopheresis .

Subjects with Refractory bronchiolitis obliterans syndrome who agree to participate in the study will be informed of the following: to limit the use (and attendant risks) of Extracorporeal Photopheresis therapy to those patients who are most likely to benefit, their eligibility to receive Extracorporeal Photophereis within the study will be determined by the study team's analysis of their pre-enrollment pulmonary function testing along with input from their physician.

Subjects with Newly-Diagnosed Bronchiolitis Obliterans syndrome who agree to participate in the study will be informed that they will be randomly assigned to either a control group (Control) who will receive the local Standard of Care for management of their Bronchiolitis Obliterans Syndrome or to an Early Photopheresis Intervention group who will receive Extracorporeal Photopheresis as first line management of Bronchiolitis Obliterans Syndrome.

The protocol states specific inclusion and exclusion criteria for both the Refractory Bronchiolitis Obliterans syndrome participant and the newly diagnosed Bronchiolitis Obliterans syndrome participant. Once eligibility is confirmed and the patient has provided informed consent, all Forced Expiratory Volume measurements captured within the 12 months prior to enrollment will be entered in the electronic database. Based on the slope of the Forced Expiratory Volume and achievement of a statistically significant rate of decline in lung function in the Forced Expiratory Volume the Refractory Bronchiolitis Obliterans syndrome participant will be electronically assigned to either Extracorporeal Photopheresis treatment or Observation. The newly diagnosed Bronchiolitis Obliterans syndrome participant will be randomized to either Extracorporeal Photopheresis treatment and standard immunosuppression therapy or Control which is Standard immunosuppression Therapy.

The participant will be assigned a unique identification number created from the electronic data base. The patient demographics, co-morbidities, medical history including date of lung transplantation, underlying disease necessitating lung transplantation, vital signs, height, weight, and current immunosuppression regimen will be entered at baseline. A Quality of Life Questionnaire will be asked at baseline and every 3 months the first year and then annually. A pulmonary function test will be captured every 30 days on all patients except the Refractory Bronchiolitis Obliterans syndrome participant assigned to Observation. Pulmonary function tests will be ordered on the Observation patient at the physician's discretion. Certain de-identified source documents will be required and verified on all forms electronically submitted. Data points will be verified against de-identified source by the Data Coordinating Center. The online data entry portal and study database will contain a mechanism to a) clearly denote the status of each submitted Case Report Form, including whether the case report form is complete; b) list the source documentation needed c) indicate if the site staff member and investigator have attested to the validity of the data on the Case Report Form; and d) indicate if the Data Coordinating Center has verified the accuracy of key elements of the study data and what data queries remain. This centralized monitoring will complement our on-site monitoring visits. For most sites an initial on site monitoring visit will be soon after the first three patients are enrolled to ensure that the site personnel understand study processes and expectations, and to permit early completion of additional training to address any deficiencies. Should remote or on-site monitoring reveal areas of particular deficiency or concern, the monitoring plan will be adjusted to focus on those particular areas for the site. In general, sites and patients affiliated with a major violation will be monitored with greater completeness. Sites deemed to be largely compliant with the protocol and regulatory requirements based upon the initial monitoring visit are expected to have subsequent visits performed at a reduced level of frequency. Overall, the study team will seek to optimize resource use by focusing on the most critical data elements that may impact subject safety and/or data quality and integrity.

Participants who receive Extracorporeal Photopheresis treatment will receive 24 Extracorporeal Photopheresis treatments over the 6-month period following enrollment.

Allowed Treatment for Refractory Bronchiolitis Obliterans syndrome patients in the Observation will be ordered at the physicians discretion.

Treatment for the Newly Diagnosed Bronchiolitis Obliterans syndrome patients in the Control Arm of the randomized control trial will be dictated by the standard of care within each enrolling institution and will involve changes in immunosuppressive agents. These patients will not be eligible to receive Extracorporeal Photopheresis treatment.

Other than Extracorporeal Photopheresis, no other interventions for Bronchiolitis Obliterans syndrome will be used except for Azithromycin for patients in the randomized Early Photopheresis Intervention.

An improvement in the Forced Expiratory Volume measurement taken from the pulmonary function test will be used to assess the success or the benefit of the Extracorporeal Photopheresis treatment. Patient's will have spirometry the first week of therapy, and repeated every 30 days for the first year, and then annually. All patients will be followed for 5 years.There are considerations for crossover built into the protocol.

Statistical Methods.A clinical response will be determined using Forced Expiratory Volume as primary endpoint and will be defined as a 50% or greater reduction in the rate of decline of Forced Expiratory Volume assessed by comparing the average rate of Forced Expiratory Volume decline over the 6 months prior to Extracorporeal Photopheresis against the average rate of Forced Expiratory Volume decline over the 12 months following initiation of Extracorporeal Photophereis.

Survival Primary Outcome: Mortality three years after diagnosis of Bronchiolitis Obliterans syndrome using standard of care management of Bronchiolitis Obliterans syndrome is 52%. Assuming 15% exclusion related to early crossover and a 5% loss to follow-up of enrolled patients, 739 patients who meet the standardized criteria for Bronchiolitis Obliterans syndrome would need to be enrolled and randomly assigned to either the Early Photopheresis Intervention or control cohorts to detect a difference. The outcomes between the two Bronchiolitis Obliterans syndrome disease severity strata will be assessed separately. The patient will be followed for up to five years or until their date of death and the following data will be collected annually after the first year: Spirometry results, the number of maintenance Extracorporeal Photopheresis treatments performed and Quality Of Life surveys will be tabulated.

Details
Condition Bronchiolitis Obliterans Syndrome
Treatment Extracorporeal photopheresis (ECP)
Clinical Study IdentifierNCT02181257
SponsorWashington University School of Medicine
Last Modified on25 January 2021

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