Extracorporeal Photopheresis for Medicare Recipients of Lung Allografts
- Conditions
- Bronchiolitis Obliterans Syndrome (BOS)
- Interventions
- Combination Product: Extracorporeal Photopheresis (ECP)Other: No intervention in the SOC / Retrospective Chart review.
- Registration Number
- NCT02181257
- Lead Sponsor
- Washington University School of Medicine
- Brief Summary
The primary aims of this study is to determine the efficacy and tolerability of Extracorporeal Photopheresis (ECP) for the treatment of either Refractory Bronchiolitis Obliterans Syndrome (BOS) patients (258 at cessation of enrollment April 7, 2022) or Newly Diagnosed (22 as of enrollment Hold February 2022) Bronchiolitis Obliterans Syndrome 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 ECP for either refractory or New BOS.
- Detailed 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 in the form of bronchiolitis obliterans syndrome (BOS) 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 BOS 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, BOS is diagnosed and staged by the decline in Forced Expiratory Volume in 1 Second (FEV1) measurement from a pulmonary function test.
In general, BOS 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 (ECP) has been used at some centers as a salvage treatment for progressive BOS. ECP 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 ECP is 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, the Centers for Medicare \& Medicaid Services issued a Decision Memo stating that ECP is covered for Medicare beneficiaries for the treatment of BOS following lung allograft transplantation only when the procedure is provided under a clinical research study.
This study looks at (1) Early detection of refractory BOS using a standardized, more frequent spirometry monitoring approach (i.e., defined as using frequent laboratory based spirometry every 4-8 weeks) and (2) Early implementation of ECP in both participants with early stage refractory BOS and also as first line therapy in a subset of participants at the initial diagnosis of BOS, 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-ECP FEV1 decline) might prove to have predictive value in identifying subsets of BOS patients that are likely, or unlikely, to experience reduced rate of decline or stabilization in FEV1 following ECP treatment. Therefore this study will look to enroll a large series of patients from multiple U.S. centers to confirm that ECP significantly reduces the rate of FEV1 decline in BOS 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 ECP therapy. Enrollment is now complete and ended April 6, 2002. Patients are now in follow-up and will be followed no later than the end of the study December 2028.
This study includes a randomized controlled trial that will compare outcomes in patients with newly diagnosed BOS who receive either conventional (i.e., that involves the standard of care at the respective enrolling center) or ECP for first line management of New BOS. The randomized controlled trial component of the study will enable evaluation of potential survival and quality of life benefits of early treatment of BOS with first-line ECP. The randomized control trial was placed on hold in February of 2022. Twenty-two patients were enrolled study wide. Patients are now in follow-up and will be followed no later than the end of the study December 2028.
Subjects with Refractory BOS who agreed to participate in the study were informed of the following: to limit the use (and attendant risks) of ECP therapy to those patients who are most likely to benefit, their eligibility to receive ECP 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 BOS who agreed to participate in the study were 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 BOS or to an Early Photopheresis Intervention (EPI) group who will receive ECP as first line management of BOS.
The protocol states specific inclusion and exclusion criteria for both the Refractory BOS participant and the newly diagnosed BOS participant. Once eligibility is confirmed and the patient has provided informed consent, all FEV1 measurements captured within the 12 months prior to enrollment will be entered in the electronic database. Based on the slope of the FEV1 decline over time and achievement of a statistically significant rate of decline in lung function in the FEV1 the Refractory BOS participant will be electronically assigned to either ECP treatment or Observation. The newly diagnosed BOS participant will be randomized to either ECP treatment and standard immunosuppression therapy or Control treatment which is Standard immunosuppression Therapy alone.
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 for the first year on all patients except the Refractory BOS participant assigned to Observation. Pulmonary function tests will be captured every 30 days for the first six months for the Observation patient. Following the first six months, the timing of pulmonary function testing must be every 3 months at the very least to maintain eligibility for ECP Treatment. 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 remote monitoring visits during COVID. For most sites an initial remote site monitoring visit will occur 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 ECP treatment will receive 24 treatments over the 6-month period following enrollment.
Allowed Treatment for Refractory BOS patients in the Observation will be ordered at the physicians discretion.
Treatment for the Newly Diagnosed BOS 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 ECP treatment.
Other than ECP, no other interventions for BOS will be used except for Azithromycin for patients in the randomized Early Photopheresis Intervention arm.
An improvement in the FEV1 measurement taken from the pulmonary function test will be used to assess the success or the benefit of the ECP treatment. Patients will have spirometry the first week of therapy, which is repeated every 30 days for the first year, and then annually in the Refractory BOS cohort assigned to ECP treatment. Patient's will have spirometry the first week of therapy, and repeated every 30 days for the first year, and then every 2 months in the NEW BOS cohort. All patients will be followed no later than December 2028. There were considerations for crossover built into the early versions of the protocol.
Statistical Methods. The primary outcome in the RCT or New BOS will look at cumulative all cause mortality and the rate of decline of lung function: A 25% or greater difference in the percentage of patients within each of the two arms (Control vs Early photopheresis Intervention(EPI) who achieve a clinical response as defined as 50% or greater reduction in the rate of FEV1 decline as assessed by comparing the average rate of FEV1 decline over the 6 months prior to ECP against the average rate of FEV1 decline over the 12 months following randomization.
The primary endpoint in the Refractory BOS registry involves a change in the rate of FEV1 decline assessed by comparing the average rate of FEV1 decline over the 6 months prior to ECP against the average rate of FEV1 decline over the 12 months following initiation of ECP. A clinical response will be determined using FEV1 as the primary endpoint and will be defined as a 50% or greater reduction in the rate of decline of FEV1 assessed by comparing the average rate of FEV1 decline over the 6 months prior to ECP against the average rate of FEV1 decline over the 12 months following initiation of ECP. A clinical response will be defined as a 50% or greater reduction in the rate of decline of FEV1 before and after the ECP. The second primary endpoint will include all cause and CLAD related mortality.
The participants will be followed until their death but no later than December 2028 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.
In parallel, data will be collected retrospectively from up to 250 lung transplant recipients (through an IRB approved waiver of consent) who developed NEW BOS and were treated with standard of care (SOC) therapy and did not receive ECP treatment. The addition of a propensity matched standard of care BOS Cohort may promote a more robust assessment of the potential clinical impact of ECP.
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- All
- Target Recruitment
- 280
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Newly Diagnosed Bronchiolitis Obliterans (NEW BOS) Extracorporeal Photopheresis (ECP) Participants with NEW BOS will be randomized to Early Photopheresis Intervention (EPI) or Control (Standard of Care). EPI patients will receive 24 treatments in a 6-month period and may continue maintenance treatments. Twenty-two (22) NEW BOS participants were enrolled nationwide. The Control group will receive local Standard of Care for the management of BOS. Therapy will involve changes in immunosuppressive agents. Standard of Care Comparator Retrospective Chart review No intervention in the SOC / Retrospective Chart review. Data for the SOC comparator will be obtained via a retrospective data capture mechanism either medical chart review or electronic medical record query that meet all of the inclusion criteria and through an IRB approved waiver of consent. The SOC comparator data will be identical to the data collected for the Refractory BOS patients with the exception of inclusion of all spirometry values after transplant. Refractory Bronchiolitis Obliterans Syndrome (REFRACTORY BOS) Extracorporeal Photopheresis (ECP) Participants with REFRACTORY BOS will be electronically assigned to either ECP treatment or Observation based on the participant's pre-enrollment Forced Expiratory Volume in 1 second (FEV1). Values from pulmonary function tests from the preceding 12 months will be entered into a web-based treatment allocation which will perform an automated calculation. Patients who have a statistically significant rate of decline within the preceding 6 months, and a derived protocol defined slope, will be assigned to the ECP Treatment arm. If a patient does not meet these criteria, the participant will be assigned to the Observation arm. Two hundred and fifty-eight (258) participants were enrolled with Refractory BOS nationwide.
- Primary Outcome Measures
Name Time Method REFRACTORY BOS: All cause and CLAD related mortality 5 years following enrollment or the initial ECP. A measure looking at total number of deaths from any cause and total number of CLAD related deaths. Outcome 1 (above) and this Outcome 4 will be assessed with two comparisons as follows:(1) Comparison of the spirometric endpoint within the patients enrolled in the rBOS Arm when each patient is used as their own control. (2) The ECP Treatment Cohort (i.e., rBOS patients within the ECP Registry initially assigned to ECP treatment that have completed the six-month ECP regiment) will be compared to a propensity matched standard of care cohort based on one or more potential spirometric values (e.g. % of baseline FEV1 and possibly rate of FEV1 decline at enrollment and/or comorbidity variables at BOS diagnosis). The standard of care cohort will be captured using data obtained via a retrospective chart review at each collaborating site.
REFRACTORY BOS: Change in the rate of FEV1 decline. Baseline vs 12 months following the initiation of ECP. Comparing the average rate of FEV1 (from pulmonary function test (PFT) or spirometry) decline over the 6 months prior to ECP against the average rate of FEV1 decline over the 12 months following initiation of ECP. A clinical response will be defined as a 50% or greater reduction in the rate of decline of FEV1 before and after the ECP treatment.
NEW BOS: Cumulative All-cause mortality 5 Years following randomization Survival in patients assigned to ECP treatment compared to survival in patients assigned to standard of care. A measure looking at total number of deaths from any cause.
NEW BOS: Change in the rate of FEV1 decline Baseline vs 12 months following randomization A 25% or greater difference in the percentage of patients within each of the two arms (Control vs EPI) who achieve a clinical response which is defined by a 50% or greater reduction in the rate of FEV1 decline as assessed by comparing the average rate of FEV1 decline over the 6 months prior to ECP Treatment against the average rate of FEV1 decline over the 12 months following randomization.
- Secondary Outcome Measures
Name Time Method All Participants: All-cause and CLAD related mortality following either randomization (NEW BOS) or initiation of ECP (Refractory BOS) Annually for five years A measure looking at total number of deaths from any cause and total number of CLAD related deaths.
All Participants: Effect of maintenance ECP (number of procedures and duration) on BOS progression and outcome. At the end of 5 year follow-up Look at number of maintenance ECP procedures and duration of maintenance ECP treatments and its effect on BOS progression and patient's outcome.
All Participants: Average rate of FEV1 decline over the 9 months following initiation of ECP treatment in Refractory BOS or randomization in NEW BOS or the Randomized Control Trial. Baseline vs 9 Months following randomization Look at the average rate of FEV1 decline obtained from a pulmonary function test or spirometry over the 9 months following initiation of ECP.
All Participants: Change in Health-Related Quality of Life Baseline and months 3, 6, 9, and 12, and annually up to 5 years. The Quality of Life Questionnaire has combined the Dyspnea 12, the Modified Medical Research Council Dyspnea Scale, The St Georges' Respiratory Questionnaire, and the EQ-5D-5L. The Dyspnea12 questionnaire assesses dyspnea severity and is comprised of 12 items and two domains (Physical: 7 questions, affective: 5 questions). Participants are instructed to indicate how much (None =0, Mild=1, Moderate=2, Severe=3) each item "troubled you". The Modified Medical Research Council Dyspnea Scale comprises 5 statements that describe the range of respiratory disability from none (Grade 0 ) to almost complete incapacity (Grade 5). The St. Georges addresses the frequency of respiratory symptoms and the patient's current state. Each question response has a unique weight. The lowest is 0 and the highest is 100. EQ-5D-5L comprises 5 dimensions: mobility, self-care, usual activities, pain and anxiety/depression. The Scores will be totaled and compared between the treatment and control group
NEW BOS: A 30% increase in residual of FEV1 values in BOS treatment Arm (EPI or Control); this would include all patients and spirometry monitoring sub-cohorts. 6 months after randomization Residual FEV1 obtained at one or more post enrollment time periods is defined as any of the following values: FEV1, FEV1 as % of post-transplant baseline and FEV1 as % of enrollment FEV1.
All Participants: Proportion of patients with treatment-related serious adverse events after randomization in RCT or NEW BOS or after ECP initiation in Refractory BOS Every 6 months for up to 5 years following enrollment. Review number of patients with treatment related serious adverse events in both groups.
All Participants: Diagnostic performance of our spirometric enrollment criteria After enrollment of 80 refractory BOS patients. Will be assessed with the RCT or NEW BOS patients at the end of the study. Identify patients who have a response by review of rate and statistical significance of decline in FEV1. (i.e., \> 50% decline in the rate of FEV1 decline).
NEW BOS: Incidence of pulmonary specific infections, CVC related infections and all infections. 5 years Review of the occurrence, rate, and/or frequency of the number of pulmonary specific infections, catheter related infections and all infections in the NEW BOS group
NEW BOS: Hospitalization rates between EPI and control arms 5 years after enrollment. Compare hospitalization rates between the two arms.
NEW BOS: Treatment related serious adverse events (SAEs) between EPI and control arms. Every 6 months up to 5 years after enrollment Compare treatment related SAEs between early ECP treatment intervention to the control group
REFRACTORY BOS: Additional analyses will be performed to evaluate the validity of the study's FEV1-based treatment allocation method using data from enrollees in both the Observation and ECP Treatment groups 5 years after enrollment How accurately did the FEV1 based treatment allocation method predict that the participant was placed in the right group i.e. ECP treatment vs observation.
Trial Locations
- Locations (22)
Northwestern University
🇺🇸Chicago, Illinois, United States
Ohio State University
🇺🇸Columbus, Ohio, United States
Temple University
🇺🇸Philadelphia, Pennsylvania, United States
Baylor University Medical Center
🇺🇸Dallas, Texas, United States
UT Southwestern Medical Center
🇺🇸Dallas, Texas, United States
Indiana University Health
🇺🇸Indianapolis, Indiana, United States
University of Minnesota Medical Center, Fairview
🇺🇸Minneapolis, Minnesota, United States
Duke University
🇺🇸Durham, North Carolina, United States
St. Joseph's Hospital and Medical Center
🇺🇸Phoenix, Arizona, United States
University of Florida
🇺🇸Gainesville, Florida, United States
University of Pittsburgh
🇺🇸Pittsburgh, Pennsylvania, United States
University of Kentucky
🇺🇸Lexington, Kentucky, United States
University of California San Diego
🇺🇸La Jolla, California, United States
University of Alabama at Birmingham
🇺🇸Birmingham, Alabama, United States
University of Iowa
🇺🇸Iowa City, Iowa, United States
Brigham and Women's Hospital
🇺🇸Boston, Massachusetts, United States
Spectrum Health
🇺🇸Grand Rapids, Michigan, United States
Columbia University
🇺🇸New York, New York, United States
Houston Methodist
🇺🇸Houston, Texas, United States
Inova Health System
🇺🇸Falls Church, Virginia, United States
University of Michigan Health System
🇺🇸Ann Arbor, Michigan, United States
Washington University School of Medicine
🇺🇸Saint Louis, Missouri, United States