Extracorporeal Photopheresis for Medicare Recipients of Lung Allografts

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.

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.

Eligibility Criteria:
INCLUSION Criteria for REFRACTORY BOS

1. Age (18 years old or older).
2. Medicare-eligible status
3. Lung transplant recipient (combined organ transplant recipients, e.g. heart-lung or liver-lung or lung re- transplantation recipients are eligible).
4. Patients with a diagnosis of BOS using at least two laboratory based FEV1 values obtained at least three weeks apart that are both at least 20% lower than baseline FEV1 using the International Society for Heart and Lung Transplantation (ISHLT) definition (The average of the two highest FEV1 measurements obtained at least 3 weeks apart after transplantation). The date of Diagnosis of New BOS is the first date of the two FEV1s that were used for the BOS diagnosis.
5. Refractory BOS defined as ongoing decline in FEV1 despite at least one of the following treatments:

   azithromycin, high-dose steroid, anti-thymocyte globulin, total lymphoid irradiation, sirolimus, or everolimus.
6. At minimum five recorded FEV1 measurements obtained at intervals of at least two weeks apart, over the 9 months preceding study enrollment, of which one FEV1 must be within two weeks prior to enrollment.
7. History of frequent spirometry monitoring defined as having had regular FEV1 measurements within the context of either of the following two options: (1) During the preceding four months prior to enrollment with no time interval between FEV1 measurements that exceeds 8 weeks. (2) During the preceding six months prior to enrollment with no time interval between FEV1 measurements that exceeds 12 weeks.
8. A documented clinical assessment including a physical assessment and Complete Blood Count (CBC) with White Blood Cell Count (WBC) within two weeks prior to enrollment.

INCLUSION criteria for NEWLY Diagnosed BOS

1. Age (18 years old or older)
2. Medicare-eligible status.
3. Lung transplant recipient (combined organ transplant recipients, e.g. heart-lung or liver-lung, lung re-transplantation recipients, are eligible).
4. History of close FEV1 monitoring prior to diagnosis of new BOS defined as having had either of the two monitoring approaches:

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1. Frequent laboratory based spirometry defined as having had regular FEV1 measurements within the context of either of the following two options: A. During the preceding six months prior to diagnosis of new BOS with no time interval between FEV1 measurements that exceeds 8 weeks. (Participants must be at least 6 months post transplant) B. During the preceding nine months prior to diagnosis of new BOS with no time interval between FEV1 measurements that exceeds 12 weeks (Participants must be at least 9 months post- transplant)
2. Frequent Home Spirometry through the separate IRB approved Standardized Home Spirometry Method sub-protocol. 5.Diagnosis of new BOS (i.e., "new BOS" is defined as within nine weeks of enrollment) based on laboratory-based spirometric FEV1 measurements obtained on at least two separate occasions (i.e., at least 3 weeks apart) that have declined by more than 20% from post-transplant baseline values (i.e., using ISHLT definition). The date of Diagnosis of New BOS is the first date of the two FEV1s that were used for the BOS diagnosis. Inherent to the diagnosis of new BOS is the exclusion of other potential causes of allograft dysfunction such as acute rejection, respiratory tract infection, and airway anastomotic complications. Thus, sites are encouraged to conduct appropriate evaluation for declining allograft function including bronchoscopy with bronchoalveolar lavage (BAL) and lung biopsies if clinically appropriate to exclude other potential causes of allograft dysfunction. 6. Achievement of a statistically significant rate of decline in lung function (FEV1) at the diagnosis of new BOS per the criteria in

Section 3.6 as assessed by the following criteria:

1. For patients who are monitored with laboratory based spirometry, at least five recorded FEV1 measurements obtained at intervals of at least two weeks apart, over either the 6 or 9 (i.e., depending on the frequency of spirometry testing) months preceding study enrollment accompanied by a statistically significant (p\<0.05) rate of decline of FEV1 that exceeds 30 mL/month; or
2. For patients who are monitored with home Spirometry, 4-6 recorded home spirometry FEV1 measurements obtained one week apart, over the 4-6 weeks prior to a confirmed FEV1 variance (i.e., the date of the second of two consecutive FEV1 values below the patient's normal range) along with 4-6 recorded weekly FEV1 measurements obtained after a confirmed variance accompanied by a statistically significant (p\<0.05) rate of de-cline of FEV1 that exceeds 30 mL/month 7. Documented clinical assessment including a physical assessment and a CBC with WBC within two weeks prior to enrollment.

EXCLUSION Criteria (Subjects meeting any one of these criteria will be excluded)

1. Current participation in another clinical treatment trial with an investigational agent used to manage BOS before or after enrollment.
2. Any condition that may interfere with the subject's ability to perform pulmonary function testing.
3. Known allergy or hypersensitivity to pharmacologic agents used during ECP
4. Any condition that would significantly affect the participant's ability to adhere to the protocol, affect interpretation of the study results, or put the participant at unacceptable risk for study-related complications as judged by the referring clinician. This may include a) patients with a specific acute contraindication to receiving ECP due to any acute condition such as new or evolving myocardial infarction or central nervous system disorder, hemodynamic instability or hypovolemia, acute bleeding, respiratory distress.
5. Patients with lupus erythematosus, porphyria cutanea tarda, erythropoietic protoporphyria, variegate porphyria, xeroderma pigmentosum, albinism, or other dermatologic or ocular condition that contraindicates the use of methoxsalen or markedly enhances photosensitivity in the investigator's judgment.
6. Aphakia or absence of ocular lenses
7. Pregnancy (positive pregnancy test - a urine or blood pregnancy test must be obtained within 2 weeks prior to enrollment in women of childbearing potential)
8. Inability to provide informed consent or to comply with study treatments or assessments (e.g. due to cognitive impairment or geographic distance)
9. Recent (i.e., within 2 weeks prior to enrollment) leukopenia (white blood cell count \< 30K/cumm or 3,000/mm3/ or 3.0 109 /L)
10. Patients whose decline in lung function (FEV1) is related to either Restrictive Chronic Lung Allograft Dysfunction (CLAD) or other causes that do not represent BOS such as pneumonia, heart failure, etc.

    For patients under review for eligibility for ECP for refractory BOS:
11. Patients with a post-transplant baseline FEV1 \> 3 liters and most recent FEV1 \< 900 mL
12. Patients with a post-transplant FEV1\< 3 liters and the most recent FEV1 \< 30% of post-transplant baseline
13. Rate of FEV1 decline within the last 6 or 9 months \> 300 mL/month.
14. History of receiving ECP therapy within 6 months prior to enrollment.

    For patients under review for eligibility for RCT:
15. Patients post-transplant treated with any agent that depletes T lymphocytes for In-duction, acute cellular rejection or for any other reason can only be enrolled 12 months after the last dose of these agents assuming they meet enrollment inclusion criteria. T Lymphocyte depleting therapies include (but not limited to):

    ⦁ monoclonal antibodies such as Alemtuzumab (Campath) that target CD52 T cell receptors

    ⦁ polyclonal antibodies such as anti-thymocyte globulin (ATG) via immunization of rabbits (rATG) to either human thymocytes or Jurkat cells or via immunization of horses (hATG) to human thymocytes

    ⦁ Radiation. Anti-B cell agents that do not deplete T lymphocytes such as Rituximab can be used and will not affect eligibility.
16. Any patient who at least 6 months after transplant is treated with an escalated dose of steroids (i.e., prednisone greater than 30 mg/day or that exceeds 900 mg in a 30 day period or equipotent doses of other steroids like Solumedrol ) for more than one month for an acute decline in lung function that is suspected to be secondary to acute cellular rejection.

INCLUSION CRITERIA for Refractory BOS Standard of Care Comparator using data obtained from a retrospective chart review

1. Age (18 years or older) 2. Identification of Insurance Payer (Medicare bs third party payers) 3. Lung transplant recipient (combined organ transplant recipients, e.g. heart-lung or liver- lung recipients), or lung re-transplantation are eligible) before 2022.

4. Development of BOS between 2016-2022 and was NOT treated with ECP and must be at least one year after transplant.

5. Availability of at least three spirometry values within 14 months prior to the BOS diagnosis.

EXCLUSION CRITERIA for Refractory BOS Standard of Care Comparator using data obtained from a retrospective chart review

1. Participation in a clinical treatment trial with an investigational agent used to manage BOS
2. Pregnancy
3. Patients whose decline in lung function (FEV1) is related to either Restrictive CLAD or other causes that do not represent BOS such as pneumonia, heart failure, etc.
4. History of receiving ECP Therapy for BOS