Extracorporeal Photopheresis for the Management of Progressive Bronchiolitis Obliterans Syndrome in Medicare-Eligible Recipients of Lung Allografts
试验速览
- 阶段
- 3 期
- 状态
- 进行中（未招募）
- 入组人数
- 280
- 试验地点
- 27
- 主要终点
- REFRACTORY BOS: All cause and CLAD related mortality
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •for REFRACTORY BOS
- •Age (18 years old or older).
- •Medicare-eligible status
- •Lung transplant recipient (combined organ transplant recipients, e.g. heart-lung or liver-lung or lung re- transplantation recipients are eligible).
- •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.
- •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.
- •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.
- •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.
- •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
- •Age (18 years old or older)
- •Medicare-eligible status.
- •Lung transplant recipient (combined organ transplant recipients, e.g. heart-lung or liver-lung, lung re-transplantation recipients, are eligible).
- •History of close FEV1 monitoring prior to diagnosis of new BOS defined as having had either of the two monitoring approaches:
- •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)
- •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.
- •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:
- •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
- •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
- •Documented clinical assessment including a physical assessment and a CBC with WBC within two weeks prior to enrollment.
排除标准
- •(Subjects meeting any one of these criteria will be excluded)
- •Current participation in another clinical treatment trial with an investigational agent used to manage BOS before or after enrollment.
- •Any condition that may interfere with the subject's ability to perform pulmonary function testing.
- •Known allergy or hypersensitivity to pharmacologic agents used during ECP
- •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.
- •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.
- •Aphakia or absence of ocular lenses
- •Pregnancy (positive pregnancy test - a urine or blood pregnancy test must be obtained within 2 weeks prior to enrollment in women of childbearing potential)
- •Inability to provide informed consent or to comply with study treatments or assessments (e.g. due to cognitive impairment or geographic distance)
- •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)
- •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:
- •Patients with a post-transplant baseline FEV1 > 3 liters and most recent FEV1 < 900 mL
- •Patients with a post-transplant FEV1< 3 liters and the most recent FEV1 < 30% of post-transplant baseline
- •Rate of FEV1 decline within the last 6 or 9 months > 300 mL/month.
- •History of receiving ECP therapy within 6 months prior to enrollment.
- •For patients under review for eligibility for RCT:
- •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.
- •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)
- •Identification of Insurance Payer (Medicare bs third party payers)
- •Lung transplant recipient (combined organ transplant recipients, e.g. heart-lung or liver- lung recipients), or lung re-transplantation are eligible) before
- •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
- •Participation in a clinical treatment trial with an investigational agent used to manage BOS
- •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.
- •History of receiving ECP Therapy for BOS
研究组 & 干预措施
Newly Diagnosed Bronchiolitis Obliterans (NEW BOS)
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.
干预措施: Extracorporeal Photopheresis (ECP) (Combination Product)
Refractory Bronchiolitis Obliterans Syndrome (REFRACTORY BOS)
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.
干预措施: Extracorporeal Photopheresis (ECP) (Combination Product)
Standard of Care Comparator 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.
干预措施: No intervention in the SOC / Retrospective Chart review. (Other)
结局指标
主要结局
REFRACTORY BOS: All cause and CLAD related mortality
时间窗: 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.
时间窗: 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
时间窗: 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
时间窗: 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.
次要结局
- All Participants: All-cause and CLAD related mortality following either randomization (NEW BOS) or initiation of ECP (Refractory BOS)(Annually for five years)
- All Participants: Effect of maintenance ECP (number of procedures and duration) on BOS progression and outcome.(At the end of 5 year follow-up)
- 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)
- All Participants: Change in Health-Related Quality of Life(Baseline and months 3, 6, 9, and 12, and annually up to 5 years.)
- 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)
- 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.)
- 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.)
- NEW BOS: Incidence of pulmonary specific infections, CVC related infections and all infections.(5 years)
- NEW BOS: Hospitalization rates between EPI and control arms(5 years after enrollment.)
- NEW BOS: Treatment related serious adverse events (SAEs) between EPI and control arms.(Every 6 months up to 5 years after enrollment)
- 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)