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Extracorporeal Photopheresis for the Management of Progressive Bronchiolitis Obliterans Syndrome in Medicare-Eligible Recipients of Lung Allografts (ECP Registry)

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborators:
Centers for Medicare and Medicaid Services
Mallinckrodt
Information provided by (Responsible Party):
Washington University School of Medicine
ClinicalTrials.gov Identifier:
NCT02181257
First received: July 1, 2014
Last updated: November 22, 2016
Last verified: November 2016
  Purpose

The purpose of this study is to determine if Extracorporeal Photopheresis (ECP) is effective in the treatment of progressive Bronchiolitis Obliterans Syndrome (BOS) in patients after lung transplantation. Lung transplantation has become the treatment of choice for selected patients with end-stage lung disease. However, long-term survival after transplantation remains disappointing. Chronic rejection (bronchiolitis obliterans syndrome [BOS]) has emerged as the leading obstacle to better long-term outcomes, and represents the leading cause of death beyond the first year after transplantation. BOS is diagnosed by the decline in the FEV1 measurement from a pulmonary function test. The management of BOS has been disappointing. In general, BOS is treated by intensifying the immunosuppressive regimen. 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 as a salvage treatment for progressive BOS with favorable clinical results in many cases showing patient improvement. On May 2, 2012, the Center for Medicare Services issued a decision memo statin the ECP is covered for Medicare beneficiaries for the treatment of BOS following lung allograft transplantation only wehn the procedure is provided under a clinical research study. It is highly unlikely that providers that currently order ECP for their BOS patients who have already failed optimized immunosuppressive drug therapy would be willing to randomize half of their patients to continue on their failed drug therapy.What is not well understood at this time, however, is whether certain coexisting disease states or patient-related demographic, functional, treatment-related or diagnostic variables 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. This is a Registry study to enroll 160 patients from multiple U.S. centers to (1) confirm that ECP significantly reduces the rate of FEV1 decline in BOS patients refractory to standard immunosuppressive drug therapy, and (2) capture and assess specified patient demographic, treatment-related, diagnostic, functional and co-morbidity- related variables that may predict outcomes after ECP therapy.


Condition Intervention
Bronchiolitis Obliterans Syndrome (BOS) Drug: Methoxsalen

Study Type: Observational [Patient Registry]
Study Design: Observational Model: Cohort
Time Perspective: Prospective
Target Follow-Up Duration: 1 Year
Official Title: Extracorporeal Photopheresis for the Management of Progressive Bronchiolitis Obliterans Syndrome in Medicare-Eligible Recipients of Lung Allografts

Resource links provided by NLM:


Further study details as provided by Washington University School of Medicine:

Primary Outcome Measures:
  • 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 6 months following initiation of ECP [ Time Frame: 1 year ]
    The study will prospectively capture FEV1 through spirometry during the course of ECP therapy and out to one year in accordance with the following schedule: Days 0, 30, 60, 90, 120,150, 180, 240, 300 and 365. Spirometry from Day 0 through Day 120 may be performed within 7 days to accommodate patient/provider scheduling needs, and generally will coincide with a scheduled ECP treatment. Spirometry from Day 150 through Day 365 may be per formed within 14 days to meet patient/provider scheduling needs.


Secondary Outcome Measures:
  • Average rate of FEV1 decline over the 12 months following initiation of ECP [ Time Frame: 12 months ]
    The study will prospectively capture FEV1 through spirometry during the course of ECP therapy and out to one year in accordance with the following schedule: Days 0, 30, 60, 90, 120,150, 180, 240, 300 and 365. Spirometry from Day 0 through Day 120 may be performed within 7 days to accommodate patient/provider scheduling needs, and generally will coin cide with a scheduled ECP treatment. Spirometry from Day 150 through Day 365 may be per formed within 14 days to meet patient/provider scheduling needs.


Other Outcome Measures:
  • All-cause mortality at 12 months following initiation of ECP [ Time Frame: 12 months ]
    Observational only

  • Proportion of patients with treatment related serious adverse events [ Time Frame: 12 months ]

    A Serious Adverse Event is any adverse event that results in death, a life-threatening adverse experience, a persistent or significant disability/incapacity, inpatient hospitalization or prolongation of existing hospitalization, emergency department visit or activation of an acute response team, pregnancy abortion, or a congenital anomaly, birth defect, or cancer in a neonate/infant born to a female subject. Medical events that do not strictly fulfill these criteria should be considered SAEs if they seriously jeopardize the subject or require aggressive medical or surgical intervention to prevent one of the above outcomes.

    Patients will be monitored and followed clinically according to each site's standard clinical practice. Sites should follow their local IRB's guidelines in terms of reporting AEs and SAEs to the local IRB



Estimated Enrollment: 160
Study Start Date: January 2015
Estimated Study Completion Date: December 2018
Estimated Primary Completion Date: July 2018 (Final data collection date for primary outcome measure)
Groups/Cohorts Assigned Interventions
prospective single-arm cohort. Drug: Methoxsalen
Procedure ECP Treatments will be performed using Therakos UVAR XTS system or the Therakos CELLEX system

Detailed Description:

There is evidence to support that ECP benefits these patients, but we don't know how to predict which patients will benefit most. Patients will will be identified by physician investigators and co-investigators, and study staff, and through review of relevant administrative databases that are maintained for routine clinical care purposes (e.g. lung transplantation division database, pulmonary function laboratory database, etc.), subject to local IRB approval. Once eligibility is confirmed and the patient is provided informed consent, the patient will be assigned a unique case 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 medication regimen, maintenance immunosuppression and any changes in medication should be entered on the electronic case report forms. All FEV1 measurements captured within the 6 months prior to enrollment should be entered in the electronic case report forms.Certain source documents will be required and verified on all forms electronically submitted. Necessary source documents will be clearly requested on the electronic case report forms.

Patients should receive 24 ECP treatments over the 6-month period following enrollment, in accordance with the following schedule:

  • 8 to 10 treatments over the first 30 days following treatment initiation;
  • 8 to 10 treatments in the next 60 days (months 2 and 3);
  • 6 treatments in the next 90 days (months 4 through 6) at a rate of 2 treatments per month.

During ECP, blood is taken from the body through a standard venous catheter and the cells are separated by centrifugation via a specialized pheresis machine. The machine treats the blood with an agent called methoxsalen that becomes active when exposed to an ultraviolet light inside the machine. This changes the white blood cells to better enable them to reduce rejection and better suppress BOS. The machine then returns the blood into the patient through the catheter. .

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. Patient's will have spirometry the first week of therapy, Day 30, 60, 90, 120, 150, 180, 240, 300, and at one year.

Statistical Methods -Based on a 95% power analysis and assuming a 5% loss to follow-up of enrolled patients, 160 patients will need to be enrolled to detect at least a 50% reduction in the rate of FEV1 decline at one-year follow-up. A 50% decrease in the rate of FEV1 decline can importantly extend survival and improve the opportunity to receive a new lung allograft, as well as delay time to onset of severe physical limitations. Our power analysis was based on findings from our previously published 60 patient series. Specifically, we first calculated values that reflected the difference between pre-intervention and post-intervention FEV1 slope values. The corresponding values for standard deviation of slope differences were adjusted for possible greater variability in the post-treatment period in this study. These values for derived slope differences (50% of 87 ml/month) and corresponding standard deviation values (150) were then used to calculate required enrollment using a treatment effect of 50% reduction of FEV1 decline and using a power of 95%. This analysis, with 5% late loss, indicates a required enrollment of 160 patients.

  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Probability Sample
Study Population
Lung allograft patients with progressive bronchiolitis obliterans syndrome
Criteria

Inclusion Criteria:

  • Adult age (at least 18 years old).
  • Medicare-eligible status
  • Lung transplant recipient (combined organ transplant recipients, e.g. heart- lung liver-lung recipients, are eligible).
  • Progressive 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 four FEV1 measurements obtained at intervals of one to six weeks apart, over the 6 months preceding initial ECP treatment (may include an FEV1 measurement on or just prior to the first ECP procedure date).

Exclusion Criteria:

  • Participation in another clinical treatment trial with an investigational agent.
  • 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 patients with 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, or respiratory distress.
  • Inability to provide informed consent or to comply with study treatments or assessments (e.g. due to cognitive impairment or geographic distance).
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02181257

Locations
United States, Alabama
University of Alabama at Birmingham
Birmingham, Alabama, United States, 35226
United States, California
University of California San Diego
La Jolla, California, United States, 92093
United States, Indiana
Indiana University Health
Indianapolis, Indiana, United States, 46202
United States, Iowa
University of Iowa
Iowa City, Iowa, United States, 52242
United States, Michigan
University of Michigan Health System
Ann Arbor, Michigan, United States, 48109
United States, Minnesota
University of Minnesota Medical Center, Fairview
Minneapolis, Minnesota, United States, 55455
United States, Missouri
Washington University School of Medicine
St. Louis, Missouri, United States, 63110
United States, New York
Columbia University
New York, New York, United States, 10032
United States, Ohio
The Cleveland Clinic
Cleveland, Ohio, United States, 44195
United States, Pennsylvania
University of Pittsburgh
Pittsburgh, Pennsylvania, United States, 15213
Sponsors and Collaborators
Washington University School of Medicine
Centers for Medicare and Medicaid Services
Mallinckrodt
Investigators
Principal Investigator: George J. Despotis, M.D. Washington University St. Louis School of Medicine
  More Information

Publications:
Responsible Party: Washington University School of Medicine
ClinicalTrials.gov Identifier: NCT02181257     History of Changes
Other Study ID Numbers: CAG-00324R2
Study First Received: July 1, 2014
Last Updated: November 22, 2016

Keywords provided by Washington University School of Medicine:
Bronchiolitis Obliterans Syndrome
Lung Transplantation
Extracorporeal Photopheresis
Methoxsalen

Additional relevant MeSH terms:
Syndrome
Bronchiolitis
Bronchiolitis Obliterans
Disease
Pathologic Processes
Bronchitis
Bronchial Diseases
Respiratory Tract Diseases
Lung Diseases, Obstructive
Lung Diseases
Respiratory Tract Infections
Methoxsalen
Photosensitizing Agents
Dermatologic Agents

ClinicalTrials.gov processed this record on June 23, 2017