Extracorporeal Photopheresis for Medicare Recipients of Lung Allografts

NCT02181257 | Active Not Recruiting Phase 3 DMC FDA Drug FDA Device

• 1 other identifier: 201402035
• Study Type: interventional
• Target: 280
• Locations: 1 country
• Sites: 22

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.

Conditions

Bronchiolitis Obliterans Syndrome (BOS)

Keywords

Bronchiolitis Obliterans Syndrome; Lung Transplantation; Extracorporeal Photopheresis; Methoxsalen; Chronic lung allograft dysfunction (CLAD)

Outcome Measures

Primary Outcomes (4)

• REFRACTORY BOS: Change in the rate of FEV1 decline.

  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.

  Baseline vs 12 months following the initiation of ECP.

• NEW BOS: Cumulative All-cause mortality

  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.

  5 Years following randomization

• NEW BOS: Change in the rate of FEV1 decline

  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.

  Baseline vs 12 months following randomization

• REFRACTORY BOS: All cause and CLAD related mortality

  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.

  5 years following enrollment or the initial ECP.

Secondary Outcomes (11)

• 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: All-cause and CLAD related mortality following either randomization (NEW BOS) or initiation of ECP (Refractory BOS)

  Annually for five years

• 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: Change in Health-Related Quality of Life

  Baseline and months 3, 6, 9, and 12, and annually up to 5 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

Study Arms (3)

Newly Diagnosed Bronchiolitis Obliterans (NEW BOS)

OTHER

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.

Combination Product: Extracorporeal Photopheresis (ECP)

Refractory Bronchiolitis Obliterans Syndrome (REFRACTORY BOS)

OTHER

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.

Combination Product: Extracorporeal Photopheresis (ECP)

Standard of Care Comparator Retrospective Chart review

OTHER

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.

Other: No intervention in the SOC / Retrospective Chart review.

Interventions

Extracorporeal Photopheresis (ECP) COMBINATION_PRODUCT

Procedure: ECP treatments will be performed using one of two Therakos systems. Both systems use the drug Methoxsalen

Newly Diagnosed Bronchiolitis Obliterans (NEW BOS); Refractory Bronchiolitis Obliterans Syndrome (REFRACTORY BOS)

No intervention in the SOC / Retrospective Chart review. OTHER

SOC Retrospective chart review similar to a control group

Standard of Care Comparator Retrospective Chart review

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• 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)

You may not qualify if:

• 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.

Sponsors & Collaborators

• Washington University School of Medicine: lead
• Centers for Medicare and Medicaid Services/ Coverage and Analysis Group: collaborator
• Therakos, Inc: collaborator
• The Foundation for Barnes-Jewish Hospital: collaborator

Study Sites (22)

University of Alabama at Birmingham

Birmingham, Alabama, 35226, United States

Location

St. Joseph's Hospital and Medical Center

Phoenix, Arizona, 85013, United States

Location

University of California San Diego

La Jolla, California, 92093, United States

Location

University of Florida

Gainesville, Florida, 32610, United States

Location

Northwestern University

Chicago, Illinois, 60611, United States

Location

Indiana University Health

Indianapolis, Indiana, 46202, United States

Location

University of Iowa

Iowa City, Iowa, 52242, United States

Location

University of Kentucky

Lexington, Kentucky, 40506, United States

Location

Brigham and Women's Hospital

Boston, Massachusetts, 02115, United States

Location

University of Michigan Health System

Ann Arbor, Michigan, 48109, United States

Location

Spectrum Health

Grand Rapids, Michigan, 45903, United States

Location

University of Minnesota Medical Center, Fairview

Minneapolis, Minnesota, 55455, United States

Location

Washington University School of Medicine

St Louis, Missouri, 63110, United States

Location

Columbia University

New York, New York, 10032, United States

Location

Duke University

Durham, North Carolina, 27710, United States

Location

Ohio State University

Columbus, Ohio, 43210, United States

Location

Temple University

Philadelphia, Pennsylvania, 19140, United States

Location

University of Pittsburgh

Pittsburgh, Pennsylvania, 15213, United States

Location

Baylor University Medical Center

Dallas, Texas, 75246, United States

Location

UT Southwestern Medical Center

Dallas, Texas, 75390, United States

Location

Houston Methodist

Houston, Texas, 77030, United States

Location

Inova Health System

Falls Church, Virginia, 22042, United States

Location

Related Publications (5)

• Burton CM, Carlsen J, Mortensen J, Andersen CB, Milman N, Iversen M. Long-term survival after lung transplantation depends on development and severity of bronchiolitis obliterans syndrome. J Heart Lung Transplant. 2007 Jul;26(7):681-6. doi: 10.1016/j.healun.2007.04.004.

  PMID: 17613397 BACKGROUND

• Hadjiliadis D, Steele MP, Govert JA, Davis RD, Palmer SM. Outcome of lung transplant patients admitted to the medical ICU. Chest. 2004 Mar;125(3):1040-5. doi: 10.1378/chest.125.3.1040.

  PMID: 15006966 BACKGROUND

• Morrell MR, Despotis GJ, Lublin DM, Patterson GA, Trulock EP, Hachem RR. The efficacy of photopheresis for bronchiolitis obliterans syndrome after lung transplantation. J Heart Lung Transplant. 2010 Apr;29(4):424-31. doi: 10.1016/j.healun.2009.08.029. Epub 2009 Oct 22.

  PMID: 19853479 BACKGROUND

• Reviewed in: Centers for Medicare and Medicaid Services. Final Decision Memorandum for Extracorporeal Photophresis (CAG-00324R), April 2012

  RESULT

• Chionis L, Grossman BJ, Hachem R, Commean P, Derfler MC, Vedantham S, Dodds K, Spitznagel E, Atkinson J, Despotis G. The efficacy of extracorporeal photopheresis to arrest bronchiolitis obliterans in lung allograft recipients was compared between two automated photopheresis instruments. Transfusion. 2018 Dec;58(12):2933-2941. doi: 10.1111/trf.14913. Epub 2018 Oct 12.

  PMID: 30312482 DERIVED

MeSH Terms

Conditions

Bronchiolitis Obliterans Syndrome

Interventions

Photopheresis

Condition Hierarchy (Ancestors)

Organizing Pneumonia; Bronchiolitis Obliterans; Bronchiolitis; Bronchitis; Bronchial Diseases; Respiratory Tract Diseases; Lung Diseases, Obstructive; Lung Diseases; Graft vs Host Disease; Immune System Diseases

Intervention Hierarchy (Ancestors)

PUVA Therapy; Ultraviolet Therapy; Phototherapy; Therapeutics; Extracorporeal Circulation; Surgical Procedures, Operative

Study Officials

• George J. Despotis, M.D.

  Washington University St. Louis School of Medicine

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: REFRACTORY BOS - Participants are electronically assigned to either ECP Treatment or Observation (Standard Immunosuppression Therapy) NEW BOS Participants are randomized to ECP Treatment or Control (Standard Immunosuppression Therapy

Study Record Dates

• First Submitted: July 1, 2014
• First Posted: July 3, 2014
• Study Start: January 1, 2015
• Primary Completion (Estimated): April 1, 2027
• Study Completion (Estimated): December 1, 2028
• Last Updated: April 17, 2025

Record last verified: 2025-04

Locations

US (22)