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Extracorporeal Photopheresis for Medicare Recipients of Lung Allografts (ECP)

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ClinicalTrials.gov Identifier: NCT02181257
Recruitment Status : Recruiting
First Posted : July 3, 2014
Last Update Posted : July 12, 2021
Sponsor:
Collaborators:
Centers for Medicare and Medicaid Services
Mallinckrodt
Information provided by (Responsible Party):
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 (240) or newly diagnosed (400-450) Bronchiolitis Obliterans Syndrome (BOS) in 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.

Condition or disease Intervention/treatment Phase
Bronchiolitis Obliterans Syndrome (BOS) Combination Product: Extracorporeal Photopheresis (ECP) Phase 3

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 690 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

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

Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Extracorporeal Photopheresis for the Management of Progressive Bronchiolitis Obliterans Syndrome in Medicare-Eligible Recipients of Lung Allografts
Study Start Date : January 2015
Estimated Primary Completion Date : December 2025
Estimated Study Completion Date : December 2025

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Medicare

Arm Intervention/treatment
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.

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)

Procedure:

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


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.
Combination Product: Extracorporeal Photopheresis (ECP)

Procedure:

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





Primary Outcome Measures :
  1. REFRACTORY BOS: Change in the rate of FEV1 decline. [ Time Frame: Baseline vs 12 months following the initiation of ECP. ]
    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 treatment.

  2. NEW BOS: All-cause mortality [ Time Frame: Annually for 5 Years following randomization ]
    Survival in patients assigned to ECP treatment compared to survival in patients assigned to standard of care.

  3. NEW BOS: Change in the rate of FEV1 decline [ Time Frame: 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 :
  1. All Participants: Rate of FEV1 decline over the 9 months following initiation of treatment [ Time Frame: Baseline vs 9 Months following randomization ]
    Compare survival in patients assigned to ECP treatment to patients assigned to standard of care

  2. All Participants: All-cause mortality following either randomization (NEW BOS) or initiation of ECP (Refractory BOS) [ Time Frame: Annually for five years ]
    Compare survival in patients assigned to ECP treatment to patients assisgned standard of care.

  3. All Participants: Proportion of patients with treatment-related serious adverse events [ Time Frame: Every 6 months for up to 5 years following enrollment. ]
  4. All Participants: Change in Health-Related Quality of Life [ Time Frame: 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

  5. All Participants: Effect of maintenance ECP (number of procedures and duration) on BOS progression and outcome. [ Time Frame: Annually to 5 years ]
  6. All Participants: Diagnostic performance of our spirometric enrollment criteria [ Time Frame: 3, 6, and 12 months following ECP treatment ]
    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).

  7. NEW BOS: Comparison of Home Spirometry vs Laboratory Spirometry [ Time Frame: Every 6 months up to 5 years. ]
    Comparison of subjects enrolled based on monitoring with Home Spirometry vs Laboratory Spirometry for the following outcome parameters: (1) Mortality (2) Quality of life (3) Spirometric parameters (e.g. FEV1)

  8. NEW BOS: Look at a 30% difference in residual of FEV1 values in BOS treatment Arm (EPI or Control); this would include all patients and spirometry monitoring sub-cohorts. [ Time Frame: Every six months up to 5 years after enrollment ]
    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.

  9. NEW BOS: Incidence of pulmonary specific infections, CVC related infections and all infections. [ Time Frame: 5 years ]
  10. NEW BOS: Hospitalization rates between EPI and control arms and spirometry monitoring subcohorts. [ Time Frame: Every 6 months up to 5 years after enrollment. ]
  11. NEW BOS: Treatment related serious adverse events (SAEs) between EPI and control arms and spirometry monitoring (Home spirometry and frequent lab monitoring) subcohorts. [ Time Frame: Every 6 months up to 5 years after enrollment ]
  12. 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 [ Time Frame: Annually up to 5 years ]


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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: (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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02181257


Contacts
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Contact: Mary Clare Derfler, RN, MSN 314-747-2372 derflerm@wustl.edu
Contact: Kathy Twichell 314-747-1653 ktwichell@wustl.edu

Locations
Show Show 23 study locations
Sponsors and Collaborators
Washington University School of Medicine
Centers for Medicare and Medicaid Services
Mallinckrodt
Investigators
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Principal Investigator: George J. Despotis, M.D. Washington University St. Louis School of Medicine
Additional Information:

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

Other Publications:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Washington University School of Medicine
ClinicalTrials.gov Identifier: NCT02181257    
Other Study ID Numbers: 201402035
First Posted: July 3, 2014    Key Record Dates
Last Update Posted: July 12, 2021
Last Verified: July 2021
Keywords provided by Washington University School of Medicine:
Bronchiolitis Obliterans Syndrome
Lung Transplantation
Extracorporeal Photopheresis
Methoxsalen
Additional relevant MeSH terms:
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Bronchiolitis
Bronchiolitis Obliterans
Syndrome
Disease
Pathologic Processes
Bronchitis
Respiratory Tract Infections
Infections
Bronchial Diseases
Respiratory Tract Diseases
Lung Diseases, Obstructive
Lung Diseases