Extracorporeal Photopheresis for Medicare Recipients of Lung Allografts

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 bronchiolitis obliterans syndrome 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 Bronchiolitis Obliterans Syndrome 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 Bronchiolitis
Obliterans Syndrome is diagnosed and staged by the decline in Forced Expiratory Volume
measurement from a pulmonary function test.

In general, bronchiolitis obliterans syndrome 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 has been used at some centers as a salvage treatment for
progressive bronchiolitis obliterans syndrome. Extracorporeal photopheresis 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 extracorporeal photopheresisis
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, Centers for Medicare & Medicaid Services issued a Decision Memo stating that
Extracorporeal photopheresis is covered for Medicare beneficiaries for the treatment of
bronchiolitis obliterans syndrome following lung allograft transplantation only when the
procedure is provided under a clinical research study.

This study looks at (1) Early detection of bronchiolitis obliterans or refractory
bronchiolitis obliterans syndrome using a standardized, more frequent spirometry monitoring
approach (i.e., defined as using either more frequent laboratory based spirometry every 4-8
weeks) and (2) Early implementation of Extracorporeal photopheresis in both participants with
early stage refractory bronchiolitis obliterans syndrome and also as first line therapy in a
subset of participants at the initial diagnosis of bronchiolitis obliterans syndrome, 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-Extracorporeal Photopheresis - Forced Expiratory
Volume decline) might prove to have predictive value in identifying subsets of bronchiolitis
obliterans syndrome patients that are likely, or unlikely, to experience reduced rate of
decline or stabilization in Forced Expiratory Volume following extracorporeal photopheresis
treatment. Therefore this study will look to enroll a large series of patients from multiple
United States centers to confirm that Extracorporeal Photopheresis significantly reduces the
rate of Forced Expiratory Volume decline in bronchiolitis obliterans syndrome 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 Extracorporeal Photopheresis therapy.

This study includes a randomized controlled trial that will compare outcomes in patients with
an initial diagnosis of bronchiolitis obliterans syndrome or New bronchiolitis obliterans
syndrome who receive either conventional (i.e., that involves the standard of care at the
respective enrolling center) or Extracorporeal Photopheresis for first line management of New
bronchiolitis obliterans syndrome. The randomized controlled trial component of the study
will enable evaluation of potential survival and quality of life benefits of early treatment
of bronchiolitis obliterans syndrome with first-line Extracorporeal Photopheresis .

Subjects with Refractory bronchiolitis obliterans syndrome who agree to participate in the
study will be informed of the following: to limit the use (and attendant risks) of
Extracorporeal Photopheresis therapy to those patients who are most likely to benefit, their
eligibility to receive Extracorporeal Photophereis 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 Bronchiolitis Obliterans syndrome who agree to participate in
the study will be 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 Bronchiolitis
Obliterans Syndrome or to an Early Photopheresis Intervention group who will receive
Extracorporeal Photopheresis as first line management of Bronchiolitis Obliterans Syndrome.

The protocol states specific inclusion and exclusion criteria for both the Refractory
Bronchiolitis Obliterans syndrome participant and the newly diagnosed Bronchiolitis
Obliterans syndrome participant. Once eligibility is confirmed and the patient has provided
informed consent, all Forced Expiratory Volume measurements captured within the 12 months
prior to enrollment will be entered in the electronic database. Based on the slope of the
Forced Expiratory Volume and achievement of a statistically significant rate of decline in
lung function in the Forced Expiratory Volume the Refractory Bronchiolitis Obliterans
syndrome participant will be electronically assigned to either Extracorporeal Photopheresis
treatment or Observation. The newly diagnosed Bronchiolitis Obliterans syndrome participant
will be randomized to either Extracorporeal Photopheresis treatment and standard
immunosuppression therapy or Control which is Standard immunosuppression Therapy.

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 on all patients except the
Refractory Bronchiolitis Obliterans syndrome participant assigned to Observation. Pulmonary
function tests will be ordered on the Observation patient at the physician's discretion.
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 on-site monitoring visits. For most sites an initial on site monitoring
visit will be soon 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 Extracorporeal Photopheresis treatment will receive 24
Extracorporeal Photopheresis treatments over the 6-month period following enrollment.

Allowed Treatment for Refractory Bronchiolitis Obliterans syndrome patients in the
Observation will be ordered at the physicians discretion.

Treatment for the Newly Diagnosed Bronchiolitis Obliterans syndrome 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 Extracorporeal Photopheresis treatment.

Other than Extracorporeal Photopheresis, no other interventions for Bronchiolitis Obliterans
syndrome will be used except for Azithromycin for patients in the randomized Early
Photopheresis Intervention.

An improvement in the Forced Expiratory Volume measurement taken from the pulmonary function
test will be used to assess the success or the benefit of the Extracorporeal Photopheresis
treatment. Patient's will have spirometry the first week of therapy, and repeated every 30
days for the first year, and then annually. All patients will be followed for 5 years.There
are considerations for crossover built into the protocol.

Statistical Methods.A clinical response will be determined using Forced Expiratory Volume as
primary endpoint and will be defined as a 50% or greater reduction in the rate of decline of
Forced Expiratory Volume assessed by comparing the average rate of Forced Expiratory Volume
decline over the 6 months prior to Extracorporeal Photopheresis against the average rate of
Forced Expiratory Volume decline over the 12 months following initiation of Extracorporeal
Photophereis.

Survival Primary Outcome: Mortality three years after diagnosis of Bronchiolitis Obliterans
syndrome using standard of care management of Bronchiolitis Obliterans syndrome is 52%.
Assuming 15% exclusion related to early crossover and a 5% loss to follow-up of enrolled
patients, 739 patients who meet the standardized criteria for Bronchiolitis Obliterans
syndrome would need to be enrolled and randomly assigned to either the Early Photopheresis
Intervention or control cohorts to detect a difference. The outcomes between the two
Bronchiolitis Obliterans syndrome disease severity strata will be assessed separately. The
patient will be followed for up to five years or until their date of death 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.

INCLUSION Criteria for REFRACTORY BOS

1. Age (18 years old or older).

2. Medicare-eligible (i.e., patients with both Part A and Part B) status

3. Lung transplant recipient (combined organ transplant recipients, e.g. heart-lung or
liver-lung 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).

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 6 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 during the preceding four months prior to enrollment with no time
interval between FEV1 measurements that exceeds 8 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 (i.e., patients with both Part A and Part B)

3. Lung transplant recipient (combined organ transplant recipients, e.g. heart-lung or
liver-lung 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:

Frequent laboratory based spirometry defined as having had regular FEV1 measurements
during the preceding six months prior to diagnosis of new BOS with no time interval
between FEV1 measurements that exceeds 8 weeks.

Frequent Home Spirometry through a Standardized Home Spirometry Method: this Method is
currently being finalized and will not be utilized to meet this close monitoring
enrollment criteria until it is InIRB approved.

5. Diagnosis of new BOS (i.e., "new BOS" is defined as within six 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). 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:

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 the
6 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 (subject to Institutional Review Board (IRB) approval),
the Standardized Home Spirometry Method will define the specific criteria that will be
used for these patients.

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.

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; or b) 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.

5. Aphakia or absence of ocular lenses

6. Pregnancy (positive pregnancy test - a urine or blood pregnancy test must be obtained
within 2 weeks prior to enrollment in women of childbearing potential)

7. Inability to provide informed consent or to comply with study treatments or
assessments (e.g. due to cognitive impairment or geographic distance)

8. Recent (i.e., within 2 weeks prior to enrollment) leukopenia (white blood cell count <
3,000 K/cumm)

9. 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:

10. The most recent FEV1 < 900 mL

11. Rate of FEV1 decline within the last 6 months > 300 mL/month.

For patients under review for eligibility for RCT:

12. any patient who at least one year after transplant is treated with either lymphocyte
depleting therapy or with an escalated dose of steroids (i.e., prednisone greater than
30 mg/day) for more than one month for an acute decline in lung function that is
suspected to be secondary to acute cellular rejection.