Conditions: Steroid Refractory Acute Graft Versus Host Disease
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 29
Healthy volunteers: no

Brief summary:
This is a single-arm, open-label, multicenter study of the efficacy of UVADEX® (methoxsalen) Sterile Solution in conjunction with THERAKOS® CELLEX® Photopheresis Systems (ECP) in pediatric participants with steroid-refractory aGvHD. The study is composed of Screening, Treatment, and Follow-up Periods.

Detailed description:
Screening:

After the informed consent/assent form (ICF) is signed, the screening assessments will be performed in a single visit to establish the eligibility of the participant, based on inclusion and exclusion criteria, as well as aGvHD grading. Scheduling of the first week of ECP treatments and the arrangements for availability of typed and cross-matched donor packed red blood cells (PRBCs) for transfusion, if required, will be made in advance of participants entering the Treatment Period.

Treatment Period:

Once eligibility is established, participants will enter the 12-week ECP Treatment Period. The availability of typed and cross-matched donor PRBCs for transfusion during treatment, if needed, should be established prior to the scheduling of ECP treatments.

Participants will be allowed to continue standard aGvHD prophylaxis regimens (e.g., cyclosporine, tacrolimus, methotrexate, mycophenolate mofetil) without the addition of new therapies. Participants will be allowed to discontinue prophylaxis regimens for reasons of toxicity, and will also be allowed to switch to another prophylaxis medication within the same class (e.g., the calcineurin inhibitors cyclosporine and tacrolimus) for reasons of toxicity.

All participants enrolled in this trial will have received corticosteroids for the treatment of aGvHD. After entering the treatment period on study, tapering of steroids by total weekly decrements of 12.5% to 25% of the steroid dose at initiation of ECP therapy is permitted after a sustained response of aGvHD has been observed for at least 3 consecutive days, with the suggested goal to decrease the starting steroid dose by at least 50% 4 weeks after initiation of ECP.

Follow-Up Period:

After completion of the 12-week Treatment Period, participants may continue ECP treatment on commercial product at the Principal Investigator's discretion. Acute GvHD status will be assessed 4 weeks after completion of the Treatment Period. Participant survival will be assessed by passive follow-up (chart review) 26 weeks after initiation of ECP treatment.

Arms:
arm 1: Participants receive methoxsalen 20 µg/ml in conjunction with ECP procedure three times per week for Weeks 1 to 4, and two times per week for Weeks 5 to 12.

Interventions: intervention 1: Methoxsalen intervention 2: Extracorporeal Photopheresis (ECP)
Intervention descriptions: intervention 1: Sterile solution used in conjunction with photopheresis procedure. intervention 2: None

Protocol document:
Prot_SAP_000.pdf: 
Official Title: 
NCT Number: 
Document Date: 
Single-Arm Study to Assess the Efficacy of UVADEX® (methoxsalen) Sterile 
Solution in Conjunction with the THERAKOS® CELLEX® Photopheresis 
System in Pediatric Patients with Steroid-Refractory Acute Graft-vs-host 
Disease (aGvHD) 
NCT02524847 
Protocol Amendment 2: 27 July 2017 


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Single-Arm Study to Assess the Efficacy of UVADEX® (methoxsalen) Sterile Solution in 
Conjunction with the THERAKOS® CELLEX® Photopheresis System in Pediatric Patients 
with Steroid-Refractory Acute Graft-vs-host Disease (aGvHD)
Sponsor:
Therakos, Inc.
10 N High Street
West Chester, PA 19380 USA
610-235-2877
Contract Research
Organization:
 USA
Principal Investigator:
, MD
Protocol No.:
TKS-2014-001
IND No.:
40,482
EudraCT No.:
2014-004806-14
Study Drug Name:
UVADEX® (methoxsalen) Sterile Solution 
Development Phase:
III
Date of Protocol Amendment 2: 27 July 2017
Date of Protocol Amendment 1: 15 March 2016
Date of Original Protocol:
12 June 2015
The study will be conducted according to the protocol and in compliance with Good Clinical 
Practice (GCP), the Declaration of Helsinki, and other applicable regulatory requirements.
This document contains confidential information of Therakos, Inc.
Acceptance of this document constitutes agreement by the recipient that no unpublished 
information contained herein will be published or disclosed without prior written approval by 
Therakos, Inc. This document may be disclosed to appropriate Institutional Review 
Boards/Independent Ethics Committees under the condition that they are requested and kept 
confidential. Do not copy or distribute without written permission from the Sponsor.
CONFIDENTIAL


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PROTOCOL AMENDMENT 2 DATED: 27 July 2017
SUMMARY OF CHANGES
Protocol Amendment 2 was developed to modify the existing protocol. Amendment 2 will make 
the clinical study more successful and the protocol will be more detailed for the Investigators. 
The major protocol changes are summarized below. Additional minor revisions were made to the 
protocol to improve other descriptions and tables.
The major protocol changes are summarized as follows:
1. Modified inclusion criterion #2 from Grade B-C to Grade B-D, specified that Grade D organ
involvement would be limited to liver and skin and updated language related to the
assessment of steroid refractory status (Section 4.1).
2. Modified inclusion criterion #3 to specify that the Lansky Scale will be used in the study
(Section 4.1).
3. Modified the recording period for adverse events from ICF signing to Week 16 of the study
(Section 8.1.4).
4. Modified the descriptive language in exclusion criterion (#21, systemic therapy) and
prohibited medications from: immunomodulatory to immunosuppressive (Sections 4.2 and
6.5.1).
5. Modified the SUSARs definition and description (Section 8.1.8).
6. Removed the requirement for biomarkers from the study protocol (Sections 3.2.3 and 9.3.3).
7. Added an inclusion criterion related to Patients with a lack of complete response after
2 weeks of steroid treatment (Section 4.1).
8. Removed prior exclusion criterion #4 (Development of aGvHD after donor lymphocyte
infusion) (Section 4.2).




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SIGNATURE PAGE
Declaration of the Principal Investigator
Title:
Single-Arm Study to Assess the Efficacy of UVADEX® (methoxsalen) Sterile Solution in 
Conjunction with the THERAKOS® CELLEX® Photopheresis System in Pediatric Patients with 
Steroid-Refractory Acute Graft-vs-host Disease (aGvHD)
This study protocol, TKS-2014-001 Amendment 2, was subjected to critical review. The 
information it contains is consistent with current knowledge of the risks and benefits of the 
investigational product(s), as well as with the moral, ethical, and scientific principles governing 
clinical research as set out in the Declaration of Helsinki, 1996, and the guidelines on Good 
Clinical Practice and other applicable regulatory requirements.
____________________________________________
_______________________
Principal Investigator (signature)
Date
____________________________________________
Principal Investigator (printed name)
____________________________________________
Site


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PROTOCOL SYNOPSIS
Title
Single-Arm Study to Assess the Efficacy of UVADEX® (methoxsalen) 
Sterile Solution in Conjunction with the THERAKOS® CELLEX®
Photopheresis System in Pediatric Patients with Steroid-Refractory 
Acute Graft-vs-host Disease (aGvHD)
Study duration
Treatment duration per patient: 12 weeks
Study center
Multicenter
Objectives
Primary objective:

To evaluate the efficacy of extracorporeal photopheresis (ECP) in
pediatric patients with steroid-refractory aGvHD.
Secondary objectives:

To assess the safety of ECP.

To assess the duration of response to ECP.

To assess the steroid-sparing effect of ECP.

To assess the organ-specific response to ECP.
Study endpoints
Primary:

The primary endpoint is the proportion of patients who achieve an
overall response (complete response [CR] + partial response [PR]) after 
4 weeks (Day 28) of ECP treatment, or fewer treatments if they 
discontinued treatment.
Patients will be evaluated by the treating physician for the presence or 
absence of aGvHD manifestations of the skin, liver, and gut. Source
data will be collected for each patient and entered into the electronic 
Case Report Form (eCRF), and a scoring algorithm will be applied to 
calculate the grade of aGvHD using the modified International Bone 
Marrow Transplant Registry (IBMTR) Severity Index (
Appendix A:
Modified IBMTR Severity Index). Patients weighing < 50 kg will be 
evaluated according to a modified version of the IBMTR criteria that 
accounts for stool output on an mL/kg/day basis.
Secondary:

Safety parameters including vital signs, laboratory tests, and
spontaneously reported adverse events (AEs) and serious adverse events 
(SAEs).

Proportion of patients who achieve an overall response 8 weeks
(Day 56) and 12 weeks (Day 84) after initiation of ECP treatment.

Duration of response (defined as the length of time a patient maintains a
response through Week 16 of the Follow-up Period on a per-patient 
basis).

Proportion of patients who achieve an overall response after 4 weeks
(Day 28), 8 weeks (Day 56), and 12 weeks (Day 84) of ECP treatment 
according to the modified Glucksberg criteria (
Appendix B: Modified 
Glucksberg Criteria).
-
Source data will be collected for each patient and entered into the
eCRF, and a scoring algorithm will be applied to calculate the 
grade of aGvHD using the modified Glucksberg Criteria.

Cumulative dose of daily steroids administered from diagnosis of
aGvHD to 12 weeks (Day 84) after initiation of ECP treatment.

Organ-specific grade at 4 weeks (Day 28), 8 weeks (Day 56), and 12


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weeks (Day 84) after initiation of ECP treatment.
Exploratory:
Number of patients
48 patients with steroid-refractory aGvHD grade B-D.
Study design
This is a single-arm, open-label, multicenter study of the efficacy of 
UVADEX (methoxsalen) Sterile Solution in conjunction with THERAKOS 
CELLEX Photopheresis Systems in pediatric patients with steroid-refractory 
aGvHD. The study is composed of Screening, Treatment, and Follow-up 
Periods.
Screening:
After the informed consent/assent form (ICF) is signed, the screening 
assessments will be performed in a single visit to establish the eligibility of 
the patient, based on inclusion and exclusion criteria, as well as aGvHD 
grading. Scheduling of the first week of ECP treatments and the 
arrangements for availability of typed and cross-matched donor packed red 
blood cells (PRBCs) for transfusion, if required, will be made in advance of 
patients entering the Treatment Period.
Treatment Period:
Once eligibility is established, patients will enter the 12-week ECP 
Treatment Period. The availability of typed and cross-matched donor PRBCs 
for transfusion during treatment, if needed, should be established prior to the 
scheduling of ECP treatments.
Patients will be allowed to continue standard aGvHD prophylaxis regimens 
(e.g., cyclosporine, tacrolimus, methotrexate, mycophenolate mofetil) 
without the addition of new therapies. Patients will be allowed to 
discontinue prophylaxis regimens for reasons of toxicity, and will also be 
allowed to switch to another prophylaxis medication within the same class 
(e.g., the calcineurin inhibitors cyclosporine and tacrolimus) for reasons of 
toxicity.
All patients enrolled in this trial will have received corticosteroids for the 
treatment of aGvHD. After entering the treatment period on study, it is 
suggested that the steroid dose be decreased by 12.5% to 25% of the dose 
after the initiation of ECP therapy if a sustained response of aGvHD has 
been observed for at least 3 consecutive days. The suggested goal is to have 
decreased the starting steroid dose by at least 50% at 4 weeks after initiation 
of ECP.
Special Warnings and Precautions for Use
Patients should be explicitly instructed to wear ultraviolet A (UVA)-
absorbing, wrap-around sunglasses and cover exposed skin or use a 
sunblock (SPF 15 or higher) for the 24 hour period following treatment with 
methoxsalen, whether exposed to direct sunlight, or indirect sunlight through 
a glass window.


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Follow-Up Period:
After completion of the 12-week Treatment Period, patients may continue 
ECP treatment on commercial product at the discretion of the Principal 
Investigator. Acute GvHD status will be assessed 4 weeks after completion 
of the Treatment Period. Patient survival will be assessed by passive follow-
up (chart review) 26 weeks after initiation of ECP treatment.
Patient 
population
Inclusion criteria
Patients must meet all of the following criteria:
1.
Male or female 1 to 21 years of age at the time of consent.
2.
Steroid-refractory grade B-D aGvHD

Steroid-refractory is defined as a failure to respond to steroid
treatment, with failure to respond defined as any grade B-D
(IBMTR grading) aGvHD that shows progression ≥3 days, or
no improvement by 5 days of treatment with 2 mg/kg/day of
methylprednisolone or equivalent in patients with lower GI or
liver disease, or skin disease associated with bullae. Grade D
organ involvement will be limited to skin and liver.

Steroid refractory may also be defined as a failure to respond
to 1 mg/kg/day of methylprednisolone or equivalent in patients
with disease confined to upper GI disease or lesser degrees of
skin GvHD.

Patients with lack of complete response after 2 weeks of
steroid treatment.
3.
A Lansky Scale Performance Status score ≥ 30.
4.
Laboratory values are within the following limits, assessed within
3 days of the first study treatment:

Absolute neutrophil count > 0.5 × 109/L

Creatinine level < 2 times the upper limit of normal
5.
For patients with isolated upper gastrointestinal (GI) symptoms, pre-
Screening biopsy results to confirm diagnosis of aGvHD.
6.
Female patients of childbearing potential and nonsterilized males who
are sexually active with a female partner must be practicing highly
effective, reliable, and medically approved contraceptive regimen
throughout their participation in the study and for 3 months following
the last ECP treatment. Or, for the US only, abstinence may be used in
place of an approved contraceptive regimen. Females of childbearing
potential are those who have reached the onset of menarche, or 8 years
of age, whichever comes first. Approved contraceptive methods for
female patients of childbearing potential or nonsterilized males who are
sexually active with a female partner are as follows:

Barrier methods of contraception: condom or occlusive cap
(diaphragm or cervical/vault caps) with spermicidal
foam/gel/film/cream/suppository.

Established use of oral, injectable, or implanted hormonal
methods of contraception.

Placement of an intrauterine device or intrauterine system.
7.
Signed informed consent/assent is obtained before conducting any study
procedures; the parent, legal guardian, or legally authorized
representative of a minor must also provide written informed consent.
Exclusion 
criteria
Any of the following would exclude the patient from participation in the 
study:
1.
Currently enrolled in another clinical trial for the treatment of aGvHD.
2.
Use of any experimental regimens or medication(s) for aGvHD


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treatment.
3.
Treatment with > 2.0 mg/kg/day of methylprednisolone equivalents for
aGvHD within 30 days prior to the first study treatment.
4.
Overt signs of relapse of the underlying condition.
5.
Uncontrolled viral, fungal, or bacterial infection.
6.
Platelet count < 20.0 × 109/L, despite platelet transfusion.
7.
Total bilirubin value ≥ 15 mg/dL.
8.
Inability to tolerate the extracorporeal volume shifts associated with
ECP treatment.
9.
Uncontrolled GI bleeding.
10. Veno-occlusive liver disease.
11. Life expectancy < 4 weeks.
12. Patient requires invasive ventilation or vasopressor support.
13. Known human immunodeficiency virus (HIV) or hepatitis B or C virus
infection (proof of seronegativity within 6 months of screening is
required).
14. Known allergy or hypersensitivity to methoxsalen, Uvadex, or its
excipients.
15. Known hypersensitivity or allergy to heparin and Anticoagulant Citrate
Dextrose Formula-A (ACD-A).
16. Co-existing photosensitive disease (e.g., porphyria, systemic lupus
erythematosus, albinism) or aphakia.
17. Coagulation disorders that cannot be corrected with simple transfusion.
18. Co-existing melanoma, basal cell, or squamous cell skin carcinoma.
19. Previous splenectomy.
20. White blood cell count greater than 25,000 mm3.
21. Currently being treated with any systemic immunosuppressive or
biologic therapy for the treatment of a medical condition other than
aGvHD.
22. Female patient is breastfeeding or pregnant.
23. Any medical concerns that may pose risk to the patient.
24. Any psychological, familial, sociological, and/or geographical condition
that may potentially hamper compliance with the study protocol and the
follow-up schedule.
Study treatment
Patients will receive ECP (UVADEX [methoxsalen] Sterile Solution) in 
conjunction with the CELLEX System.
Dosage and frequency of 
administration
The dose of UVADEX (methoxsalen) Sterile Solution used to inoculate the 
buffy coat will be calculated according to the CELLEX System Operator’s 
Manual based on the treatment volume collected during the plasma/buffy 
coat collection process using the following formula:
Treatment Volume in mL × 0.017 = Dose of UVADEX (methoxsalen) 
Sterile Solution (in mL) required for administration into the 
recirculation bag. Each mL of solution contains 20 µg of UVADEX
(methoxsalen) Sterile Solution.
After the cells are inoculated with UVADEX (methoxsalen) Sterile Solution, 
the buffy coat/plasma suspension is irradiated with ultraviolet A (UVA) light 
and then re-infused back into the patient.
Extracorporeal photopheresis will be administered using the CELLEX 
System and UVADEX (methoxsalen) Sterile Solution in the mode of 
administration recommended by the approved labeling for UVADEX 
(methoxsalen) Sterile Solution, except for the treatment frequency. ECP will 
be administered by trained ECP operators only.
Extracorporeal photopheresis will be administered as follows:


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
Weeks 1-4: 3 treatments per week.

Weeks 5-12: 2 treatments per week.
Week 1 (7 days) begins when the first ECP treatment is received (Day 
1 of Week 1). The availability of typed and cross-matched donor 
PRBCs for transfusion during treatment, if needed, should be 
established prior to the scheduling of ECP treatments.
Extracorporeal photopheresis treatments given within ± 2 days of the 
expected treatment week will not be considered a protocol deviation.
Patients must be enrolled and receive their first ECP treatment within 
1 week (7 days) after being diagnosed as having steroid-refractory aGvHD.
All patients will be evaluated for a response in their aGvHD manifestations 
at least once each week through Week 12, or the visit at which a patient 
ceases to receive treatment, if before Week 12. The assessment of aGvHD 
status should occur after the last ECP treatment of the week has been 
completed.
Principal Investigators should consult 
Appendix D: Fluid Balance 
Management and the CELLEX System Operator’s Manual for information 
on minimum hematocrit and extracorporeal volume.
It is anticipated that most patients will receive ECP treatments in this 
protocol via a central venous catheter. However, Principal Investigators may 
choose to administer ECP treatments via peripheral venous access if 
clinically prudent.
Study assessments
Grading and Assessment of aGvHD:

Acute GvHD will be assessed for each organ system by the treating 
physician, and source data will be collected for each patient and entered 
into the eCRF. A scoring algorithm will then be applied to calculate the 
grade of aGvHD using the modified IBMTR Severity Index and the 
modified Glucksberg criteria. Acute GvHD status will be assessed at 
screening and once per week throughout the Treatment and at each 
Follow-up Period by the treating physician.

The formal statistical analysis and evaluation of response is based on at 
least 4-weeks of ECP treatment only.
Cumulative Steroid Dose:
Cumulative daily steroid dose from diagnosis of aGvHD along with all other 
concomitant medications will be recorded every week during the Treatment 
Period (Week 12).
Adverse Events:
Adverse events will only be recorded from ICF signing until Week 16. 
Following Week 16, there will be a passive chart review which will not 
include the collection of AEs.
Treatment Failure:
Treatment failure is defined as the addition of next-line systemic therapy for 
the treatment of aGvHD. Next-line treatment is defined as any additional 
systemic treatment not used for initial treatment of aGvHD, or for 
prophylaxis. Next-line treatment also includes an increase in steroid dose to 
> 2.0 mg/kg/day of methylprednisolone equivalents because of a flare during 
steroid tapering. A flare is defined as any increase in aGvHD symptoms 
after an initial response (CR or PR).
Power and sample size
A total of 48 patients with steroid-refractory grade B-D aGvHD will be 
enrolled and receive at least one ECP treatment. The trial is designed to test 
the null hypothesis that standard therapy has an overall response (CR+PR) 


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rate of 10% versus the alternate hypothesis that ECP plus standard therapy 
has a CR+PR rate not equal to 10% (the expected rate ≥27%).  The overall 
Type I error rate and power for this design are 5% and 90.4%, respectively.
This single-arm trial will have 1 interim analysis and a final analysis After 
the first 24 patients enrolled into the study have completed at least 4 weeks
of ECP treatment, significance will be declared if the CR+PR 2-sided P
value vs the stated alternative is < 0.005, corresponding to an observed 
CR+PR rate > 48%.  A final analysis will be performed after all 48 patients 
enrolled into the study have been treated for at least 4 weeks.  In this final 
analysis, significance will be declared if the CR+PR 2-sided P value vs the 
stated null is < 0.049.  
Statistical methods
All baseline demographic and disease characteristics will be summarized.
The primary endpoint of overall response (CR+PR) at Day 28 (Week 4) will 
be summarized by frequency tabulation and analyzed using exact Binomial 
test and confidence interval. Secondary endpoints of response at Week 8 
(Day 56) and Week 12 (Day 84) will be analyzed in the same manner. Other 
endpoint data collected in the Treatment and Follow-up Period will be 
summarized appropriately.
All AE data will be fully listed by investigator terms and Medical Dictionary 
for Regulatory Activities (MedDRA) preferred term. Adverse event data will 
be summarized by system organ classification and preferred term. Vital 
signs and laboratory values will be summarized by visit and numbers of 
patients, with excursions outside the normal reference range summarized.
Patients who voluntarily cease to receive treatment early will not be 
replaced. Patients may be replaced if they are enrolled in the trial but are not 
treated. If a patient has received any ECP treatments and is administered a 
second-line therapy other than ECP, or discontinues study treatment, that 
patient will be considered a nonresponder and may not be replaced.


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TABLE OF CONTENTS
SIGNATURE PAGE...................................................................................................................3
SIGNATURE PAGE...................................................................................................................4
PROTOCOL SYNOPSIS............................................................................................................5
TABLES IN TEXT...................................................................................................................14
FIGURES IN TEXT..................................................................................................................14
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS..............................................15
1.
INTRODUCTION .............................................................................................................17
1.1
Background.................................................................................................................17
2.
STUDY OBJECTIVES......................................................................................................21
2.1
Primary Objective .......................................................................................................21
2.2
Secondary Objectives..................................................................................................21
3.
OVERALL DESIGN AND PLAN OF THE STUDY.........................................................22
3.1
Overview ....................................................................................................................23
3.2
Endpoints....................................................................................................................23
3.2.1
Primary Endpoint.................................................................................................23
3.2.2
Secondary Endpoints............................................................................................23
3.2.3
Exploratory Endpoints .........................................................................................24
3.3
Criteria for Defining Response....................................................................................24
3.4
Rationale for the Study Design....................................................................................25
3.5
Risk/Benefit Ratio.......................................................................................................25
4.
STUDY POPULATION ....................................................................................................27
4.1
Inclusion Criteria ........................................................................................................27
4.2
Exclusion Criteria .......................................................................................................28
5.
STUDY PRODUCT...........................................................................................................29
5.1
Identity .......................................................................................................................29
5.1.1
UVADEX (methoxsalen) Sterile Solution ............................................................29
5.2
Packaging, Labeling, and Storage................................................................................29
5.3
Drug and Device Accountability .................................................................................29
5.3.1
Shipment and Receipt ..........................................................................................29
5.3.2
Accountability Logs.............................................................................................30
6.
TREATING THE PATIENT..............................................................................................31
6.1
Instruments .................................................................................................................31
6.1.1
Packaging, Labeling, and Storage of Procedural Kits ...........................................31
6.2
UVADEX Administration...........................................................................................31


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6.2.1
Selection of Timing and ECP Treatment in the Study...........................................32
6.2.2
Extracorporeal Photopheresis Stop/Hold Parameters............................................32
6.2.3
Extracorporeal Volume ........................................................................................32
6.2.4
Anticoagulation During ECP................................................................................33
6.3
Corticosteroids............................................................................................................33
6.3.1
Selection and Timing of Corticosteroid Doses in the Study..................................33
6.4
Acute GvHD Prophylaxis............................................................................................33
6.5
Concomitant Medications............................................................................................34
6.5.1
Prohibited Concomitant Medications ...................................................................34
6.6
Early Cessation of Study Participation ........................................................................34
6.6.1
Early Cessation of Study Treatment .....................................................................34
7.
STUDY CONDUCT..........................................................................................................36
7.1
Schedule of Assessments.............................................................................................36
7.2
Study Assessments and Procedures .............................................................................38
7.2.1
Screening Period..................................................................................................38
7.2.2
Treatment Period..................................................................................................42
7.2.3
Follow-up Period .................................................................................................47
7.2.4
Early Study Termination Visit..............................................................................50
8.
SAFETY PARAMETERS .................................................................................................51
8.1
Adverse Events ...........................................................................................................51
8.1.1
Collection of Adverse Events...............................................................................51
8.1.2
Definitions...........................................................................................................51
8.1.3
Assessment of Adverse Events.............................................................................52
8.1.4
Recording Adverse Events...................................................................................54
8.1.5
Reporting Serious Adverse Events .......................................................................54
8.1.6
Follow-up of Serious Adverse Events ..................................................................56
8.1.7
Protocol-Specified Serious Adverse Events..........................................................56
8.1.8
Suspected Unexpected Serious Adverse Reactions...............................................57
8.1.9
Pregnancy............................................................................................................57
8.1.10
Medical Device Reporting....................................................................................58
8.2
Data Safety Monitoring Board.....................................................................................58
9.
STATISTICAL METHODS ..............................................................................................59
9.1
Planned Sample Size...................................................................................................59
9.2
Overview of Study Design ..........................................................................................59
9.3
Efficacy Analyses .......................................................................................................59
9.3.1
Analysis of Primary Endpoint ..............................................................................59
9.3.2
Analysis of Secondary Endpoints.........................................................................60
9.3.3
Analysis of Exploratory Endpoints.......................................................................60


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9.4
Safety Parameters........................................................................................................61
10.
ETHICAL, LEGAL, AND ADMINISTRATIVE ASPECTS ..........................................62
10.1
Data Quality Assurance...............................................................................................62
10.2
Case Report Forms and Source Documentation...........................................................62
10.2.1
Data Collection....................................................................................................62
10.3
Access to Source Data.................................................................................................63
10.4
Data Processing...........................................................................................................63
10.5
Archiving Study Records ............................................................................................63
10.6
Good Clinical Practice ................................................................................................63
10.7
Informed Consent/Assent............................................................................................64
10.8
Protocol Approval and Amendment ............................................................................64
10.9
Duration of the Study..................................................................................................64
10.10
Premature Termination of the Study ........................................................................64
10.11
Confidentiality.........................................................................................................65
10.12
Other Ethical and Regulatory Issues ........................................................................65
10.13
Liability and Insurance ............................................................................................65
10.14
Publication Policy....................................................................................................65
11.
REFERENCES...............................................................................................................66
12.
APPENDICES................................................................................................................69
12.1
Appendix A: Modified IBMTR Severity Index............................................................69
12.2
Appendix B: Modified Glucksberg Criteria.................................................................70
12.3
Appendix C: Lansky Scale ..........................................................................................71
12.4
Appendix D: Fluid Balance Management....................................................................72
12.5
Appendix E: Blood Prime Technique Flow Sheet (Example).......................................88
12.6
Appendix F: ACD-A Recommendations for the Therakos CELLEX Photopheresis 
System...................................................................................................................................90
12.7
Appendix G: Percent Body Surface Area Assessment .................................................93


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TABLES IN TEXT
Table 1. Schedule of Assessments.............................................................................................36
Table 2. Contact Information for Reporting Serious Adverse Events..................................55
Table 3. Contact Information US and EU Medical Monitors ...............................................55
Table 4. Criteria for Modified IBMTR Severity Index for aGvHD......................................69
Table 5. Modified Glucksberg Criteria for aGvHD...............................................................70
Table 6. Lansky Performance Status Scale............................................................................71
Table 7. Estimated Extracorporeal Volume Relative to % Hematocrit, Access Mode and 
Return Bag Threshold Value..................................................................................................74
Table 8. Estimated Extracorporeal Volume (ECV)—Range of Settings...............................75
Table 9. Body Build Factors and Safe Extracorporeal Blood Volume (ECV) Limits ..........77
FIGURES IN TEXT
Figure 1. Study Schematic ......................................................................................................22
Figure 2. Prime Access............................................................................................................82
Figure 3. Rule of Nines............................................................................................................93


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
ACD-A
Anticoagulant citrate dextrose formula-A
AE
Adverse event
aGvHD
Acute graft-vs-host disease
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
ATC
Anatomical Therapeutic Chemical
BSA
Body surface area
BUN
Blood urea nitrogen
CBC
Complete blood count
cGvHD
Chronic graft-vs-host disease
CR
Complete response
CTCAE
Common Terminology Criteria for Adverse Events
CTCL
Cutaneous T-cell lymphoma
CVL
Central venous line
DRL
Drug Reference List
DSMB
Data Safety Monitoring Board
ECP
Extracorporeal photopheresis
eCRF
Electronic case report form
EDC
Electronic Data Capture
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GGT
Gamma-glutamyltransferase
GI
Gastrointestinal
GvHD
Graft-vs-host disease
HCG
Human chorionic gonadotropin
HIV
Human immunodeficiency virus
HSCT
Hematopoietic stem cell transplantation
IBMTR
International Bone Marrow Transplant Registry
ICF
Informed consent/assent form
ICH
International Council for  Harmonisation
IEC
Independent Ethics Committee
IND
Investigational New Drug
INR
International normalized ratio
IRB
Institutional Review Board
IWRS
Interactive Web Response System 
MedDRA
Medical Dictionary of Regulatory Activities
NIH
National Institutes of Health
OR
Overall response
PR
Partial response
PRBCs
Packed red blood cells
PT/PTT
Prothrombin time/partial thromboplastin time
SAE
Serious adverse event
SUSAR
Suspected unexpected serious adverse reaction
Treg
Regulatory T cell
UVA
Ultraviolet A
WBC
White blood cell


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VGPR
Very good partial response
WHO
World Health Organization


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1.
INTRODUCTION
1.1 BACKGROUND
Graft-vs-host Disease
Graft-vs-host disease is the major complication of allogeneic hematopoietic stem cell 
transplantation (HSCT), in which newly transplanted donor T cells recognize and attack host 
histocompatibility antigens on the transplant recipient’s organs [Ferrara et al., 2009]. Graft-
versus-host disease is clinically separated into an acute form (aGvHD) and a chronic form 
(cGvHD) that were historically defined as GvHD before or after Day 100, respectively.
Advances in HSCT practice have altered the presentation and natural history of aGvHD and 
cGvHD; therefore, clinical manifestations and histologic findings are now used to differentiate 
between the 2 diseases [Filipovich et al., 2005]. Acute GvHD can present as classic aGvHD 
(occurring within 100 days after transplant) or as persistent, recurrent, or late-onset aGvHD 
(occurring more than 100 days after transplant), without diagnostic or distinctive signs of 
cGvHD [Hart et al., 2013].
Incidence rates of aGvHD in adults range from 10% to 80% following allogeneic HSCT, with 
symptoms typically presenting 2 to 3 weeks posttransplant [Garnett et al., 2013]. Acute GvHD 
also occurs in a substantial proportion of children. Reports from large pediatric transplant studies 
have demonstrated a cumulative incidence of grade II-IV aGvHD ranging from 28% to 56% 
[Giebel et al., 2003, Rocha et al., 2000, Kanold et al., 2003]. While bone marrow is 
predominantly used as the source for HSCT in pediatric patients, the risk of aGvHD is greater 
when alternative donor sources are used, including unrelated cord blood and peripheral blood 
stem cells [Jacobsohn, 2008].
A recent study evaluating the risk and prognostic factors for development of aGvHD based on 
the National Institutes of Health (NIH) consensus criteria found that the incidence of aGvHD in 
patients (N = 775) who underwent allogeneic HSCT was 44.7% overall [Lee et al., 2013].
Among patients with aGvHD, classic presentation was associated with lower survival than late-
onset (P = 0.044). Additionally, more pronounced disease (e.g., visceral organ involvement 
[P = 0.002], severity at onset [P = 0.035], and advanced disease [P < 0.001]) were significantly 
associated with lower survival [Lee et al., 2013]. Acute GvHD is also an important risk factor for 
the later development of cGvHD. The primary target organs of aGvHD are skin, gut, and liver, 
and disease severity is graded from I to IV [Przepiorka et al., 1995] using the modified 
Glucksberg criteria, or from A to D [Rowlings et al., 1997] using the International Bone Marrow 
Transplant Registry (IBMTR) Severity Index. The grade of aGvHD correlates to overall survival, 
as an analysis of 1,294 patients receiving an allogeneic transplant for chronic myelogenous 
leukemia demonstrated that transplant-related mortality for aGvHD grades 0 to IV was 28%, 
27%, 43%, 68%, and 92%, respectively, with a distinct separation between grades 0 to I and II to 
IV [Gratwohl et al., 1995]. In a retrospective comparison of the IBMTR Severity Index with the 
Glucksberg criteria in 2,129 patients receiving cyclosporine and methotrexate for GvHD 
prophylaxis, the relative risk of treatment failure for grade A to D was 0.85, 1.21, 2.19, and 5.68, 
respectively [Rowlings et al., 1997]. Patients with grade A aGvHD have a similar risk of 
treatment failure compared with patients without aGvHD, and those with grade B to D aGvHD 
have incrementally increased risks [Rowlings et al., 1997]. Furthermore, patients with grade IV 
aGvHD have a markedly increased transplant-related mortality compared with grades 0 to III 


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[Gratwohl et al., 1995], and grade D patients have decreased leukemia-free survival compared 
with grades A to C [Rowlings et al., 1997].
Although the treatment of aGvHD with corticosteroids has long been accepted as a first-line 
systemic therapy, a complete response (CR) to first-line systemic corticosteroids was observed in 
only 20% (92/456) of evaluable patients with aGvHD in a retrospective study (median age 
[range] of entire patient population, 23 years [0.8 to 62]) [Martin et al., 1990]. Steroids are 
associated with a number of side effects, including immunosuppression, hyperglycemia, 
osteopenia, and avascular bone necrosis [Garnett et al., 2013], and long-term use of these agents 
can cause growth retardation and delayed puberty in pediatric patients [Lawitschka et al., 2012].
Current research evaluating second-line agents based on a number of clinical endpoints does not 
support or exclude any of these agents from consideration as a second-line therapy for steroid-
refractory aGvHD [Martin et al., 2012].
The pathophysiology of aGvHD is thought to involve excessive inflammation caused by 
activation of alloreactive donor T cells [Ferrara et al., 1996]. Modulation of this reaction by 
means other than medication could provide benefit in the GvHD population. Extracorporeal 
photopheresis in combination with conventional corticosteroids is a second-line option for 
patients with aGvHD. This is an especially promising approach for the pediatric patient 
population due to
the toxic effects of prolonged treatment
with steroids or other 
immunosuppressive agents currently used for the treatment of aGvHD.
Extracorporeal Photopheresis
Extracorporeal photopheresis is a leukapheresis-based immunomodulatory therapy indicated for 
the palliative treatment of skin manifestations in patients with cutaneous T-cell lymphoma 
(CTCL) unresponsive to other forms of treatment [Ferrara et al., 1996]. Extracorporeal 
photopheresis has been studied in a number of other autoimmune-mediated disorders, including 
acute and chronic GvHD in both adult and pediatric patients, rejection after solid organ 
transplantation, systemic sclerosis, Crohn’s disease, and type 1 diabetes [Knobler et al., 2014].
Extracorporeal photopheresis consists of the ex vivo exposure of autologous peripheral 
leukocytes to UVADEX® (methoxsalen) Sterile Solution and UVA irradiation, followed by 
reinfusion of the cells to the patient. Photoactivated UVADEX (methoxsalen) Sterile Solution 
covalently binds to DNA, causing apoptosis of treated cells after reinfusion [Bladon and Taylor, 
1999].
Systemic exposure to UVADEX (methoxsalen) Sterile Solution following extracorporeal 
photopheresis (ECP) is minimal. The total dose of methoxsalen used to inoculate cells in 
conjunction with the THERAKOS integrated system is less than 1/200th of the oral dose. Plasma 
levels obtained as part of other clinical studies have shown no detectable level (< 10 ng/mL) 30 
minutes after reinfusion of the treated cell suspension containing the UVADEX (methoxsalen) 
Sterile Solution in > 80% of patients [Moon et al., 2014, Therakos Inc., 2013].
Evidence from preclinical and clinical studies supports a role for systemic immunomodulation as 
the mechanism of action in GvHD patients treated with ECP. Broadly, the complex mechanism 
by which ECP induces immunomodulation in GvHD can be described by its effects on shifting 
the immunologic milieu from a pro-inflammatory, type 1 T-helper cell (Th1)-mediated response 
to an anti-inflammatory, type 2 T-helper cell (Th2)-mediated environment, and inducing a degree 


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of lasting immune tolerance via upregulation of regulatory T cells (Tregs) [Bruserud et al., 
2014].
Extracorporeal photopheresis has been studied as a second-line treatment for acute and chronic 
GvHD, although the majority of studies have been small and retrospective in nature. In a 
prospective Phase 2 study of ECP as second-line therapy in 59 adult patients with aGvHD, a CR
after 3 months of ECP treatment was observed in 82% of patients with skin involvement and in 
61% of patients with either liver or gut involvement [Greinix et al., 2006]. Furthermore, patients 
achieving a CR had a significantly higher overall 4-year survival compared with those who did 
not achieve a CR (59% versus 11%, P < 0.0001) [Greinix et al., 2006]. A more recent 
retrospective study demonstrated an overall response (complete+partial response; CR+PR) of 
66% and a CR of 54% in 57 adult and pediatric patients receiving ECP for aGvHD [Jagasia et 
al., 2013]. In a retrospective study of 33 pediatric patients treated with ECP for aGvHD, the 
overall response rate after a median of 8 treatments (range 2 to 20 treatments) was 76% and a CR 
was observed in 76%, 75%, and 60% of patients with skin, gut, and liver involvement, 
respectively [Messina et al., 2003]. Furthermore, the 5-year overall survival was significantly 
better in ECP responders compared with nonresponders (69% versus 12%, P = 0.001) [Messina 
et al., 2003]. Extracorporeal photopheresis is well tolerated, with an excellent safety profile in 
children and adults. In a prospective analysis of 27 children who underwent ECP for acute (n = 
12) or chronic (n = 15) GvHD, clinical adverse events (AEs) were observed in 11% and 9% of 
patients, respectively; no infectious events could be attributed to the ECP procedure [Kanold et 
al., 2007]. Furthermore, no significant differences in clinical tolerance were found in 8 GvHD 
patients with low body weight (< 25 kg) versus other patients [Kanold et al., 2007].
A number of factors should be considered when performing ECP on pediatric patients. Several 
studies have emphasized that the use of ECP in children presents specific challenges, including 
low body weight, vascular access, extracorporeal volume, metabolic and hematologic problems, 
and psychological tolerance [Messina et al., 2003, Kanold et al., 2007, Schneiderman et al., 
2010]. The newer CELLEX® System is equipped with continuous flow separation that reduces 
treatment times and extracorporeal volumes compared with the UVAR XTS® System [Bohbot et 
al., 2012, Kapadia et al., 2015] and has also been shown to treat an increased percentage of 
mononuclear cells and reduce the incidence of patient-related complications compared with the 
UVAR XTS System based on a retrospective chart review of 10 patients with steroid-refractory 
acute or chronic GvHD [Kapadia et al., 2015]. Although the optimal treatment schedule and 
duration of ECP treatment have yet to be established, aGvHD patients are routinely administered 
ECP 2 to 3 times a week initially, followed by progressive tapering. Early initiation of ECP has 
also been associated with better outcomes [Gonzalez Vicent et al., 2010]. Clinical practice 
guidelines recommend ECP as first-line therapy for pediatric patients with grade IV aGvHD 
along with conventional immunosuppressants, and as second-line therapy for grade II to III 
steroid-refractory aGvHD [Kanold et al., 2007].
The safety, tolerability, and efficacy of the CELLEX System alone have also recently been 
investigated [Rangarajan et al., 2013, Uygun et al., 2014]. Rangarajan et al reported on the safety 
of 385 ECP procedures performed in 9 children and young adults treated for acute or chronic 
GvHD [Rangarajan et al., 2013]. The median age was 13.5 years (range, 3.7 to years) and 
median weight was 49.2 kg (range, 18.5 to 86.3 kg). The mean duration per procedure was 106 
minutes (range, 60 to 205 minutes). The study reported 1 episode of central venous line (CVL)-
associated thrombosis and 1 episode of delayed bleeding. Furthermore, 4 episodes of viral 


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reactivation, 4 CVL-associated infections (over 1,142 catheter days), and 1 episode of systemic 
inflammatory response syndrome were reported.
No patient experienced symptomatic 
hypotension or hypocalcemia [Rangarajan et al., 2013]. The study concluded that use of the 
CELLEX System for the treatment of children and young adults with GvHD was safe and well 
tolerated.
Uygun et al reported on 12 pediatric patients with aGvHD, cGvHD, or overlap syndrome
[Uygun et al., 2014]. The age of patients with aGvHD ranged from 1.5 to 12 years, and weight 
ranged from 7 to 68 kg. Improvement was observed in 70% of aGvHD patients (7/10, including 
4 patients with overlap syndrome) and in 66% of cGvHD patients (4/6, including 4 patients with 
overlap syndrome), and the initial response to ECP was observed after a median of 4 treatments
(range, 2 to 10). Nine of 11 patients with skin involvement and 5 of 8 patients with 
gastrointestinal (GI) involvement responded to treatment; all 4 patients with liver involvement 
failed to respond to ECP. No deterioration in general health conditions were observed, except in 
1 patient who had GI GvHD with bloody diarrhea. The study concluded that the CELLEX 
System is a safe and effective treatment option for pediatric patients [Uygun et al., 2014].


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2.
STUDY OBJECTIVES
2.1 PRIMARY OBJECTIVE

To evaluate the efficacy of ECP in pediatric patients with steroid-refractory aGvHD.
2.2 SECONDARY OBJECTIVES

To assess the safety of ECP.

To assess the duration of response to ECP.

To assess the steroid-sparing effect of ECP.

To assess the organ-specific response to ECP.


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3.
OVERALL DESIGN AND PLAN OF THE STUDY
This is a single-arm, open-label, multicenter study to demonstrate the efficacy of UVADEX 
(methoxsalen) Sterile Solution in conjunction with the THERAKOS CELLEX Photopheresis 
System in pediatric patients with steroid-refractory aGvHD having received the existing standard 
of care (Figure 1).
Figure 1. Study Schematic
ECP, extracorporeal photopheresis; GvHD, graft versus host disease; OR, overall response.  
Steroid-Refractory Acute
GvHD grade B-D
Screening
12 Weeks treatment
SOC + ECP
(N = 48)
Interim Analysis
Eligible?
Final Analysis
Screening
Failure
OR after first 24 
patients enrolled have 
been followed for 4 
weeks: P < 0.005
Declare Efficacy
OR after all patients 
enrolled have been 
followed for 4 weeks: 
P < 0.049
Declare Efficacy
No
Yes
Primary Endpoint 4 weeks
Seconday Endpoints 8 weeks & 
12 weeks
End of Study:                 
4 week post treatment follow-
up (16 weeks)
10 Week Survival follow-up 
(completes full 26 weeks of 
study)


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3.1 OVERVIEW
Screening will occur in a single visit during which patients will be evaluated for eligibility and 
for the grading of aGvHD. Patients with steroid-refractory aGvHD grade B-D who meet the 
eligibility criteria will be treated with UVADEX (methoxsalen) Sterile Solution in conjunction 
with the CELLEX System. Patients must be enrolled and receive their first ECP treatment within 
1 week (7 days) after being diagnosed as having steroid-refractory aGvHD. Patients are expected 
to receive the stated number of ECP treatments per treatment week (7 days) ± 2 days, and a total 
of no more than 12 ECP treatments for the first 28 days. A maximum of 28 ECP treatments will 
be given per patient during the 12-week treatment period. Conventional steroids will continue to 
be administered and tapered based on a sustained response to ECP. The primary endpoint is the 
proportion of patients reaching an overall response (CR+PR) after 4 weeks (Day 28) of ECP 
treatment, or fewer treatments if they discontinued treatment, regardless of steroid tapering.
The addition of next-line systemic therapy for aGvHD will be considered a treatment failure.
Next-line treatment is defined as any additional systemic treatment not used for initial treatment 
of aGvHD, or for prophylaxis. Next-line treatment also includes an increase in steroid dose to 
> 2.0 mg/kg/day of methylprednisolone equivalents because of a flare during steroid tapering. A 
flare is defined as any increase in aGvHD symptoms after an initial response (CR or PR).
Patients will be allowed to continue standard aGvHD prophylaxis regimens (e.g., cyclosporine, 
tacrolimus, methotrexate, and mycophenolate mofetil) without the addition of new therapies.
Patients will be allowed to discontinue prophylaxis regimens for reasons of toxicity, and will 
also be allowed to switch to another prophylaxis medication within the same class (e.g., the 
calcineurin inhibitors cyclosporine and tacrolimus) for reasons of toxicity.
After completion of the 12-week Treatment Period, patients may continue ECP treatment on 
commercial product at the discretion of the Principal Investigator. Acute GvHD status will be 
assessed 4 weeks after completion of the Treatment Period, and survival will be assessed by 
passive follow-up (chart review) 26 weeks after initiation of ECP treatment.
3.2 ENDPOINTS
3.2.1
Primary Endpoint

The proportion of patients who achieve an overall response (CR+PR) after 4 weeks (Day 28) 
of ECP treatment, or fewer treatments if they discontinued treatment
-
Patients will be evaluated by the treating physician for the presence or absence of 
aGvHD manifestations of the skin, liver, and gut. Source data will be collected for 
each patient and entered into the electronic Case Report Form (eCRF) and a scoring 
algorithm will be applied to calculate the aGvHD grade using the modified IBMTR 
Severity Index (
Appendix A: Modified IBMTR Severity Index). Patients weighing 
< 50 kg will be evaluated according to a modified version of the IBMTR criteria that 
accounts for stool output on an mL/kg/day basis.
3.2.2
Secondary Endpoints

Safety parameters including vital signs, laboratory tests, and spontaneously reported AEs and 
SAEs.


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
Proportion of patients who achieve an overall response 8 weeks (Day 56) and 12 weeks 
(Day 84) after initiation of ECP treatment.

Duration of response (defined as the length of time a patient maintains a response through 
Week 16 of the Follow-up Period on a per-patient basis).

Proportion of patients who achieve an overall response after 4 weeks (Day 28), 8 weeks 
(Day 56), and 12 weeks (Day 84) of ECP treatment according to the modified Glucksberg 
criteria (
Appendix B: Modified Glucksberg Criteria).
-
Source data will be collected for each patient and entered into the eCRF, and a scoring 
algorithm will be applied to calculate the grade of aGvHD using the modified Glucksberg 
Criteria.

Cumulative dose of daily steroids administered from diagnosis of aGvHD to 12 weeks 
(Day 84) after initiation of ECP treatment.

Organ-specific grade at 4 weeks (Day 28), 8 weeks (Day 56), and 12 weeks (Day 84) after 
initiation of ECP treatment.
3.2.3
Exploratory Endpoints
 
 
 
 
3.3 CRITERIA FOR DEFINING RESPONSE
The criteria for defining response are as follows:

Overall response: CR + PR
o
CR: complete resolution of all signs and symptoms of aGvHD in all evaluable organs 
without addition of next-line systemic treatment.
o
PR: improvement of 1 stage in 1 or more aGvHD target organs without progression in 
others and without addition of next-line systemic treatment (see Section 3.1 for 
information regarding next-line treatment).

No response: Mixed Response or Stable Disease or Progression
o
Mixed Response: at least 1 stage improvement of at least 1 organ, with at least 1 stage 
worsening in at least 1 other organ.
o
Stable Disease: no significant change in any organ system.
o
Progression: worsening in 1 or more organs by 1 or more stage without improvement 
in any involved organ.

Very good partial response (VGPR) [Martin et al., 2009]:
o
Skin: no rash, or residual erythematous rash involving < 25% of the body surface, 
without bullae (residual faint erythema and hyperpigmentation do not count).


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o
Liver: total serum bilirubin concentration < 2 mg/dL or < 25% of baseline at 
enrollment.
o
Gut: tolerating food or enteral feeding, predominantly formed stools, no overt GI 
bleeding or abdominal discomfort, and no more than occasional nausea or vomiting.
3.4 RATIONALE FOR THE STUDY DESIGN
Although the treatment of aGvHD with corticosteroids has long been accepted as a first-line 
systemic therapy, a durable CR to corticosteroids has been reported in only 24% to 40% of 
aGvHD patients [Greinix et al., 2006]. There is also an unmet need in patients with steroid-
refractory aGvHD, as many of the second-line treatment options are associated with infrequent 
durable response rates and increased risk of life-threatening infection and viral reactivation
[Martin et al., 2012]. Furthermore, long-term use of steroids can cause growth retardation and 
delayed puberty in pediatric patients [Lawitschka et al., 2012]. There are currently no approved 
agents for the treatment of aGvHD. However, in clinical practice guidelines and expert 
consensus recommendations, ECP is recommended as second-line therapy in combination with 
corticosteroids for patients with steroid-refractory aGvHD [Dignan et al., 2012, Das-Gupta et al., 
2014a], including pediatric patients [Kanold et al., 2007, Pierelli et al., 2013, Bredeson et al., 
2014].
The clinical efficacy that has been reported in the literature on the use of ECP in pediatric 
patients with steroid-refractory aGvHD, as previously described, has provided the rationale for 
further investigation of this treatment approach in these patients. This single-arm trial will be the 
first prospective, multicenter investigation of ECP in pediatric patients with steroid-refractory 
aGvHD. Guidance received from the U.S. Food and Drug Administration (FDA) indicated that a 
single-arm trial that shows a meaningful rate of durable response in an endpoint reasonably 
likely to predict clinical benefit in a population with no available therapy could support an 
application for accelerated approval. The primary endpoint of overall response (CR+PR) after 
4 weeks (28 days) of ECP treatment was chosen because this has been qualified as reasonably 
likely to predict long-term outcomes for steroid-refractory aGvHD [MacMillan et al., 2002, 
Levine et al., 2008, Inamoto et al., 2014]. Two interim analyses will occur after approximately 
1/3 (N=19) and 2/3 (N=38) of the patients have completed at least 4 weeks of ECP treatment, or 
fewer treatments if they discontinued treatment, for steroid-refractory aGvHD. Standard therapy 
has an overall response (CR+PR) rate of 10%. 
3.5
RISK/BENEFIT RATIO
Pediatric patients with steroid refractory aGvHD are an underserved patient population for whom 
there is a lack of controlled data on the risks associated with treatment options. Current therapies 
used for the treatment of steroid refractory aGvHD have ranged from increasing the dose of 
steroids, to the addition of polyclonal or monoclonal antibodies, or additional 
immunosuppressive/chemotherapeutic interventions. These therapies are associated with high 
rates of infection, including invasive fungal, bacterial, and viral infections. In addition to 
immunosuppression, the use of steroids in pediatric patients is associated with a number of 
serious and oftentimes lasting side effects including: hyperglycemia, osteopenia, and avascular 
bone necrosis [Garnett et al., 2013].
The UVADEX with CELLEX technology being evaluated in this trial has a well-established 
safety profile based on both post-marketing data and off-label pediatric use. In addition, there is 


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published literature that suggests that ECP has effectiveness and tolerability in the steroid 
refractory pediatric aGvHD patient population. 
The benefit of this proposed trial is to evaluate a safety and efficacy of a promising alternative 
treatment for the treatment of pediatric patients with aGvHD. A further benefit of the proposed 
trial is the opportunity to produce validated results for this rare disease by collecting controlled 
data from multiple international sites. 


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4.
STUDY POPULATION
4.1 INCLUSION CRITERIA
Males and females 1 to 21 years of age who have steroid-refractory grade B-D aGvHD. Steroid-
refractory is defined as a failure to respond to steroid treatment, with failure to respond defined 
as any grade B-D (IBMTR grading) aGvHD that shows progression ≥3 days or no improvement 
by 5 days, of treatment with 2 mg/kg/day methylprednisolone or equivalent in patients with 
lower GI or liver disease, or skin disease associated with bullae. Grade D organ involvement will 
be limited to skin and liver. Steroid refractory may also be defined as a failure to respond to 
1 mg/kg/day of methylprednisolone or equivalent in patients with disease confined to upper GI 
disease or lesser degrees of skin GvHD.
Patients must meet all of the following criteria:
1. Male or female 1 to 21 years of age at the time of consent
2. Steroid-refractory grade B-D aGvHD.

Steroid-refractory is defined as a failure to respond to steroid treatment, with failure 
to respond defined as any grade B-D (IBMTR grading) aGvHD that shows 
progression ≥3 days, or no improvement by 5 days of treatment with 2 mg/kg/day 
methylprednisolone or equivalent in patients with lower GI or liver disease, or skin 
disease associated with bullae. Grade D organ involvement will be limited to skin and 
liver.

Steroid refractory may also be defined as a failure to respond to 1 mg/kg/day of 
methylprednisolone or equivalent in patients with disease confined to upper GI 
disease or lesser degrees of skin GvHD.

Patients with lack of complete response after 2 weeks of steroid treatment.
3. A Lansky scale Performance Status score ≥ 30.
4. Laboratory values are within the following limits, assessed within 3 days of the first study 
treatment:

Absolute neutrophil count > 0.5 × 109/L.

Creatinine level < 2 times the upper limit of normal.
5. For patients with isolated upper GI symptoms, pre-Screening biopsy results to confirm 
diagnosis of aGvHD.
6. Female patients of childbearing potential and nonsterilized males who are sexually active 
with a female partner must be practicing highly effective, reliable, and medically approved 
contraceptive regimen throughout their participation in the study and for 3 months following 
the last ECP treatment. Or, for the US only, abstinence may be used in place of an approved 
contraceptive regimen. Females of childbearing potential are those who have reached the 
onset of menarche, or 8 years of age, whichever comes first. Approved contraceptive 
methods for female patients of childbearing potential or nonsterilized males who are sexually 
active with a female partner are as follows:

Barrier methods of contraception: condom or occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/suppository.

Established use of oral, injectable, or implanted hormonal methods of contraception.

Placement of an intrauterine device or intrauterine system.


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7. Signed informed consent/assent is obtained before conducting any study procedures; the 
parent, legal guardian, or legally authorized representative of a minor must also provide
written informed consent.
4.2 EXCLUSION CRITERIA
Any of the following would exclude the patient from participation in the study:
1. Currently enrolled in another clinical trial for the treatment of aGvHD.
2. Use of any experimental regimens or medication(s) for aGvHD treatment.
3. Treatment with > 2.0 mg/kg/day of methylprednisolone equivalents for aGvHD within
30 days prior to the first study treatment.
4. Overt signs of relapse of the underlying condition.
5. Uncontrolled viral, fungal, or bacterial infection.
6. Platelet count < 20.0 × 109/L, despite platelet transfusion.
7. Total bilirubin value ≥ 15 mg/dL.
8. Inability to tolerate the extracorporeal volume shifts associated with ECP treatment.
9. Uncontrolled GI bleeding.
10. Veno-occlusive liver disease.
11. Life expectancy < 4 weeks.
12. Patient requires invasive ventilation or vasopressor support.
13. Known human immunodeficiency virus (HIV) or hepatitis B or C virus infection (proof of 
seronegativity within 6 months of screening is required).
14. Known allergy or hypersensitivity to methoxsalen, Uvadex, or its excipients.
15. Known hypersensitivity and allergy to heparin and Anticoagulant Citrate Dextrose Formula-
A (ACD-A).
16. Co-existing photosensitive disease (e.g., porphyria, systemic lupus erythematosus, albinism) 
or aphakia.
17. Coagulation disorders that cannot be corrected with simple transfusion.
18. Co-existing melanoma, basal cell, or squamous cell skin carcinoma.
19. Previous splenectomy.
20. White blood cell count greater than 25,000 mm3.
21. Currently being treated with any systemic immunosuppressive or biologic therapy for the 
treatment of a medical condition other than aGvHD.
22. Female patient is breastfeeding or pregnant.
23. Any medical concerns that may pose risk to the patient.
24. Any psychological, familial, sociological, and/or geographical condition that may potentially 
hamper compliance with the study protocol and follow-up schedule.


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5.
STUDY PRODUCT
5.1 IDENTITY
UVADEX (methoxsalen) Sterile Solution will be supplied by Therakos, Inc. at no cost.
5.1.1
UVADEX (methoxsalen) Sterile Solution
The active ingredient in UVADEX (methoxsalen) Sterile Solution is 8-methoxypsoralen 
(methoxsalen). Methoxsalen is a naturally occurring photoactive substance found in the seed of 
the Ammi majus (umbelliferae plant). It belongs to a class of compounds known as psoralens or 
furocoumarins. The chemical name is 9-methoxy-7H-furo[3,2-g][1]-benzopyran-7-one. The 
formulation of the drug is a sterile liquid at a concentration of 20 µg/mL in a 10-mL vial. A 
complete description of the pharmacokinetic activity of methoxsalen is available in the 
Investigator’s Brochure.
Adverse events associated with the ECP process during CTCL clinical trials in adult patients 
include venous access complications, transient fever and worsening of the underlying CTCL skin
rash, and transient hypotension associated with hypovolemia. A complete description of the AEs 
documented in studies using UVADEX (methoxsalen) Sterile Solution is provided in the 
Investigator’s Brochure.
UVADEX (methoxsalen) Sterile Solution is currently approved and marketed in the United 
States, Canada, United Kingdom, Germany, France, Denmark, Italy, and Austria for use in the 
palliative treatment of the skin manifestations of CTCL unresponsive to other therapies. The 
safety of UVADEX (methoxsalen) Sterile Solution has not been established in the pediatric 
population.
5.2 PACKAGING, LABELING, AND STORAGE
UVADEX (methoxsalen) Sterile Solution is packaged in 10-mL, 13-mm, U.S. Pharmacopeia 
Type I borosilicate amber glass vials. The closure is a 13-mm, gray butyl rubber stopper 
laminated with 0.1-mm fluorocarbon polymer film. A 13-mm aluminum flip-off cap, with a clear 
lacquer foil and purple plastic flip-off button, is used to seal the stoppered vials. UVADEX 
(methoxsalen) Sterile Solution must be stored at between 15°C and 30°C (U.S. labeling) or 
< 25°C (European labeling). UVADEX (methoxsalen) Sterile Solution will be labeled according 
to country-specific guidelines and language and will be labeled as “Investigational Product.”
5.3 DRUG AND DEVICE ACCOUNTABILITY
5.3.1
Shipment and Receipt
Clinical supplies, including UVADEX (methoxsalen) Sterile Solution and CELLEX System 
Procedural Kits (DAK), will be initially shipped and re-supplied automatically through the 
Interactive Web Response System (IWRS). Once a shipment has been initiated, the site designee 
will receive an email notification with the contents and tracking number of the incoming 
shipment.
When clinical supplies, including UVADEX (methoxsalen) Sterile Solution and CELLEX 
System Procedural Kits (DAK), are received at each study site, the receipt of supplies should be 
confirmed within the IWRS. This receipt will include the total number of supplies received, the 


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date received, and the condition of the supplies at time of receipt. The supplies should also be 
recorded on the Investigational Drug and Device Log, respectively. This receipt is to be 
confirmed by a staff member appointed by the Principal Investigator to account for 
investigational supplies. The packing list of this shipment should be kept at the site and filed 
with the Investigational Drug/Device Log.
Note: UVADEX must be stored in a temperature controlled setting upon receipt as soon as 
possible. If this does not occur ≤ 1 week from the ship date, the product will be invalid.
In the event that drug or devices do not arrive at a study site, the 
 
study monitor should be notified immediately. If the number of investigational products received 
at a site does not correspond with the number indicated on the packing list, this should be 
confirmed in the IWRS.
5.3.2
Accountability Logs
An accurate record of all supplies received and used at each site should be maintained and 
updated regularly. The use of CELLEX System Procedural Kits will be recorded on the 
Investigational Device Inventory Log. UVADEX (methoxsalen) Sterile Solution use will be 
recorded on the Investigational Drug Log. In the event that study drugs or devices are damaged, 
an account should be made on the appropriate log and in the IWRS system.
At the conclusion of the study, all remaining CELLEX System Procedural Kits must be returned 
to the 
 or destroyed at the site according to the Clinical 
Monitoring Plan. Once all study products have been accounted for and verified by Therakos, Inc.
or its designated agent, unused vials of UVADEX (methoxsalen) Sterile Solution will be 
destroyed.


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6.
TREATING THE PATIENT
6.1 INSTRUMENTS
A CELLEX System must be available for treatment of study patients for the duration of the 
study. Each site must have personnel who are technically competent in performing ECP.
6.1.1
Packaging, Labeling, and Storage of Procedural Kits
CELLEX System Procedural Kits will be supplied by Therakos, Inc. at no cost. CELLEX 
System Procedural Kits should be stored in a secure location, at room temperature. All supplied 
kits are labeled with “Clinical Trial Use Only.”
6.2 UVADEX ADMINISTRATION
Extracorporeal photopheresis will be administered using the CELLEX System and UVADEX 
(methoxsalen) Sterile Solution in the mode of administration recommended by the approved 
labeling for UVADEX (methoxsalen) Sterile Solution, except for the treatment frequency. ECP 
will be administered by trained ECP operators only.
During the ECP process, UVADEX (methoxsalen) Sterile Solution will be injected directly into 
the recirculation bag (each mL of solution contains 20 µg of methoxsalen) of the extracorporeal 
circuit after completion of the buffy coat collection, immediately before initiating 
photoactivation. The dose of UVADEX (methoxsalen) Sterile Solution used to inoculate these 
cells will be calculated according to the CELLEX System Operator’s Manual based on the 
treatment volume collected during the plasma/buffy coat collection process, using the following 
formula:
Treatment Volume, as displayed on the CELLEX System screen, in mL × 0.017 = Dose of 
UVADEX (methoxsalen) Sterile Solution (in mL) required for administration into the 
recirculation bag. Each mL of solution contains 20 µg of methoxsalen.
After the cells are inoculated with UVADEX (methoxsalen) Sterile Solution, the buffy 
coat/plasma suspension is irradiated with ultraviolet A (UVA) light and then re-infused back into 
the patient.
For details on how patients should be treated, including information on minimum hematocrit and 
extracorporeal volume, Principal Investigators should consult the CELLEX System Operator’s 
Manual and 
Appendix D: Fluid Balance Management.
The selection and timing of ECP treatments is based on the Principal Investigator’s assessment 
of patient status such that ECP will be administered according to the stated treatment schedule
(± 2 days). The availability of typed and cross-matched donor PRBCs for transfusion during 
treatment, if needed, should be established prior to the scheduling of ECP treatments.
It is anticipated that most patients will receive ECP treatments in this protocol via a central 
venous catheter. However, Principal Investigators may choose to administer ECP treatments via 
peripheral venous access if clinically prudent.


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6.2.1
Selection of Timing and ECP Treatment in the Study
The selection and timing of ECP treatments is based on the Principal Investigator’s assessment 
of patient status such that ECP will be administered 3 times per week every week for 4 weeks
(Weeks 1-4), followed by 2 times per week every week for 8 weeks (Weeks 5-12).
Patients must be enrolled and receive their first ECP treatment within 1 week (7 days) after being 
diagnosed as having steroid-refractory aGvHD. Patients are expected to receive the stated 
number of treatments per treatment week (7 days) ± 2 days, and a total of no more than 12 ECP 
treatments for the first 28 days. A maximum of 28 and a minimum of 1 ECP treatments will be 
given per patient during the 12-week treatment period.
Week 1 (7 days) begins when the first ECP treatment is received (Day 1 of Week 1). 
Extracorporeal photopheresis treatments given within ± 2 days of the expected treatment week 
will not be considered a protocol deviation.
After completion of the 12-week Treatment Period, patients may continue ECP treatment on 
commercial product at the discretion of the Principal Investigator.
6.2.2
Extracorporeal Photopheresis Stop/Hold Parameters

STOP: If there is evidence of anaphylaxis or life-threatening allergic reaction thought to be 
related to ECP. ECP must be discontinued and cannot be restarted.

STOP: If there is evidence of an urgent or life-threatening medical issue requiring immediate 
treatment. ECP may be restarted, at the discretion of the Principal Investigator, if the event is 
considered to be unrelated to ECP and the patient has been stable for at least 24 hours.

HOLD: If a patient experiences a fever, i.e. a skin temperature of > 101.3°F (38.5°C), that is 
related to infection, the ECP should not be given until 24 hours after the skin temperature has 
decreased to 101.3°F (38.5°C).

HOLD: ECP should not be given within 72 hours of a positive blood culture, unless there is 
clinical suspicion of a contaminant (e.g., staph coagulase negative species) rather than a true 
infection and repeat cultures are negative within 24 hours of the positive sample.

HOLD: ECP should not be given in the setting of sepsis or hemodynamic instability but held 
and rescheduled when the patient has been hemodynamically stable for at least 24 hours.

HOLD: ECP should not be given if the patient has clinically significant bleeding within 12 
hours of a planned ECP treatment.

HOLD: ECP should not be given on the same days as surgical or invasive procedures, 
including colonoscopy. At the discretion of the Principal Investigator, bone marrow biopsy 
and other procedures associated with low risk of bleeding may be performed on the same day 
as ECP.
6.2.3
Extracorporeal Volume
The American Association of Blood Banks’ guidelines set a maximum extracorporeal blood 
volume to be ≤15% of the patient’s Total Blood Volume. A new calculation of Total Blood 
Volume is necessary before each treatment to estimate the safe extracorporeal blood volume that 
may be allowed for the patient undergoing treatment. These calculations should be performed 


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using the current weight and current hematocrit (the latter drawn after the last photopheresis 
treatment and within 48 hours before the next photopheresis treatment).
Maximum extracorporeal blood volume for patients weighing < 30 kg should not exceed 10% of 
the patient’s Total Blood Volume. Patients who do not meet the safe minimal extracorporeal 
volumes listed in 
Appendix D: Fluid Balance Management should only be treated using a 
blood prime procedure. Patients who require but are not candidates for blood priming should not 
be enrolled and/or treated in the study. Please refer to 
Appendix E: Blood Prime Technique
Flow Sheet for a worksheet to be used during the blood prime process and to 
Appendix 
D:
Fluid Balance Management for detailed information on fluid management.
6.2.4
Anticoagulation During ECP
Anticoagulant Citrate Dextrose Formula-A (ACD-A) may be used instead of or in addition to
heparin during ECP at the physician’s discretion according to the patient’s medical needs, 
provided that center-specific guidelines for the use of ACD-A with ECP and trained staff are 
available. Centers using ACD-A must have physician-approved protocols in place for managing 
hypocalcemia, a side effect of ACD-A administration. Protocols should include:

Monitoring of ionized calcium levels.

Determination of maximum RETURN flow rate parameters.

Oral and/or intravenous calcium replacement.
General guidelines for monitoring and treating citrate toxicity are available in 
Appendix 
F:
ACD-A Recommendations for the Therakos CELLEX Photopheresis System; however,
institutional guidelines and the judgment of medical staff must be used to dictate the appropriate 
intervention.
6.3 CORTICOSTEROIDS
6.3.1
Selection and Timing of Corticosteroid Doses in the Study
All patients enrolled in this trial will have received corticosteroids for the treatment of aGvHD.
After entering the treatment period on study, it is suggested that the steroid dose be decreased by
12.5% to 25% of the dose after the initiation of ECP therapy if a sustained positive response to
aGvHD has been observed for at least 3 consecutive days. The suggested goal is to have 
decreased the starting steroid dose by at least 50% at 4 weeks after initiation of ECP.
For patients taking a steroid other than methylprednisolone for the treatment of aGvHD, the daily 
dose should be converted to methylprednisolone equivalents at screening (to ensure the patient 
qualifies). Note, the steroid type and dose should be entered into the eCRF without this 
conversion.
6.4 ACUTE GVHD PROPHYLAXIS
Patients will be allowed to continue standard aGvHD prophylaxis regimens (e.g., cyclosporine, 
tacrolimus, methotrexate, and mycophenolate mofetil), without the addition of new therapies.
Patients will be allowed to discontinue prophylaxis regimens for reasons of toxicity and will also 
be allowed to switch to another prophylaxis medication within the same class (e.g., the 
calcineurin inhibitors cyclosporine and tacrolimus) for reasons of toxicity.


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6.5 CONCOMITANT MEDICATIONS
Any medication the patient takes, including herbal and other nontraditional remedies, during the 
16-week study is considered a concomitant medication. All concomitant medications must be 
recorded in the eCRF. The following information must be recorded in the eCRF for each 
concomitant medication: generic name, route of administration, start date, stop date, dosage
(average daily dose is acceptable), and indication. Any changes in the dosage or regimen of a 
concomitant medication must be recorded in the eCRF.
At Screening, medications that patients have taken during the last 30 days, including current 
medications, will be recorded. Prior administration of immunosuppressive agents to treat aGvHD 
other than steroids is not permitted. The prior use of non-absorbable corticosteroids is permitted. 
All concomitant medications taken by patients during the study to Week 16, including those 
medications taken between visits, will be recorded on the Prior and Concomitant Medication 
Report Form of the eCRF.
6.5.1
Prohibited Concomitant Medications
Prohibited concomitant medications include those used for the treatment of aGvHD (with the 
exception of steroids), medications that are not considered part of a standard prophylactic 
regimen, and systemic immunosuppressive or biologic therapies used for the treatment of other 
medical conditions.
6.6 EARLY CESSATION OF STUDY PARTICIPATION
If the Principal Investigator, the Sponsor, or the Medical Monitor becomes aware of conditions 
that suggest a risk to safe participation in the study, study treatment will be discontinued. If the 
Principal Investigator, based on his/her medical judgment, determines there is a risk to the 
patient with continued participation in the study, the patient will be withdrawn. The study may 
also be terminated early for all patients at the Sponsor’s discretion. Conditions that may warrant 
termination include, but are not limited to:

The discovery of an unexpected, significant, or unacceptable risk to the patients enrolled 
in the study.

Failure to enroll patients at an acceptable rate.

A decision on the part of the Sponsor to suspend or discontinue development of the drug.

Recommendation by the Data Safety Monitoring Board (DSMB).
6.6.1
Early Cessation of Study Treatment
Patients may voluntarily stop receiving therapy at any time. The patient’s legal guardian/legally 
authorized representative may choose to stop a patient’s therapy at any time.
If a patient voluntarily ceases to receive therapy, the primary reason must be requested and, if 
provided, will be recorded on the Study Termination page of the eCRF.
The Principal Investigator and/or the Sponsor may also judge that early cessation of treatment is 
warranted for any one of the following reasons:

Occurrence of AEs that pose a risk to safe participation.


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
Abnormal laboratory value(s) that pose a risk to safe participation.

Abnormal test procedure result(s) that pose a risk to safe participation.

Unsatisfactory therapeutic effect.

Condition no longer requires treatment.

Significant protocol deviation.

Patient non-compliance with protocol requirements.
Unless a patient/legal guardian/legally authorized representative withdraws study consent, 
patients will continue to be followed as per the trial protocol and clinical assessment schedule to 
ensure that full, intent-to-treat follow-up data are obtained.
For patients who are lost to follow-up, the Principal Investigator should show due diligence by 
documenting in the source documents steps taken to contact the patient (e.g., dates of telephone 
calls, emails).
Patients who voluntarily cease to receive treatment early will not be replaced. Patients will be 
replaced if they are enrolled in the trial but are not treated.
If a patient has received any ECP treatments and is administered a second-line therapy other than 
ECP for the treatment of aGvHD, or discontinues study treatment, that patient will be considered 
a nonresponder and may not be replaced.


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7.
STUDY CONDUCT
7.1 SCHEDULE OF ASSESSMENTS
Table 1. Schedule of Assessments
Assessments and Procedures
Screening
Treatment Period, weeks (+/- 2 days)
Follow-
Up 
Period, 
weeks
Early Study 
Termination
1
2
3
4 (Day 28)
Primary 
Endpoint
5
6
7
8 (Day 56)
Secondary 
Endpoint
9
10
11
12 (Day 84) 
Secondary 
Endpoint
16
26
Informed consent/assent form
X
Inclusion/exclusion criteria
X
Focused medical history
X
Transplant history
X
Corticosteroid dosing
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Complete physical examination
X
X
X
X
X
X
Targeted physical examination
X
X
X
X
X
X
X
X
X
Urine Pregnancy test a
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital signs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Lansky Performance Status
X
X
X
X
X
X
Local laboratory analyses b
X
X
X
X
X
X
X
X
X
X h
X
X
X
X
X
Assess aGvHD status c
X
X
X
X
X
X
X
X
X
X
X
X
Xi
X
X
Baseline total bilirubin level and aGvHD 
assessment d
X
Total bilirubin level and primary endpoint 
aGvHD status assessment e
X
Total bilirubin level and secondary 
endpoint aGvHD status assessment f
X
X
Number of ECP treatments g
3
3
3
3
2
2
2
2
2
2
2
2


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Concomitant medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Nonrelapse mortality
X
X
X
X
X
X
X
X
X
X
X
X
X
Survival
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Early study termination j
X
a. If the result of the urine test is positive, blood must be drawn for a serum human chorionic gonadotropin (HCG) level and analyzed locally. A serum test may be 
performed in place of the urine test.
b At a minimum, a bilirubin level should be checked before the first ECP treatment of each week to assist in assessing aGvHD status of the previous week. Platelets and 
total WBC count should be checked before each scheduled ECP treatment as clinically indicated to ensure that they meet pre-ECP safety parameters. Hematocrit 
should be checked according to the CELLEX System Operator’s Manual. Ionized calcium may be checked, at the discretion of the Principal Investigator. A new 
calculation of Total Blood Volume is necessary before each treatment to estimate the safe extracorporeal blood volume that may be allowed for the patient undergoing 
treatment. These calculations should be performed using the current weight (recorded at the first visit of the week) and current hematocrit (drawn after the last 
photopheresis treatment and within 48 hours before the next photopheresis treatment).
c After the baseline aGvHD assessment at the beginning of Week 1, aGvHD assessments should be performed within the weekly treatment window (± 2 days) after the 
last ECP treatment of each treatment week.
d A baseline aGvHD assessment, including blood sampling for total bilirubin should be performed before the first ECP treatment of Week 1.
e The assessment of aGvHD for the primary endpoint must occur at Day 28 (± 2 days) and must include a total bilirubin level.
f The assessment of aGvHD for the secondary endpoint must occur at Days 56 and 84 (± 2 days) and must include a total bilirubin level.
g Patients should be told emphatically to wear UVA-absorbing, wrap-around sunglasses and to cover exposed skin or use a sunblock (SPF 15 or higher) for the 24 hour 
period following treatment with methoxsalen, whether exposed to direct or indirect sunlight in the open or through a glass window.
h These laboratory assessments should be performed monthly, before the first ECP treatment of the week at Weeks 5 and 9:
• CBC with differential (WBC, platelets, hemoglobin, hematocrit, neutrophils, lymphocytes, basophils, eosinophils, and monocytes); absolute neutrophil count.
• Electrolyte panel (sodium, potassium, chloride, bicarbonate, BUN, creatinine, and glucose), BUN/creatinine ratio, calcium, phosphorous, and magnesium.
• AST, ALT, GGT, total bilirubin, direct bilirubin, indirect bilirubin, alkaline phosphatase, and lactate dehydrogenase.
i The assessment of aGvHD must be +/- 2 days of the endpoint assessments
jEarly study termination applies to only to those patients who discontinue ECP prior to 12 weeks of treatment and do not remain on the study.


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7.2 STUDY ASSESSMENTS AND PROCEDURES
7.2.1
Screening Period
The Screening Period begins once a patient signs the ICF, and will consist of at least one 
screening visit. If a patient does not meet the eligibility criteria, the patient will be considered a 
“screening failure” and will be discharged from the study. A small set of eCRF pages (i.e., a 
“Screening Failure Packet”) will be completed for those patients who are not eligible for this 
study.
Informed Consent/Assent
Patient consent/assent must be obtained before a patient’s participation in ANY study-
related procedures. A copy of the signed and dated ICF will be given to the patient, legal 
guardian or legally authorized representative. The original signed and dated ICF will be 
maintained at the study site. The date(s) of signed consent must be recorded in the eCRF.
For more information, see Section 10.7 Informed Consent/Assent.
Inclusion/Exclusion Criteria
The inclusion and exclusion criteria MUST be assessed for patient eligibility at screening
and recorded on the Inclusion Criteria and Exclusion Criteria Forms of the eCRF.
Patients who do not meet the inclusion and exclusion criteria will be considered 
“screening failures” and will be discharged from the study.
Focused Medical History
The medical history should include any medical condition that the patient recalls or that 
is part of the medical record that is relevant to the condition under study. Any condition 
present at the onset of the study should be noted. Any condition NOT listed on the 
Medical History and Review of Symptoms Form of the eCRF will be considered an AE if 
it occurs during the course of the study (i.e., any time after the patient has signed the 
ICF). Any condition that increases in frequency or worsens as compared to the Medical 
History and Review of Symptoms Form of the eCRF will also be considered an AE.
Transplant History
Background information about a patient’s transplant (e.g., date of transplant, type of bone 
marrow transplant, underlying condition [malignant or non-malignant]) will be recorded 
on the Transplant History Form of the eCRF.
Corticosteroid Dosing History
The patient’s steroid dosing for the treatment of aGvHD for the 30 days prior to 
screening must be documented on the Corticosteroid Dosage Form of the eCRF. Dosages 
will be recorded as given in the eCRF, but the methylprednisolone equivalent dosage 
must be assessed to ensure compliance to the 2.0 mg/kg dosage required for inclusion 
into the study.
Physical Examination
A qualified health-care professional will give each patient a complete physical 
examination in order to capture general health by organ system. Patient height and weight 
will also be recorded.


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Pregnancy Test
At the screening visit, a urine dipstick pregnancy test will be performed through local 
laboratory for all females of childbearing potential, defined as those who have reached 
the onset of menarche or 8 years of age, whichever comes first. A serum test may also be 
performed in place of a urine dipstick. If the urine dipstick result is positive, blood must 
be drawn for a serum human chorionic gonadotropin (HCG) level and analyzed locally. A 
positive serum HCG result will prohibit the patient from enrollment into the study.
Vital Signs
Diastolic and systolic blood pressure, pulse rate, respiratory rate, and temperature will be 
taken at the screening visit.
Lansky Performance Status
A qualified health-care professional (physician, physician’s assistant, nurse practitioner) 
will evaluate the patient’s Health Performance Status using the Lansky Performance 
Status Scale ( Appendix C: Lansky Scale).
Local Laboratory Analyses
Laboratory assessments (including pregnancy tests) will be performed through a local 
laboratory. The data obtained should be entered into the eCRF.
Clinically significant laboratory abnormalities should be recorded as AEs according to 
the Principal Investigator’s judgment. Blood samples may be obtained through standard 
venipuncture technique or through a venous access catheter, according to institutional 
guidelines.
At the screening visit, a blood sample will be collected for the purpose of assessing 
eligibility and processed for:

CBC with differential (WBC, platelets, hemoglobin, hematocrit, neutrophils, 
lymphocytes, basophils, eosinophils, and monocytes) and an absolute neutrophil 
count.

Electrolyte panel (sodium, potassium, chloride, bicarbonate, BUN, creatinine, and
glucose), blood urea nitrogen (BUN)/creatinine ratio, calcium, phosphorus, and 
magnesium.

AST, ALT, gamma-glutamyltransferase (GGT), total bilirubin, direct bilirubin, 
indirect bilirubin, alkaline phosphatase, and lactate dehydrogenase.

Coagulation panel (PT/PTT, INR).
If any of these samples were drawn within the preceding 72 hours and the results are 
available, they do not have to be re-drawn and may be used to assess eligibility.
A total bilirubin level will also be assessed before the first ECP treatment of the study at 
Week 1, and this value will be used for the baseline assessment of a patient’s aGvHD 
status.
Please refer to Section 4.1 and Section 4.2 for the values of specific local laboratory 
results that would exclude patients from this study.


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Assessment of aGvHD Status
Patients will be evaluated to confirm that they have steroid-refractory aGvHD grade B-D.
Steroid-refractory is defined as progressive aGvHD after 3 days of or no response after 5
days of starting systemic steroids at a dose of 1.0 mg/kg/day methylprednisolone or 
equivalent. Patients with grade A are not eligible for this study. Grade D organ 
involvement will be limited to skin and liver.
Patients will be evaluated by the treating physician for the presence or absence of aGvHD 
manifestations of the skin, liver, and gut. Source data will be collected for each patient 
and entered into the eCRF, and a scoring algorithm will later be applied to calculate the 
grade of aGvHD using the modified IBMTR Severity Index and the modified Glucksberg 
criteria.
Skin aGvHD Staging
Only active rash (erythema) is considered in body surface area (BSA) calculations.
Hyper- (e.g., brown/tanned rash) or hypopigmentation representing post-inflammatory 
changes are not included in the BSA assessment. Skin involvement will be reported as % 
BSA using the Rule of Nines (
Appendix 
G:
Percent 
Body 
Surface 
Area 
Assessment) [Waslen, 1986] and/or presence of bullae.
Other common etiologies for skin symptoms include drug rash, conditioning regimen 
toxicity, infection, and cytokine storm/engraftment syndrome.
Liver aGvHD Staging
Bilirubin will be assessed on the day of the first ECP treatment, and this value will be 
used for the baseline assessment of a patient’s aGvHD status. Total bilirubin (not 
direct/conjugated bilirubin) will be used for staging.
Other common etiologies for liver symptoms include drug toxicity, conditioning regimen 
toxicity, veno-occlusive disease, total parenteral nutrition, cholestasis, and infection.
Gut aGvHD Staging
Stool output will be reported as volumes for all inpatients and as episodes (frequency and 
consistency) for all outpatients. Patients weighing ≥ 50 kg will be graded using total stool 
volume per day (mL/day), while patients weighing < 50 kg will be evaluated for gut 
symptoms according to mL/kg/day, as a function of body weight.
For patients who weigh < 50 kg, every effort should be made to collect stool volumes as 
a daily average in milliliters over a 3-day period. For diarrhea volumes, report liquid stool 
volume in the following order:
1. Average of 3 consecutive days, if available.
2. Otherwise, the 3 days closest to each other within 1 week.
3. Otherwise, the average of 2 consecutive days.
4. Otherwise, the maximum volume from the isolated day(s) available.
Formed or mostly formed stools should not be quantified or counted in the estimation of 
liquid stool volume. It will be noted on the source document, if urinary mixing is present.


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For inpatients in diapers, the volume will be calculated from the weight of the diaper 
before and after use. For outpatients, Patient Stool Volume records will be provided, 
according to usual site practice, along with instructions for collection and measurements.
Stool volume collection should be done without regard to the ECP treatment schedule.
When diarrhea is reported as episodes instead of individual volumes, episodes of non-
quantified liquid stool will be counted as 200 mL each for patients ≥ 50 kg and 4 mL/kg 
for patients < 50 kg.
When gross blood is present:

Bloody diarrhea is staged as 4, even if low volume.

Blood-streaked low volume (< 500 mL/day or < 10 mL/kg/day) stools (as can be seen 
with bleeding hemorrhoids, for example) are staged as 0.
For stage D or stage 4 gut involvement, severe pain is defined as:

Pain that requires the start of narcotic use, or an increase in on-going narcotic use 
PLUS.

Pain that significantly impacts performance status, as determined by the treating 
physician.
Other common etiologies for GI symptoms include drug toxicity, conditioning regimen 
toxicity, and infection.
Upper GI aGvHD Staging
For patients with isolated upper GI symptoms, pre-Screening biopsy results will be used 
to confirm the diagnosis of aGvHD. The determination that nausea, vomiting and/or 
anorexia are persistent is based on clinical judgment. As a general rule, nausea lasting 
fewer than 3 days, fewer than 2 vomiting episodes per day for at least 2 days, and 
anorexia without weight loss should not be considered persistent.
Other common etiologies for upper GI symptoms include drug toxicity, conditioning 
regimen toxicity, infection, and total parenteral nutrition.
Concomitant Medications
Medications that patients have taken during the last 30 days, including current 
medications, will be recorded. Medications for the treatment of aGvHD will be captured 
individually on a separate eCRF page(s). Other medications that patients are taking at 
screening will be captured on the Concomitant Medication Form (Section 6.5).
Concomitant medications for screening failures will not be recorded on the eCRF.
Adverse Events
Patients will be asked about AEs that may have occurred after the patient signed and 
dated the ICF. Each patient will be asked about AEs using the non-specific question, 
“How have you been since your last visit?” Any AEs elicited by this question will be 
recorded on the Adverse Event Report Form of the eCRF, as well as any AEs 
spontaneously volunteered by the patient or observed by the study staff.


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7.2.2
Treatment Period
The following assessments and procedures should be performed during the Treatment Period.
Not all of the assessments and procedures listed below are to be performed at every scheduled 
visit (e.g., selected assessments are performed at Weeks 4 and 8). For the timing of when to 
administer individual assessments and procedures, see the Schedule of Assessments in Table 1, 
Section 7.1. Unless otherwise indicated, assessments should be performed before the first ECP 
treatment of the week.
Corticosteroid Dose Record
The patient’s steroid dosing for the treatment of aGvHD must be documented on the 
Corticosteroid Dosage Form of the eCRF. Dosages should be recorded without 
modification (although average daily dose is acceptable).
Methylprednisolone 
equivalence will be calculated later.
Physical Examination
A qualified health-care professional will give each patient a complete physical 
examination to document any changes in the general health of the patient by organ 
system. The complete physical examinations will be performed after all other 
assessments included in Weeks 4, 8, 12 and 16 have been completed. Targeted physical 
examinations will be performed after all other assessments included in Weeks 1, 2, 3, 5, 
6, 7, 9, 10, and 11 have been completed. Patient height and weight will also be recorded 
each week. In those weeks when patients are reporting to the study site multiple times, 
height and body weight need only be recorded at the first visit.
A new calculation of Total Blood Volume is necessary before each treatment to estimate 
the safe extracorporeal blood volume that may be allowed for the patient undergoing 
treatment. These calculations should be performed using the current weight (recorded at 
the first visit of the week) and current hematocrit (drawn after the last photopheresis 
treatment and within 48 hours before the next photopheresis treatment).
Pregnancy Test
A urine dipstick pregnancy test will be performed at screening and weekly for all females 
of childbearing potential (defined as those who have reached the onset of menarche or 8 
years of age, whichever comes first) on the day of the first scheduled treatment of the 
week, before the start of the day’s therapy. A serum test may also be performed in place 
of a urine dipstick. If the urine dipstick result is positive, blood must be drawn for a
serum HCG level and analyzed locally before any ECP treatment. A positive serum HCG 
result necessitates automatic withdrawal of the patient from active treatment, and no 
further ECP treatmens can be performed.


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Vital Signs
Vital signs (diastolic and systolic blood pressures, pulse rate, respiratory rate, and 
temperature) will be taken before and at the end of each ECP treatment.
Lansky Performance Status
A qualified health-care professional (physician, physician’s assistant, nurse practitioner) 
will evaluate the patient’s Health Performance Status using the Lansky Performance 
Status Scale ( Appendix C: Lansky Scale) after 4, 8 and 12 weeks of ECP treatment.
Local Laboratory Analyses
Laboratory assessments (including pregnancy tests) will be performed through a local 
laboratory. The data obtained should be entered into the eCRF.
Clinically significant laboratory abnormalities should be recorded as AEs according to 
the Principal Investigator’s judgment. Blood samples may be obtained through standard 
venipuncture technique or through a venous access catheter, according to institutional 
guidelines.
During the Treatment Period, blood will be collected at the indicated times and processed 
for the following:
Before the First Scheduled ECP Treatment of the Study at Week 1

Total bilirubin, to be used for the baseline aGvHD status assessment.
Before Each Scheduled ECP Treatment (Weeks 1-12)

Hematocrit, as indicated in the CELLEX System Operator’s Manual.

Platelets, as clinically indicated.

WBC count, as clinically indicated.

Ionized calcium, as clinically indicated and/or according to institiutional guidelines 
(particularly for patients whose ECP treatments include the use of ACD-A as an 
anticoagulant).

Total bilirubin, to be used for the prior weekly assessment of aGvHD status
o
Levels drawn before the first ECP treatment of Week 5 and Week 9
should be used for the Primary and Secondary Enpoint aGvHD status 
assessments, respectively. On Days 28 and 56, the bilirubin assessments 
must be done within ± 2 days.
Monthly Before the First ECP Treatment of the Week at Weeks 5 and 9

CBC with differential (WBC, platelets, hemaglobin, hematocrit, neutrophils, 
lymphocytes, basophils, eosinophils, and monocytes) and an absolute neutrophil 
count.

Electrolyte panel (sodium, potassium, chloride, bicarbonate, BUN, creatinine, and 


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glucose), BUN/creatinine ratio, calcium, phosphorous, and magnesium.

AST, ALT, GGT, total bilirubin, direct bilirubin, indirect bilirubin, alkaline 
phosphatase, and lactate dehydrogenase.
During ECP Treatments (Weeks 1-12)

Laboratory analyses needed to assess patients should be drawn at the discretion of the 
Principle Investigator.
At Screening and Weekly (Weeks 1-12) for All Females of Childbearing Potential

Urine dipstick pregnancy testing (for females age 8 or those who have reached the 
onset of menarche, whichever comes first). A serum test may also be performed in 
place of a urine dipstick.

Serum HCG level immediately after any positive urine pregnancy test.
Any laboratory test results that are needed to manage aGvHD or other medical conditions 
should be drawn outside  this schedule as clinically indicated.
Assessment of aGvHD Status
All patients will be evaluated for a response in their aGvHD manifestations at least once 
each week through Week 12 (or the visit at which the patient ceases to receive treatment, 
if before Week 12). The assessment of aGvHD status should occur after the last ECP 
treatment of the week, with the exception of bilirubin levels, which will be tested prior to 
the first ECP treatment of the following week.
Patients will be evaluated by the treating physician for the presence or absence of aGvHD 
manifestations of the skin, liver, and gut. Source data will be collected for each patient 
and entered into the eCRF, and a scoring algorithm will be applied to calculate the grade 
of aGvHD using the modified IBMTR Severity Index and the modified Glucksberg 
criteria. Acute GvHD status will be assessed at baseline (at Week 1 before the first ECP 
treatment of the study) and once a week, after the last ECP treatment of each week 
(Weeks 1-12).
Skin aGvHD Staging
Only active rash (erythema) is considered in body surface area (BSA) calculations.
Hyper- (e.g., brown/tanned rash) or hypopigmentation representing post-inflammatory 
changes are not included in the BSA assessment. Skin involvement will be reported as 
% BSA using the Rule of Nines (
Appendix 
G:
Percent 
Body 
Surface 
Area
Assessment) and/or presence of bullae.
Other common etiologies for skin symptoms include drug rash, conditioning regimen 
toxicity, infection, and cytokine storm/engraftment syndrome.
Liver aGvHD Staging
Bilirubin will be determined from a single blood sample drawn before the first treatment 
of the following week. Total bilirubin (not direct/conjugated) will be used for staging.
Other common etiologies for liver symptoms include drug toxicity, conditioning regimen 
toxicity, veno-occlusive disease, total parenteral nutrition, cholestasis, and infection.


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Gut aGvHD Staging
Stool output will be reported as volumes for all inpatients and as episodes (frequency and 
consistency) for all outpatients. Patients weighing ≥ 50 kg will be graded using total stool 
volume per day (mL/day), while patients weighing < 50 kg will be evaluated for gut 
symptoms according to mL/kg/day, as a function of body weight.
For patients who weigh < 50 kg, every effort should be made to collect stool volumes as 
a daily average in milliliters over a 3-day period and must be completed before the first 
ECP treatment of the next treatment week. For diarrhea volumes, report liquid stool 
volume in the following order:
1. Average of 3 consecutive days, if available.
2. Otherwise, the 3 days closest to each other within 1 week.
3. Otherwise, the average of 2 consecutive days.
4. Otherwise, the maximum volume from the isolated day(s) available.
Formed or mostly formed stools should not be quantified or counted in the estimation of 
liquid stool volume. It will be noted on the source documents, if urinary mixing is 
present. For patients in diapers, the volume will be calculated from the weight of the 
diaper before and after use. For outpatients, Patient Stool Volume Records will be 
provided, according to usual site practice, along with instructions for collection and 
measurements. Stool volume collection should be done without regard to the ECP 
treatment schedule.
When diarrhea is reported as episodes instead of individual volumes, episodes of non-
quantified liquid stool will be counted as 200 mL each for patients ≥ 50 kg and 4 mL/kg 
for patients < 50 kg.
When gross blood is present:

Bloody diarrhea is staged as 4, even if low volume.

Blood-streaked low volume (< 500 mL/day or < 10 mL/kg/day) stools (as can be seen 
with bleeding hemorrhoids, for example) are staged as 0.
For stage D or stage 4 gut involvement, severe pain is defined as:

Pain that requires the start of narcotic use, or an increase in on-going narcotic use 
PLUS.

Pain that significantly impacts performance status, as determined by the treating 
physician.
Other common etiologies for GI symptoms include drug toxicity, conditioning regimen 
toxicity, and infection.


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Upper GI aGvHD Staging
The determination that nausea, vomiting and/or anorexia are persistent is based on 
clinical judgment. As a general rule, nausea lasting fewer than 3 days, fewer than 2 
vomiting episodes per day for at least 2 days, and anorexia without weight loss should not 
be considered persistent.
Other common etiologies for upper GI symptoms include drug toxicity, conditioning 
regimen toxicity, infection, and total parenteral nutrition.
ECP Treatments
Patients should be scheduled to receive the first ECP treatment as soon as possible upon 
confirmation of eligibility. Patients must be enrolled and receive their first ECP treatment 
within 1 week (7 days) after being diagnosed as having steroid-refractory aGvHD. Week 
1 (7 days) begins on the day the first ECP treatment is received (Day 1 of Week 1). The 
availability of typed and cross-matched donor PRBCs for transfusion during treatment, if 
needed, should be established prior to the scheduling of ECP treatments.
Prior to an ECP treatment, each patient will be assessed by a qualified health-care 
professional to verify that the patient is acceptable for ECP treatment. This assessment 
will include vital signs (diastolic and systolic blood pressures, pulse rate, respiratory rate 
and temperature) that will be taken before and at the end of each ECP treatment. Local 
laboratory analyses will be drawn before each ECP treatment, as specified above. If a 
patient’s WBC count is < 1.0 × 109/L or platelet count is < 20.0 × 109/L, that patient 
should NOT be treated with ECP until the WBC count is ≥1.0 × 109/L and platelet count 
is ≥20.0 × 109/L (platelet transfusions ARE permitted). This stipulation may require that 
patients receive one or more transfusions before the first or subsequent ECP treatments.
Principal Investigators must use a coagulation-screening test of their choice in verifying a 
patient as acceptable for ECP treatment. The threshold value of the coagulation-screening 
test used to allow a patient to receive ECP treatment will be based upon a Principal
Investigator’s own clinical judgment. Patient monitoring during ECP treatment will be 
done according to institutional protocols in alignment with the CELLEX System 
Operator’s Manual. Ionized calcium, if applicable, will be assessed before and during 
ECP treatments at the discretion of the Principal Investigator and according to 
institutional protocols.
For more information on ECP treatments, see the CELLEX System Operator’s Manual.
Scheduling
The study coordinator will arrange the scheduling of ECP treatments according to the 
following schedule:

Weeks 1-4: 3 treatments per week.

Weeks 5-12: 2 treatments per week.
Patients are expected to receive the stated number of treatments per treatment week 
(7 days) ± 2 days, and a total of no more than 12 ECP treatments for the first 28 days.


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Extracorporeal photopheresis treatments given within ± 2 days of the expected treatment 
week will not be considered a protocol deviation.
Week 1 (7 days) begins when the first ECP treatment is received (Day 1 of Week 1). The 
availability of typed and cross-matched donor PRBCs for transfusion during treatment, if 
needed, should be established prior to the scheduling of ECP treatments.
After completion of the 12-week Treatment Period, patients may continue ECP treatment 
on commercial product at the discretion of the Principal Investigator.
Special Warnings and Precautions for Use
Patients should be explicitly instructed to wear UVA-absorbing, wrap-around sunglasses 
and cover exposed skin or use a sunblock (SPF 15 or higher) for the 24 hour period 
following treatment with methoxsalen, whether exposed to direct sunlight or indirect 
sunlight through a glass window.
Primary and Secondary aGvHD Endpoint Assessments (Weeks 4, 8, and 12)
Assessments of aGvHD status (including total bilirubin, corticosteroid dosing, Lansky 
Performance Status, etc.) for the purpose of the primary and secondary endpoint analyses 
should be performed at Days 28 (±2), 56 (±2) and 84 (±2), respectively.
Concomitant Medications
All concomitant medications taken by patients during the Treatment Period, including 
those medications taken between visits, will be recorded on the Prior and Concomitant 
Medication Report Form of the eCRF. Concomitant medications should be recorded on a 
weekly basis.
Adverse Events
Patients will be asked about AEs that may have occurred after the patient signed and 
dated the ICF. Each patient will be asked about AEs using the non-specific question, 
“How have you been since your last visit?” Any AEs elicited by this question will be 
recorded on the Adverse Event Report Form of the eCRF, as well as any AEs 
spontaneously volunteered by the patient or observed by the study staff.
Nonrelapse Mortality
Nonrelapse mortality is defined as death due to any cause, with death due to relapse as a 
competing risk [Das-Gupta et al., 2014b].
Survival
Recipient Death Information must be entered into the eCRF within 24 hours of 
knowledge of a patient’s death. Once the cause of death is determined, the information 
must be recorded in the eCRF.
7.2.3
Follow-up Period
The following assessments and procedures should be performed during the Follow-up Period.
Not all of the assessments and procedures listed below are to be performed at every scheduled 


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visit. For the timing of when to administer individual assessments and procedures, see the 
Schedule of Assessments in Table 1, Section 7.1.
Corticosteroid Dose Record
The patient’s steroid dosing for the treatment of aGvHD must be documented on the 
Corticosteroid Dosage Form of the eCRF. Dosages will be recorded as is (average daily 
dose is acceptable). Methylprednisolone equivalence will be calculated later.
Physical Examination
A qualified health-care professional will give each patient a complete physical 
examination to document any changes in the general health of the patient by organ 
system. Patient height and weight will also be recorded.
Local Laboratory Analyses
Laboratory assessments will be performed through a local laboratory. Clinically 
significant laboratory abnormalities should be recorded as AEs according to the Principal 
Investigator’s judgment. Blood samples may be obtained through standard venipuncture 
technique or through a venous access catheter, according to institutional guidelines.
Blood will be collected and processed for the following:

Total bilirubin, to be used for the weekly assessment of aGvHD status.

CBC with differential (WBC, platelets, hemaglobin, hematocrit, neutrophils, 
lymphocytes, basophils, eosinophils, and monocytes) and an absolute neutrophil 
count.

Electrolyte panel (sodium, potassium, chloride, bicarbonate, BUN, creatinine, and 
glucose), BUN/creatinine ratio, calcium, phosphorous, and magnesium.

AST, ALT, GGT, total bilirubin, direct bilirubin, indirect bilirubin, alkaline 
phosphatase, and lactate dehydrogenase.
Any laboratory test results that are needed to manage aGvHD or other medical conditions 
should be drawn outside  this schedule as clinically indicated.
Assessment of aGvHD Status
Patients will be evaluated by the treating physician for the presence or absence of aGvHD 
manifestations of the skin, liver, and gut. Source data will be collected for each patient 
and entered into the eCRF, and a scoring algorithm will be applied to calculate the grade 
of aGvHD using the modified IBMTR Severity Index and the modified Glucksberg 
criteria.


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Skin aGvHD Staging
Only active rash (erythema) is considered in body surface area (BSA) calculations.
Hyper- (e.g., brown/tanned rash) or hypopigmentation representing post-inflammatory 
changes are not included in the BSA assessment. Skin involvement will be reported as 
% BSA using the Rule of Nines (
Appendix 
G:
Percent 
Body 
Surface 
Area 
Assessment) and/or presence of bullae.
Other common etiologies for skin symptoms include drug rash, conditioning regimen 
toxicity, infection, and cytokine storm/engraftment syndrome.
Liver aGvHD Staging
Bilirubin will be determined from a single blood sample. Total bilirubin (not 
direct/conjugated) will be used for staging.
Other common etiologies for liver symptoms include drug toxicity, conditioning regimen 
toxicity, veno-occlusive disease, total parenteral nutrition, cholestasis, and infection.
Gut aGvHD Staging
Stool output will be reported as volumes for all inpatients and as episodes (frequency and 
consistency) for all outpatients. Patients weighing ≥ 50 kg will be graded using total stool 
volume per day (mL/day), while patients weighing < 50 kg will be evaluated for gut 
symptoms according to mL/kg/day, as a function of body weight.
For patients who weigh < 50 kg, every effort should be made to collect stool volumes as 
a daily average in milliliters over a 3-day period. For diarrhea volumes, report liquid stool 
volume in the following order:
1. Average of 3 consecutive days, if available.
2. Otherwise, the 3 days closest to each other within 1 week.
3. Otherwise, the average of 2 consecutive days.
4. Otherwise, the maximum volume from the isolated day(s) available.
Formed or mostly formed stools should not be quantified or counted in the estimation of 
liquid stool volume. It will be noted on the source document, if urinary mixing is present.
For patients in diapers, the volume will be calculated from the weight of the diaper before 
and after use. For outpatients, Patient Stool Volume Records will be provided, according 
to usual site practice, along with instructions for collection and measurements. Stool 
volume collection should be done without regard to the ECP treatment schedule.
When diarrhea is reported as episodes instead of individual volumes, episodes of non-
quantified liquid stool will be counted as 200 mL each for patients ≥ 50 kg and 4 mL/kg 
for patients < 50 kg.
When gross blood is present:

Bloody diarrhea is staged as 4, even if low volume.

Blood-streaked low volume (< 500 mL/day or < 10 mL/kg/day) stools (as can be seen 
with bleeding hemorrhoids, for example) are staged as 0.


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For stage D or stage 4 gut involvement, severe pain is defined as:

Pain that requires the start of narcotic use, or an increase in on-going narcotic use 
PLUS.

Pain that significantly impacts performance status, as determined by the treating 
physician.
Other common etiologies for GI symptoms include drug toxicity, conditioning regimen 
toxicity, and infection.
Upper GI aGvHD Staging
The determination that nausea, vomiting and/or anorexia are persistent is based on 
clinical judgment. As a general rule, nausea lasting fewer than 3 days, fewer than 2 
vomiting episodes per day for at least 2 days, and anorexia without weight loss should not 
be considered persistent.
Other common etiologies for upper GI symptoms include drug toxicity, conditioning 
regimen toxicity, infection, and total parenteral nutrition.
Concomitant Medications
All concomitant medications taken by patients, including those medications taken 
between visits, will be recorded on the Prior and Concomitant Medication Report Form 
of the eCRF.
Adverse Events
Patients will be asked about AEs that may have occurred after the patient signed and 
dated the ICF. Each patient will be asked about AEs using the non-specific question, 
“How have you been since your last visit?” Any AEs elicited by this question will be 
recorded on the Adverse Event Report Form of the eCRF, as well as any AEs 
spontaneously volunteered by the patient or observed by the study staff.
Nonrelapse Mortality
Nonrelapse mortality is defined as death due to any cause, with death due to relapse as a 
competing risk [Das-Gupta et al., 2014b].
Survival
Recipient Death Information must be entered into the eCRF within 24 hours of 
knowledge a patient’s death. Once the cause of death is determined, the information must 
be recorded in the eCRF. Passive follow-up (chart review) will be performed to assess 
survival at Week 26.
7.2.4
Early Study Termination Visit
End of study assessments (Schedule of Assessments in Table 1, Section 7.1) will be completed 
for those patients who discontinue ECP, prior to completing 12 weeks of treatment, and will not 
remain in the study. The Early Study Termination page of the eCRF must be completed for these 
patients, with the reason for withdrawal from the study. For those patients who terminate early, 
every effort should be made to perform the early termination assessments.


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8.
SAFETY PARAMETERS
8.1 ADVERSE EVENTS
8.1.1
Collection of Adverse Events
It is the responsibility of the Principal Investigator to collect all AEs (both serious and 
nonserious) derived by spontaneous, unsolicited reports of patients, by observation, and by 
routine open questionings (e.g., “How have you felt since I last saw you?”).
8.1.2
Definitions
An AE is any untoward medical occurrence that occurs in a patient or clinical investigation 
patient administered a pharmaceutical product or an investigational medicinal product, and does 
not necessarily have to have a causal relationship with this treatment. An AE can therefore be 
any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of an investigational product, whether or not 
considered related to the product. Adverse events will be graded according to the Common 
Terminology Criteria for Adverse Events (CTCAE), version 4.0 and will be coded using 
MedDRA based on the verbatim term collected in the eCRF.
All AEs, including intercurrent illnesses, occurring during the study will be documented in the 
eCRF. Underlying disease, hospitalization for the study purpose, and abnormal laboratory results 
associated with an underlying disease will not be considered AEs. Relapse of underlying 
malignancy will not be considered an AE or serious AE (SAE) but will be captured and analyzed 
separately. Underlying disease will not be considered an AE unless it meets any of the 
seriousness criteria—in particular, hospitalization and deaths. Concomitant illnesses that existed 
before entry into the study will not be considered AEs unless they worsen during the treatment 
period. Pre-existing conditions will be recorded in the eCRF on the Medical History or 
appropriate page. Adverse events will be captured from the time of ICF signing until completion 
of the study (Week 16) or early cessation of treatment for any reason.
The underlying disease is defined as:
1.
Clinical disease that was the reason for the bone marrow or stem cell transplant 
(e.g. malignancy, immunodeficiency disorder, Sickle Cell Disease, etc).
2.
Typical, expected clinical manifestations of patients who have received bone 
marrow transplant or stem cell transplant.
3.
Typical, expected clinical manifestations of patients with acute graft-vs-host
disease.
The following signs, symptoms, laboratory results, and diseases are considered AEs:
1.
Signs and symptoms not related to the underlying disease.
2.
Signs and symptoms not typical following bone marrow transplant or stem cell 
transplant.
3.
Abnormal laboratory results not related to the underlying disease that are 
clinically significant (expert clinical judgment required by the investigator to 
assess if an abnormal laboratory result is clinical significant/not clinically 
significant).


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4.
Underlying disease that worsens and meets criteria for a SAE during the study.
5.
Concomitant illnesses that existed before entry into the study that worsen during 
the treatment period.
6.
Death due to any cause.
The following signs, symptoms, laboratory results, diseases are not considered an AE:
1.
Underlying disease that does not meet criteria for being a serious AE (see Section 
8.1.3.1).
2.
Hospitalization related to study enrollment procedures, treatments, etc.
3.
Hospitalization for elective or planned procedure to treat a preexisting condition 
that has not worsened and does not result in another serious outcome (e.g. death, 
hospital prolongation, etc).
4.
Abnormal laboratory results associated with the underlying disease (as 
determined by expert clinical judgment of the investigator).
5.
Concomitant illnesses that existed before entry into the study that do not worsen 
during the treatment period.
8.1.3
Assessment of Adverse Events
Each AE will be assessed by the Principal Investigator with regard to seriousness, intensity, and 
causality.
8.1.3.1
Seriousness
An SAE is defined as any untoward medical occurrence that:

Results in death.

Is a life-threatening adverse drug/device experience (this means that the patient is at risk of 
death at the time of the event; it does not mean that the event hypothetically might have 
caused death if it were more severe).

Requires inpatient hospitalization or prolongation of existing hospitalization.

Results in persistent or significant disability or incapacity.

Is a congenital anomaly or birth defect.

Is an important medical event that may not be immediately life-threatening or result in death 
or hospitalization, but that may jeopardize the patient or require intervention to prevent one 
of the above outcomes.
ANY SAE (INCLUDING DEATH) DUE TO ANY CAUSE, WHICH OCCURS DURING 
THE COURSE OF THIS INVESTIGATION, WHETHER OR NOT RELATED TO THE 
INVESTIGATIONAL DRUG, MUST BE REPORTED WITHIN 24 HOURS BY FAX TO 
.
Medical and scientific judgment should be exercised in deciding whether a case is serious.
Therakos, Inc. and/or its delegate (
) will determine if an event 
requires expedited reporting.


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8.1.3.2
Intensity
The intensity of each AE must be assessed by the Principal Investigator using one of the 
following categories and recorded in the eCRF:

Mild: an AE that does not interfere with usual activities.

Moderate: an AE that interferes with usual activities.

Severe: an AE that prevents usual activities.
8.1.3.3
Causality
The Principal Investigator will assess the causality/relationship between the study treatment and 
the AE, and record that assessment in the eCRF. The most likely cause of an SAE (e.g., disease 
under treatment, concomitant disease, and concomitant medications) will be indicated on the 
eCRF with details of the cause.
The causal relationship of the AE to study drug will be described for:

Probable: the AE meets one of these criteria.
-
Follows a reasonable temporal sequence from administration of the study drug.
-
Could not be reasonably explained by the patient’s clinical state, environmental or toxic 
factors, or other therapies administrated to the patient.
-
Disappears or decreases on cessation or reduction in dose of the study drug.
-
Follows a known pattern of response to the study drug.
-
Reappears or worsens on rechallenge.

Possible: the AE meets one of these criteria
-
Follows a reasonable temporal sequence from administration of the study drug
-
Could be reasonably explained by the patient’s clinical state, environmental or toxic 
factors, or other therapies administrated to the patient
-
Follows a known pattern of response to the study drug

Unlikely: the AE meets one of these criteria
-
Does not follow a reasonable temporal sequence from administration of the study drug.
-
Could be reasonably explained by the patient’s clinical state, environmental or toxic 
factors, or other therapies administrated to the patient.
-
Does not follow a known pattern of response to the study drug.
-
Does not reappear or worsen on rechallenge.

Not related:
-
The AE does not meet the above criteria.
-
There is sufficient information that the etiology of the AE is not related to the study drug.


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For SAEs, the Principal Investigator will assess whether the event is related to UVADEX, the 
ECP procedure, concomitant medication, an underlying condition, other (specify), or unknown.
If the SAE is assessed as related to UVADEX, the likelihood of the relationship will be assessed 
by the Principal Investigator as Probable, Possible, or Unlikely.
8.1.4
Recording Adverse Events
Adverse events will only be recorded from ICF signing until Week 16. Following Week 16 there 
will be a passive chart review which will not include the collection of AEs. Any AEs occurring 
after the end of the study should be reported to the Sponsor by the Investigator if the Principal 
Investigator considers that there is a causal relationship with the study treatment.
All AEs (including AEs resulting from active standard of care medication and study device), 
regardless of the relationship to study drug, will be recorded in the eCRF. In addition, the 
technician performing the ECP procedure will observe and record any AEs that occur during the 
procedure. Treatment will be stopped if the patient cannot tolerate the procedure.
All AEs recorded in the eCRF should contain a brief description of the event, date of onset, date 
of resolution, intensity, treatment required, relationship to study drug(s) and/or device, action 
taken with the study drug and/or device, outcome, and whether the event is classified as serious.
8.1.5
Reporting Serious Adverse Events
All SAEs will be recorded from the time of ICF signing until completion of the study. All SAEs, 
regardless of the relationship to the study drug(s) or study procedure(s), must be reported by the 
Principal Investigator, or his/her designee, within 24 hours of observation/discovery or 
notification of the event. Instructions for reporting an SAE are provided in this section. The 
name(s) and contact details of the individual(s) who should be contacted regarding safety issues 
or questions regarding the study are also included in Table 2.


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Table 2. Contact Information for Reporting Serious Adverse Events
FAX all SAE Reports
SAE Hotline (questions)
Safety Fax Line:
US: 
 
AT: 
 
HU: 
 
FR: 
 
GE: 
IT:
 
SP: 
 
PL: 
 
UK: 
US: 
 
AT: 
 
HU: 
 
FR: 
GE:
 
IT:
 
SP:
 
PL: 
 
UK: 
Email (backup):
Table 3. Contact Information US and EU Medical Monitors
, MD 
 (US) 
 
Office: 
 
Fax: 
 
Email:
, MD, PhD 
 (EU) 
 
Office: 
 
Fax: 
 
Email: 
The Principal Investigator, Sponsor, and 
 Safety will review each SAE report and will 
evaluate the seriousness, causal relationship, and/or expectedness of the event to study treatment.
Hospitalization due to disease progression will be considered an SAE. Hospitalization for an 
elective or planned procedure to treat a preexisting condition will not be considered an SAE 
unless it results in one of the other outcomes previously described. Hospitalizations only for 
study agent administration will not be considered an SAE. Details for the reporting of suspected 
unexpected serious adverse reactions (SUSARs) can be found in Section 8.1.8.


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Serious AE reporting instructions:

Provide the Medical Monitor with the Principal Investigator’s name, your name, the 
telephone number where you can be reached, and the protocol number and title.

Fax the SAE form and any supporting documentation to the Medical Monitor within 24 hours
of becoming aware of the event.
The minimum information required for an initial report:

Sender of the report (name, address of Principal Investigator).

Patient identification (by enrollment number, initials, and/or birth date—NOT by patient 
name).

Protocol number.

Description of SAE.

Causality assessment.
After receipt of the initial report, 
 Safety will review the information and, if necessary, 
contact the Principal Investigator to obtain further information for assessment of the event.
 
Safety will be responsible for all information processing and reporting according to local legal 
requirements following ICH E6 guidelines. Where necessary, Principal Investigators will inform 
the authorities in their own countries.
8.1.6
Follow-up of Serious Adverse Events
All SAEs experienced by a patient, irrespective of the suspected causality, will be monitored 
until the event has resolved, until any abnormal laboratory values have returned to baseline or 
stabilized at a level acceptable to the Principal Investigator and Medical Monitor, until there is a 
satisfactory explanation for the changes observed, or until the patient is lost to follow-up or the 
event is unlikely to resolve.
The Data Safety Monitoring Board (DSMB) meets on a quarterly basis to review all the SAEs 
(unblinded), the most frequent AEs (blinded aggregate data), and laboratory data of interest, and 
will make recommendation to the study team regarding the safety aspect of the study. The safety 
review team consists of medical experts who are not involved in the study.
8.1.7
Protocol-Specified Serious Adverse Events
In order to minimize expedited reporting on non-informative SAEs, the following list of events 
do not need to be reported individually in an expedited manner, as they are anticipated due to 
disease progression and/or the use of concomitant therapies. These events include:

Relapse of an underlying pre-transplant malignant condition, progression of aGvHD 
symptoms, pancytopenia, vomiting, diarrhea, GI bleeding, bloody stools, GI perforation, 
myelosuppression, leukopenia, AST elevation ALT elevation, elevated bilirubin, 
hepatotoxicity, thrombocytopenia, red cell aplasia, hypogammaglobulinemia, anorexia, 
nephrotoxicity, seizures, and anemia;

Tuberculosis infection, tuberculosis reactivation, CMV infection, VZV infection, herpes 
simplex virus infection, CMV reactivation, VZV reactivation, herpes simplex virus 
reactivation, parasitic infections, bacterial central line infection, bacterial sepsis, fungal 
central line infection, and fungal sepsis.


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8.1.8
Suspected Unexpected Serious Adverse Reactions
A SUSAR is defined as any untoward and unintended response to a study drug, which is not 
listed in the applicable product information, which is assessed by the sponsor and or study 
investigator as being unexpected and meets one of the following serious criteria: results in death, 
is life-threatening, requires hospitalization or prolongation of an existing hospitalization, results 
in persistent or significant disability or incapacity, or is a congenital anomaly or birth defect:

If the SUSAR is fatal or life-threatening, regulatory authorities and ethics committees will be 
notified within 7 calendar days after the Sponsor learns of the event. Additional follow-up 
information (cause of death, autopsy report, and hospital report) should be reported within an 
additional 8 days (15 days total).

If the SUSAR is not fatal or life-threatening but is otherwise serious (meets the other 
seriousness criteria in Section 8.1.3.1), regulatory authorities and ethics committees will be 
notified within 15 calendar days after the Sponsor learns of the event.
The Sponsor will notify the Principal Investigators of relevant information about SUSARs that 
could adversely affect the safety of patients in a timely fashion. Follow-up information may be 
submitted if necessary.
The Sponsor will also provide annual safety updates to the regulatory authorities and ethics 
committees responsible for the trial. These updates will include information on SUSARs and 
other relevant safety findings.
8.1.9
Pregnancy
The Sponsor has a responsibility to monitor the outcome of pregnancies where there has been 
maternal exposure to the investigational drug.
Pregnancy alone is not regarded as an AE unless there is a suspicion that the study drug(s) may 
have interfered with the effectiveness of a contraceptive medication.
Elective abortions without complications should not be handled as AEs unless they were 
therapeutic abortions (see below). Hospitalization for normal delivery of a healthy newborn 
should not be considered an SAE.
All pregnancies must be reported by the Principal Investigator to 
 Safety on the initial 
pregnancy report form within 30 days after becoming aware of the pregnancy. The Principal 
Investigator must follow up and document the course and the outcome of all pregnancies even if 
the patient was discontinued from the study or if the study has finished.
All outcomes of pregnancy must be reported by the Principal Investigator to 
 Safety on the 
pregnancy outcome report form within 30 days after he/she has gained knowledge of the normal 
delivery or elective abortion.
Any SAE that occurs during pregnancy must be recorded on the SAE report form (e.g., maternal 
serious complications, spontaneous or therapeutic abortion, ectopic pregnancy, stillbirth, 
neonatal death, congenital anomaly, birth defect) and reported within 24 hours in accordance 
with the procedure for reporting SAEs.


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If a partner of a male study patient who has been exposed to study drug becomes pregnant, every 
effort should be made to monitor the pregnancy and outcome of pregnancy. A separate ICF will 
be provided for the partner before any data are collected regarding the pregnancy.
8.1.10
Medical Device Reporting
All device malfunctions during the 12-week study period should be reported to the Therakos, 
Inc. support hotline. The Mallinckrodt Critical Care Customer Care phone numbers are 
877-566-9466 in the United States and 00800-843-725-67 in Europe. The caller should identify 
his/her involvement in this clinical study.
Device malfunctions should also be recorded in the eCRF. Any AEs resulting from the 
malfunction will be recorded in the eCRF.
8.2 DATA SAFETY MONITORING BOARD
A DSMB will be in place to oversee the study. The DSMB will be an external committee 
composed of various specialists (also relevant to the pediatric bone marrow transplant population 
being studied). Details will be provided in the DSMB Charter.
The DSMB will be responsible for ongoing review of enrollment, safety, and, if requested by the 
DSMB, efficacy data. They will provide regular assessments on the safety and overall risk-to-
benefit ratio of the study conduct, advise Therakos, Inc. of the need for any protocol 
modifications/amendments to minimize potential risk for patients, and make recommendations 
including stopping of enrollment and/or treatment, if needed.
A 
 Safety designee will be responsible for the timely coordination and delivery of the data to 
the DSMB on a regular basis.


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9.
STATISTICAL METHODS
9.1 PLANNED SAMPLE SIZE
A total of 48 patients with steroid-refractory grade B-D aGvHD will be enrolled and receive at 
least one ECP treatment. The trial is designed to test the null hypothesis that standard therapy has 
an overall response (CR+PR) rate of 10% versus the alternate hypothesis that ECP plus standard 
therapy has a CR+PR rate not equal to 10% (the expected rate  ≥27%).  The overall Type I error 
rate and power for this design are 5% and 90.4%, respectively. 
9.2 OVERVIEW OF STUDY DESIGN
This single-arm trial will have 1 planned interim analysis and a final analysis.
The primary endpoint is whether a patient achieves an overall response (defined as a complete 
response (CR) or partial response (PR)). The trial is designed to test the null hypothesis that 
standard therapy has an overall response (CR+PR) rate of 10% versus the alternate hypothesis 
that ECP plus standard therapy has a CR+PR rate not equal to 10% (the expected rate  ≥27%). 
After the first 50% (24/48) of the patients have been treated for at least 4 weeks (or fewer if 
patients discontinued treatment), significance will be declared if the CR+PR 2-sided P value 
versus the stated alternative is < 0.005, corresponding to an observed CR+PR rate > 48%.  Based 
on the primary endpoint analysis and review of the safety results available at the time of the 
interim analysis, consideration will be given, in the absence of safety concerns, to continue or 
stop the study for success or futility. Enrollment will not be placed on hold during the interim 
analysis. A final analysis will be performed after all 48 patients have been treated for at least 4 
weeks.  In this final analysis, significance will be declared if the CR+PR 2-sided P value versus 
the stated null is < 0.049.  The overall Type I error rate and power for this design are 5% and 
90.4%, respectively.  
9.3 EFFICACY ANALYSES
A formal statistical analysis plan will be developed prior to first patient entered that will provide 
full details of analysis methods and analysis populations.
9.3.1
Analysis of Primary Endpoint
The primary endpoint is the proportion of patients who achieve an overall response (CR+PR) 
after 4 weeks (Day 28), or fewer treatments if they discontinued treatment, of ECP treatment.
Patients must receive at least one treatment. Patients will be evaluated by the treating physician 
for the presence or absence of aGvHD manifestations of the skin, liver, and gut; source data will 
be collected for each patient and entered into the eCRF, and a scoring algorithm will be applied 
to calculate the grade of aGvHD using the modified IBMTR Severity Index. If a Patient is 
administered a second-line therapy other than ECP for the treatment of aGvHD, or discontinues 
study treatment, that Patient will be considered a nonresponder. The primary endpoint will be 
summarized by frequency tabulation and analyzed using exact Binomial test and confidence 
interval. The formal statistical analysis and evaluation of response is based on at least 4-weeks 
ECP treatment data only.


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9.3.2
Analysis of Secondary Endpoints
The secondary endpoints are:

Safety parameters including vital signs, laboratory tests, and spontaneously reported AEs and 
SAEs.

Proportion of patients who achieve an overall response 8 weeks (Day 56) and 12 weeks (Day 
84) after initiation of ECP treatment.

Duration of response, defined as the length of time a patient maintains a response through
Week 16 of the Follow-up Period on a per-patient basis.

Proportion of patients who achieve an overall response after 4 weeks (Day 28), 8 weeks (Day 
56) and 12 weeks (Day 84) of ECP treatment according to the modified Glucksberg criteria
-
Source data will be collected for each patient and entered into the eCRF, and a scoring 
algorithm will be applied to calculate the grade of aGvHD using the modified Glucksberg 
criteria.

Cumulative dose of daily steroids administered from diagnosis of aGvHD to 12 weeks 
(Day 84) after initiation of ECP treatment.

Organ-specific grade at 4 weeks (Day 28), 8 weeks (Day 56) and 12 weeks (Day 84) after 
initiation of ECP treatment.
Overall response (CR+PR) rate at 8 weeks (Day 56) and response determined by the Glucksberg 
criteria will be summarized by frequency tabulation and analyzed using exact Binomial test and 
confidence interval. Supportive analysis of response rates over time will be achieved by means 
of generalized linear mixed effects modelling. Daily steroid dose will be analyzed using mixed 
model repeated measures analysis. Duration of response will be summarized by Kaplan-Meier 
curve; the median duration of response and 95% confidence interval will be presented.
9.3.3
Analysis of Exploratory Endpoints
Exploratory endpoints include:
 
 
 


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9.4 SAFETY PARAMETERS
Safety parameters for each patient include vital signs, laboratory tests, and spontaneously 
reported AEs and SAEs. Adverse events will be graded according to the Common Terminology 
Criteria for Adverse Events (CTCAE), version 4.0 and will be coded using MedDRA based on 
the verbatim term collected in the eCRF. Adverse event data will be summarized by system 
organ classification and preferred term. Vital signs and laboratory values will be summarized by 
visit and numbers of patients with excursions outside the normal reference range summarized.


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10. ETHICAL, LEGAL, AND ADMINISTRATIVE ASPECTS
10.1
DATA QUALITY ASSURANCE
The Sponsor or Sponsor designee will conduct a site visit to verify the qualifications of each 
Principal Investigator, inspect the site facilities, and inform the Principal Investigator of the 
responsibilities and procedures for ensuring adequate and correct documentation.
The Principal Investigator is required to maintain adequate and accurate medical records which 
include all data collected for each study participant. All information recorded on the eCRFs for 
this study must be verifiable against original source documentation (i.e., medical records).
Sponsor or designee Quality Assurance representatives may visit study sites to review data 
produced during the course of the study, and to assess compliance with applicable regulations 
pertaining to the conduct of clinical studies.
10.2
CASE REPORT FORMS AND SOURCE DOCUMENTATION
All data obtained during this study should be captured in the Electronic Data Capture (EDC) 
system promptly. All source documents from which EDC system entries are derived should be 
placed in the patients’ medical records. Measurements for which source documents are usually 
available include laboratory assessments.
The original EDC system entries for each patient during the 12-week period may be checked 
against source documents at the study site by the designated site monitor. After review by the 
site monitor, completed EDC system entries will be uploaded for processing. Instances of 
missing or uninterpretable data will be discussed with the Principal Investigator for resolution.
The specific procedures to be used for data entry and query resolution using the EDC system will 
be provided to study sites in a training manual. In addition, site personnel will receive training on 
the EDC system.
10.2.1
Data Collection
Access to the eCRFs will be carefully controlled and configured according to each individual’s 
role throughout the study. In general, only the Principal Investigator and authorized staff will be 
able to enter data and make corrections in the eCRFs.
The eCRF should be completed for each patient included in the study and should reflect the latest 
observations on the patients participating in the study. Therefore, the eCRFs are to be completed 
as soon as possible during or immediately after the patient’s visit or assessment. The Principal 
Investigator must verify that all data entries in the eCRF are accurate and correct. If some 
assessments cannot be done, or if certain information is unavailable, not applicable, or unknown, 
the Principal Investigator should indicate this in the eCRF. Manual checks will identify any 
clinical data discrepancies for resolution. Corresponding queries will be loaded into the system 
and the site will be informed about new issues to be resolved on-line. All discrepancies will be 
solved on-line directly by the Investigator or by authorized staff. Off-line edit checks will be 
done to examine relationships over time and across panels to facilitate quality data.
After completion, the Principal Investigator will be required to approve the eCRF pages 
containing the clinical data.
Data about all study drugs dispensed to the patient will be tracked on eCRFs.


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10.3
ACCESS TO SOURCE DATA
During the course of the study, a monitor will make site visits to review protocol compliance, 
compare eCRFs and individual patients’ medical records, assess drug accountability, and ensure 
that the study is being conducted according to pertinent regulatory requirements. Electronic case 
report form entries will be verified with source documentation. The review of medical records 
will be performed in a manner to ensure that patient confidentiality is maintained.
Checking of the eCRFs for completeness and clarity, and cross-checking with source documents, 
will be required to monitor the progress of the study. Moreover, regulatory authorities of certain 
countries, Institutional Review Boards (IRBs), Independent Ethics Committees (IECs), and/or 
the Sponsor’s Clinical Quality Assurance Group or designee may wish to carry out such source 
data checks and/or on-site audit inspections. Direct access to source data will be required for 
these inspections and audits; they will be carried out giving due consideration to data protection 
and medical confidentiality. The Principal Investigator assures the Sponsor and designee of the 
necessary support at all times. Local/country specific data protection law is applicable and will 
be followed.
10.4
DATA PROCESSING
All data will be entered by site personnel into the eCRFs.
The Data Cleaning Specification, to be developed during the initiation phase of the study, will 
include specifications for consistency and plausibility checks on data, and also include rules for 
data handling (e.g., what fields are entered for Screen Failures).
Previous and concomitant medications will be coded using the World Health Organization 
(WHO) Drug Reference List (DRL), which employs the Anatomical Therapeutic Chemical 
(ATC) classification system. Medical history/current medical conditions and AEs will be coded 
using MedDRA terminology.
The versions of the coding dictionaries can be obtained or provided by Therakos, Inc.
10.5
ARCHIVING STUDY RECORDS
According to ICH guidelines, essential documents should be retained for a minimum of 2 years 
after the last approval of a marketing application in an ICH region, and until there are no pending 
or contemplated marketing applications in an ICH region, or until at least 2 years have elapsed 
since the formal discontinuation of clinical development of the investigational product. However, 
these documents should be retained for a longer period if deemed necessary by other applicable 
regulatory requirements.
10.6
GOOD CLINICAL PRACTICE
The procedures set out in this study protocol are designed to ensure that the Sponsor and 
Principal Investigator abide by the principles of the GCP guidelines of the ICH and the 
Declaration of Helsinki (1996). The study also will be carried out in compliance with local legal 
requirements.


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10.7
INFORMED CONSENT/ASSENT
Before each patient is admitted to the study, informed consent/assent will be obtained from the 
patient (or his/her parent, legal guardian or legally authorized representative) according to the 
regulatory and legal requirements of the participating country. The ICF must be dated and 
retained by the Principal Investigator as part of the study records. The Principal Investigator will 
not undertake any investigation specifically required only for the clinical study until valid 
consent/assent has been obtained. The terms of the consent/assent and when it was obtained must 
also be documented in the eCRF.
If a protocol amendment is required, the ICF may need to be revised to reflect the changes to the 
protocol. If the ICF is revised, it must be reviewed and approved by the appropriate IRB and 
Ethics Committee and signed by all patients subsequently enrolled in the study as well as those 
currently enrolled in the study.
10.8
PROTOCOL APPROVAL AND AMENDMENT
Before the start of the study, the study protocol and/or other relevant documents will be approved 
by the IRBs, Ethics Committees and Competent Authorities (if applicable) in accordance with 
local legal requirements. The Sponsor must ensure that all ethical and legal requirements have 
been met before the first patient is enrolled in the study.
The protocol and IRB approval will be submitted to the Investigational New Drug (IND) 
application for the product to the U.S. Food and Drug Administration for notification/comment.
This protocol is to be followed exactly. To alter the protocol, amendments must be written, 
approval must be received from the appropriate personnel, and approval must be received from 
the IRB or Ethics Committees before implementation (if appropriate
per regulatory 
requirements). Following approval, the protocol amendment(s) will also be submitted to the IND 
under which the study is being conducted and to Competent Authorities (if appropriate per 
regulatory requirements).
Administrative changes may be made without the need for a formal amendment. All amendments 
will be distributed to all protocol recipients, with appropriate instructions.
10.9
DURATION OF THE STUDY
For an individual patient, the maximum duration of treatment will be up to 12 weeks, not 
including the Week 26 Overall Survival assessment. The study is expected to last approximately 
3 years.
10.10 PREMATURE TERMINATION OF THE STUDY
If the Principal Investigator, the Sponsor, or the Medical Monitor becomes aware of conditions 
or events that suggest a possible hazard to patients should the study continue, the study may be 
terminated after appropriate consultation among the relevant parties. The study may also be 
terminated early at the Sponsor’s discretion in the absence of such findings.
Conditions that may warrant termination include, but are not limited to:

Discovery of an unexpected, significant, or unacceptable risk to patients enrolled in the 
study.


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
Failure to enroll patients at an acceptable rate.

Recommendation of the DSMB.
10.11 CONFIDENTIALITY
All study findings and documents will be regarded as confidential. The Principal Investigator and 
members of his/her research team must not disclose such information without prior written 
approval from the Sponsor.
The anonymity of participating patients must be maintained. Patients will be identified on eCRFs 
and other documents submitted to 
 by their patient number, 
initials, and/or birth date—NOT by patient name. Documents not to be submitted to 
 
 that identify the patient (e.g., the signed ICF) must be maintained in 
confidence by the principal Investigator.
10.12 OTHER ETHICAL AND REGULATORY ISSUES
If a significant safety issue is identified, either from an individual case report or from a review of 
aggregate data, then the Sponsor will issue prompt notification to all parties—regulatory 
authorities, Principal Investigators, IRBs, Ethics Committees and Competent Authorities (if 
applicable).
A significant safety issue is one that has a significant effect on the course of the clinical trial or 
program (including the potential for suspension of the trial program or amendments to protocols) 
or warrants immediate update of informed consent/assent.
10.13 LIABILITY AND INSURANCE
It is assumed that the Principal Investigators have reasonable third-party liability insurance 
coverage in accordance with all local legal requirements. The civil liability of the Principal 
Investigator, the persons instructed by him/her, and the hospital, practice, or institution at which 
they are employed, with respect to financial loss due to personal injury and other damage that 
may arise as a result of the carrying out of this study, are governed by the applicable law.
10.14 PUBLICATION POLICY
As this is a Therakos, Inc.-sponsored study, Therakos, Inc. will be responsible for publication of 
study results. The results of this study may be published in a medical publication or journal or 
may be used for teaching purposes. Additionally, this study and its results may be submitted for 
inclusion in all appropriate health authority registries as well as for publication on health 
authority study registry Web sites as required by local health authority regulations.


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BOHBOT, A., LIU, V., LIOURE, B., et al. (2012) New Technical Developments. IN GREINIX, 
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BREDESON, C., RUMBLE, R. B., VARELA, N. P., et al. (2014) Extracorporeal photopheresis 
in the management of graft-versus-host disease. Curr Oncol, 21, e310-25.
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(photochemotherapy) in the treatment of acute and chronic graft versus host disease: 
immunological mechanisms and the results from clinical studies. Cancer Immunol 
Immunother, 63, 757-77.
DAS-GUPTA, E., DIGNAN, F., SHAW, B., et al. (2014a) Extracorporeal photopheresis for 
treatment of adults and children with acute GvHD: UK consensus statement and review 
of published literature. Bone Marrow Transplant.
DAS-GUPTA, E., GREINIX, H., JACOBS, R., et al. (2014b) Extracorporeal photopheresis as 
second-line treatment for acute graft-versus-host disease: impact on six-month freedom 
from treatment failure. Haematologica, 99, 1746-52.
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graft-versus-host disease. Br J Haematol, 158, 30-45.
FERRARA, J. L., COOKE, K. R., PAN, L. & KRENGER, W. (1996) The 
immunopathophysiology of acute graft-versus-host-disease. Stem Cells, 14, 473-89.
FERRARA, J. L., LEVINE, J. E., REDDY, P. & HOLLER, E. (2009) Graft-versus-host disease. 
Lancet, 373, 1550-61.
FILIPOVICH, A. H., WEISDORF, D., PAVLETIC, S., et al. (2005) National Institutes of Health 
consensus development project on criteria for clinical trials in chronic graft-versus-host 
disease: I. Diagnosis and staging working group report. Biol Blood Marrow Transplant,
11, 945-56.
GARNETT, C., APPERLEY, J. F. & PAVLU, J. (2013) Treatment and management of graft-
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12.
APPENDICES
12.1
APPENDIX A: MODIFIED IBMTR SEVERITY INDEX
Table 4. Criteria for Modified IBMTR Severity Index for aGvHD
Indexa
Skin Involvement
Liver Involvement
GI Involvement
Upper GI Involvement
Stage 
Extent 
of Rash
Stage 
Total 
Bilirubin 
(mg/dL)
Stage 
Volume of 
Diarrhea (stool 
output/day)
Stage 
Clinical 
Features
Patients
< 50 kg
Patients
≥ 50 kg
A
1
< 25%
0
< 2
(< 34 
µmol/L)
0
< 10 
mL/kg/d
< 500 
mL/d 
0
Bb
2
25-50%
or
1-2
2-6
(34-102 
µmol/L)
or
1-2
10-30 
mL/kg/d
500-
1500 
mL/d 
or
1
Nausea, vomiting, 
anorexia, 
epigastric pain or 
burning, and/or 
food intolerance 
with a positive 
upper GI biopsy
C
3
> 50%
or
3
6-15
(103-255 
µmol/L)
or
3
> 30 
mL/kg/d
> 1500 
mL/d 
–
D
4
Bullae
or
4
> 15
(> 255 
µmol/L)
or
4
Severe abdominal 
pain with or without 
ileus
–
a Assign Index based on maximum involvement in an individual organ. 
b Grade B aGvHD includes patients with stage 2 skin and no visceral aGvHD, or stage 0-2 skin and stage 1-2 visceral 
aGvHD. 


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12.2
APPENDIX B: MODIFIED GLUCKSBERG CRITERIA
Table 5. Modified Glucksberg Criteria for aGvHD
Stage
Skin
Liver (bilirubin mg/dL)
Gut (stool output/day)
Patients
< 50 kg
Patients
≥ 50 kg
0
No GvHD rash
< 2.0
< 10 mL/kg/day
< 500 mL/day or 
persistent nausea
1
Maculopapular rash 
< 25% BSA
2.0-3.0
< 10-19.9 
mL/kg/day or 
persistent nausea, 
vomiting or 
anorexia, with a 
positive upper GI 
biopsy
500-999 mL/day 
or persistent 
nausea, vomiting 
or anorexia, with 
a positive upper 
GI biopsy
2
Maculopapular rash 
25%-50% BSA
3.1-6.0
20-30 mL/kg/day
1000-1500 
mL/day
3
Maculopapular rash 
> 50% BSA
6.1-15.0
> 30 mL/kg/day
> 1500 mL/day
4
Generalized erythroderma 
plus bullous formation
> 15.0
Severe abdominal pain with or without 
ileus
Grade
Skin
Liver
Gut
I
Stages 1-2
None
None
II
Stage 3 or
Stage 1 or
Stage 1
III
―
Stages 2-3 or
Stage 2-4
IV
Stage 4 or
Stage 4
―
BSA, body surface area; GI, gastrointestinal; GvHD, graft-versus-host disease.
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