Conditions: Secondary Progressive Multiple Sclerosis
Allocation: RANDOMIZED | Intervention model: SINGLE_GROUP
Enrollment: 13
Healthy volunteers: no

Brief summary:
In this research study, the investigators will determine whether a procedure called Extracorporeal Photopheresis (ECP) is helpful in preventing progression of disability in people with SPMS when compared to monthly corticosteroid infusions. This study will determine whether ECP has an effect on inflammatory cells in people with SPMS and whether it has a beneficial therapeutic effect.

Detailed description:
This is a Phase II randomized, open-label study to evaluate the efficacy of extracorporeal photopheresis (ECP) versus IVMP on disability progression in subjects with SPMS. At the initial screening visit, an extensive medical history will be obtained and a detailed neurological examination will be performed to determine eligibility. Subjects who meet eligibility criteria will be enrolled in one of two study arms. Subjects will be randomized at a 1:1 ratio to receive ECP (study arm) or active treatment with intravenous methylprednisolone pulses (control arm) administered every 4 Weeks (1 gram per infusion) for 52 weeks.

ECP will be administered according to the following schedule:

Study Arm: Weeks 1-8: 3 times per week Weeks 9-16: Twice per week Weeks 17-36: Treatment on two consecutive days every 2 weeks (or optionally, one treatment per week) Weeks 37-43: Once every 2 weeks Weeks 44-52: Once every 4 Weeks

All subjects, including patients who receive corticosteroids, will be evaluated using the MSFC tool at baseline and every 3 months through 2 years. They will also be scored using the EDSS at baseline and every 3 months through 2 years. Subjects in the control arm will be evaluated by MSFC and EDSS during the week prior to their next intravenous methylprednisolone infusion and every three months from baseline through two year mark. Blood will be collected for immune function (cytokines) testing at baseline, and months 3, 6, 9 and 12. MRI will be done at baseline as well as months 6 and 12 following initiation of treatment; if the disability measurements are stable or improved at any point in time, then ECP will be continued per protocol..

Patients in the ECP arm should have all of their treatments with the CELLEX ® System. Patients randomized to the ECP arm must receive their treatment within 5 days of baseline visit.

In the ECP process, UVADEX ® (methoxsalen) Sterile Solution will be injected directly the recirculation bag of the extracorporeal circuit after completion of the buffy coat collection. The dose of UVADEX® (methoxsalen) Sterile Solution will be calculated based on the standard treatment volume formula.

Arms:
arm 1: Patients will receive 1 gram of IV SoluMedrol over 1 hour, once every month for 12 months. arm 2: Patient will receive an Extracorporeal Photopheresis treatment at a set frequency over the course of 1 year. The treatment takes about 2-3 hours per session to complete. The treatment schedule is as follows:

ECP will be administered according to the following schedule:

Study Arm: Weeks 1-8: 3 times per week Weeks 9-16: Twice per week Weeks 17-36: Treatment on two consecutive days every 2 weeks (or optionally, one treatment per week) Weeks 37-43: Once every 2 weeks Weeks 44-52: Once every 4 Weeks

Interventions: intervention 1: SoluMedrol intervention 2: Extracorporeal Photopheresis
Intervention descriptions: intervention 1: Infusion of drug subcutaneously, once a month. intervention 2: This intervention is the placement of up to two IV's to extract your blood as a set volume, separate out the white cells and return the red cells to your body. Then the white cells are treated with a drug called UVADEX (methoxsalen), excited by a UV light and returned to your body. Once IV is to withdraw your blood and the other is to return your blood to your body.

Protocol document:
Prot_SAP_000.pdf: 
 
Clinical Study Protocol 
Protocol Number HUM 83301 
 
 
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July 24, 2015 
 
 
A Randomized, Controlled, Open‐Label Study to Evaluate the Efficacy of Extracorporeal 
Photopheresis (ECP) versus Corticosteroids in the Treatment of Patients with Secondary 
Progressive Multiple Sclerosis (SPMS) 
Sponsor: 
Daniel R Couriel, MD.  
Director Adult BMT Program and ECP 
Division of Hematology/Oncology 
University of Michigan, Ann Arbor, MI 
  
Clinical Monitor: 
University of Michigan Institue of Clinical and 
Health Research (MICHR) 
Principal or Coordinating 
Investigator  
Daniel R Couriel, MD  
Director, Adult BMT Program and ECP 
Division of Hematology/Oncology 
University of Michigan, Ann Arbor, MI 
Benjamin Segal, MD 
Holton Garrett Family Professor of Neurology 
Director, Multiple Sclerosis Center 
Department of Neurology 
University of Michigan, Ann Arbor, MI 
IDE No.: 
G140079 
Study Device and Drug Name: 
THERAKOS® CELLEX® Photopheresis Systems 
Development Phase: 
Investigator Initiated Protocol 
Protocol Version and date: 
Version 3.0 July 24, 2015 
 
 
 
 
 
 
The study will be conducted according to the protocol and in compliance with Good Clinical 
Practice (GCP), with the Declaration of Helsinki, and with other applicable regulatory 
requirements. 
This document contains confidential information of University of Michigan. 
Do not copy or distribute without written permission from the Sponsor. 
CONFIDENTIAL 
 
 


 
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SIGNATURE PAGE 
 
 
 
Declaration of Sponsor or Responsible Medical Officer 
Title: A Randomized, Controlled, Open-Label Study to Evaluate the Efficacy of 
Extracorporeal Photopheresis (ECP) versus Corticosteroids in the Treatment of Patients with 
Secondary Progressive Multiple Sclerosis (SPMS) 
 
This study protocol was subjected to critical review. The information it contains is consistent 
with current knowledge of the risks and benefits of the investigational product, 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. 
 
_____________________________________ 
_____________________ 
Daniel R Couriel, MD 
Date 
Director, Adult BMT Program and ECP 
Division of Hematology/Oncology 
University of Michigan  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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Declaration of the Principal Co-Principal Investigator 
Title: A Randomized, Controlled, Open-Label Study to Evaluate the Efficacy of 
Extracorporeal Photopheresis (ECP) versus Corticosteroids in the Treatment of Patients with 
Secondary Progressive Multiple Sclerosis (SPMS) 
 
This study protocol was subjected to critical review and has been approved by the Sponsor. 
The information it contains is consistent with the current risk/benefit evaluation of the 
investigational product as well as with the moral, ethical and scientific principles governing 
clinical research as set out in the Declaration of Helsinki, as amended in 1996 and the 
guidelines on Good Clinical Practice. 
 
 
Principal Investigator  
 
 
 
_____________________________________ 
_____________________ 
Daniel R Couriel, MD 
Date 
Director, Adult BMT Program and ECP 
Division of Hematology/Oncology 
University of Michigan  
 
 
 
Co-Principal Investigator  
 
 
 
_____________________________________ 
_____________________ 
Benjamin M Segal, MD 
Date 
Holtom Garrett Family Professor of Neurology  
Director, Multiple Sclerosis Center 
Department of Neurology 
 
University of Michigan  


 
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PROTOCOL SYNOPSIS 
Investigator Name and 
contact information 
Daniel R Couriel, MD.  
Director Adult BMT Program and ECP 
Division of Hematology/Oncology 
University of Michigan  
dcouriel@umich.edu. Tel 734-936-8785 
Benjamin M. Segal, MD. Holtom-Garrett Family 
Professor of Neurology and Director of Multiple 
Sclerosis Center 
University of Michigan  
bmsegal@umich.edu Tel 734-615-5635 
Title 
A Randomized, Controlled, Open-Label Study to Evaluate 
the Efficacy of Extracorporeal Photopheresis (ECP) versus 
Corticosteroids in the Treatment of Patients with Secondary 
Progressive Multiple Sclerosis (SPMS) 
Study Duration 
2 years 
Study Center 
University of Michigan (Single Center) 
Objectives  
 
Primary objective: To evaluate the effect of ECP 
compared to pulsed corticosteroids on accumulation of 
disability at 12 months (i.e. 52 weeks, see below Section 9.1 
for schedule) in individuals with secondary progressive 
multiple sclerosis (SPMS).  Disability will be assessed 
using a composite measure that takes into account changes 
in the Expanded Disability Status Scale (EDSS) score and 
components of the Multiple Sclerosis Functional Composite 
(MSFC) score.  
Secondary Objectives:  
 To assess the effect of ECP versus corticosteroids on 
plasma levels of immunological factors and the 
frequency of circulating myelin-reactive Th1 and 
Th17 cells   
 To determine whether changes in immunological 
parameters that occur following initiation of ECP or 
corticosteroids correlate with clinical outcomes 
 To assess the impact of ECP versus corticosteroids 
on EDSS scores every 3 month time point through 2 
years compared to baseline 
 To assess the impact of ECP versus corticosteroids 
on MSFC three dimensional composite z-score  at 
every 3 month time point through 2 years compared 


 
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to baseline 
 To assess the effect of ECP on risk of clinical 
relapse 
 To assess the effect of ECP versus corticosteroids on 
the frequency of gadolinium- enhancing T1 
weighted lesions on cranial MRI scans obtained at 
months 6 and 12 compared to baseline 
 To assess the effect of ECP versus corticosteroids on 
interval changes in T2 weighted lesion number and 
volume at months 6 and 12 compared to baseline.   
 To assess the tolerability and the safety profiles of 
ECP versus corticosteroids  
Number of Subjects 
N=66 subjects (33 per treatment arm)  
Study design 
 
This is a Phase II, open-label, randomized, study of ECP 
versus pulsed corticosteroids in patients with SPMS. 
Subjects will be randomized at a 1:1 ratio to receive ECP 
(study arm) or active treatment with intravenous 
methylprednisolone pulses (control arm) administered every 
4 weeks (1 gram per infusion) for 12 months.  All subjects 
will undergo longitudinal MSFC and EDSS testing at 
baseline and every 3 months through 2 years (See Section 
9.1 for timing of schedule of assessments)).   
Blood will be collected for immunological testing at 
baseline, months 3, 6, 9 and 12. Subjects will also undergo 
neuroimaging with brain MRI at baseline and months 6 and 
12 following initiation of treatment 
Study endpoints 
 
Primary: Proportion of subjects with no evidence of 
disease progression at 2 years, defined as a minimum 
change from baseline in one or more of the following: 
 20% or greater increase in the timed 25 foot walk 
 20% or greater increase in the 9 hole peg test 
 1 point or greater increase in EDSS score in subjects 
with baseline EDSS scores between 3 and 5.5 
 0.5 point or greater increase in EDSS score in 
subjects with baseline EDSS scores equal to or 
greater than 6 
Secondary:(1) change in plasma levels of immunological 
factors and frequencies of IFN and IL-17 MBP-specific 
PBMC at months 3, 6, 9 and 12 compared with baseline;  
(2) adverse events;  (3) MSFC 3 dimensional composite z-
score every 3 months through 2 years compared to baseline; 


 
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(4) EDSS score every 3 months through 2 years comparedto 
baseline; (5) percentage of subjects with improvement (as 
defined for the primary endpoint) at months 6 and 12; (6) 
occurrence of clinical relapse at any point in the study; (7) 
interval change in T2 lesion number and volume on MRI 
scans obtained at months 6 and 12 compared to baseline; (8) 
the number and volume of gadolinium enhancing lesions on 
MRI scans obtained at months 6 and 12; (9) interval change 
in the number and volume of gadolinium enhancing lesions 
on MRI scans obtained at months 6 and 12 compared to 
baseline. 


 
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Patient 
Population 
Inclusion 
Criteria 
Subjects will be entered into this study only if they meet the 
all of the following criteria: 
1. Patients with SPMS based on the Recommended 
Diagnostic Criteria for MS and clinical course. 
Secondary progression is defined by a progressive 
increase in disability (of at least 6 months duration) 
in the absence of relapses or independent of 
relapses. 
2. Demonstrate EDSS scores between 3 to 6.5 at 
screening.  
3. Documented EDSS progression in the 2 years prior 
to screening of  1 point or greater for patients with 
an EDSS score less than 6 at baseline, and greater 
than or equal to 0.5 for patients with an EDSS score 
greater than or equal to 6.0 at baseline. If 
documented EDSS scores are not available, a written 
summary of the clinical evidence of disability 
progression over the last 2 years, and retrospective 
assessment of EDSS score from data in the medical 
records, must be submitted for review by the 
principal investigators.   
4. Documented absence of clinical relapse within 2 
years of screening 
5. Age ≥ 18 ≤ 75 years 
6. Weight > 40 kg. 
7. Absolute Neutrophil count ≥ 2,000 per μL 
8. Hematocrit ≥ 28 % and platelet count > 100,000 per 
μL (with or without transfusion support) 
9. Willingness to use at least 1 reliable method of birth 
control (e.g. abstinence, oral contraceptives, 
intrauterine devices, barrier method with spermicide, 
or surgical sterilization) throughout the study for all 
men and women of childbearing potential 
10. Willingness to participate in all study visits and 
procedures, as outlined in the informed consent  
11. Patients able to give informed consent. 
 


 
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Exclusion 
Criteria 
Patients fulfilling any of the following criteria are not 
eligible for inclusion in this study: 
1) Absolute medical contraindication to corticosteroid 
treatment 
2) Absolute medical contraindication to receive ECP 
3) Clinical relapse within 2 years of screening 
4) Laboratory evidence of any of the following: 
a) WBC  < 2,000 cells per uL 
b) Serum transaminase levels > x 2 UNL 
c) Creatinine Clearance < 60 mL/min 
d) HgbA1C > 6%  
5) Concurrent diagnosis of a neurological condition  that 
would interfere with the assessment of MS, or an 
autoimmune disease or inflammatory condition that is 
chronically treated with immunosuppressive agents, 
including systemic corticosteroids. 
6) Evidence of known infection with human 
immunodeficiency virus (HIV) or active (not including 
latent) Hepatitis B (laboratory testing is not required if 
virus status is already known) 
7) Uncontrolled infection requiring treatment at study entry 
8) Hypersensitivity or allergy to psoralen (methoxasalen) 
9) Hypersensitivity or allergy to both heparin and citrate 
products (If hypersensitive or allergic to only one of 
these products, exclusion does not apply) 
10) Inability to tolerate fluid changes associated with ECP 
(e.g. inadequate renal, hepatic, pulmonary and cardiac 
function leading to enable patient to tolerate 
extracorporeal volume shifts associated with ECP) 
11) Presence of aphakia or photosensitive disease (systemic 
lupus erythematosis, porphyrias, albinism, etc.) 
12) Women who are pregnant and/or lactating. 
13) Use of any investigational drug/treatment at the time of 
enrollment or within the previous 60 days, or five 
elimination half-lives, or until the expected 
pharmodynamic effect has returned to baseline, 
whichever is longer. 
14)  Initiation of dalfampridine or change in the dose of 
dalfampridine within 6 months prior to randomization 
  


 
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Exclusion 
Criteria 
15. Treatment with any of the medications or procedures 
listed below: 
a) Glatiramer acetate, interferon-beta, fingolimod, 
teriflunomide or dimethylfumarate within 3 months 
prior to randomization 
b) Natalizumab within 3 months prior to randomization 
c) Cyclophosphamide within 1year prior to 
randomization 
d)  Mitoxantrone within 1 years prior to randomization 
e) Rituximab, within 6 months prior to randomization 
f) Ofatumumab, ocrelizumab, cladribine, daclizumab 
within 2 years prior to randomization 
g) Intravenous immunoglobulin within 6 months prior 
to randomization 
h) Plasmapheresis within 6 months prior to 
randomization 
16) Corticosteroids within 3 months prior to screening, with 
the following exceptions: Topical ointments or creams, 
or eye drops that contain corticosteroids; Intranasal 
Steroids or Oral Steroids given in a single dose as a 
premedication for a procedure such as gadolinium-
enhanced MRI. 
17) Inability to undergo MRI scans. Contraindication to 
gadolinium due to past allergic, hypersensitive or 
adverse reaction or impaired renal function. Patients 
receiving a steroid prep prior to Gadolinium 
administration due to history of hypersensitivity or 
allergy to other agents or due to prior mild reaction to 
Gadolinium will not be excluded from the study. 
18) Any other disease or condition which, in the opinion of 
the investigator, could interfere with participation in the 
study according to the study protocol, or with the ability 
of the patients to cooperate and comply with study 
procedures. 
19) Poor venous access 
20) Previous history of skin cancer, 
leukemia/lymphoma/myeloma or bone marrow 
transplant. 
21) Patients taking Coumadin who are unable to switch 
from oral anticoagulants to enoxaparin.  
 
 


 
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22. Heparin-induced thrombocytopenia 
23. Poor cardiac function 
24. Severe hypotension 


 
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Study treatment 
Study Arm: ECP, Control Arm: Pulsed 
corticosteroids 
Dosage and frequency 
of administration 
 
Study Arm: Weeks 1-8: 3 times per week 
Weeks 9-16: Twice per week 
Weeks 17-36: Treatment on two consecutive days 
every 2 weeks (or optionally, one treatment per 
week) 
Weeks 37-44: Once every 2 weeks 
Weeks 45-52: Once every 4 Weeks 
Control Arm: Pulsed corticosteroids (1 gm. of MP 
IV every month) for 52 Weeks.   
Duration of 
Administration 
1 year (52 weeks) 
Statistical methods 
 
An intent to treat approach will be used.  The 
proportion of subjects who show no evidence of 
disease progression, as defined above, will be 
compared between treatment groups using the Chi-
square test.   Two-sample t-tests or Wilcoxon rank 
sum tests will be used to assess treatment differences 
in continuous outcomes and chi-square or Fisher’s 
exact tests will be used for categorical outcomes.   
Power and Sample Size 
 
Assuming that the proportion of subjects in the 
corticosteroid treatment who show no evidence of 
disease progression at Week 52 is 30%, 66 subjects 
(33 per treatment arm) provides at least 80% power 
to detect a treatment difference of 30% (i.e., 60% of 
the ECP treated subjects will improve at Week 17), 
based on the normal approximation of the binomial 
distribution and a one-sided Type I error of 5%.   
 


 
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LIST OF STUDY PERSONNEL 
Sponsors 
Daniel R Couriel, MD. Director Adult BMT Program 
and ECP. University of Michigan 
 
Principal Investigator  
Daniel R Couriel, MD.  
Director Adult BMT Program and ECP.  
University of Michigan  
dcouriel@umich.edu. Tel 734-936-8785 
Co-Principal Investigator 
Benjamin M. Segal, MD.  
Holtom-Garrett Family Professor of Neurology and 
Director of Multiple Sclerosis Center, University of 
Michigan  
bmsegal@umich.edu Tel 734-615-5635 
SAE/Adverse Event 
Reporting 
 
Daniel Couriel, MD 
Tel: 734-936-8785 
Laboratory 
 
University of Michigan Clinical Laboratories for routine 
studies 
Neuroimmunology Laboratory, Dept. of Neurology for 
research studies (Dr. Segal, Director) 


 
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TABLE OF CONTENTS 
PROTOCOL SYNOPSIS .................................................................................................. 4 
LIST OF STUDY PERSONNEL .................................................................................... 11 
TABLE OF CONTENTS ................................................................................................ 12 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS .............................. 16 
1 INTRODUCTION...................................................................................................... 18 
1.1 Background ......................................................................................................... 18 
1.2 Rationale ............................................................................................................. 20 
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 ............................................................................................................. 22 
3.2 Endpoints ............................................................................................................ 24 
3.2.1 
Primary Endpoint ................................................................................. 24 
3.2.2 
Secondary Endpoints ........................................................................... 24 
3.3 Justification of the Study Design ...................................................................... 26 
4 STUDY POPULATION ............................................................................................ 26 
4.1 Inclusion Criteria ............................................................................................... 26 
4.2 Exclusion Criteria .............................................................................................. 27 
5 PATIENT WITHDRAWAL AND REPLACEMENT ........................................... 28 
6 TREATMENT ............................................................................................................ 31 
6.1 Control Arm: Corticosteroid Treatment ......................................................... 31 
6.2 Study Arm: Extracorporeal Photopheresis ..................................................... 31 
7 STUDY PRODUCT ................................................................................................... 31 
7.1 Identity ................................................................................................................ 31 
7.1.1 
THERAKOS Photopheresis System .................................................... 31 
7.1.2 
UVADEX® (methoxsalen) Sterile Solution ......................................... 31 
7.2 Packaging, Labeling and Storage ..................................................................... 32 
7.3 Drug Accountability ........................................................................................... 34 
7.3.1 
Shipment and Receipt .......................................................................... 32 
7.3.2 
Accountability Logs ............................................................................. 34 
7.3.3 
Study Instrument ................................................................. ……………. 
7.4 Compliance ......................................................................................................... 34 
7.5 Concomitant Medications .................................................................................. 34 
8 PARAMETERS AND METHODS OF ASSESSMENT ........................................ 36 
8.1 Efficacy Parameters ........................................................................................... 36 


 
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8.1.1 
MSFC ................................................................................................... 36 
8.1.2 
EDSS .................................................................................................... 36 
8.1.3 
MRI ...................................................................................................... 37 
8.2 Safety Parameters .............................................................................................. 37 
8.2.1 
Immunological Studies ........................................................................ 37 
8.2.2 
Adverse Events .................................................................................... 37 
8.2.2.1 Collection of Adverse Events ............................................................ 37 
8.2.2.2 Definitions ......................................................................................... 37 
8.2.2.3 Assessment of Adverse Events ........................................................... 38 
8.2.2.4 Recording Adverse Events ................................................................ 39 
8.2.2.5 Reporting Serious Adverse Events .................................................... 39 
8.2.2.6 Follow-up of Adverse Events ............................................................ 40 
8.2.2.7 Suspected Unexpected Serious Adverse Reactions ........................... 41 
8.2.2.8 Pregnancy ......................................................................................... 41 
8.2.2.9 Complaint Reporting/Device Malfunctions ...................................... 40 
8.2.3 
Laboratory Parameters ......................................................................... 40 
8.2.4 
Vital Signs ............................................................................................ 41 
8.2.5 
Physical Examinations ......................................................................... 44 
8.2.6 
Medical History and Interim History ................................................... 44 
9 STUDY CONDUCT ................................................................................................... 45 
9.1 Schedule of Assessments .................................................................................... 45 
9.2 Observations by Visit ......................................................................................... 47 
9.2.1 
Screening.............................................................................................. 47 
9.2.2 
Baseline (Week 1) ................................................................................ 47 
9.2.3 
Weeks 1-26 .......................................................................................... 47 
9.2.4 
Week 26 ............................................................................................... 48 
9.2.5 
Weeks 36-52 ........................................................................................ 48 
9.2.6 
Week 52/End of Study ......................................................................... 49 
9.2.7 
Early Termination Visit ....................................................................... 49 
10 STATISTICAL METHODS ................................................................................... 50 
10.1 Planned Sample Size and Number of Study Centers .................................... 50 
10.2 Efficacy Analyses .............................................................................................. 50 
10.2.1 
Analysis of Primary Endpoint .............................................................. 50 
10.2.2 
Analysis of Secondary Endpoints ........................................................ 50 
10.2.3 
Interim Analyses .................................................................................. 51 
10.3 Safety Analyses ................................................................................................. 51 
10.4 Determination of Sample Size ......................................................................... 51 
11 ETHICAL, LEGAL, AND ADMINISTRATIVE ASPECTS .............................. 50 
11.1 Data Quality Assurance ................................................................................... 50 
11.2 Case Report Forms and Source Documentation ........................................... 50 
11.2.1 
Data Collection .................................................................................... 50 
11.3 Access to Source Data ...................................................................................... 50 
11.4 Data Processing ................................................................................................ 53 


 
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11.5 Archiving Study Records ................................................................................. 53 
11.6 Good Clinical Practice ..................................................................................... 53 
11.7 Informed Consent ............................................................................................. 53 
11.8 Protocol Approval and Amendment ............................................................... 53 
11.9 Duration of the Study ....................................................................................... 54 
11.10 Premature Termination of the Study ............................................................ 54 
11.11 Confidentiality ................................................................................................. 54 
11.12 Other Ethical and Regulatory Issues ............................................................. 54 
11.13 Publication Policy ............................................................................................ 54 
11.14 Monitoring of the Study .................................................................................. 52 
12 REFERENCE LIST ................................................................................................. 56 
13 APPENDICES .......................................................................................................... 56 
13.1 Appendix 1 MSFC Forms ................................................................................ 57 
13.2 Appendix 2 EDSS ............................................................................................. 64 
  
65 
13.3 Appendix 3: Corticosteroids Side Effects ...................................................... 76 
13.3.1 
Side Effects .......................................................................................... 76 
13.3.2 
Warnings: ............................................................................................. 77 
13.3.3 
PRECAUTIONS .................................................................................. 78 
13.4 Appendix 4: UVADEX ® (methoxysalen) Label ........................................... 80 
13.5 Appendix 5: Therakos ® Cellex ® Photopheresis System ............................ 82 
 
Tables in Text 
Table 1: Laboratory Assessments ................................................................................ 41 
Table 2: Schedule of Assessments ............................................................................... 46 
 
Figures in Text 
Figure 1: Study Design ................................................................................................ 24 
 
List of Appendices 
APPENDIX 1  MSFC 
APPENDIX 2 EDSS 
APPENDIX 3: Corticosteroid Safety and AEs 
APPENDIX 4: UVADEX® (methoxysalen) label 
APPENDIX 5: Cellex® Photopheresis ® System Label 
 


 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
AE 
Adverse event 
ALT 
Alanine aminotransferase (previously known as serum glutamic 
pyruvic transaminase, SGPT) 
AST 
Aspartate aminotransferase (previously known as serum glutamic 
oxaloacetic transaminase, SGOT) 
BBB 
Blood Brain Barrier 
CI 
Confidence interval 
CNS 
Central Nervous System 
CRF 
Case report form 
CS 
Corticosteroids 
CTCL 
Cutaneous T-cell lymphoma 
DMA 
Disease Modifying Agents 
DRL 
Drug Reference List 
ECP 
Extracorporeal Photopheresis 
EDSS  
Expanded Disability Status Scale 
eCRF 
Electronic case report form 
EDC 
Electronic Data Capture 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl transpeptidase 
GVHD 
Graft vs. Host Disease 
HIV 
Human immunodeficiency virus 
9-HPT 
9-Hole Peg Test 
IEC 
Independent Ethics Committee 
ICH 
International Conference on Harmonization 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
ITT 
Intent-to-treat 
IVRS 
Interactive Voice Response System 
MedDRA 
Medical Dictionary of regulatory activities 
MP 
Methylprednisolone 
MS 
Multiple Sclerosis 
MSFCS 
Multiple Sclerosis Functional Composite 
PASAT 
Paced Auditory Serial Addition Test  
PPMS 
Primary Progressive Multiple Sclerosis 
QoL 
Quality of Life 


 
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RRMS 
Remitting Relapsing Multiple Sclerosis 
SAE 
Serious adverse event 
SD 
Standard deviation 
SPMS 
Secondary Progressive Multiple Sclerosis 
SUSAR 
Suspected unexpected serious adverse reaction 
UNL 
Upper Limits of Normal 
USA 
United States of America 
UV 
Ultraviolet  
UVA 
Ultraviolet Wave Length A 
WHO 
World Health Organization 
 
 


 
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1. INTRODUCTION 
1.1 
Background 
Multiple Sclerosis 
Multiple Sclerosis (MS) is chronic inflammatory disease affecting the central nervous system 
(CNS). MS is the most common cause of non-traumatic neurological disability among young 
adults in the Western Hemisphere. It affects over 400,000 individuals in the United States alone, 
approximately 2.5 million people worldwide, and its incidence is on the rise. The symptoms of 
MS are protean, reflecting the multifocal nature of the disease. They include visual loss, spastic 
paraparesis, numbness, urinary incontinence, gait imbalance, fatigue, double vision, tremor and 
cognitive impairment.   
 
In the majority of cases, MS initially follows a relapsing-remitting (RRMS) course characterized 
by discrete episodes of neurological symptoms separated by clinically quiescent periods. 
Peripheral blood leukocytes cross the blood-brain-barrier (BBB) and infiltrate the brain, spinal 
cord and optic nerves to drive parenchymal lesion formation. Clinical exacerbation correlates 
with the development of lesions in “eloquent” areas. Natural history studies have shown that the 
incidence of relapses and breaches in the BBB decrease with disease duration (Filippi et al., 
1997).  However, the majority of individuals with RRMS ultimately enter a secondary 
progressive (SP) stage, characterized by the gradual accumulation of neurological disability. The 
molecular and cellular basis for this transition is unclear, and the role of inflammation during the 
SP stage is a subject of active debate.  In fact, immunomodulatory disease modifying agents 
(DMA) that are used to manage RRMS tend to lose efficacy following transition to a SPMS 
stage (Panitch et al., 2004, Paolillo et al., 1999).  Such observations have led to the proposal that 
the gradual accumulation of disability in SPMS is driven by neurodegeneration, manifested as 
neuronal cell death, Wallerian degeneration and astrogliosis, independent of the autoimmune 
assault that predominates earlier in the disease course (Trapp and Nave, 2008).   
 
Conversely, a substantial body of data indicates that autoimmune inflammation is still relevant, 
and contributes to CNS tissue damage, during the SP stage. Others and we have found increased 
frequencies of circulating Th1 and Th17 cells in individuals with SPMS as well as RRMS 
(unpublished data). Neuropathological studies demonstrate widespread microglial activation and 
diffuse lymphocyte infiltration in the cerebral white matter of individuals with SPMS, as 
opposed to the lymphocyte-rich perivascular infiltrates that are characteristic of the RR stage 
(Frischer et al. 2009; Kutzelnigg. et al. 2005). Serafini and colleagues discovered lymphoid 
follicles in the sulci of brain specimens from patients with SP, but not RR, MS (Serafini et al., 
2004). Hence,  the nature of the aberrant immune response appears to evolve over the disease 
course, possibly explaining why the efficacy of individual disease modifying agents differs 
between the RR and SP phases. Mitoxantrone is the only  therapy approved for the treatment of 
SPMS in the United States.  However, the efficacy of mitoxantrone in SPMS patients without 
superimposed relapses is unknown and the considerably toxicities associated with this 
chemotherapy (including risk of leukemia and cardiomyopathy) limit its use.  Therefore there is 
a considerable need for the development of new therapies that will slow or arrest disability 
progression in progressive MS without imposing considerable health risks. 
 


 
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Extracorporeal Photopheresis 
ECP has been used clinically for nearly 20 years as an FDA-approved therapy for the palliative 
treatment of cutaneous T-cell Lymphoma (CTCL). This therapy is an apheresis-based process 
whereby autologous leukocytes are treated with a photoactivatable compound, 8-
methyoxypsoralen, followed by exposure to ~1.5 J/cm2 of UVA light and reinfused. This occurs 
in a point-of-care, patient-connected, sterile, closed-loop system.  ECP has been applied for 
treatment to a wide variety of  immunologic conditions, with minimal side effects. 
 
UVADEX® (methoxsalen) Sterile Solution is a liquid methoxsalen (8-methyoxypsoralen) for ex 
vivo use in ECP therapy. It was developed to introduce methoxsalen as a liquid into the buffy 
coat bag during the ECP collection process followed by exposure of the cells to UVA light. In 
ECP therapy, when cells have absorbed the drug and are exposed to UVA radiation, covalent 
crosslinks between pyrimidine bases form within the deoxyribonucleic acid helix, preventing 
replication and leading to apoptotic cell death. Non-nucleated blood components, such as red 
blood cells, are not affected. At the end of the photoactivation cycle, the photoactivated cells are 
then reinfused back to the patient. 
 
ECP has been used for treatment of SPMS in one small, pilot, controlled study (Rostami et 
al1999) and in several uncontrolled (Poehlau et al.,1997, Besnier et al., 2002) studies with 
inconclusive results. The heterogeneity of schedules and the short duration of therapy in these 
publications further complicate interpretation of the results. 
 
At our center, 3 patients with documented SPMS were treated with ECP, following the 
procedures described in this protocol (Unpublished data). Two of these patients with SPMS 
treated with an intensive ECP regimen have shown objective improvements at 4 months; these 
improvements have persisted even after the treatments were tapered. At 4 months, the first 
patient no longer needed assistance to walk, and had significant improvement in all 3 
components of the MSFC as follows: 53% in 25-foot walk, 67% in 9-hole peg test (9-HPT) and 
17% in PASAT cognitive test. The second patient required a walker at the beginning of therapy, 
and at 4 months started ambulating comfortably with a cane. This patient maintained his 25-foot 
walk score, and had a 64% improvement in the 9-HPT and 20% in the PASAT cognitive test.  
 
The Multiple Sclerosis Functional Composite (MSFC), see also Appendix 1 
  
In this study, the MSFC scores  (See Section 8.1.1) will be used as a primary outcome  
measurement. (Fischer et al., 2001) The MSFC is a validated composite measure developed by 
the National MS Society’s Clinical Outcomes Assessment Task Force. The composite consists of 
the following components: a timed 25-foot walk (T25FW) test to measure leg function and 
ambulation; the timed nine-hole peg test (9HPT) to measure upper extremity dexterity and 
function; and the 3-second version of the paced auditory serial addition test-3 (PASAT), to 
measure neuropsychological function.  Each component score is converted to a z-score by 
normalizing to a reference population.  This instrument  was designed in such a way that a single 
trained technician can administer this scale for consistency.  


 
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The Expanded Disability Status Scale (EDSS), see also Appendix 1 
In addition, EDSS score (See Section 8.1.2) will be measured. Based on a standard neurological 
examination, the EDSS is a composite score that is commonly used to quantify disability level in 
patients with MS (Kurtzke et al, 1983). The composite is derived from ratings of 7 functional 
systems commonly affected in MS: visual, brainstem, pyramidal, cerebellar, sensory, 
bowel/bladder and cerebral function.  Higher scores indicate higher disability.  Scores of less 
than 6.0 indicate independent ambulation, without the need for an assistive device such as a cane, 
walker, or wheelchair.  The EDSS has become the standard disability score used in all of the 
recent product development trials.  
Magnetic Resonance Imaging (MRI) 
Longitudinal MRI studies have shown that the majority of MS lesions are asymptomatic. MRI is 
a sensitive tool for monitoring disease activity and for revealing asymptomatic dissemination of 
lesions in space and time. The pattern and evolution of MRI lesions can be highly suggestive of 
MS, and imaging studies are often an important component of the diagnostic work-up of 
demyelinating disease. (Traboulsee et al., 2006).  Interval changes in the number and volume of 
T2 weighted lesions and the frequency of  gadolinium enhanced T1 weighted lesions (indicative 
of new lesion formation) are often used as outcome measures in clinical trials of therapeutic 
agents in relapsing MS.  
 
Corticosteroid Administration: Intravenous methylprednisolone (IVMP)  
Pulsed intravenous corticosteroid therapy, in the form of IVMP  at a dose of 1 g monthly for 1 
year, was chosen as an active comparator for the control arm.  Corticosteroid pulses are widely 
used in clinical practice to improve energy and motor stamina in individuals with progressive 
MS . They have a favorable side effect profile. This treatment has not been rigorously tested in 
placebo-controlled, double-blind Phase 3 clinical trials. However, a randomized, controlled, 
single blind phase 2 clinical trial of regular pulses of IVMP administered to MS patients over 5 
years showed beneficial effects including prevention or delay of whole brain atrophy and 
disability progression, and suppression of T1-weighted MRI lesion formation (Zivodinov et al., 
2001)  
The present study is designed to assess the safety and efficacy of ECP therapy compared with 
pulsed corticosteroids in patients with documented SPMS.  
 
1.2 
Rationale 
 
Great strides have been made in the development of drugs that are therapeutically beneficial in 
RRMS, resulting in the introduction of 10 DMAs approved by the Food and Drug 
Administration (FDA) for clinical use.  In contrast, the treatment of SPMS remains suboptimal.  
The only FDA sanctioned drug for the management of progressive MS is mitoxantrone, a 
chemotherapeutic agent that is modestly effective and carries significant toxicities, including 
cardiomyopathy and leukemia.  There is a dire need for novel agents that stabilize the disease 
course in patients with SPMS without imposing undue risks. 


 
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Although focal blood-brain-barrier breakdown and perivascular infiltrates are relatively more 
common in RRMS, a substantial body of data indicates that autoimmune inflammation is still 
relevant, and contributes to CNS tissue damage, during the SP stage. However, 
neuropathological studies indicate that the nature of the aberrant immune response evolves over 
the disease course and might explain why the efficacy of DMAs differs between the RR and SP 
phases.  Our anecdotal experience at the UM suggests that ECP might be effective in the 
treatment of SPMS when administered using a more frequent and prolonged schedule than that 
used in previous studies.  Based on this, and its favorable safety profile (both in MS and other 
conditions), we believe that a more rigorous evaluation of our protocol in SPMS is warranted. 
 


 
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2. STUDY OBJECTIVES 
 
2.1 Primary Objective 
To evaluate the effect of ECP compared to IVMP on accumulation of disability at 1 year (52 
weeks) in individuals with secondary progressive multiple sclerosis (SPMS).  Disability will be 
assessed using a composite measure that takes into account changes in the EDSS and 
components of the MSFC score.  
 
2.2 Secondary Objectives 
 To assess the effect of ECP versus corticosteroids on plasma levels of immunological 
factors and the frequency of circulating myelin-reactive Th1 and Th17 cells   
 To determine whether changes in immunological parameters that occur following 
initiation of ECP or corticosteroids correlate with clinical outcomes 
 To assess the impact of ECP versus corticosteroids on Expanded Disability Status Scale 
(EDSS) scores every 3 months through 2 years compared to baseline 
 To assess the impact of ECP versus corticosteroids on MSFC three dimensional 
composite z-score every 3 months through 2 years compared to baseline 
 To assess the effect of ECP on risk of clinical relapse 
 To assess the effect of ECP versus corticosteroids on the frequency of gadolinium- 
enhancing T1 weighted  lesions on cranial MRI scans obtained at months 6 and 12 
compared to baseline 
 To assess the effect of ECP versus corticosteroids on interval changes in T2 weighted 
lesion number and volume at months 6 and 12 compared to baseline.   
 To assess the tolerability and the safety profiles of ECP versus corticosteroids 
 
 


 
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3. OVERALL DESIGN AND PLAN OF THE STUDY 
3.1 Overview 
This is a Phase II randomized, open-label study to evaluate the efficacy of extracorporeal 
photopheresis (ECP) versus IVMP on disability progression in subjects with SPMS.  At the 
initial screening visit, an extensive medical history will be obtained and a detailed neurological 
examination will be performed to determine eligibility. Subjects who meet eligibility criteria will 
be enrolled in one of two study arms.  Subjects will be randomized at a 1:1 ratio to receive ECP 
(study arm) or active treatment with intravenous methylprednisolone pulses (control arm) 
administered every 4 Weeks (1 gram per infusion) for 52 weeks. 
 
ECP will be administered according to the following schedule:  
Study Arm: Weeks 1-8: 3 times per week 
Weeks 9-16: Twice per week 
Weeks 17-36: Treatment on two consecutive days every 2 weeks (or optionally, one treatment 
per week) 
Weeks 37-43: Once every 2 weeks 
Weeks 44-52: Once every 4 Weeks 
 
All subjects, including patients who receive corticosteroids, will be evaluated using the MSFC 
tool at baseline and every 3 months through 2 years (See Section 9.1 for timing of the schedule 
of assessments).  They will also be scored using the EDSS at baseline and every 3 months 
through 2 years. Subjects in the control arm will be evaluated by MSFC and EDSS during the 
week prior to their next intravenous methylprednisolone infusion. Blood will be collected for 
immune function (cytokines) testing at baseline, and months 3, 6, 9 and 12. MRI will be done at 
baseline as well as months 6 and 12 following initiation of treatment; if the disability 
measurements are stable or improved at any point in time, then ECP will be continued per 
protocol..  
Patients in the ECP arm should have all of their treatments with the CELLEX ® System. Patients 
randomized to the ECP arm must receive their treatment within 5 days of baseline visit.  
In the ECP process, UVADEX ® (methoxsalen) Sterile Solution will be injected directly the 
recirculation bag of the extracorporeal circuit after completion of the buffy coat collection. The 
dose of UVADEX® (methoxsalen) Sterile Solution will be calculated based on the standard 
treatment volume formula (See Section 6.2). 
 
 
 
 
 
 
 
 


 
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For the schedule of assessments, please refer to Section 0. 
 
 
Figure 1: Study Design  
.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECP=Extracorporeal Photopheresis MRI: Magnetic Resonance Imaging 
1 Frequency of ECP treatments: 
Three times weekly for weeks 1-8, followed by a taper to twice weekly for weeks 9-16 and then twice 
consecutively every 2 weeks (or alternatively once weekly) for weeks 17-36, then once every 2 weeks for weeks 
37-43, and once every 4 weeks for weeks 44-52.  
2 Pulsed corticosteroids, IVMP (1 g IV methylprednisolone) every 4 Weeks for 52 Weeks.  
3 EDSS and MSFC will be assessed every 3 months through 2 years  
 
Screening Assessment 
(Week -4) 
Randomization  
 
ECP Arm 1 
Pulsed Corticosteroids Arm 2 
Study complete at Week 52,  
EDSS, MSFC and MRI3 
Month 6, obtain MRI.  
 
Continue ECP to Month 9 (Week 36 ) 
and conduct EDSS and MSFC scoring.  
 
Month 6, obtain MRI.  
 
Study complete at Week 52,  
EDSS, MSFC and MRI3 


 
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3.2 
 Endpoints 
3.2.1 Primary Endpoint 
Proportion of subjects with no evidence of disease progression at week 52.  Progression is 
defined as a minimum change from baseline in one or more of the following parameters: 
 20% or greater increase in the timed 25 foot walk 
 20% or greater increase in the 9 hole peg test 
 1 point or greater increase in EDSS score in subjects with baseline EDSS scores between 
3 and 5.5 
 0.5 point or greater increase in EDSS score in subjects with baseline EDSS scores equal 
to or greater than 6 
3.2.2 Secondary Endpoints 
 Change in Plasma levels of Immunological Factors and Frequencies of IFN and IL-
17 MBP-specific PBMC at Months 3, 6, 9 and 12 compared with baseline    
 MSFC 3 dimensional composite z-score every 3 months through 2 years compared to 
baseline  
 EDSS score every 3 months through 2 years compared to baseline  
 Percentage of subjects with improvement (as defined for the primary endpoint) at 
Months 3, 6, 9 and 12 compared to baseline 
 Occurrence of clinical relapse at any point in the study 
 Interval change in T2 lesion number and volume on MRI scans obtained at months 6 
and 12 compared to baseline 
 The number and volume of gadolinium enhancing lesions on MRI scans obtained at 
months 6 and 12 compared to baseline 
 Interval change in the number and volume of gadolinium enhancing lesions on MRI 
scans obtained at months 6 and 12 compared to baseline. 
 Toxicity and Adverse events in both arms   
 
 
 
 
 
 
 
 
 


 
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3.3 Justification of the Study Design  
Mitoxantrone is the only therapy FDA-approved for the treatment of SPMS in the United States.  
However, the efficacy of mitoxantrone in SPMS patients without superimposed relapses is 
unknown and the considerably toxicities associated with this chemotherapy (including nausea, 
alopecia, menstrual disorders, urinary tract infections, amenorrhea and SAEs such as secondary 
acute myelogenous leukemia, hepatotoxicity and cardiomyopathy) limit its use. 
 
In contrast, ECP has an excellent safety and toxicity profile, even in patients using it long term.  
Experience with a similar dosing schedule has shown an excellent safety profile. In a Phase 2 
randomized study of ECP versus no ECP in chronic GVHD, Flowers et al treated 48 patients 
with ECP three times weekly on week 1, and then twice weekly from weeks 2 through 12. 
Treatments were tapered thereafter according to response, and there was no difference in the 
incidence of adverse events between patients receiving ECP (n=48) and the control arm (n=47).   
Infections, particularly pneumonia, were the main adverse event, likely related to chronic GVHD 
itself. Couriel et al treated 71 patients with 2-4 treatments per week, with taper according to 
response. Only 4 patients developed toxicity that was mild, reversible and did not require 
discontinuation of therapy. These events included: abdominal pain, variations in blood pressure 
and fever. Jagasia et al , and Greinix et al used similar treatment schedules in 64 and 59 patients 
respectively, with no reported toxicities. Abreu et al treated 28 patients with Crohn’s Disease 
twice weekly for the first 4 weeks, and then twice weekly every other week for 24 weeks. Only 2 
patients required discontinuation for adverse events attributed to ECP, including nausea, malaise 
and fever with an increase in CRP. Again, these adverse events are difficult to separate from the 
manifestations of the disease, and the authors conclude that the treatment was well tolerated. In a 
UK Consensus Statement on the use of ECP in GVHD (Scarisbrick et al), the expert panel 
reported separately on schedules for GVHD and those used for CTCL. The reason for this was 
that the “accelerated” regimen was reported to gain rapid control of GVHD with 2 to 3 
consecutive treatments every 1 to 3 weeks.  Considering MS is an autoimmune disorder, we 
opted for the schedules more commonly used in other autoimmune diseases like chronic GVHD 
or Crohn’s Disease.  
 
If ECP is proven to be therapeutically efficacious in SPMS, it will revolutionize the treatment of 
that disorder. Intravenous methylprednisolone pulses will be used in the comparator arm. Pulse 
corticosteroids are commonly used as an adjunctive therapy or monotherapy to manage 
symptoms in SPMS (Zephir H et al. 2005) A randomized, controlled, single blind phase II clinical 
trial of regular pulses of intravenous methylprednisolone administered to MS patients over 5 
years showed beneficial effects including prevention or delay of whole brain atrophy and 
disability progression, and suppression of T1-weighted MRI lesion formation (Zivodinov, et al.  
2001). Furthermore, prolonged treatment with pulsed intravenous methylprednisolone was safe 
and well tolerated. Additionally, with the current design, patients who did receive mitoxantrone 
prior to accrual will still be able to participate in this study, unless they received treatment with it 
in the last two years. 
 
Patients must be at least 18 years of age and must be able to provide informed consent.  


 
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4. STUDY POPULATION 
The study population will consist of patients with SPMS. Patients must be able to provide 
written consent and meet all the inclusion criteria and none of the exclusion criteria. 
4.1 Inclusion Criteria 
1. Patients with SPMS based on the Recommended Diagnostic Criteria for MS and clinical 
course. Secondary progression is defined by a progressive increase in disability (of at 
least 6 months duration) in the absence of relapses or independent of relapses. 
2. Demonstrate EDSS scores between 3 to 6.5 at screening.  
3. Documented EDSS progression in the 2 years prior to screening of  1 point or greater for 
patients with an EDSS score less than 6 at baseline, and greater than or equal to 0.5 for 
patients with an EDSS score greater than or equal to 6.0 at baseline. If documented EDSS 
scores are not available, a written summary of the clinical evidence of disability 
progression over the last 2 years, and retrospective assessment of EDSS score from data 
in the medical records, must be submitted for review by the principal investigators.   
4. Documented absence of clinical relapse within 2 years of screening 
5. Age ≥ 18 ≤ 75 years 
6. Weight > 40≤ 150 kg. 
7. Absolute Neutrophil count ≥ 2,000 per μL 
8. Hematocrit ≥ 28 % and platelet count > 100,000 per μL (with or without transfusion 
support) 
9. Willingness to use at least 1 reliable method of birth control (e.g. abstinence, oral 
contraceptives, intrauterine devices, barrier method with spermicide, or surgical 
sterilization) throughout the study for all men and women of childbearing potential 
10. Willingness to participate in all study visits and procedures, as outlined in the informed 
consent  
11. Patients able to give informed consent. 
12. Patients must have adequate peripheral venous access to initiate ECP therapy. 
 
4.2 Exclusion Criteria 
1. Absolute medical contraindication to corticosteroid treatment 
2. Absolute medical contraindication to receive ECP 
3. Clinical relapse within 2 years of screening 
4. Laboratory evidence of any of the following: 
a. WBC  < 2,000 cells per uL 
b. Serum transaminase levels > x 2 UNL 
c. Creatinine Clearance < 60 mL/min 
d. HgbA1C > 6%  


 
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5. Concurrent diagnosis of a neurological condition that would interfere with the assessment 
of MS, or an autoimmune disease or inflammatory condition that is chronically treated 
with immunosuppressive agents, including systemic corticosteroids. 
6. Evidence of known infection with human immunodeficiency virus (HIV) or active (not 
including latent) Hepatitis B (laboratory testing is not required if virus status is already 
known) 
7. Uncontrolled infection requiring treatment at study entry 
8. Hypersensitivity or allergy to psoralen (methoxalen) 
9. Hypersensitivity or allergy to both heparin and citrate products (If hypersensitive or 
allergic to only one of these products, exclusion does not apply) 
10. Inability to tolerate fluid changes associated with ECP (e.g. inadequate renal, hepatic, 
pulmonary and cardiac function leading to enable patient to tolerate extracorporeal 
volume shifts associated with ECP) 
11. Presence of aphakia or photosensitive disease (systemic lupus erythematosis, porphyrias, 
albinism, etc.) 
12. Women who are pregnant and/or lactating. 
13. Use of any investigational drug/treatment at the time of enrollment or within the previous 
60 days, or five elimination half-lives, or until the expected pharmodynamic effect has 
returned to baseline, whichever is longer. 
14. Initiation of dalfampridine or change in the dose of dalfampridine within 6 months prior 
to randomization 
15. Treatment with any of the medications or procedures listed below: 
 Glatiramer acetate, interferon-beta, fingolimod, teriflunomide or 
dimethylfumarate within 3 months prior to randomization  
 Natalizumab within 3 months prior to randomization 
 Cyclophosphamide within 1 year prior to randomization 
  Mitoxantrone within 1 years prior to randomization 
 Rituximab within 6 months prior to randomization  
 Ofatumumab, ocrelizumab, cladribine, daclizumab within 2 years prior to 
randomization 
  Intravenous immunoglobulin within 6 months prior to randomization 
 Plasmapheresis within 6 months prior to randomization  
16. Corticosteroids within 3 months prior to screening, with the following exceptions: 
Topical ointments or creams, or eye drops that contain corticosteroids; Intranasal Steroids 
or Oral Steroids given in a single dose as a premedication for a procedure such as 
gadolinium-enhanced MRI. 
17. Inability to undergo MRI scans 
18. Contraindication to gadolinium due to past allergic, hypersensitive or adverse reaction or 
impaired renal function. Patients receiving a steroid prep prior to Gadolinium 
administration due to history of hypersensitivity or allergy to other agents or due to prior 
mild reaction to Gadolinium will not be excluded from the study.Any other disease or 


 
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condition which, in the opinion of the investigator, could interfere with participation in 
the study according to the study protocol, or with the ability of the patients to cooperate 
and comply with study procedures. 
19. Poor venous access 
20. Previous history of skin cancer, leukemia/lymphoma/myeloma or bone marrow 
transplant. 
21. Patients taking Coumadin who are unable to switch from oral anticoagulants to 
enoxaparin.  
22. Heparin-induced thrombocytopenia 
23. Poor cardiac function 
24. Severe hypotension 


 
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5. PATIENT WITHDRAWAL AND REPLACEMENT 
Patients may withdraw from the study at any time without penalty and for any reason without 
prejudice to his or her future medical care. 
Patients must be withdrawn under the following circumstances: 
 The patient withdraws consent 
 Pregnancy (see Section 8.2.2.9) 
 Unacceptable toxicity including patients on corticosteroids who develop psychosis or aseptic 
necrosis of the femoral head 
Patients may be required to withdraw after discussion with the investigator for the following 
reasons: 
 AE(s) 
 At the discretion of the investigator 
 Violation of eligibility criteria 
 Deviation from the treatment plan specified in the protocol (e.g., incorrect administration of 
the study drug, failure to attend study visits, etc.) 
 The treating physician can withdraw the patient from the study at any time and for any 
medical reason that he/she deems necessary 
 The patient has a right to withdraw at any time, for any medical or other reasons. 
 Patients who experience a clinical relapse (defined as neurological event characterized by 
new or worsening symptoms lasting 48 hours after a stable period of at least 30 days and is 
considered in the judgment of the investigator to be a clinical relapse). Patients who fail 
therapy will be off study, and further therapy will be at the discretion of the treating 
neurologist. The study will not cover any form of therapy after the patient is off study.  
 Patients who have interval accumulation of T1 or T2 lesions and/ or gadolinium enhancing 
T1 lesions on the month 6 MRI scan 
 In all cases, the reason(s) for withdrawal, and the primary reason, must be recorded on the 
case report form (CRF) or similar.  
 
Withdrawn patients will be replaced.  
 
 
 
 


 
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6. TREATMENT  
6.1 Control Arm: Corticosteroid Treatment 
Patients randomized to the control arm will receive corticosteroids in Pulses of 1 gram of 
intravenous methylprednisolone every 4 Weeks for 52 Weeks. 
6.2 Study Arm: Extracorporeal Photopheresis 
ECP will administered according to the following schedule:  
Study Arm: Weeks 1-8: 3 times per week 
Weeks 9-16: Twice per week 
Weeks 17-36: Treatment on two consecutive days every 2 weeks (or optionally, one treatment 
per week) 
Weeks 37-43: Once every 2 weeks 
Weeks 44-52: Once every 4 Weeks 
The CELLEX® System are integrated photopheresis systems that are approved in US and 
Europe, and marked specifically to perform photopheresis. With the CELLEX® System, whole 
blood is drawn from the patient, centrifuged and separated into its components:  plasma, white 
blood cells, and red blood cells. The white blood cells and a portion of the plasma are collected 
in a separate chamber for treatment. The remaining plasma and red blood cells are returned to the 
patient untreated. This collection process is repeated over several cycles. The buffy coat 
suspension of white blood cells is then exposed to a predetermined amount of UVA light (photo 
activation) after being inoculated with UVADEX® (methoxsalen) Sterile Solution. Following the 
photo activation of the buffy coat suspension, the treated cells are returned to the patient. 
Every attempt should be made to process 1500-2000 mL of blood during each treatment. 
UVADEX® (methoxsalen) Sterile Solution is supplied in a 10 mL single-use vial. Each mL of 
solution contains 20 mcg of UVADEX® (methoxsalen) Sterile Solution. Each vial contains 
10 mL of UVADEX® (methoxsalen) Sterile Solution, which is more drug than necessary for 
most treatments. However, the vials are designed for a single use. Therefore, there will be 
surplus of drug remaining in the vial at the conclusion of each treatment. Study center staff 
should NOT attempt to reuse any portion of this unused study drug once the seal has been 
compromised. The remaining UVADEX® (methoxsalen) Sterile Solution should be discarded 
after verification of dose by the study monitor as per study reference manual. 
In the ECP process, UVADEX® (methoxsalen) Sterile Solution will be injected directly into the 
Recirculation Bag of the extracorporeal circuit after completion of the buffy coat collection, just 
prior to initiating photo activation. The dose of UVADEX® (methoxsalen) Sterile Solution used 
to inoculate these cells will be calculated 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 
*As displayed on the CELLEX® System screen 
Example: If 240 mL of the treatment volume is collected, the dose administered equals: 
 (240 mL) x (0.017) = 4.08 mL  
 4.08 rounded to the nearest tenth is 4.1 mL  


 
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Therefore, a dose of 4.1 mL of UVADEX® (methoxsalen) Sterile Solution should be 
administered to the recirculation bag. 
After the cells are inoculated with UVADEX® (methoxsalen) Sterile Solution, the buffy 
coat/plasma suspension is irradiated with ultraviolet-A light and then reinfused back into the 
patient. 
For further information, please refer to the Investigator’s Brochure. 


 
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7. STUDY PRODUCT  
7.1 Identity 
Extracorporeal Photopheresis procedural kits and UVADEX® (methoxsalen) Sterile Solution will 
be supplied by Therakos, Inc. at no cost. A CELLEX® System) must be available for treatment of 
study patients for the duration of the study.  
THERAKOS Photopheresis System  
The CELLEX® System is an integrated photopheresis systems that are approved in US and 
Europe, and marked specifically to perform photopheresis.  
Patients in the ECP arm will have all of their ECP treatments with the same CELLEX® System.   
For further information, please refer to the Investigator’s Brochure. 
In this protocol, UVADEX® (methoxsalen) Sterile Solution will be used in conjunction with the 
CELLEX® System. Please refer to the Operator’s Manual for complete information and 
instructions for operating the CELLEX® Systems (https://therakos.com). The Therakos ® 
Photopheresis Systems and kits will be ancillary clinical supplies. 
7.1.1 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 mcg/mL in a 10 mL vial. A 
complete description of the pharmacokinetic activity of methoxsalen is available in the 
Investigator’s Brochure. 
Systemic exposure to UVADEX® (methoxsalen) Sterile Solution following ECP is minimal. The 
total dose of methoxsalen used to inoculate these cells is less than 1/200th of the oral dose used 
in conjunction with the UVAR XTS® System. Plasma levels obtained as part of other clinical 
studies have shown no detectable level (<10 ng/mL) 30 minutes after the reinfusion of the treated 
cell suspension containing the UVADEX® (methoxsalen) in >75% of patients. 
Adverse events associated with the ECPs process during CTCL clinical trials 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 in the US, UK, Germany, and 
Austria for use in the palliative treatment of the skin manifestations of CTCL unresponsive to 
other therapies. 
7.2 Packaging, Labeling and Storage 
UVADEX® (methoxsalen) Sterile Solution is packaged in 10 mL, 13 mm, United States 
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. 


 
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UVADEX® (methoxsalen)  Sterile Solution must be stored at between 15°C and 30°C (USA 
labeling) or less than 25°C (European labeling). 
Procedural kits should be stored in a secure location, at room temperature, and labeled with 
“Clinical Trial Use Only”. 
UVADEX® (methoxsalen)  Sterile Solution will be labeled according to the US regulations, and 
will be labeled as “Investigational Product”. 
Corticosteroids will be obtained from the Pharmacy at the University of Michigan.  
 
7.3 Drug Accountability 
7.3.1 Shipment and Receipt 
At the time clinical supplies UVADEX® (methoxsalen) Sterile Solution and Procedural Kits are 
received at the University of Michigan, a “Receipt of Investigational Drug/Device” form will be 
completed. This receipt will include the total number of supplies received, the date received, and 
the condition of the supplies at time of receipt. This form is to be signed and dated by the staff 
member appointed by the investigator to account for investigational supplies. The white copy of 
this form is to be returned to the Therakos clinical department or its designated representative. 
The yellow copy of the form should be kept at the site and filed with the investigational 
drug/device log. 
In the event that drug or devices do not arrive at the study center by the date indicated on the 
form or the number of investigational products received at the site does not correspond with the 
number indicated on the form, Therakos clinical department should be notified immediately. 
7.3.2 Accountability Logs 
An accurate record of all supplies received and used at the University of Michigan should be 
maintained and updated regularly. Procedural kit use 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 drug or devices are damaged, an account should 
be made on the appropriate log. 
At the conclusion of the study, all remaining procedural kits must be returned to the Therakos or 
destroyed at the site according to the clinical monitoring plan. Once all study products have been 
accounted for and verified by Therakos or its designated agent, unused vials of UVADEX® 
(methoxsalen) Sterile Solution will be destroyed. 
7.3.3 Investigational Device 
An Investigational device, the CELLEX® System, is available at the University of Michigan. 
7.4 Compliance 
Study drug used, dosage administered, and intervals between visits will be recorded during the 
study. 
7.5 Concomitant Medications  
Any medication the patient takes other than the study drug, including herbal and other non-
traditional remedies during the 52 Week study, is considered a concomitant medication. All 
concomitant medications must be recorded in the CRF. The following information must be 


 
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recorded in the CRF for each concomitant medication: generic name, route of administration, 
start date, stop date, dosage, and indication. Any changes in the dosage or regimen of a 
concomitant medication must be recorded in the CRF. 
At Screening, patients will be asked what medications they have taken during the last 30 days 
and what concomitant medication they are taken. At each subsequent study visit, patients will be 
asked what concomitant medications they are currently taking. 
The following drugs/therapies are permitted at the investigator’s discretion: 
 Medications to prevent infection (pneumocystis, viruses and fungal organisms, etc.) per 
institutional practice. 
 Venous access for ECP (at investigator’s discretion and per institutional practice). 
 Systemic steroids may be administered for clinical relapse or the emergence of gadolinium 
enhancing MRI lesions. 
The following drugs/therapies are prohibited during the treatment period of the study: 
 Tysabri® (natalizumab) or other intravenous DMA 
 Initiation of dalfampridine or change in the dose of dalfampridine within 6 months prior to 
randomization 
 Treatment with any of the medications or procedures listed below: 
 Glatiramer acetate, interferon-beta, fingolimod, teriflunomide or dimethylfumarate within 3 
months prior to randomization  
 Natalizumab within 3 months prior to randomization 
 Cyclophosphamide within 1year prior to randomization 
 Mitoxantrone within 1 years prior to randomization 
 Rituximab within 6 months prior to randomization, 
 Ofatumumab, ocrelizumab, cladribine, daclizumab within 2 years prior to randomization 
  Intravenous immunoglobulin within 6 months prior to randomization 
 Plasmapheresis within 1 year prior to randomization  
Corticosteroids within 3 months prior to screeing, with the following exceptions: Topical 
ointments or creams, or eye drops that contain corticosteroids; Intranasal Steroids or Oral 
Steroids given in a single dose as a premedication for a procedure such as gadolinium-enhanced 
MRI. 


 
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8. PARAMETERS AND METHODS OF ASSESSMENT 
8.1 Efficacy Parameters 
8.1.1 MSFC 
The MSFC components can be found in Appendix 1. This scoring system should be administered 
after reading the manual to ensure that a standardized format should be followed. The MSFC 
consists of the following components and should be done in the following order:  
1. Trial 1: Timed 25-Foot Walk 
2. Trial 2: Timed 25 Foot Walk 
3. Trial 1: Dominant Hand, 9-HPT 
4. Trial 2: Dominant Hand, 9-HPT 
5. Trial 1: Non-Dominant Hand, 9-HPT 
6. Trial 2: Non-Dominant Hand, 9-HPT 
7. PASAT-3” 
An individual component should be discontinued only if the patient meets the discontinue 
criteria for that component. Other components should still be administered.  
Every effort should be made to use the same testing room and the same designated area for the 
Timed 25 Foot Walk at every visit. It is essential that that the potential for external distraction be 
kept to a minimum. If the space designated for the  Timed 25 Foot Walk is in a public hallway, 
complete privacy may be impossible, however, every attempt must be made to keep the patient’s 
path clear of obstacles (human and inanimate). No one other than the examiner and the patient 
should be in the testing room during 9-HPT and PASAT. The first time a subject takes the 
PASAT, practice sequences are initially administered a maximum of 3 times. 
The response definitions are as below: 
An MSFC score is created from the tests done above. Details can be found in the publication 
referenced (Fischer et al). The composite consists of Z score from the components tested and 
compared using normals to standardize the scored. The MSFCS is a continuous variable that can 
be used as any numerical variable in analyses. The value is subject to tests appropriate for 
continuous variables, such as t-tests, Analysis of variance and regression analysis as well as 
nonparametric test. A composite based on such Z-scores can also measure change in 
performance over time. By computing the composite at one point in time and measuring the 
patient at a later point in time, the arithmetic difference between MSFC scores can be used to 
measure improvement or worsening.  
 
8.1.2 EDSS 
The EDSS form can be found in Appendix 2. The scores are calculated from the Functional 
System Score (FSS). EDSS and FSS will be determined by a single neurologist at baseline, and 
every 3 months through 2 years.  
 
The EDSS is an ordinal scale with a 0.5-point increments ranging from 0-10.0. (increasing score 
indicates worsening) and based largely on ambulatory impairment in its middle range (EDSS 
4.5-7.5 points).  


 
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0= normal neurological exam 
10-death due to MS 
Score 6 is still ambulatory with assistance 
Score of 7 means patient must use a wheelchair. 
 
8.1.3 MRI  
All patients will be evaluated with cranial MRI examination on a 1.5 tesla strength magnet at 
baseline and months 6 and 12 using the following sequences: axial T2-weighted, axial and 
sagittal T1 weighted, axial and sagittal fluid attenuated inversion recovery  (FLAIR), post 
Gadolinium axial and coronal T1 weighted images. The total number of gadolinium enhancing 
T1-weighted lesions and interval changes in the number and size of T-weighted, FLAIR and T1-
weighted lesions will be determined by a board certified neuro-radiologist.  
 
8.2 Safety Parameters 
8.2.1 Immunological Studies 
The following immune parameters will be measured at baseline, and again at 3, 6, 9 and 12 
months. Frequency of myelin basic protein-specific IFN or IL-17 producing PBMC, Frequency 
of tetanus toxoid –specific IFN or IL-17 producing PBMC, plasma levels of  IFN, IL-17, IL-4, 
IL-10, IL-12, IL-21, IL-23, CCL2, GRO, CXCL8, CXCL10, CCL11, CXCL13, GM-CSF, G-
CSF and neutrophil elastase.  Additional inflammatory molecules might be measured based on 
preliminary findings. 
 
8.2.2 Adverse Events 
8.2.2.1 Collection of Adverse Events 
It is the responsibility of the investigator to collect all AEs (both serious and non-serious) 
derived by spontaneous, unsolicited reports of patients, by observation and by interval open 
questioning. 
8.2.2.2 Definitions 
An AE is any untoward medical occurrence that occurs in a patient or clinical investigation 
subject administered a pharmaceutical product, and which does not necessarily have to have a 
causal relationship with this treatment. An AE can therefore be any unfavorable and unintended 
sign (including a clinical significant abnormal laboratory finding), symptom, or disease 
temporally associated with the use of an investigational product, whether or not considered 
related to the product. 
All AEs, including intercurrent illnesses, occurring during the study will be documented in the 
CRF. Underlying disease worsening (MS), hospitalization for routine study activities, and 
abnormal laboratory results associated with MS, will not be considered as AEs. Relapse of 
underlying malignancy will not be considered as an AE/SAE but will be captured and analyzed 
separately. MS will not be considered as an AE, unless it meets any of the seriousness criteria, in 


 
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particular hospitalization or death. Concomitant illnesses, which existed prior to entry into the 
study, will not be considered AEs unless they worsen during the treatment period. Pre-existing 
conditions will be recorded in the CRF on the Medical History or appropriate page. AEs will be 
captured after informed consent signed until 30 days post the completion of the last intervention. 
(Week 52).  
8.2.2.3 Assessment of Adverse Events 
Each AE will be assessed by the investigator with regard to the following categories. 
8.2.2.3.1 Seriousness 
A serious AE (SAE) is defined as any untoward medical occurrence that at any dose: 
 Results in death; 
 Is life-threatening;  
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(s) 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. Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions 
that do not result in hospitalization; or development of drug dependency or drug abuse. 
Medical and scientific judgment should be exercised in deciding whether a case is serious.  
8.2.2.3.2 Intensity 
The intensity of each AE must be assessed by the investigator using one of the following 
categories, and recorded in the CRF: 
 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. 
8.2.2.3.3 Causality 
The investigator will assess the causality / relationship between the study treatment groups 
(corticosteroids or ECP) and the AE and record that assessment in the CRF.  
The most likely cause of an SAE (e.g., disease under treatment, concomitant disease, 
concomitant medication, other) will be indicated on the CRF with details of the concomitant 
disease or medication or other cause. 
The causal relationship of the AE to study drug/device will be described in terms of: 
 Probable: the AE: 
– Follows a reasonable temporal sequence from administration of the study drug/device. 
– Could not be reasonably explained by the patient’s clinical state, environmental or toxic 
factors or other therapies administrated to the subject. 
– Disappears or decreases on cessation or reduction in dose of the study drug/device. 


 
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– Follows a known pattern of response to the study drug/device. 
– Reappears or worsens upon rechallenge. 
 Possible: the AE: 
– Follows a reasonable temporal sequence from administration of the study drug/device. 
– Could be reasonably explained by the patient’s clinical state, environmental or toxic 
factors or other therapies administrated to the subject. 
– Follows a known pattern of response to the study drug/device. 
 Unlikely: the AE 
– Does not follow a reasonable temporal sequence from administration of the study 
drug/device. 
– Could be reasonably explained by the patient’s clinical state, environmental or toxic 
factors or other therapies administrated to the subject. 
– Does not follow a known pattern of response to the study drug/device. 
– Does not reappear or worsen upon 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/device. 
For SAEs related or possibly related to ECP, the investigators will also provide an assessment of 
whether the SAE is related to the drug, UVADEX® (methoxsalen) Sterile Solution or the 
procedure/device. 
8.2.2.4 Recording Adverse Events 
Adverse event reporting will extend from signing of informed consent until completion of study 
(Week 52) or 30 days after the last study intervention. Adverse events occurring after the end of 
the study should be reported to the Sponsor by the investigator if the investigator considers there 
is a causal relationship with the study treatment.  
All AEs (including AEs resulting from active standard of care medication and study instrument), 
regardless of the relationship to study drug, will be recorded in the CRF.  
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 AE reports should contain a brief description of the event, date of onset, date of resolution, 
intensity, treatment required, relationship to study drug, action taken with the study drug, 
outcome, and whether the event is classified as serious. 
8.2.2.5 Reporting Serious Adverse Events 
All SAEs, regardless of relationship to the study agent(s) or study procedure(s), must be reported 
to the investigator, or his designee, within 24 hours of observation 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 the Box on page 39 and in the Study Reference Manual. 
The Investigator will review each SAE report and the investigator will evaluate the seriousness 
and the causal relationship of the event to study treatment. In addition, the Investigator will 
evaluate the expectedness according to the reference document (Investigator Brochure, Device 


 
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Instructions for Use (IFC) and the informed consent document). Based on the Investigator’s 
assessment of the event, a decision will be made concerning the need for further action.  
Hospitalization due to MS progression will be considered as an SAE. Hospitalization for an 
elective or planned procedure to treat a preexisting condition will not be considered as an SAE 
unless it results in one of the other outcomes listed above. Hospitalizations for study agent 
administration only will not be considered as SAEs. Details for the reporting of suspected 
unexpected serious adverse reactions (SUSARs) can be found in Section 8.2.2.7. 
All SAEs will be recorded from signing of informed consent until the end of the study (Week 
52). 
Safety contact for study: 
Safety Line Number: 734-936-8785 
Safety Fax Line:  
Email:  Daniel Couriel <dcouriel@med.umich.edu> 
Investigator Responsible for SAE reporting: Dr. Daniel R. Couriel 
 
 
SAE reporting Instructions: 
 Fax the SAE form and any supporting documentation to the Investigator. 
 Telephone the Investigator to confirm that you have faxed a SAE form  
 Provide investigator’s name, your name, the telephone number where you can be reached, 
and the protocol number and title. 
The minimum information required for an initial report is: 
 Sender of report (name, address of investigator). 
 Patient identification (screening/randomization number, initials, NOT patient name). 
 Protocol number. 
 Description of SAE. 
 Causality assessment. 
After receipt of the initial report, the Investigator will review the information and, if necessary, 
contact the involved physician to obtain further information for assessment of the event. The 
Investigator or his designee will be responsible for all information processing and reporting 
according to legal requirements following ICH E6 guidelines. The Sponsor-Investigator will be 
responsible for all safety reporting to the FDA.   Details for the reporting of SUSARs and 
UADE’s can be found in Section 8.2.2.7 
8.2.2.6 Follow-up of Adverse Events 
All AEs experienced by a patient, irrespective of the suspected causality, will be monitored until 
the event has resolved, any abnormal laboratory values have returned to baseline or stabilized at 
a level acceptable to the investigator, until there is a satisfactory explanation for the changes 
observed, or until the patient is lost to follow-up or event is unlikely to resolve. 
Data and Safety Monitoring Board (DSMB) 
To protect the interests of research subjects and ensure that they are not exposed to undue risk, 
this trial will be monitored by an independent DSMB, consisting of appropriate medical experts 


 
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with no formal involvement with the subjects or the investigation and will function 
independently of the Clinical Study Team. 
 
The Blood and Marrow Transplantation 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.  Based on 
the safety data, the DSMB may recommend that the trial be modified or stopped or may request 
an interim analysis for efficacy.   
 
8.2.2.7 Suspected Unexpected Serious Adverse Reactions  
Any AE that is serious, associated with the use of the study drug, and unexpected (defined as the 
nature or severity of event, which is not consistent with the applicable product information [i.e. 
Investigator’s Brochure]) (SUSARs) has additional reporting requirements, as described below.  
 If the SUSAR is fatal or life-threatening, associated with the use of the study drug, and 
unexpected, regulatory authorities and ethics committees will be notified within 7 calendar 
days after the Sponsor learns of the event. Additional follow-up (cause of death, autopsy 
report, and hospital report) information should be reported within an additional 8 days 
(15 days total).  
 If the SUSAR is not fatal or life-threatening but is otherwise serious, associated with the use 
of the study drug, and unexpected, regulatory authorities and ethics committees will be 
notified within 15 calendar days after the Sponsor learns of the event.  
The Sponsor will notify the 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. 
 
Unanticipated Adverse Device Effects (UADE) 
An unanticipated adverse device effect (UADE) means any serious adverse effect on health or 
safety or any life-threatening problem or death caused by, or associated with a device, if that 
effect, problem, or death was not previously identified in nature, severity, or degree of incidence 
in the investigational plan or application, or any other unanticipated serious problem associated 
with the device that relates to the rights, safety, or welfare of the subjects. 
 
UADEs will be reported to the FDA as outlined nad required under 21 CFR p812.150(b)(1).  
 
8.2.2.8 Pregnancy 
The Sponsor has a responsibility to monitor the outcome of pregnancies where there has been 
maternal exposure to the investigational drug.  


 
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Pregnancy alone is not regarded as an AE unless there is a suspicion that the investigational 
product 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 a SAE. 
All pregnancies must be reported by the investigator to the FDA on the initial pregnancy report 
form within 30 days after becoming aware of the pregnancy. The investigator must follow up and 
document the course and the outcome of all pregnancies even if the subject was discontinued 
from the study or if the study has finished. 
All outcomes of pregnancy must be reported by the Sponsor-Investigator to the FDA 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. 
If a spouse of a male study subject who has been exposed to the Investigational Medicinal 
Product becomes pregnant, every effort should be made to monitor the pregnancy and outcome 
of pregnancy. A separate informed consent will be provided for the spouse prior to any data 
being collected regarding the pregnancy.  
8.2.2.9 Complaint Reporting/Device Malfunctions 
All device malfunctions should be reported to Therakos’ support Hotline. The customer technical 
support phone numbers are 877-865-6850 in the US. Dialer should identify his/her involvement 
in this clinical study. 
Device malfunctions do not have to be recorded in the CRF. Any AEs resulting from the 
malfunction will be reported in the CRF per Section 8.2.2. 
8.2.3 Laboratory Parameters 
Clinical laboratory assessments will be performed by the UM Hospital Clinical Laboratory at the 
University of Michigan. Research laboratory studies to measure immunological parameters will 
be conducted the Neuroimmunology Research Laboratory in the Department of Neurology at the 
University of Michigan (Dr. Segal, Director). 
Blood samples should be taken using standard venipuncture techniques. Blood samples should 
be processed according to the procedure described in the laboratory manual.  
Laboratory parameters will be determined in accordance with the Schedule of Assessments on 
Table 2. 
 
 


 
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Table 1: Laboratory Assessments 
Hematology: 
Complete CBC 
Chemistry: 
Creatinine 
Glucose 
Triglycerides 
Urea 
Uric acid 
Bilirubin 
Cholesterol 
Sodium 
Potassium 
Liver Function 
Tests 
Alkaline phosphatase 
Aspartate transaminase  
Alanine transaminase 
 
Immune 
Parameters 
Myelin basic protein –specific IFN or IL-17 producing PBMC, 
Frequency of tetanus toxoid –specific IFN or IL-17 producing 
PBMC, plasma levels of  IFN, IL-17, IL-4, IL-10, IL-12, IL-21, IL-
23, CCL2, GRO, CXCL8, CXCL10, CCL11, CXCL13, GM-CSF, 
G-CSF and neutrophil elastase 
Clinically significant laboratory abnormalities should be recorded as AEs according to 
investigator’s judgment. The maximum total amount of blood that will be taken during the study 
from an individual patient for research studies is 60 ml per blood draw.  There will be a total of 
five blood draws, separated by intervals of 9 weeks or longer. Patients on ECP will have an 
additional blood draw of 5 ccs prior to every procedure to determine hematocrit and platelet 
count.  
8.2.4 Vital Signs 
The following vital signs will be assessed in accordance with the Schedule of Assessments 
(Table 2): 
 Weight and Height (height will be measured only at Screening); 
 Blood pressure (systolic and diastolic; mmHg); 
 Heart rate (beats per minute); 
 Body temperature (°C); 
 Respiration rate (breaths per minute). 
These variables should be collected after the patient has been sitting for 5 minutes. 


 
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8.2.5 Physical Examinations 
A brief physical examinations will be performed in accordance with the Schedule of 
Assessments (Table 2).   
8.2.6 Medical History and Interim History 
A complete medical history will be performed at start of study and a briefer interim history 
performed at each visit.  


 
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9. STUDY CONDUCT 
9.1  Schedule of Assessments 
The schedule of assessments is shown in months, as it facilitates better comprehension, 
preventing potential errors, in the interpretation of the exact timing for each assessment. On the 
other hand, in order to facilitate integration with the weekly-based schedule of ECP, and also 
budget considerations, we use the following transformation between weeks and months when 
addressing the schedule of assessments: 
a- 3 months: Week 12+/-2 week 
b- 6 months: Week 24 +/-2week 
c- 9 months: Week 36 +/-2 week 
d- 12 months or 1 year: Week 52 +/- 1 month 
 
The schedule of assessments is shown in Table 2. 
 


  
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Table 2: 
Schedule of Assessments 
Procedures 
Screening 
(-30days) 
Baseline5  
(Week 2) 
Month 3 
 
Month 6 
 
Month 9 
 
 12 months/1year 
Til End of Study 
(evey 3 months through 2 
years)8 
Informed Consent 
X 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
Vital Signs  
 
X 
X 
X 
X 
X 
 
Medical History/ Interim History 1 
X 
X 
X 
X 
X 
X 
 
Physical Examination 
 
X 
X 
X 
X 
X 
 
MSFC8 
 
X 
X 
X 
X 
X 
X 
EDSS8 
 
X 
X 
X 
X 
X 
X 
MRI 
 
X 
 
X 
 
X 
 
Pregnancy Test2 
X 
 
 
 
 
 
 
Immune Parameters Measurement 
 
X 
X 
X 
X 
X 
 
Clinical Laboratory Tests3 
X 
X 
 
 
 
X 
 
Pre-study/Concomitant 
MedicationsMRI 
X 
XX 
X 
XX 
X 
XX 
 
Adverse Events 
X 
X 
X 
X 
X 
X 
 
Randomization to ECP5,6 vs IVMP7 
X 
 
 
 
 
 
 
 
1 Including history of MS, progression from RRMS to onset of SPMS. A complete history at start of study and interim history at each visit.  
2For women of childbearing potential. 
3 Both at screening and prior to each ECP procedure, a small amount of blood (2-4 teaspoons) will be drawn to evaluate CBC and chemistries. 
4Subjects will be  randomized at a 1:1 ratio to either ECP.or IVMP  
5Patients should have ECP within 14 days of baseline visit.   
6The frequency of ECP treatments will be: 
Weeks 1-8: 3 x/ week 
Weeks 9-16: 2x/week 
Weeks 17-36: 2x/2 weeks 
Weeks 37-43: 1x / every 2 weeks 
Weeks 44-52: 1x/ every 4 Weeks 
7 Corticosteroid is administered on a pulse basis and consists of 1 gram of methylprednisolone I.V. every 4 Weeks for 52 Weeks.  
8These test will occur every three month through 2 years.


  
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9.2 Observations by Visit 
Visits and assessments should occur within the schedule in Table 2 according to study. All times 
should be recorded using the 24-hour clock (e.g., 23:20, not 11:20 pm). 
9.2.2 Screening  
 If patient has had an appt with a physical exam in the last 30 days, that can be used for this 
screen. 
 Obtain written informed consent. 
 Verify inclusion and exclusion criteria 
 Demographics and medical history  
 MS Scoring and History 
 Pregnancy test (for women of child-bearing potential patients only), whether to be done on 
urine or blood will be at investigator’s discretion or per institutional practice. 
 Collect blood sample for laboratory assessment (Table 1) (note: samples will be sent to local 
laboratories)  
 Record pre-study/concomitant medication 
 Randomization 1:1 
9.2.3 Baseline (Week 1)  
A baseline visit should be performed and 1st ECP scheduled within 14days. 
 Physical examination. 
 Interim History 
 Vital signs. 
 MSFC 
 MRI 
 EDSS 
 Blood for immune parameters (sent to the University of Michigan Neuroimmunology 
Research Laboratory) 
 Collect blood sample for laboratory assessment (Table 1)  
 Record concomitant medication. 
 Assessment of pre-treatment events (AEs occurring from ICF signed to baseline visit). 
 Start ECP within 14 days of baseline as defined in the schedule of assessments 
9.2.4 Month 3/Week 12  
 At this point patients who are assigned to ECP arm will have been tapered from 3 treatments 
weekly to two treatments weekly.  
 Patients randomized to the ECP arm must receive their first ECP treatment within 14 days of 
baseline visit. 
 Before ECP, on each day of treatment, blood samples will be collected for CBC or other 
clinical routine testing as needed, and no less that weekly.  
 Patients admitted to the corticosteroid arm will receive a treatment once every month as 
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o The following will also be performed at this time point: Interim history, vital signs, 
physical exam. 
o Blood for immune parameters (sent to the UM Neuroimmunology Research 
Laboratory) 
o MSFC 
o EDSS 
o Adverse Events 
o Concomitant Medications 
 
9.2.5 Month 6/Week 24 
At this point patients on ECP will have been tapered to two treatments (on 2 consecutive days) 
every 2 weeks. If preferred, patients may be given the option of receiving one weekly treatment 
(as opposed to two treatments on 2 consecutive days) a schedule modification  
 Before ECP on each day of treatment blood samples will be collected for the laboratory tests 
on Table 1 and sent to the University of Michigan Clinical Laboratory  
 Patients admitted to the corticosteroid arm will receive a treatment once every month as 
stated above 
 The following will also be performed at this time point:  
o Interim history, vital signs, physical exam. 
o Blood for immune parameters (sent to the UM Neuroimmunology Research 
Laboratory) 
o MSFC 
o EDSS 
o Adverse Events 
o Concomitant Medications 
o MRI with Gadolinium 
 
9.2.6 Month 9/ Week 36  
On weeks 37-43, ECP-treated patients transition to one treatment every two weeks and for  
Patients admitted to the corticosteroid arm will receive a treatment once every month 
 Before ECP on each day of treatment blood samples will be collected for the laboratory tests 
on Table 1 and sent to the University of Michigan laboratory to perform testing as described 
above.  
 Patients admitted to the corticosteroid arm will receive a treatment once every month as 
stated above 
 The following will also be performed at this time point:  
o Interim history, vital signs, physical exam. 
o Blood for immune parameters (sent to the UM Neuroimmunology Research 
Laboratory) 


  
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o MSFC 
o EDSS 
o Adverse Events 
o Concomitant Medications 
 
9.2.7 Week 52 through the End of Study 
 From Weeks 44-52, patients will receive one ECP treatment every 4 weeks  
 Patients admitted to the corticosteroid arm will receive a treatment once every month 
 Before ECP on each day of treatment blood samples will be collected for the tests outlined on 
Table 1 
 The following will also be performed at this time point:  
o Interim history, vital signs, physical exam. 
o Blood for immune parameters (sent to the UM Neuroimmunology  
      Research Laboratory) 
o MSFC(every 3 months through 2 years) 
o EDSS (every 3 months through 2 years) 
o Adverse Events 
o Concomitant Medications 
o MRI with Gadolinium 
 
9.2.8 Early Termination Visit 
 Patients who withdraw from the study before Week 52 but at the time of a scheduled visit must 
complete Week 52 assessments. If a patient withdraws between scheduled visits, the patient must 
come into the clinic to perform the Week 52 assessments. This study does not allow for cross-
over between study group to control group or vice-versa while on study.  


  
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10. STATISTICAL METHODS 
Any deviations from the planned analyses will be described and justified in the final integrated 
study report. 
10.1 
Planned Sample Size and Number of Study Centers  
It is planned to recruit approximately 66 patients (33 per treatment arm). This is a single center 
study.  
Patients will be randomized on a 1:1 basis to corticosteroids or ECP arm. 
Patients randomized to the ECP treatment arm must receive their first treatment within 5 days of 
the baseline visit.  
For the randomization of patients, the investigator will use an Interactive Voice Response 
System (IVRS). Details can be found in the trial master file. IVRS will assign patients to a 
treatment group based on the pre-defined randomization list. 
10.2 
Efficacy Analyses 
10.2.1 Analysis of Primary Endpoint 
The primary end point is the proportion of subjects with no evidence of disease progression, as 
defined below, at Week 52. Intent to treat approach will be used.  Progression is defined as a 
minimum change from baseline in one or more of the following parameters: 
 20% or greater increase in the timed 25 foot walk 
 20% or greater increase in the 9 hole peg test 
 1 point or greater increase in EDSS score in subjects with baseline EDSS scores between 
3 and 5.5 
 0.5 point or greater increase in EDSS score in subjects with baseline EDSS scores equal 
to or greater than 6 
The proportion of subjects who have not progressed clinically, based on the above criteria, at 
Week 52 after initiation of study therapy will be compared between treatment groups using the 
Chi-square test.    
The early drop-outs, including patients who withdraw will be considered as non-responders.  
 
10.2.2 Analysis of Secondary Endpoints 
The secondary endpoints include: 
 Change in Plasma levels of Immunological Factors and Frequencies of IFN and IL-17 
MBP-specific PBMC at months 3, 6, 9 and 12 compared with baseline    
 MSFC 3 dimensional composite z-score at every 3 month time point through 2 years 
compared to baseline  
 Expanded Disability Status Scale (EDSS) score at every 3 month time point through 2 
years compared to baseline  
 Percentage of subjects with improvement (as defined for the primary endpoint) at 
months 3, 6, 9 and 12 compared to baseline 
 Occurrence of clinical relapse at any point in the study 


  
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 Interval change in T2 lesion number and volume on MRI scans obtained at months 6 
and 12 compared to baseline 
 The number and volume of gadolinium enhancing lesions on MRI scans obtained at 
months 6 and 12 compared to baseline 
 Interval change in the number and volume of gadolinium enhancing lesions on MRI 
scans obtained at months 6 and 12 compared to baseline. 
 Toxicity and Adverse events in both arms  
For continuous outcomes, two-sample t-tests or Wilcoxon rank sum tests will be used to compare 
the treatment arms.  For categorical outcomes, Chi-square tests or Fisher’s exact test will be used 
to compare the treatment arms.  The proportion of subjects who experience adverse events and 
serious adverse events will be summarized by treatment group descriptively; no inferential tests 
will be performed. 
 
10.2.3 Interim Analyses 
There will not be any planned interim analyses for efficacy assessments. 
10.3 
Safety Analyses 
Safety parameters for each patient include vital signs, laboratory testing, including chemistry 
panel and complete blood count, and AE reporting, including AEs resulting from active 
concomitant standard of care medication. These parameters will be tabulated in line listings 
along with basic demographic information such as sex and age by clinical site and by treatment 
arms. 
10.4 
Determination of Sample Size 
Assuming that the proportion of subjects in the corticosteroid treatment who show no evidence 
of clinical progression at 52 (12 months) is 30%, 66 subjects (33 per treatment arm) provides at 
least 80% power to detect a treatment difference of 30% (i.e., 60% of the ECP treated subjects 
will show no evidence of clinical progression at 12 months), based on the normal approximation 
of the binomial distribution and a one-sided Type I error of 5%.   


  
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11. ETHICAL, LEGAL, AND ADMINISTRATIVE ASPECTS 
11.1 
Data Quality Assurance 
This is an investigator initiated research protocol. The investigator will assure that the study will 
be conducted according to Good Clinical Practice Guidelines as outlined in ICH E6. The 
investigative team will prepare the CRFs needed for the study.  
The investigator will prepare and maintain adequate and accurate case histories designed to 
record all observations and other data pertinent to the study for each study participant. All 
information recorded on the CRFs for this study must be consistent with the patients’ source 
documentation (i.e., medical records). 
11.2 
Case Report Forms and Source Documentation 
The CRF’s will be the basis for data entry for this study.  The investigator will assure that the 
data are correctly entered into the CRFs and the study monitor for the study will assure that this 
corresponds to the source documentation. Any discrepancies will be corrected as needed and 
signed off by the investigator.  
11.2.1 Data Collection  
Access and right to the CRFs will be carefully controlled and configured according to each 
individual’s role throughout the study. In general, only the investigator and authorized staff will 
be able to enter data and make corrections in the CRFs. 
The CRF 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 CRFs are to be completed 
as soon as possible during or immediately after the patient’s visit or assessment. The investigator 
must verify that all data entries in the CRF are accurate and correct. If some assessments cannot 
be done, or if certain information is unavailable, not applicable or unknown, the Investigator 
should indicate this in the CRF. 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 investigator will be required to sign off the clinical data 
Data about all study drugs dispensed to the patient will be tracked on CRFs. 
11.3 
Access to Source Data 
During the course of the study, a designated clinical monitor will review protocol compliance, 
compare CRFs and individual patient’s medical records, assess drug accountability, and ensure 
that the study is being conducted according to pertinent regulatory requirements. CRF 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 CRFs for completeness and clarity, and crosschecking with source documents, 
will be required to monitor the progress of the study. Moreover, regulatory authorities, 
Institutional Review Boards (IRBs) 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.  


  
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11.4 
Data Processing 
All data will be entered by site personnel into the CRFs.  
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 ATC classification system. Medical 
history/current medical conditions and AEs will be coded using the Medical dictionary for 
regulatory activities (MedDRA) terminology. 
The versions of the coding dictionaries can be obtained or provided by Therakos.   
11.5 
Archiving Study Records 
According to International Conference on Harmonization (ICH) guidelines, essential documents 
should be retained for a minimum of 2 years after final publication and until there are no pending 
or contemplated publication or 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 required by the applicable legal requirements. 
11.6 
Good Clinical Practice 
The procedures set out in this study protocol are designed to ensure that the study will be 
conducted in accordance with the principles of the Good Clinical Practice guidelines of the ICH, 
and of the Declaration of Helsinki (1996). The study also will be carried out in keeping with 
local legal requirements.  
11.7 
Informed Consent 
Before each patient is admitted to the study, informed consent will be obtained from the patient 
(or his/her legally authorized representative) according to the regulatory and legal requirements 
of the participating country. This consent form must be dated and retained by the investigator as 
part of the study records. The investigator will not undertake any investigation specifically 
required only for the clinical study until valid consent has been obtained. The terms of the 
consent and when it was obtained must also be documented in the CRF. 
If a protocol amendment is required, the informed consent form may need to be revised to reflect 
the changes to the protocol. If the IRB requests, patients that are currently enrolled in the study  
will be re-consented with the revised consent.  
11.8 
Protocol Approval and Amendment 
Before the start of the study, the study protocol and/or other relevant documents will be approved 
by the IRB, 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  Device Exemption (IDE) 
for the product to the FDA for notification/comment.  
This protocol is to be followed exactly. To alter the protocol, amendments must be written, 
receive approval from the appropriate personnel, and receive IRB approval prior to 
implementation (if appropriate). Following approval, the protocol amendment(s) will also be 
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Administrative changes (not affecting the patient benefit/risk ratio) may be made without the 
need for a formal amendment. All amendments will be distributed to all protocol recipients, with 
appropriate instructions. 
11.9 
Duration of the Study 
For an individual patient, the maximum duration of the study for each patient will be up to 52 
weeks (excluding up to 1 week screening). The total study is expected to last 2 years.  
11.10 
Premature Termination of the Study 
If the Sponsor-Investigator, or the DSMB becomes aware of conditions or events that suggest a 
possible hazard to patients if the study continues, the study may be terminated after appropriate 
consultation between the relevant parties. The study may also be terminated early at the Sponsor-
Investigator’s discretion in the absence of such a finding. 
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; 
11.11 
Confidentiality 
All study findings and documents will be regarded as confidential.  
The anonymity of participating patients must be maintained. Patients will be identified on CRFs 
and other documents by their patient number, initials and/or birth date, not by name.  
11.12 
Other Ethical and Regulatory Issues  
If a significant safety issue is identified, either from an individual case report or review of 
aggregate data, then the Sponsor will issue prompt notification to all parties – regulatory 
authorities, investigators and IRB. 
A significant safety issue is one that has a significant impact 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. 
11.13 
Publication Policy 
Since this is an investigator-sponsored research, the Investigator will publish the records as per 
the policy of the University of Michigan.  
 
11.14     Monitoring of the Study 
 
To assure adequate protection of the rights of human subjects, per 21 CFR §812.40, 812.43 and 
812.46, this study will be monitored by the University of Michigan Institute of Clinical and 
health research (MICHR) Routine monitoring will be scheduled at appropriate intervals, with 
more frequent visits occurring at the beginning of the study.  A site activation visit will take 
place, followed by routine monitoring visits.  Additional visits can be scheduled at the request of 
the Study Team, Steering Committee or Data and Safety Monitoring Board (DSMB). 
 


  
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The established monitoring plan will ensure the quality and integrity of the data throughout the 
study conduct to verify adherence to the protocol, completeness and accuracy of study data and 
samples collected, dispensing and inventory of the device, and compliance with regulations. 


  
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12. REFERENCE LIST 
 
Abreu, M.T., et al., Extracorporeal photopheresis for the treatment of refractory Crohn's disease: 
results of an open-label pilot study. Inflamm Bowel Dis, 2009. 15(6): p. 829-36. 
 
Besnier  DP et al. Extracorporeal photochemotherapy for secondary chronic progressive multiple 
sclerosis: a pilot study. Photodermatol. Photoimmuneol. Photomed. 2002; 18:36-41. 
 
Cavallitti G et al. Extracorporeal photochemotherapy: a safety and tolerability pilot study with 
preliminary efficacy results in refractory relapsing-remitting multiple sclerosis. Neurol. Sci. 
2002;27:24-32. 
 
Comi G. Extracorporeal phototherapy in multiple sclerosis. Neur. Sci. 2006;27:3-4.  
 
Couriel, D., et al., Extracorporeal photopheresis for acute and chronic graft-versus-host disease: 
does it work? Biol Blood Marrow Transplant, 2006. 12(1 Suppl 2): p. 37-40. 
 
Filippi et al. Magnetization transfer ratio changes in a symptomatic lesion of a patient at 
presentation with possible multiple sclerosis. J Neurol Sci. 1997 Oct 3; 151(1): 79-81. 
 
Fischer JS et al. Multiple Sclerosis Functional Composite: Administration and Scoring Manual. 
National Multiple Sclerosis Society. 2001. 
 
Frischer JM, Bramow S, Dal-Bianco A, et al. The relation between inflammation and 
neurodegeneration in multiple sclerosis brains. Brain. 2009;132:1175-89.  
 
Flowers, M.E., et al., A multicenter prospective phase 2 randomized study of extracorporeal 
photopheresis for treatment of chronic graft-versus-host disease. Blood, 2008. 112(7): p. 2667-
74. 
 
Greinix, H.T., et al., The effect of intensified extracorporeal photochemotherapy on long-term 
survival in patients with severe acute graft-versus-host disease. Haematologica, 2006. 91(3): p. 
405-8. 
 
Jagasia, M.H., et al., Classic and overlap chronic graft-versus-host disease (cGVHD) is 
associated with superior outcome after extracorporeal photopheresis (ECP). Biol Blood Marrow 
Transplant, 2009. 15(10): p. 1288-95. 
 
Kurtzke JF Rating Neurologic impairment in multiple sclerosis. An expanded disability status 
scale (EDSS). Neurology 1983; 33:1444-1452 
 
Kutzelnigg  A. et al. Cortical demyelination and diffuse white matter injury in multiple sclerosis. 
Brain. 2005 Nov; 128(Pt. 11): 2705-12. Epub 2005 Oct 17. 
 
Lassman H. Cortical lesions in multiple sclerosis: inflammation vs. neurodegeneration. Brain. 
2012; 135(Pt 10): 2904-5.  


  
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Panitch, H et al North American Study Group on Interferon beta-1b in Secondary Progressive 
MS. Neurology. 2004 Nov 23; 63(10): 1788-95. 
 
Paolilllo et al Quantitative MRI in patients with secondary progressive MS treated with 
monoclonal antibody Campath 1H. Neurology. 1999 Sep 11; 53(4): 751-7. 
 
Poehlau D. et al. Photopheresis—a possible treatment of multiple sclerosis? Report of two cases. 
J. Clin Apheresis. 1997; 12:154-155. 
 
Rommer PS and Stuve. O. Management of Secondary Progressive Multiple Sclerosis: 
Prophylactic Treatment—Past, Present and  Future Aspects. Curr. Treatment Options in 
Neurology. 2013; 15:241-258. 
 
Rostami AM et al. A double blind placebo-controlled trial of extracorporeal photopheresis in 
chronic progressive multiple sclerosis. Mult. Scler. 1999;5:198-205.  
 
Scarisbrick, J.J., et al., U.K. consensus statement on the use of extracorporeal photopheresis for 
treatment of cutaneous T-cell lymphoma and chronic graft-versus-host disease. Br J Dermatol, 
2008. 158(4): p. 659-78. 
 
Serafini B. et al  Detection of ectopic B-cell follicles with germinal centers in the meninges of 
patients with secondary progressive multiple sclerosis. Brain Pathol. 2004 Apr; 14(2): 164-74. 
 
Traboulsee AL and Li DK. The role of MRI in the diagnosis of multiple sclerosis. Advances 
Neurology. 2006; 98:125-46. 
 
Trapp BD,  and Nave KA.  Multiple sclerosis: an immune or neurodegenerative disorder? Annu 
Rev Neurosci. 2008; 31:247-69. doi: 10.1146/annurev.neuro.30.051606.094313. Review. 
 
Zéphir H, de Seze J, Dujardin K, Dubois G, Cabaret M, Bouillaguet S, Ferriby D, Stojkovic T, 
Vermersch P. One-year cyclophosphamide treatment combined with methylprednisolone 
improves cognitive dysfunction in progressive forms of multiple sclerosis. 2005 Jun; 11(3): 360-
3). Mult Scler. 2005 Jun; 11(3): 360-3. 
 
Zivadinov R, Rudick RA, De Masi R, Nasuelli D, Ukmar M, Pozzi-Mucelli RS, Grop A, Cazzato 
G, Zorzon M. Effects of IV methylprednisolone on brain atrophy in relapsing-remitting MS. 
Neurology. 2001 Oct 9; 57(7): 1239-47. 
 
 
 
 
 


  
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13. APPENDICES 
13.1 
Appendix 1 MSFC Forms 
 


  
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Instructions for carrying out the tests found in the original reference booklet.  
 


  
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13.2 
Appendix 2 EDSS 


  
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13.3 
Appendix 3: Corticosteroids Side Effects 
13.3.1 Side Effects 
Fluid and Electrolyte Disturbances  
Sodium retention;  Congestive heart failure in susceptible patients;  Hypertension; Fluid 
retention ; Potassium loss-Hypokalemic alkalosis 
Musculoskeletal Muscle weakness Loss of muscle mass Steroid  
Myopathy; Osteoporosis; Tendon rupture, particularly of the Achilles tendon; Vertebral 
compression fractures; Aseptic necrosis of femoral and humeral heads; Pathologic fracture of 
long bones 
Gastrointestinal  
Peptic ulcer with possible perforation and hemorrhage; Pancreatitis; Abdominal 
distention Ulcerative esophagitis, Increases in alanine transaminase (ALT, SGPT), aspartate 
transaminase (AST, SGOT), and alkaline phosphatase have been observed following 
corticosteroid treatment. These changes are usually small, not associated with any clinical 
syndrome and are reversible upon discontinuation. 
Dermatologic  
Impaired wound healing; Petechiae and ecchymosis; May suppress reactions to skin tests; 
 Thin fragile skin;  Facial erythema;  Increased sweating 
Neurological  
Increased intracranial pressure with papilledema (pseudo-tumor cerebri) usually after treatment; 
 Convulsions;  Vertigo;  Headache 
Endocrine  
Development of Cushingoid state,  Suppression of growth in children;  Secondary 
adrenocortical and pituitary unresponsiveness particularly in times of stress, as in trauma, 
surgery or illness;  Menstrual irregularities;  Decreased carbohydrate tolerance; 
 Manifestations of latent diabetes mellitus; Increased requirements of insulin or oral 
hypoglycemic agents in diabetics 
Ophthalmic  
Posterior sub capsular cataracts Increased intraocular pressure;  Glaucoma;  Exophthalmos 
 


  
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Metabolic  
Negative nitrogen balance due to protein catabolism . 
The following additional reactions have been reported following oral as well as parenteral 
therapy: Urticaria and other allergic, anaphylactic or hypersensitivity reactions. 
13.3.2 Warnings:  
In patients on corticosteroid therapy subjected to unusual stress, increased dosage of rapidly 
acting corticosteroids before, during, and after the stressful situation is indicated. 
 
Corticosteroids may mask some signs of infection, and new infections may appear during their 
use. Infections with any pathogen including viral, bacterial, fungal, protozoan or helminthic 
infections, in any location of the body, may be associated with the use of corticosteroids alone or 
in combination with other immunosuppressive agents that affect cellular immunity, humoral 
immunity, or neutrophil function.1These infections may be mild, but can be severe and at times 
fatal. With increasing doses of corticosteroids, the rate of occurrence of infectious complications 
increases.2 There may be decreased resistance and inability to localize infection when 
corticosteroids are used. 
 
Prolonged use of corticosteroids may produce posterior sub capsular cataracts, glaucoma with 
possible damage to the optic nerves, and may enhance the establishment of secondary ocular 
infections due to fungi or viruses. 
 
Usage in pregnancy: Since adequate human reproduction studies have not been done with 
corticosteroids, the use of these drugs in pregnancy, nursing mothers or women of child-bearing 
potential requires that the possible benefits of the drug be weighed against the potential hazards 
to the mother and embryo or fetus. Infants born of mothers, who have received substantial doses 
of corticosteroids during pregnancy, should be carefully observed for signs of hypoadrenalism. 
 
Average and large doses of hydrocortisone or cortisone can cause elevation of blood pressure, 
salt and water retention, and increased excretion of potassium. These effects are less likely to 
occur with the synthetic derivatives except when used in large doses. Dietary salt restriction and 
potassium supplementation may be necessary. All corticosteroids increase calcium excretion. 
 
Administration of live or live, attenuated vaccines is contraindicated in patients receiving 
immunosuppressive doses of corticosteroids. Killed or inactivated vaccines may be administered 
to patients receiving immunosuppressive doses of corticosteroids; however, the response to such 
vaccines may be diminished. Indicated immunization procedures may be undertaken in patients 
receiving non-immunosuppressive doses of corticosteroids. 
 
The use of MEDROL (methylprednisolone) Tablets in active tuberculosis should be restricted to 
those cases of fulminating or disseminated tuberculosis in which the corticosteroid is used for the 
management of the disease in conjunction with an appropriate antituberculous regimen. 
 


  
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If corticosteroids are indicated in patients with latent tuberculosis or tuberculin reactivity, close 
observation is necessary as reactivation of the disease may occur. During prolonged 
corticosteroid therapy, these patients should receive chemoprophylaxis. 
 
Persons who are on drugs which suppress the immune system are more susceptible to infections 
than healthy individuals. Chicken pox and measles, for example, can have a more serious or even 
fatal course in non-immune children or adults on corticosteroids. In such children or adults, who 
have not had these diseases or been properly immunized against them, particular care should be 
taken to avoid exposure. How the dose, route and duration of corticosteroid administration 
affects the risk of developing a disseminated infection is not known. The contribution of the 
underlying disease and/or prior corticosteroid treatment to the risk is also not known. If exposed, 
to chickenpox, prophylaxis with varicella zoster immune globulin (VZIG) may be indicated. If 
exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be 
indicated. (See the respective package inserts for complete VZIG and IG prescribing 
information.) If chicken pox develops, treatment with antiviral agents may be considered. 
Similarly, corticosteroids should be used with great care in patients with known or suspected 
Strongyloides (threadworm) infestation. In such patients, corticosteroid-induced 
immunosuppression may lead to Strongyloides hyper infection and dissemination with 
widespread larval migration, often accompanied by severe enterocolitis and potentially fatal 
gram-negative septicemia. 
13.3.3 PRECAUTIONS 
General Precautions 
Drug-induced secondary adrenocortical insufficiency may be minimized by gradual reduction of 
dosage. This type of relative insufficiency may persist for months after discontinuation of 
therapy; therefore, in any situation of stress occurring during that period, hormone therapy 
should be reinstituted. Since mineralocorticoid secretion may be impaired, salt and/or a 
mineralocorticoid should be administered concurrently. 
 
There is an enhanced effect of corticosteroids on patients with hypothyroidism and in those with 
cirrhosis. 
 
Corticosteroids should be used cautiously in patients with ocular herpes simplex because of 
possible corneal perforation. 
The lowest possible dose of corticosteroid should be used to control the condition under 
treatment, and when reduction in dosage is possible, the reduction should be gradual. 
 
Psychic derangements may appear when corticosteroids are used, ranging from euphoria, 
insomnia, mood swings, personality changes, and severe depression, to frank psychotic 
manifestations. Also, existing emotional instability or psychotic tendencies may be aggravated 
by corticosteroids. 
 
Steroids should be used with caution in nonspecific ulcerative colitis, if there is a probability of 
impending perforation, abscess or other pyogenic infection; diverticulitis; fresh intestinal 
anastomoses; active or latent peptic ulcer; renal insufficiency; hypertension; osteoporosis; and 
myasthenia gravis. 
 


  
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Growth and development of infants and children on prolonged corticosteroid therapy should be 
carefully observed. 
 
Kaposi's sarcoma has been reported to occur in patients receiving corticosteroid therapy. 
Discontinuation of corticosteroids may result in clinical remission. 
 
Although controlled clinical trials have shown corticosteroids to be effective in speeding the 
resolution of acute exacerbations of multiple sclerosis, they do not show that corticosteroids 
affect the ultimate outcome or natural history of the disease. The studies do show that relatively 
high doses of corticosteroids are necessary to demonstrate a significant effect.  
 
Since complications of treatment with glucocorticoids are dependent on the size of the dose and 
the duration of treatment, a risk/benefit decision must be made in each individual case as to dose 
and duration of treatment and as to whether daily or intermittent therapy should be used. 
 
REFERENCES 
1 Fekety R. Infections associated with corticosteroids and immunosuppressive therapy. In: 
Gorbach SL, Bartlett JG, Blacklow NR, eds. Infectious Diseases. Philadelphia: WBSaunders 
Company 1992:1050-1. 
2 Stuck AE, Minder CE, Frey FJ. Risk of infectious complications in patients taking 
glucocorticoids. Rev Infect Dis 1989:11(6):954-63. 
 
 


  
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13.4 
Appendix 4: UVADEX ® (methoxysalen) Label 
 
 


  
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13.5 
Appendix 5: Therakos ® Cellex ® Photopheresis System  
Details of the Therakos Photopheresis System can be found on this website: 
 
http://www.therakos.com/healthcare-professionals/photopheresis