Clinical trial NCT03021317
Conditions: Multiple Sclerosis
Sponsor: University of Chicago
Start date: 2016-12-20; Completion date: 2020-10-07
Enrollment: 5 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
ACTHAR is a FDA approved drug for MS relapses. The purpose of the study is to examine the efficacy of this agent in improving relapses as measured by advanced MRI and laboratory techniques:

1. Advanced serial MRI studies on patients during and after an acute MS relapse. MRI will be performed at baseline, 1 month after the 1st dose of ACTHAR, and months 3, 6, and 12. ACTHAR will be administered for 10 days. Patients will start ACTHAR within 48 hours of relapse assessment.
2. Serial immune assays on patients during and after an acute MS relapse. Serum and blood samples with be collected at baseline, last day of ACTHAR (day 10 of therapy), 1 month post 1st dose, and months 3 and 6.

Detailed description:
Multiple sclerosis (MS) is a demyelinating disease of the CNS. In a vast majority of patients, its clinical course is characterized by transient attacks of acute neurological compromise, followed by variable degree of recovery. Each relapse leaves a patient with some degree of residual disability. Higher number and longer duration of relapses are associated with greater loss of function. Hence, it is imperative that these relapses are optimally treated and curtailed in duration to allow for maximal recovery and repair.

ACTH (ACTHAR or IV formulation) has long been used for the treatment of MS relapses. ACTH has equivalent efficacy to high-dose IV methylprednisolone in curtailing the duration of MS relapses. ACTH has an advantage over steroids in that it has a short half-life and much less deleterious steroid effect on bone and fat metabolism. Importantly, ACTH has a unique mechanism of action on immune and brain cells through melanocortin receptors (MCRs), which promote production of regulatory and anti-inflammatory cytokines and support oligodendrocyte precursors and neuronal function, all of which could lead to better repair of MS lesions and favorable clinical outcome.

The studies proposed herein will provide a better understanding of the effects of ACTHAR in improving MRI lesion characteristics over time. The complementary immune and genetic studies will further provide evidence for the mechanism of action (MOA) of ACTHAR in improving immune dysfunction related to MS relapse. This is a one of a kind study, involving both advanced/state-of-the art MRI techniques and immune studies to assess the beneficial effects of ACTHAR in MS relapses in the same patients over time.

The primary outcome of all MRI techniques is to determine whether there is an improvement and subsequent stabilization/repair over time of tissue damage caused by inflammatory MS disease activity. Multiple conventional and nonconventional MR imaging modalities are examined here to determine which of these are the most sensitive and reliable in detecting microstructural damage and repair over time. The results of this study will also greatly impact the design of future MS trials by providing a guide for selecting the most appropriate MRI and immune methods to assess treatment efficacy in MS.

In terms of laboratory analysis, the following will be examined:

1. Determine immune subset expression in CD4+FOXP3 Tregs and CD8+CD28- T suppressor cells by flow cytometry at each visit.
2. Global gene expression profiling in MNC with 913,000 probes at each visit. Bioinformatics will include pathway analysis and ACTHAR-induced RNA signature.
3. Serum protein profiling for immune-regulated cytokines (Th1, Th2, Th17, monokines…) and neuroprotective proteins (NGF, BDNF, ACTH, HGF, CNTF, IL-10…) at each visit.
4. All data from protein and gene expression, as well as immune subset expression will be compared to our database generated from therapy-naïve stable and exacerbating MS. ACTHAR signature will analyzed based on these comparisons.

Arms: arm 1: Open label, single arm treatment study using MRI and laboratory markers to assess efficacy of ACTHAR in MS patients who are undergoing relapses.
Interventions: intervention 1: ACTHar
Intervention descriptions: intervention 1: The patients will be given 80 Units subcutaneously of ACTHAR at the time of MS relapse daily for 10 days.

Protocol documents:
Prot_SAP_000.pdf: 
1 
 
Effects of ACTHAR on Advanced MRI Surrogate Markers of Disease Activity and 
on Comprehensive Immune Signature During MS Relapses 
IRB16-1390 
NCT3021317 
Protocol Date 10/23/19 


                                                            Clinical Protocol 
 
 
Effects of ACTHAR on advanced MRI surrogate markers of disease activity and 
on comprehensive immune signature during MS relapses  
 
This investigator-initiated trial (IST) is divided into two complementary parts: 
1. Advanced serial MRI studies on patients during and after an acute MS relapse.  
MRI will be performed at baseline, 1 month after the 1st dose of ACTHAR, and 
months 3, 6, and 12.   ACTHAR will be administered for 10 days.  Patients will 
start ACTHAR within 48 hours of relapse assessment.   
2. Serial immune assays on patients during and after an acute MS relapse.  Serum 
and blood samples with be collected at baseline, last day of ACTHAR (day 10 of 
therapy), 1 month post 1st dose, and months 3 and 6. 
ACTHAR will be administered by a self-injectable syringe under the skin fat tissue 
(subcutaneous injection). The first subcutaneous injection of ACTHAR will be done in 
the clinic.  Subjects will undergo a teaching session with the PI (Dr. Javed) about how to 
give a subcutaneous injection of ACTHAR.  All subsequent injections will be self-
administered by the patient.   
At each research visit, subjects will have a physical/neurological examination, blood 
pressure, height, weight, and temperature taken at the time of visits.  Urine pregnancy 
test or urine analysis may be done if there is a clinical concern for pregnancy or urine 
infection.  This will be based on the discretion of the investigators. 
 
Part I. Investigational Plan-MRI 
1.1 
Overview 
Multiple sclerosis (MS) is a demyelinating disease of the CNS. In a vast majority of 
patients, its clinical course is characterized by transient attacks of acute neurological 
compromise, followed by variable degree of recovery.  Each relapse leaves a patient 
with some degree of residual disability.  Higher number and longer duration of relapses 
are associated with greater loss of function.  Hence, it is imperative that these relapses 
are optimally treated and curtailed in duration to allow for maximal recovery and repair.   
ACTH (ACTHAR or IV formulation) has long been used for the treatment of MS relapses 
1, 2.  ACTH has equivalent efficacy to high-dose IV methyprednisolone in curtailing the 
duration of MS relapses 3, 4. ACTH has an advantage over steroids in that it has a short 
half-life and much less deleterious steroidogenic effect on bone and fat metabolism 5. 
Importantly, ACTH has a unique mechanism of action on immune and brain cells 
through melanocortin receptors (MCRs), which promote production of regulatory and 
anti-inflammatory cytokines and support oligodendrocyte precursors and neuronal 
function, all of which could lead to better repair of MS lesions and favorable clinical 
outcome 6.  
Several studies have shown beneficial effects of ACTHAR on clinical relapses 7.  
However, there is little if any knowledge about the benefits of ACTHAR in suppressing 
inflammatory lesion activity and enhancing remyelination over time as assesed by MRI.  
Improvement in the inflammatory activity, and particularly repair, in MS lesions leads to 


                                                            Clinical Protocol 
improved clinical outcome and less residual clinical deficit.  Often during the MS course, 
the ratio of new MRI disease activity to clinical relapses can be 10:1.  Hence, 
suppression of this MRI actvity is relavant to clinical outcome.   
The studies proposed herein will provide a better understanding of the effects of 
ACTHAR in improving MRI lesion characteristics over time.  The complementary 
immune and genetic studies will further provide evidence for the mechanism of action 
(MOA) of ACTHAR in improving immune dysfunction related to MS relapse.  This is a 
one of a kind study, involving both advanced/state-of-the art MRI techniques and 
immune studies to assess the beneficial effects of ACTHAR in MS relapses in the same 
patients over time.  
 
1.2    Hypothesis: ACTHAR during acute attacks will reduce inflammation and 
promote CNS repair as assessed by conventional and advanced MRI techniques and it 
will shift the inflammatory immune response associated with a MS relapses towards a 
more regulatory and nurturing immune response.  
 
1.3 
MRI Assessments 
All images will be performed at the University of Chicago’s Magnetic Resonance 
Imaging Research Center (MRIRC). The MRIRC is fully dedicated to MRI research and 
located in the Q300 suite in the Department of Radiology of the University of Chicago 
Medical Center.  The MRIRC houses two state of the art MRI scanners and is staffed by 
2 full-time MRI technologists, research nurses, and coordinators. Dr. Carroll has over 20 
years’ experience in neurological imaging and is the Director of Neuroimaging for the 
MRIRC and will oversee all aspects of imaging.   
 
The primary outcome of all MRI techniques is to determine whether there is an 
improvement and subsequent stabilization/repair over time of tissue damage caused by 
inflammatory MS disease activity.  Multiple conventional and nonconventional MR 
imaging modalities are examined here to determine which of these are the most 
sensitive and reliable in detecting microstructural damage and repair over time.  The 
results of this study will also greatly impact the design of future MS trials by providing a 
guide for selecting the most appropriate MRI and immune methods to assess treatment 
efficacy in MS.   
 
Conventional MRI 
Quantitative T1 Gd+, T2, T1 chronic, and BPF analysis:  
Commonly used MRI metrics in most studies include a post-contrast T1 weighted 
sequence and a T2 weighted sequence.  These are useful for detecting new 
inflammatory lesions. The contrast-enhancing lesions are transient (less than 2 months 
on average) and are indicative of active lesions.  The T2 lesions are more permanent 
and are thought to develop after enhancement ceases.  Measurement of lesion load in 
terms of number and volume, both active and inactive (T1 Gd+, T2 chronic lesions, and 
T1 chronic lesions) will be examined over time.   


                                                            Clinical Protocol 
Specific Aim: determine the effects of ACTHAR in improving the characteristics of 
contrast enhancing lesions (T1 Gd+) observed at baseline and followed squentially over 
time to the development of T2 and chronic T1 signal intensities.  
 
Quantitative nonconventional MRIs (see Supplement for protocol details): 
 
Quantitative T1/T2:  Standard anatomic MRI parameters include T1-weighted 3D and 
PD/T2 sequences.  Only gross lesion characteristics such as number, size, and volume 
can be assessed using these sequences.  However, the actual signal intensities that are 
correlated with water content/lesion pathology cannot be determined with these routine 
sequences.  We have developed a unique approach to converting standard anatomic 
images acquired through routine scanning procedures to quantitative values by 
modeling of signal intensities and physics equations.  Hence, standard anatomic images 
are converted to quantitative values (T1 in milliseconds).  The greatest advantage of 
this technique is that we are able to quantify T1 characteristics of lesions from MRI 
scans done prior to the study start and compare these values to those MRI scans 
obtained on study.  Hence, T1 lesion characteristics can be assessed months before 
ACTHAR treatment and thereafter.   
 
Specific Aim: compare the effects of ACTHAR on T1 lesion characteristics over time to 
the T1 lesion features derived from previous MRI scans without ACTHAR treatment. 
 
Quantitative Perfusion:  in active MS lesions, perivascular inflammation and 
hyalinization of blood vessels is seen.  These changes in the blood vessel walls affect 
tissues hemodynamics.  Consistent with this concept, there is reduced cerebral blood 
flow (CBF) and increased mean transit time (MTT) in white matter lesions compared to 
normal appearing white matter  8. 
 
Specific Aim: examine the effects of ACTHAR in improving CBF and MTT in active MS 
lesions.   
 
Quantification of Tissue Permeability (Ktrans):  This measure is used to evaluate the 
integrity of the blood brain barrier (BBB).  Active MS lesions are characterized by intact 
BBB.  In active MS lesions, the integrity of the BBB is compromised, leading to the 
extravasation of immune cells into brain parenchyma.  This technique will specifically 
assess BBB permeability 9. 
.  
Specific Aim: examine the effects of ACTHAR in improving BBB permeability in active 
MS lesions.   
 
Oxygen Extraction Fraction:  MS relapses are often characterized by excessive fatigue 
and slow cognitive processing.   These symptoms are thought to be due to increased 
inflammatory activity in the brain during MS relapses.  There is accumulating evidence 
that cortical inflammation contributes to metabolic disturbances in MS and these are 
related to cognitive decline 10, 11.  PET studies have shown a reduction in cerebral 
oxygen metabolism in both gray and white matter 10.   
 


                                                            Clinical Protocol 
Specific aim:  Compare OEF in MS patients undergoing a relapse before and after 
ACTHAR treatment and observe any improvement in OEF indices post-relapse 
treatment.   
 
Multi-component driven equilibrium single pulse obervation of T1/T2 (mcDESPOT):  
This is a fairly new technique to assess the water content of myelin.  In an active MS 
lesion, the overall water content of the lesion increases, but the water associated with 
myelin decreases, implying loss of integrity of myelin.  Hence, a decrease in MWF is a 
marker of myelin damage 12, 13.  MS lesions are associated with a low MWF initially 
which improves over time as the lesion repairs.   
 
Specific aim:  Determine whether ACTHAR treatment is associated with an 
improvement in MWF of active (Gd+) and inactive T2 lesions over time.  
 
Magnetization transfer imaging (MTI):  this imaging modality complements MWF in 
identifying changes in the microstructure of both white matter and gray matter.   MTI 
improves over time as lesions heal/remyelinate 14, 15, 16. This technique will be used to 
assess lesion resolution/repair over time.  
 
Specific Aim: Determine whether ACTHAR treatment is associated with an improvement 
in MTR of active (Gd+) and inactive T2 lesions over time  
 
Diffusion Tensor Imaging (DTI):  This is a technique has an advantage over the MWF 
imaging and MTR in that it can interrogate both myelin (λ⊥) and axonal loss (λII) based 
on transverse and axial diffusivities.  There is evidence that alteration in DTI parameters 
in acute MS lesions have predictive value in terms of long term T1 black hole evolution 
17.  
 
Specific aim: Determine whether ACTHAR treatment is associated with an improvement 
in DTI metrics of active (Gd+) and inactive T2 lesions over time.  
 
 
Part II. 
Corresponding immune studies: 
2.1 
Overview and Rationale  
Purpose and Rationale  
MS is immune-mediated. The process involves deregulated immune response of T and 
B lymphocytes, and macrophages.  Autoreactive T cells expand, creating a shift in the 
balance of pro- and anti-inflammatory cytokines that favors inflammation. The antigen 
triggering MS is unknown.  
 
ACTH therapy produces rapid and robust recoveries during exacerbations 18-20.  ACTH 
induces anti-inflammatory and immunomodulatory functions involving T and B 
lymphocytes and macrophages; it activates the sympathetic nervous system to reduce 
inflammation; it reduces pro-inflammatory cytokines through inhibition of NF-κB 
signaling, and inhibits expression of nitric oxide and adhesion molecules; and it 
enhances production of anti-inflammatory IL-10 6, 21. 


                                                            Clinical Protocol 
 
In MS, there are defects In CD4 and CD8 regulatory cell function.  Tregs normally 
reduce and control the intensity of an immune response 22. Accumulating evidence 
indicates an immunosuppressive role for CD4+CD25+Tregs in immune-mediated 
diseases. Venken and colleagues suggested that the suppressive capacity of these 
CD4+CD25+Tregs appears to be more affected in the early phases of MS 23, but Antel 
et al. found that CD8 Tregs were more affected in the progressive phase 24.  
 
There are differences in function that correlate with expression of FOXP3, a master 
regulator in the development and function of regulatory CD4+CD25+T cells), which are 
adequate in patients with SPMS but reduced in those with RRMS 23. More recently, 
Correale and Villa investigated the role of CD8+CD25+FOXP3 cells in RRMS patients, 
as the role of CD8+ has received less recent attention than CD4+ cells 22.  
CD8+CD25+FOXP3 cells are suppressed to a greater degree in the peripheral blood 
during MS exacerbations than during remission or in healthy controls.  Likewise, in the 
cerebrospinal fluid (CSF) of MS patients during exacerbations, lower levels of CD8+ 
CD25+ FOXP3 T cells are detected, providing  evidence for a  previously unknown CNS 
mechanism involved in immune regulation in MS 22.   
 
We and others find the regulatory deficit is largely constrained to the CD8 population 22, 
25, 26.  CD8 regulatory/suppressor cell function is slightly reduced in stable MS, very low 
during attacks and progression, and rebounds during recovery 25.  The defect is 
localized to the CD8+CD28- population 22, 27, 28, a better marker than FOXP3 in this 
subpopulation 26. We have found that CD8+CD28-Treg cells are very low in therapy-
naive MS compared to healthy controls.  Some MS immune modulators can elevate 
numbers of this subpopulation, and thus enhance anti-inflammatory functions and 
reduce inflammatory Th1/Th17 functions (Figure 1 below) 29. 
 
 
 
 
 
 
 


                                                            Clinical Protocol 
Figure 1.  CD8 regulatory cell expression (CD8+CD28- T cells, arrows) is subnormal in 
MS (second panel) compared to healthy controls (first panel), however this low 
expression can be up-regulated with immune modulator (third panel). 
 
 
 
We also illustrate our capabilities for measuring gene expression (Figure 2) and serum 
proteins with multiplex 
assays (Figure 3). 
 
 
 
 
 
 
Figure 2.  Volcano 
plots of RNA 
expression in MNC 
during exacerbations, 
comparing patients on 
IFN-b therapy (L) vs. 
no therapy (R).  
Patients in left panel 
had washed out IFN-b 
therapy for 72 hours, 
yet still had markedly suppressed RNA expression for 5,000 differentially-expressed 
genes compared to therapy-naïve exacerbations in right panel.  x-axis = fold down (to L) 
or up (to R); y-axis = significance  
 
 
 
 
 
 


                                                            Clinical Protocol 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 3.  Multiplex analysis of proteins expressed by activated MNC.  Cells were 
exposed to media only or to an agent that affects MS exacerbations and progression, 
then activated for 48 hours.  Supernatants were analyzed for Th1, Th17, Th2, IFN-
stimulated genes, and adhesion molecules (shown here), in addition to monokines, B 
cell factors, and neuroprotective proteins (dns).  Columns are different patient and 
control groups, row are heat maps of average expression.  Red = increased expression 
vs. media control; Blue = decreased expression vs. control; hue = statistical 
significance, with more saturation having lower p values (more zeros). 
 
2.2 
The hypothesis is that ACTHAR treatment in MS relapses generates a 
tolerogenic immune environment that suppresses inflammation and facilitates brain 
repair.  We’ve found that CD8+CD28- suppressor cells are low in MS and are up-
regulated by several classes of immune modulators. The tolerogenic immune 
environment will be assessed in 18 ACTHAR-treated MS patients. 
 
2.3 
Overall objective is to determine Treg expression and neuroprotection 
signature, as well as identify gene and immune protein signatures in ACTH-treated MS: 
 
2.4 
Specific aims and experiment design with serum, MNC, and RNA samples 
from baseline, last day of ACTHAR (day 10 of therapy), 1 month post 1st dose, and 
months 3 and 6:  
1. Aim1. Determine immune subset expression in CD4+FOXP3 Tregs and 
CD8+CD28- T suppressor cells by flow cytometry at each visit above.    
2. Aim 2. Determine global gene expression profiling in MNC with 913,000 probes 
at each visit above.  Bioinformatics will include pathway analysis and ACTHAR-
induced RNA signature. 
3. Aim 3. Determine serum protein profiling for immune-regulated cytokines (Th1, 
Th2, Th17, monokines…) and neuroprotective proteins (NGF, BDNF, ACTH, 
HGF, CNTF, IL-10…) at each visit above. 


                                                            Clinical Protocol 
4. Aim 4. All data from protein and gene expression, as well as immune subset 
expression will be compared to our database generated from therapy-naïve 
stable and exacerbating MS. ACTHAR signature will analyzed based on these 
comparsions.  
 
2.5 
Methods 
Blood is drawn from 18 MS patients at baseline, last day of ACTHAR (day 10 of 
therapy), 1 month post 1st dose, and months 3 and 6.  Mononuclear cells (MNCs) from 
four 8cc heparin green-top tubes (40-60 million cells) are separated on Ficoll-Paque 
gradients. 30M cells are needed for flow cytometry. 20M cells are needed for total RNA 
preparation.  
 
Specific Aim 1.  Determination of ACTHAR effects on immune cell subsets in relapsing 
remitting MS (RRMS), emphasizing expression on CD8 cells including the CD8+CD28- 
regulatory subset. Flow cytometry will be conducted to determine the effect of ACTHAR 
on in vivo expression of surface markers on T cells (CD4, CD8, CD28, FOXP3). 
Reagents are from e-Biosciences and B-D.  (MAbs = CD4, CD8, CD28, CD27, CD25, 
FOXP3).  
Specific Aim 2.  Global gene expression profiling in MNC will be measured with 
913,000 probes at each sample.  Bioinformatics will include pathway analysis and 
ACTHAR-induced RNA signature. Total RNA will be isolated from 20M cells, as the 
template for synthesizing cDNA for gene expression array analysis with Affy HTA kit. 
RT-PCR will be performed for validation of specific gene signatures.    
Specific Aim 3.  Serum from each sample will be applied on Procarta multiplex assay 
plates according to manufacturer’s instruction.  Immune, neuroprotection, and other 
proteins will be measured with 40 highly-selected targeted antibodies for Th1, Th2, 
Th17, monocyte, neuroprotection, cell proliferation and death, and adhesion molecule 
panels. 
 
Specific Aim 4.  Advanced bioinformatics with Gene Set Variation Analysis:  
1.  Identify differential gene expression (DEG) between groups;  
2.  Analyze pathways by Ingenuity Pathway Analysis (IPA); 
3.  Discover transcriptional signature of genes and gene pathways; 
4.  Build a predictive model using machine learning algorithms including Random 
Forests (RFs) and Support Vector Machines (SVMs).   
 
 
2.6 
Outcomes 
This data may lead to better understanding of the mechanism of action of ACTHAR and 
identifying signatures/biomarkers in ACTHAR-treated MS.  In addition, MRI, 
CD8+CD28- cell numbers, serum proteins, and RNA may be biomarkers for efficacy. 
 
 
Part III.  Patient criteria and publications 
3.1a Inclusion Criteria 


                                                            Clinical Protocol 
This study will be restricted to adult patients (>18 years) undergoing a clinical relapse 
who also must have a contrast-enhancing CNS lesion, either clinically or non-clinically 
relevant.   Sample size under consideration is 18 patients. The population on which 
analyses will be conducted consists of all patients who have received at least 1 dose of 
study medication and for whom at least two time-points (baseline and at least one 
additional time-point) for MRI data are available (Intent-to-treat analysis). 
3.1b Exclusion Criteria 
1-Patients will be excluded if they only have a clinical relapse which is not associated 
with MRI findings of a new or enlarging MS lesion.   
2-Patient will be excluded if they cannot give written consent 
3-Patients will be excluded if they have an active infection 
4-Patients will be excluded if they already received steroids (IV or oral) within last 30 
days of receiving ACTHAR   
5-Pregnant or lactating patients will be excluded from this study. 
 
 
3.2 
Treatment failures and/or inadequate response 
Patients who have not had an adequate response to the ACTH treatment after 14 days 
may either be given a choice of getting another round of ACTH for additional 10 days or 
switching to IV Methylprednisolone 1000 mg for 3 days.   The scheduling of blood draws 
and MRIs will not be affected and continue as planed.  
 
3.3 
Concomitant disease modifying therapies (DMTs) 
Patients undergoing relapses will continue their current DMTs during the relapse.  One 
month after the relapse (after the 1 month MRI time point and blood draw), physician 
and patient will decide whether to continue their current DMT over time or switch to 
another DMT.  All DMTs and other symptomatic treatments will be recorded during the 
course of the study.   
3.4 
Statistical Analysis 
All data collected will be documented using summary tables, figures, and patient data 
listings.  For longitudinal data, mixed effects regression model will be used to 
summarize patterns over the one-year period.  All hypothesis testing will be at the 0.05 
level of significance.  Correlation analyses between specific measures will be 
accomplished using Pearson’s correlation co-efficient.  
All summary statistics will be displayed as a function of study visit or assessment time.  
Summary statistics for continuous variables will include n, mean, standard deviation, 
minimum, median, and maximum.  For categorical variables, frequencies and 
percentages will be presented.  Graphical displays will be provided as appropriate. 


                                                            Clinical Protocol 
3.5 
Criteria for study withdrawal  
Patients may withdraw from the study at any time for any reason.  A patient’s withdrawal 
from the main trial does not, by itself, constitute withdrawal of the data already collected.  
All data will be analyzed as intent-to-treat.  No replacement for patients who withdraw 
from the study after drug treatment is planned. 
3.6 
Safety instructions and emergency medical contacts 
All study related adverse events (AEs) and serious adverse events (SAEs) will be 
collected.  The medical treatment for relapses is given as part of standard medical care.  
Hence, all AE and SAEs will be handled per standard medical practices.  The 
emergency medical contacts will be provided to all patients.  
 
Risks associated with the study: 
The potential risks of drawing blood include a bruise at the site of the puncture. This 
happens rarely and inflammation of the vein and infection have been reported. Care will 
be taken to avoid these complications. 
The research-related MRI scans are not being done for diagnostic purposes. If any 
abnormalities are noted during the research scans, the treating physician will be 
informed. 
Potential risks for ACTH are listed in the package insert.  Patients will receive advice on 
the side effects as it is done in clinical practice.  The most common side effects are 
water gain, injection site reaction, mild insomnia, and flushing.  These will be managed 
as per standard medical care.  
 
The risks associated with MRI are typically claustrophobia and risks associated with 
contrast agents.  Patient's may be given some mild sedative before the MRI.  Patient's 
who have had prior allergic reaction to contrast agents will be excluded.  Also, pre-
contrast renal function will be assessed prior to the contrast MRI.  Hydration will be 
recommended after the MRI.   
 
3.7 
Data collection and management 
MRI data for this study will be recorded via MRI machine and stored and disseminated 
to PIs or Sub-PIs by the Human Imaging Research Office (HIRO) at the University of 
Chicago.  Data will be backed up and stored on-site.  Accurate and reliable data 
collection will be assured by verification and cross–check of the MRI database against 
the Investigator’s records.  Immune data will be stored on password protected 
computers, with access to only the research team.  These data will also be backed up 
routinely.   
3.8 
Ethical considerations 


                                                            Clinical Protocol 
The Investigators will ensure that this study is conducted in full conformance with the 
principles of the “Declaration of Helsinki” (last amendment October 2000, with additional 
footnotes added 2002 and 2004). 
All patients will sign the informed consent form for the study. The Consent Forms will be 
signed and dated by the patient.  The clinical records for each patient will document the 
informed consent process and that written informed consent was obtained prior to 
participation in the study. The Consent Forms will be revised whenever there are 
changes to study procedures or when new information becomes available that may 
affect the willingness of the patient to participate.  Patients will be re-consented to the 
most current version of the Consent Forms (or to a significant new information/findings 
addendum in accordance with applicable laws and IRB policy) during their participation 
in the study.  For any updated or revised Consent Forms, the clinical records for each 
patient will document the informed consent process and that written informed consent 
was obtained using the updated/revised Consent Forms for continued participation in 
the study. A copy of each signed Consent Form will be provided to the patient.  All 
signed and dated Consent Forms will remain in each patient’s study file and be 
available for verification by study monitors at any time. 
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB annually or more frequently in accordance with the requirements, 
policies, and procedures established by the IRB.   
3.9 
Confidentiality 
The Investigator and personnel will ensure that patients’ anonymity will be maintained 
and that their identities are protected from unauthorized parties.  The Investigator and 
personnel should keep a patient enrollment log showing codes, names and addresses.  
The data are kept in password protected computers.  For transmission of data, only 
patient codes are transmitted, not any PHI type of information.  The computers and 
database are all kept under locked and secure rooms. See below record keeping 
section. 
3.10 Record keeping 
All data stored electronically will be coded.  Data will be stored within a firewall and 
password protected computer system within a secured building.  Minimal, 
non-identifiable, subject/patient information (ie, subject/patient code, sex, age at time of 
scan, clinical condition) will be stored, with password protection, with the data.  
3.11 Publication 
The results of this study may be published or presented at scientific meetings.  If this is 
foreseen, the Investigator agrees to submit all manuscripts or abstracts to Mallinckrodt 
prior to submission.  This allows the Sponsor to protect proprietary information and to 


                                                            Clinical Protocol 
provide comments based on information from other studies that may not yet be 
available to the Investigator. 
 
 
 
 
 
 
 
 
 
Supplement: MRI Protocols 
 
Quantitative T1/T2: We have developed a unique approach to converting standard 
anatomic images to quantitative values through the use of modeling of signal intensities 
and physics equations that define signal intensities from specific pulse sequences. We 
are able to standardize the T1 (in milliseconds), and then standardize the standard 
anatomic images that are normally used for diagnosis. In other words, we do not 
compromise scan time, image resolution, or patient throughput.  
 
Standard anatomic MRI parameters include T1-weighted 3D (repetition time/echo time 
(TR/TE): 9.5 ms/2.3 ms, resolution: 0.63 × 0.63 × 1.2mm3) and PD/T2 (TR/TE: 
2500ms/10.7ms, resolution: 0.63×0.63×1.2mm3), and will eaqui5ee before and 15 
minutes post contrast. Image will be converted to T1 by calculating an MRI response 
function, by constraining unknowns using internal reference T1/T2 values (Normal 
Appearing White matter, Gray matter CSF).  
 
 
Quantitative Perfusion: We have developed an MRI pulse sequence that calibrates 
dynamic susceptibility images to provide images of tissue perfusion in ml/100gg/min. 
Our pulse sequence is patented and Image parameters (FOV/matrix = 220 mm/128, 3.0 
mm. 15 thick 2D slices TR/TE=1200 ms/50 ms. Fifty measurements (including 
calibration data) will be acquired in 3 minutes. Test-retest reliability of cerebral perfusion 
has been measured to be better than 14%.  
 
Quantification of Tissue Permeability (Ktrans): A saturation recovery gradient recalled 
sequence will be used both for dynamic imaging of contrast agent leakage. Each slice 
will be acquired after application of a nonselective saturation prepulse with a saturation 
time delay (TD). The following acquisition parameters will be used: flip angle of 30°, 
TR/TE =3.82 ms/1.9 ms, centric phase ordering, scan matrix size 96 × 61 (interpolated 
to 256 × 256), SENSE factor 2, field of view 240 × 182 mm2, and four slices of 8-mm 
thickness, resulting in a spatial resolution of 2.5 × 3.1 × 8 mm3. The T1 measurement 
was performed by varying the TD value (120 ms, 150 ms, 300 ms, 600 ms, 1 sec, 2 sec, 
4 sec, 8 sec, 9 sec, 10 sec). Perfusion CBF can estimated by model-free deconvolution 
both for ROIs and CBF maps, blood volume Vb and the BBB permeability Ktrans will 
estimated both by Patlak's method and the two-compartment model. 


                                                            Clinical Protocol 
 
Oxygen Extraction Fraction: As an exploratory study, we will track changes in tissues 
oxygenation using a novel single shot image acquisition based on a rosette k-space 
sampling trajectory 30. A Stack of 2D slices (3 mm thick, FOV 220/matrix 65) will be 
acquired after a single rf pulse. A maximum-likelihood recursion will yield image for 
R2*(ms), Mo and local frequency shift in tissue. dw(Hz). Frequency shifts can be 
converted directly to Oxygen Extraction Fraction through the simple algebraic 
expression: 
 
 
Multi-component driven equilibrium single pulse obervation of T1/T2 (mcDESPOT): This 
is a fairly new technique to assess the water content of myelin.  In an active MS lesion, 
the overall water content of the lesion increases but the water associated with myelin 
decreases.  The water pool associated with myelin has a very short T2 relaxation time 
compared to the other pool of intra- and extra-cellular water.  Spoiled gradient echo 
(SPGR) and balanced steady-state free precession (bSSFP) scans are collected over a 
range of flip angles (FA) at constant repetition times to allow resolution of the two-pools 
of water, as has been previously reported 12,13.  The fast relaxing pool of water has been 
called the myelin fraction water (MWF), which has been shown to correlate with tissue 
myelin fraction 31.  
Whole brain isotropic voxel size mcDESPOT imaging will be acquired using the 
following imaging parameters: FOV = 22 cm, matrix = 128 × 128, slice thickness = 2 
mm; SPGR parameters: echo time/repetition time (TE/TR) = 2.1/6.7 ms, flip angle 
(α)=[3,4, 5, 6, 7, 8, 11, 13, 18]°; bSSFP parameters: TE/TR = 1.8/3.6 ms, α= [11, 14, 20, 
24, 28, 34, 41, 51, 67]°, two phase cycles acquired per bSSFP flip angle.  The total 
mcDESPOT acquisition time is ~13 min 13.   
 
Magnetization transfer imaging (MTI): this imaging technique interrogates the transfer of 
magnetization (MT) from protons bound to macromolecules to more mobile water 
associated protons.   This MT effect is quantified by acquiring two images, one with and 
the other without a resonance pulse.   MTI will be performed using 2D gradient echo 
(GE) sequence (TR=640, TE=12, FA 20°) with and without an off resonance 
radiofrequency (RF) saturation pulse (off frequency=1.5 kHz, Gaussian envelope 
duration 7.68ms, FA=500°).    
 
MTR=(Moff –Mon)/Moff.   
 
MTR of the active and inactive lesions as well as normal appearing white and gray 
matter will be determined.  MTR of the lesions will be determined by the region of 
interest (ROI) analysis.  
 
Diffusion Tensor Imaging (DTI):  images will be acquired using single shot spin-echo 
planar pulse sequence TR= 7658 ms, TE= 70 ms, matrix size = 128 x 128, FOV = 224 x 
224 with diffusion gradients (b-value =800 s/mm2) applied in 32 noncollinear directions.  
Fractional Anisotropy, mean diffusivity, radial (λ⊥) and axial (λII) diffusivities of active 
and chronic lesions will be determined by ROI analysis.   
 


                                                            Clinical Protocol 
 
References: 
 
 
1. 
Miller H, Newell DJ, Ridley A. Multiple sclerosis. Treatment of acute exacerbations 
with corticotrophin (A.C.T.H.). Lancet 1961;2:1120-1122. 
2. 
Rose AS, Kuzma JW, Kurtzke JF, Sibley WA, Tourtellotte WW. Cooperative study in 
the evaluation of therapy in multiple sclerosis: ACTH vs placebo in acute exacerbation. 
Transactions of the American Neurological Association 1969;94:126-133. 
3. 
Abbruzzese G, Gandolfo C, Loeb C. "Bolus" methylprednisolone versus ACTH in the 
treatment of multiple sclerosis. Italian journal of neurological sciences 1983;4:169-172. 
4. 
Thompson AJ, Kennard C, Swash M, et al. Relative efficacy of intravenous 
methylprednisolone and ACTH in the treatment of acute relapse in MS. Neurology 
1989;39:969-971. 
5. 
Zaidi M, Sun L, Robinson LJ, et al. ACTH protects against glucocorticoid-induced 
osteonecrosis of bone. Proceedings of the National Academy of Sciences of the United 
States of America 2010;107:8782-8787. 
6. 
Arnason BG, Berkovich R, Catania A, Lisak RP, Zaidi M. Mechanisms of action of 
adrenocorticotropic hormone and other melanocortins relevant to the clinical management 
of patients with multiple sclerosis. Multiple sclerosis 2013;19:130-136. 
7. 
Berkovich R. Treatment of acute relapses in multiple sclerosis. Neurotherapeutics : 
the journal of the American Society for Experimental NeuroTherapeutics 2013;10:97-105. 
8. 
Sowa P, Bjornerud A, Nygaard GO, et al. Reduced perfusion in white matter lesions 
in multiple sclerosis. European journal of radiology 2015;84:2605-2612. 
9. 
Gaitan MI, Shea CD, Evangelou IE, et al. Evolution of the blood-brain barrier in newly 
forming multiple sclerosis lesions. Annals of neurology 2011;70:22-29. 
10. 
Brooks DJ, Leenders KL, Head G, Marshall J, Legg NJ, Jones T. Studies on regional 
cerebral oxygen utilisation and cognitive function in multiple sclerosis. Journal of 
neurology, neurosurgery, and psychiatry 1984;47:1182-1191. 
11. 
Kidd D, Barkhof F, McConnell R, Algra PR, Allen IV, Revesz T. Cortical lesions in 
multiple sclerosis. Brain : a journal of neurology 1999;122 ( Pt 1):17-26. 
12. 
Deoni SC, Rutt BK, Arun T, Pierpaoli C, Jones DK. Gleaning multicomponent T1 and 
T2 information from steady-state imaging data. Magnetic resonance in medicine 
2008;60:1372-1387. 
13. 
Kitzler HH, Su J, Zeineh M, et al. Deficient MWF mapping in multiple sclerosis using 
3D whole-brain multi-component relaxation MRI. NeuroImage 2012;59:2670-2677. 
14. 
van Waesberghe JH, van Walderveen MA, Castelijns JA, et al. Patterns of lesion 
development in multiple sclerosis: longitudinal observations with T1-weighted spin-echo 
and magnetization transfer MR. AJNR American journal of neuroradiology 1998;19:675-
683. 
15. 
Filippi M, Rocca MA, Horsfield MA, Comi G. A one year study of new lesions in 
multiple sclerosis using monthly gadolinium enhanced MRI: correlations with changes of 
T2 and magnetization transfer lesion loads. J Neurol Sci 1998;158:203-208. 
16. 
Filippi M, Rocca MA, Rizzo G, et al. Magnetization transfer ratios in multiple sclerosis 
lesions enhancing after different doses of gadolinium. Neurology 1998;50:1289-1293. 
17. 
Naismith RT, Xu J, Tutlam NT, et al. Increased diffusivity in acute multiple sclerosis 
lesions predicts risk of black hole. Neurology 2010;74:1694-1701. 


                                                            Clinical Protocol 
18. 
Rose AS, Kuzma JW, Kurtzke JF, et al. Cooperative study in the evaluation of therapy 
in multiple sclerosis: ACTH vs. placebo: final report. Neurology 1970;20:1-70. 
19. 
Thompson CB, Lindsten T, Ledbetter JA, et al. CD28 activation pathway regulates the 
production of multiple T-cell-derived lymphokines/cytokines. Proceedings of the National 
Academy of Sciences USA 1989;86:1333-1337. 
20. 
Sellebjerg F, Jensen J, Ryder LP. Costimulatory CD80 (B7-1) and CD86 (B7-2) on 
cerebrospinal fluid cells in multiple sclerosis. Journal of neuroimmunology 1998;84:179-
187. 
21. 
Feng X, Yau D, Holbrook C, Reder AT. Type I interferons inhibit Interleukin-10 
production in activated human monocytes and stimulate IL-10 in T cells: Implications for 
Th1-mediated diseases. Journal of interferon & cytokine research : the official journal of the 
International Society for Interferon and Cytokine Research 2002;22:311-319. 
22. 
Correale J, Villa A. Role of CD8+ CD25+ Foxp3+ regulatory T cells in multiple 
sclerosis. Annals of neurology 2010;67:625-638. 
23. 
Venken K, Hellings N, Broekmans T, Hensen K, Rummens J-L, Stinissen P. Natural 
naive CD4+CD25+CD127low regulatory T cell (Treg) development and function are disturbed 
in multiple sclerosis patients:  Recovery of memory Treg homeostasis during disease 
progression. J Immunol 2008;180:6411-6420. 
24. 
Antel JP, Bania MB, Reder AT, Cashman N. Activated suppressor cell dysfunction in 
chronic progressive multiple sclerosis. Journal of Immunology 1986;137:137-141. 
25. 
Antel JP, Arnason BGW, Medof ME. Suppressor cell function in multiple sclerosis: 
correlation with clinical disease activity. Annals of neurology 1979;5:338-342. 
26. 
Karandikar NJ, Crawford MP, Yan X, et al. Glatiramer acetate (Copaxone) therapy 
induces CD8+ T cell responses in patients with multiple sclerosis. The Journal of clinical 
investigation 2002;109:641-649. 
27. 
Karaszewski JW, Reder AT, Anlar B, Kim WC, Arnason BGW. Increased lymphocyte 
beta-adrenergic receptor density in progressive multiple sclerosis is specific for the CD8+, 
CD28- suppressor cell. Annals of neurology 1991;30:42-47. 
28. 
Crucian B, Dunne P, Friedman H, Ragsdale R, Pross S, Widen R. Alterations in levels 
of CD28-/CD8+ suppressor cell precursor and CD45RO+/CD4+ memory T lymphocytes in 
the peripheral blood of multiple sclerosis patients. Clin Diagn Lab Immunol 1995;2:249-
252. 
29. 
AT R, Wang z, Causevic S, et al. Vitamin D enhances interferon-beta-1b response in 
multiple sclerosis.  31st ECTRIMS/ACTRIMS. Barcelona, Spain2015: P533. 
30. 
Menon RG, Walsh EG, Twieg DB, et al. Snapshot MR technique to measure OEF using 
rapid frequency mapping. Journal of cerebral blood flow and metabolism : official journal of 
the International Society of Cerebral Blood Flow and Metabolism 2014;34:1111-1116. 
31. 
Laule C, Leung E, Lis DK, et al. Myelin water imaging in multiple sclerosis: 
quantitative correlations with histopathology. Multiple sclerosis 2006;12:747-753. 
 
 

ICF_001.pdf: 
10/23/2019
Page 1 of 7
  The UNIVERSITY OF CHICAGO
The Division of the Biological Sciences  The University of Chicago Medical Center
CONSENT/AUTHORIZATION BY SUBJECT FOR PARTICIPATION IN A RESEARCH 
PROTOCOL
Protocol Number: IRB16-1390
Name of Subject:  
Medical History Number:  
STUDY TITLE: Effects of ACTHAR on advanced MRI surrogate markers of disease activity and 
on comprehensive immune signature during MS relapses 
Doctors Directing Research: Adil Javed,
Anthony Reder
Xuan Feng
Veronica Penyak Cipriani
 
Address:        
Dept. of Neurology, MC-2030, 5841 S. Maryland Avenue, The University 
of Chicago
Telephone Number:                773-834-0558
You are being asked to participate in a research study. A member of the research team will explain what 
is involved in this study and how it will affect you. This consent form describes the study procedures, 
the risks and benefits of participation, as well as how your confidentiality will be maintained. Please 
take your time to ask questions and feel comfortable making a decision whether to participate or not. 
This process is called informed consent.  If you decide to participate in this study, you will be asked to 
sign this form. 
WHY IS THIS STUDY BEING DONE?
You have been asked to participate in this research study because you have been diagnosed with MS and 
are undergoing an exacerbation of your symptoms.  The cause of MS is unknown.  New lesions are seen 
in the brain or spine in patients having an MS exacerbation.  How these lesions repair after therapy over 
time is largely unknown.  Also, it is not entirely clear how the immune system changes for the better 
after treatment of MS exacerbations.  We hope to examine MRI and blood markers of damage and 
inflammation in patients undergoing MS exacerbations. 
For the MS exacerbation, you will be given ACTHAR , which is an FDA approved drug for the 
treatment of MS exacerbations/relapses.  ACTHAR has been shown to provide the same benefit in 
curtailing the symptoms of MS exacerbations, as does intravenous methylprednisolone.  Both ACTHAR 
and IV methylprednisolone are routinely used in medical practice for the treatment of MS 
exacerbations/relapses.  
We hope that the information we gather during this study will lead to better understanding of the disease 
process involved in MS, especially repair and lead to better treatments for MS exacerbations.
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The study is being sponsored by Mallinckrodt and the data will be shared with them.  Your name and 
any identifying information will be removed from these documents.
HOW MANY PEOPLE WILL TAKE PART IN THE STUDY?
About 18 people will take part in this study at the University of Chicago.
WHAT IS INVOLVED IN THE STUDY?
Subjects will have a physical/neurological examination, blood pressure, height, weight, and temperature 
taken at the time of visits.  Urine pregnancy test or urine analysis may be done if there is a clinical 
concern for pregnancy or urine infection.  This will be based on the discretion of the investigators. 
Physical exams and EDSS will be performed at each study visit.  EDSS is scoring of your neurological 
exam. ACTHAR will be given as daily subcutaneous injections over 10 days.  You will be asked to 
allow a small amount of blood to be collected around the time of your study visit.  Often during 
assessment of MS exacerbation, small amount of blood is drawn as a routine medical practice.  You may 
be asked for a small amount of additional blood sample. The amount of blood taken is small, about 15-
18 cc, which is approximately 2 tablespoons. Blood samples will be taken at the initial visit, last day of 
ACTHAR (day 10 of therapy), 1 month post 1st dose, and at months 3 and 6. 
You will also be asked to undergo MRIs to thoroughly assess inflammatory activity in the brain and 
spine during an MS exacerbation.  You will be asked to undergo additional MRI images that are more 
sensitive (yet experimental) than the MRI images for examining MS disease.  The MRI has a routine 
clinical component and a research component.  The routine clinical component will take about 20 
minutes.  The research component may take up to additional 45 minutes.  Both scans are done on the 
same scanner and on the same day, right after one another.  MRIs will be performed at the initial visit, 1 
month after the 1st dose of ACTHAR, and at months 3, 6, and 12.  During the  MRI scan, you may 
receive an intravenous contrast agent that allows better visualization of pathological changes in the brain 
or spine.  Your treating physician will discuss the risks of the contrast agent with you prior to the MRI 
session, and you may be asked to sign a separate hospital consent form for the MRI procedure.  You will 
not receive any additional contrast agent for the purposes of this research.  
If you do not have an adequate response to the ACTHAR administration after 14 days, you may either 
be given a choice of getting another round of ACTHAR for additional 10 days or switching to IV 
Methylprednisolone 1000 mg for 3 days.
During this study, your current MS medication will not change during the relapse.  However, one month 
after the relapse (after the 1 month MRI time point and blood draw), the doctor and you will decide 
whether to continue your current MS medication over time or switch to a different MS medication.  All 
medications will be recorded during the course of the study.  
During this study, Dr. Adil Javed and his research team will collect information about you for the 
purposes of this research.  Data will be collected from your medical records. The data includes the type 
and severity of your disease, lab tests, family history of related diseases, toxin exposures, your prior 
therapeutic drug use, your name, age, date of birth, sex, phone number, date of entry into the study, and 
medical record number in order to contact you with more questions or updates.  Since the cause of the 
above listed medical conditions is unknown, all of these factors may be relevant in understanding the 
disease.
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Study Schedule
Screening
-2 weeks
Baseline
(day 1)
Day 
10
Month 
1
Month 
3
Month 
6 
Month 
12
Discussion of study 
criteria
x
Review and sign 
Informed Consent Form
x
Review your medical 
history and 
demographics
x
Review changes in your 
health and medications
x
X
x
x
x
x
x
Physical examination
x
X
x
x
x
x
x
Height and weight 
x
X
x
x
x
x
x
Blood pressure, pulse 
rate, breathing rate, 
body temperature
x
X
x
x
x
x
x
Blood sample 
(approximately 13 
tablespoons at each 
visit) a
x
X
x
x
x
x
EDSS assessment
x
x 
x
x
x
x
x
MRI scans of your 
brain
X
x
x
x
x
Urine pregnancy test (if 
clinically indicated) 
x
X
x
x
x
x
x
HOW LONG WILL I BE IN THE STUDY?
You may be in this study for up to 12 months.  
Dr.  Javed or his research team may decide to take you off of the study without your consent if:

You are unable to meet the requirements of the study;

Your medical condition changes;

New information becomes available that indicates that participation in this study is not in 
your best interest; or

If the study is stopped.
WHAT ARE THE RISKS OF THE STUDY?
Blood Draw Risks
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The potential risks of drawing blood include a bruise at the site of the puncture. This happens 
occasionally. Very rarely, inflammation of the vein and infection has been reported.  Care will be taken 
to avoid these complications. 
MRI Risks
The potential risks of MRI include claustrophobia and risks associated with contrast agents. You may be 
given a mild sedative before MRI. 
The research-related MRI scans are not being done for diagnostic purposes.  If any abnormalities are 
noted during the research scans, your treating physician will be informed, and you will be instructed to 
discuss these findings with your treating physician.
There are no reports of any harmful effects to humans of the research MRI sequences proposed in this 
study.  
Contrast Agent Risks
The potential risks of contrast agent include allergic reactions, these subjects will be excluded from the 
study. Also, pre-contrast renal function will be assessed prior to the contrast MRI. Hydration will be 
recommended after the MRI.
Potential risks for ACTH:
Potential risks for ACTH are listed in the package insert.  Subjects will receive advice on the side effects 
as it is done in clinical practice.  The most common side effects are water gain, injection site reaction, 
mild insomnia and flushing. These will be managed as per standard care.
Any time you participate in a research study, there is the potential for loss of confidentiality, meaning 
that somebody outside of the research team could learn about your participation in the study.  To protect 
your confidentiality, the data we collect about you for this study, including your name and medical 
record number, will be kept in a locked room on a password-protected computer and will not be listed in 
publications.
ARE THERE ANY BENEFITS TO TAKING PART IN THE STUDY?
Knowledge about the advanced MRI and blood markers of disease activity and repair may provide us 
with information about MS and may lead to better treatment of MS relapses in the future. 
If you agree to take part in this study, there may or may not be direct medical benefit to you. 
WHAT OTHER OPTIONS ARE THERE?
Instead of being in this study, you may choose not to participate. Participation is strictly on a volunteer 
basis and you may refuse at any time.
The decision whether or not you wish to participate in this study will not affect your care at the 
University of Chicago Medical Center.
WHAT ARE THE COSTS?
Clinical services provided during a clinical trial are either research-related or related to usual medical
care. Research-related services are done to complete the research and the costs are not the responsibility
of you or your insurance.
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The costs that are considered research-related for this study may include any additional laboratory tests 
to assess your immune function, physician visits, physical/neurological exam, and research related MRIs 
that are dictated by the research protocol and are only required because you are taking a part in this 
study. The study drug ACTHAR will be provided free to you as long as you are in this study. 
Usual medical care costs include any and all services that are considered medically necessary for your
disease and would be done even if you were not part of this research study. This may include laboratory
tests, physician visits, standard/routine MRIs, procedures, and other clinical services that your physician 
orders for your standard medical care. The cost of this usual, ongoing medical care will be the 
responsibility of you or your insurance, and may include deductibles and co-payments. Similarly, this 
care will be subject to all the same requirements and restrictions of your insurance.
If you have questions about whether specific clinical services are research related or usual medical care, 
please speak to your physician or research contact person. If you suffer an unanticipated injury as a 
direct result of this research and require emergency medical treatment, the University of Chicago 
Medical Center will provide such treatment at the University of Chicago Medical Center at no cost to 
you. You must notify Dr. Javed as promptly as possible after your injury in order to receive this care. An 
injury is “unanticipated” if it is not one of the known effects of a study drug, medical device or 
procedure, and is not the result of your disease or condition. The costs of any non‐emergency care for 
such an injury will be billed to you or your insurance in the ordinary manner. If you think that you have 
suffered a research related injury, you must let Dr. Javed know right away.
WILL I BE PAID FOR MY PARTICIPATION?
You will not be paid to participate in this study.
WHAT ABOUT CONFIDENTIALITY?
Study records that identify you will be kept confidential.  Your name and medical record number will be 
kept in a locked room on a password-protected computer and will not be listed in publications.  The data 
will be accessible by Dr. Javed, and people directly working with him. Your identity will not be known 
or available to anyone outside the research team.  This information will not be part of your medical 
record.
The data collected in this study will be used for the purpose described in the form.  By signing this form, 
you are allowing the research team access to your medical records, which include Protected Health 
Information.  Protected Health Information (PHI) consists of any health information that is collected 
about you, which could include your medical history and new information collected as a result of this 
study.  The research team includes the individuals listed on this consent form and other personnel 
involved in this study at the University of Chicago.
As part of the study, Dr. Javed and his research team may report the results of your study-related 
procedures and tests to Mallinckrodt outside of the University of Chicago. This information would 
include data from your blood and spinal fluid tests and MRI along with relevant factors related to your 
history such as age, gender, and type of disease.  Please note that your information will be assigned a 
code before being sent to any of the collaborators.  Only the research team at the University of Chicago 
will be able to link the code to your name. 
Your records may be reviewed by federal agencies whose responsibility is to protect human subjects in 
research including the Food and Drug Administration (FDA) and Office of Human Research Protections 
(OHRP).  In addition, representatives of the University of Chicago, including the Institutional Review 
Board, a committee that oversees the research at the University of Chicago, may also view the records of 
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10/23/2019
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the research.  If your research record is reviewed by any of these groups, they may also need to review 
your entire medical record.
The results from experimental tests and/or MRI procedures performed as part of this study will not be 
part of your medical record.  Only the standard clinical blood work and standard clinical MRI results 
will be shared with you.  However, if the experimental immune tests and non-standard MRIs show 
clinically significant abnormalities, Dr. Javed or his research team will contact you and discuss any 
necessary evaluation.
During your participation in this study, you will have access to your medical record. Dr. Javed is not 
required to release to you research information that is not part of your medical record.
Data from this study may be used in medical publications or presentations.  Your name and other 
identifying information will be removed before this data is used.   If we wish to use identifying 
information in publications, we will ask for your approval at that time. 
This consent form will be kept by the research team for at least six years. The study results will be kept 
in your research record and be used by the research team indefinitely.  At the time of study completion, 
either the research information not already in your medical record will be destroyed or information 
identifying you will be removed from study results.  
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. 
Law.  This web site will not include information that can identify you.  At most, the Web site will 
include a summary of the results.  You can search this Web site any time.
WHAT ARE MY RIGHTS AS A PARTICIPANT?
Taking part in this study is voluntary.  If you choose not to participate in this study, your care at the 
University of Chicago/University of Chicago Medical Center will not be affected.
You may choose not to participate at any time during the study.  Leaving the study will not affect your 
care at the University of Chicago/University of Chicago Medical Center.
If you choose to no longer be in the study and you do not want any of your future health information to 
be used, you must inform Dr. Javed in writing at the address on the first page.  Dr. Javed may still use 
your information that was collected prior to your written notice. 
We will tell you about significant new information that may affect your willingness to stay in this study. 
You will be given a signed copy of this document. This consent form document does not have an 
expiration date.
WHO DO I CALL IF I HAVE QUESTIONS OR PROBLEMS?
You have talked to your doctors about this study and you had the opportunity to ask questions 
concerning any and all aspects of the research.  If you have further questions about the study, you may 
call Dr. Javed at 773-834-0558.
If you have any questions concerning your rights in this research study you may contact the Institutional 
Review Board, which is concerned with the protection of subjects in research projects.  You may reach 
the Committee office between 8:30 am and 5:00 pm, Monday through Friday, by calling (773) 702-6505 
or by writing:  The University of Chicago, Institutional Review Board, 5841 S. Maryland Ave., MC- 
7132, I-625, Chicago, Illinois  60637.
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CONSENT
SUBJECT:
The research project and the procedures associated with it have been explained to me.  The experimental 
procedures have been identified and no guarantee has been given about the possible results. I will 
receive a signed copy of this consent form for my records.
I agree to participate in this study.  I am aware that my participation is voluntary and that I do not have 
to sign this form if I do not want to be part of this research study.
Signature of Subject:  
Date:  
Time:  
   AM/PM (Circle)
PERSON OBTAINING CONSENT
I have explained to 
_________________ _______________
____ the nature and purpose of the 
study and the risks involved.  I have answered and will answer all questions to the best of my ability.  I 
will give a signed copy of the consent form to the subject.
Signature of Person Obtaining Consent:  
Date:  
Time:  
   AM/PM (Circle)
INVESTIGATOR/PHYSICIAN:
Signature of Investigator/Physician  
Date:  
Time:  
   AM/PM (Circle)
10/23/2019
Amendment ID:IRB16-1390-AM005   Date Approved: 10/23/2019   Expiration Date: 10/7/2020