Clinical trial NCT01950234
Conditions: Secondary Progressive Multiple Sclerosis Primary Progressive Multiple Sclerosis Progressive Relapsing Multiple Sclerosis
Sponsor: University of Minnesota
Start date: 2014-04-17; Completion date: 2022-12-31
Enrollment: 59 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a phase II, randomized, double-blind, placebo-controlled, multi-center study to evaluate the safety, tolerability, and efficacy of adrenocorticotropic hormone (ACTH, Acthar gel) administered as a pulsed regimen consisting of injections on three consecutive days per month in patients with progressive forms of Multiple Sclerosis (MS). Patients will be randomly assigned to either an ACTH arm or a placebo arm. The main hypotheses are that 1) pulsed ACTH will be safe and well-tolerated, and 2) pulsed ACTH will slow progression of clinical and paraclinical measures of MS progression compared to placebo.

Detailed description:

Arms: arm 1: ACTH administered subcutaneously as a pulsed regimen of 3 consecutive days per month arm 2: Placebo subcutaneous injections administered on 3 consecutive days per month
Interventions: intervention 1: ACTH intervention 2: Placebo
Intervention descriptions: intervention 1: Acthar gel intervention 2: Placebo

Protocol documents:
Prot_SAP_000.pdf: 
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1 
 
 
 
 
Treatment of progressive forms of 
Multiple Sclerosis with pulsed ACTH 
(Acthar gel) 
 
 
Adam F. Carpenter*, Susan Scarberry**, and Bhupendra 
Khatri*** 
 
 
* 
University of Minnesota (Minneapolis, MN) 
 
 
** 
Sanford Neurology (Fargo, ND) 
*** Ascension/Wheaton Franciscan Healthcare (Milwaukee, WI) 
 
 
 
 
 
 
 
 
 
 
 
 
 
Funded by: 
Mallinckrodt Pharmaceuticals, Inc. and University of 
Minnesota Foundation 


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List of Abbreviations 
 
ACTH - adrenocorticotropic hormone 
AE - adverse effect, or adverse event 
AI - ambulation index 
BRB-N - Brief Repeatable Battery of Neuropsychological tests 
CMP - comprehensive metabolic panel 
CTCAE - Common Terminology Criteria for Adverse Events 
DEXA - dual-energy X-ray absorptiometry 
DSMB - Data Safety Monitoring Board 
EDSS - expanded disability status scale 
FDA - Food and Drug Administration 
GEE - generalized estimating equation 
HgbA1C - hemoglobin A1C 
FSS - Fatigue Severity Scale 
IDS - Investigational Drug Services  
IRB - Institutional Review Board 
LCVA - low-contrast visual acuity 
MN - Minnesota 
MP - methylprednisolone 
MS - multiple sclerosis 
MSFC - Multiple Sclerosis Functional Composite 
MSWS-12 - Multiple Sclerosis Walking Scale  
ND - North Dakota 
OCT - optical coherence tomography 
PASAT - Paced Auditory Serial Addition Test 
PPMS - primary progressive multiple sclerosis 
PRMS - progressive relapsing multiple sclerosis 
RNFL - retinal nerve fiber layer 
SAE - serious adverse event 
SDMT - Symbol Digit Modalities Test 
SPMS - secondary progressive multiple sclerosis 
SRT - Selective Reminding Test 
RRMS - relapsing remitting multiple sclerosis 
T25FW - timed 25 foot walk 
WI - Wisconsin 
WLG - Word List Generation  
10/36 - 10/36 Spatial Recall Test 
6MWT - Six minute walk test 
9HP - 9-hole Peg Test 
 
 


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1.  Abstract 
 
We propose investigating the safety, tolerability and efficacy of adrenocorticotropic hormone 
(ACTH, Acthar gel) administered as a pulsed regimen consisting of injections on three 
consecutive days per month in patients with progressive forms of multiple sclerosis (MS).  
Safety and tolerability will be assessed by subject-reported adverse events as well as vital signs, 
physical examination, serologic tests and radiographic measures of bone mineral density.  
Efficacy will be assessed by changes in walking speed over the course of the study, with the 
primary endpoint a comparison of the proportion of subjects exhibiting a 20% worsening in the 
Timed 25-Foot Walk Test (T25FW).  We will also explore the effects of ACTH on slowing 
neurological deterioration via several measures of disability in these patients, including effects 
on ambulation, cognition, fatigue, vision, and global measures of disability.  Finally, we will 
measure the effect of pulsed ACTH on changes in retinal nerve fiber layer thickness, to assess an 
important paraclinical measure of neurodegeneration.  Because degenerative changes occur at a 
slow pace, a 3 year study is proposed.   
 
 
2.  Background 
 
MS has both neurodegenerative and inflammatory aspects (1-4) 
.  In secondary progressive MS (SPMS), the degenerative aspect predominates but inflammation 
persists, particularly in the early stages, in the form of both occasional acute inflammatory 
relapses and chronic low-level white matter inflammation.  Primary progressive MS (PPMS), by 
definition, has no clinical relapses but there are MRI abnormalities indicative of inflammation 
and pathological studies show changes very similar to those seen in SPMS.   
 
While great progress has been made in treating relapsing-remitting MS, there are no 
proven safe and effective treatments for progressive forms of MS.  No treatment has 
been shown to benefit patients with PPMS.  The only treatment that has been shown to 
provide some benefit in SPMS is chemotherapy; the approved immunomodulatory 
treatments (β-interferons, glatiramer acetate, natalizumab, fingolimod, teriflunomide, and 
dimethyl fumarate) have not been proven to slow disease progression in this phase of the 
disease (5). Cyclophosphamide and mitoxantrone have both been shown to slow 
progression in SPMS, particularly in its early stages, but have obvious disadvantages in 
terms of toxicity (6-10). 
 
β-interferons, natalizumab, fingolimod, teriflunomide and dimethyl fumarate have all 
been shown to slow progression in relapsing-remitting MS, presumably due to their anti-
inflammatory properties.  However, a recent study (11) of the long term effects of β-
interferons showed no reduction in the progression of disability as measured  by the time 
to reach sustained Expanded Disability Status Scale (EDSS) 6.0, suggesting that the 
benefit seen in the short term studies is not maintained.  Corticosteroids may also slow 
the progression of disability accumulation in patients with RRMS, at least in one study.  
Zivadinov et al. (12) conducted a 5 year study of RRMS patients comparing pulsed 
methylprednisolone (MP) administered for 5 consecutive days every 4 months with MP 
administered only as needed for clinical relapses.  In subjects receiving regular pulsed 


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MP there was a significant reduction in brain atrophy compared with those receiving 
steroid treatment for relapses alone.  The pulsed MP group also showed a significant 
clinical benefit; EDSS in treated patients improved from 2.1 at outset to 1.7 at completion 
while in controls the EDSS declined from 2.4 to 3.4.  A phase II study of pulsed MP in 
secondary progressive MS showed a benefit of high dose (500 mg) over low dose (10 
mg) MP in time to onset of sustained progression of disability, but no difference in the 
proportion of patients who experienced sustained disability progression (13). 
 
ACTH is FDA-approved for treatment of MS relapses, infantile spasms, and multiple 
non-neurologic disorders.  ACTH has both corticotropic and neurotropic properties (14), 
and has the potential to benefit both the inflammatory and neurodegenerative aspects of 
MS, respectively.  Because of its corticotropic properties, long term use may result in 
steroid-related adverse effects (AE’s).  Administration of steroids as a pulsed regimen has 
been generally found to be well tolerated with few of the usual AEs associated with 
chronic corticosteroid use (12), although reduction in bone mineral density has been 
reported (15).  The multiple mechanisms of ACTH action may offer advantages over 
steroids alone for the treatment of MS.  Any slowing of progression resulting from 
treatment of progressive forms of MS with ACTH could be due to its corticotropic 
effects, its neuroprotective effects, and/or corticosteroid-independent effects on the 
immune response (16).  A recent preliminary report evaluating pulsed ACTH versus 
pulsed MP as an add-on to interferons for treatment of RRMS found a significant benefit 
of pulsed ACTH (compared to pulsed MP) in reducing relapses over one year (17). 
 
 
3.  Hypotheses  
 
1. ACTH administered as a monthly pulse (consisting of three consecutive days of 
subcutaneous injection) will be safe and well-tolerated in progressive MS 
patients. 
2. Pulsed ACTH treatment will slow the progression of sustained physical disability of 
ambulation, as measured walking speed (T25FW), walking endurance (6 minute walk 
test, 6MWT), the Hauser ambulation index (AI), and the MS walking scale (MSWS-12), 
all validated measures related to ambulation in MS patients.   
3. Pulsed ACTH treatment will slow the progression of sustained cognitive disability as 
measured by the Brief Repeatable Battery of Neuropsychological Tests (BRB-N), a 
measure of cognitive impairment that has been specifically validated for MS.   
4. Pulsed ACTH treatment will reduce the proportion of subjects who show a sustained 
progression of the EDSS over the course of the study.  (EDSS is a validated measure of 
overall MS disability). 
5. Pulsed ACTH will reduce the decline in retinal nerve fiber layer thickness as measured 
by optical coherence tomography (OCT).   
 
 
 
 
 


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4.  Inclusion and Exclusion Criteria 
 
1. Inclusion criteria: 
a. Male or female patients with a confirmed diagnosis of MS by McDonald criteria 
(18). 
b. Age ≥ 18 years. 
c.  SPMS, PPMS, or PRMS (progressive relapsing MS) phenotype, according to 
Lublin and Reingold criteria (19). 
d. EDSS 2.0-6.0, inclusive. 
e. Able to understand the consent process. 
 
2. Exclusion criteria: 
a. Known intolerance of ACTH or corticosteroids. 
b. Diabetes mellitus, defined as pre-existing diagnosis, fasting blood glucose > 125 
mg/dl, or glycosylated hemoglobin ≥ 6.5%, or 2-hour blood glucose > 200 mg/dl 
in an oral glucose tolerance test.    
c. Osteoporosis, defined as pre-existing diagnosis or T-score on dual-energy X-ray 
absorptiometry (DEXA) scan of ≤ -2.5 in any of the following regions:  left 
femoral neck, left total hip, right femoral neck, right total hip, L1-L4 (combined 
score).   
d. Current serious medical condition which may interfere with subject's ability to 
complete the study, or for which pulsed ACTH therapy is contraindicated or 
might complicate current therapy (e.g. cancer, severe psychiatric illness, chronic 
infections, autoimmune disorders). 
e. Treatment with cytotoxic broad-spectrum immunosuppressive agents (including 
but not necessarily limited to mitoxantrone, cyclophosphamide, alemtuzumab, or 
cladribine) within 3 years prior to randomization or during study participation. 
f. Treatment with non-cytotoxic broad-spectrum immunosuppressive agents 
(including but not necessarily limited to corticosteroids, ACTH, azathioprine, 
mycophenolate mofetil, or methotrexate) within 3 months prior to randomization 
or during study participation. 
g. Treatment with FDA-approved MS disease-modifying therapies (β-interferon, 
glatiramer acetate, fingolimod, teriflunomide, dimethyl fumarate, daclizumab or 
ocrelizumab) will be permitted.  Treatment with these medications should be  
ongoing and stable for at least 3 months prior to randomization.  Starting, 
stopping, or changing MS disease-modifying medications during the study is 
discouraged. 
h. Treatment with natalizumab will be permitted, as long as treatment has been 
ongoing and stable for at least 3 months prior to randomization and JC virus 
antibodies are negative.  Subjects taking natalizumab should be tested for JC virus 
antibodies every 6 months during the study (per standard of care), and if JC virus 
antibodies become positive, then the subject must either discontinue natalizumab 
or withdraw from the study. 
i. Treatment with rituximab will be permitted, as long as treatment has been 
ongoing and stable for at least 3 months prior to randomization. 


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j. Treatment with dalfampridine or compounded 4-aminopyridine will be permitted 
as long as treatment has been ongoing and stable for at least 3 months prior to 
randomization. Starting or stopping dalfampridine during study participation is 
strongly discouraged.  
k. Stimulant medications for fatigue (such as methylphenidate, modafinil, 
armodafinil, amantadine or dextroamphetamine) will be permitted, but subjects 
will be asked to not take these medications on study visit days until all study 
procedures/assessments are completed. 
l. Women who are pregnant, planning to become pregnant over the course of the 
study, or breastfeeding. 
m. Concurrent participation in another study involving the use of blinded 
investigational drug. 
 
3. Pre-screening considerations 
a. Pre-screening for osteoporosis and diabetes: Since the study budget does not 
contain funds to cover the cost of screen failures, it is recommended that subjects 
be pre-screened for osteoporosis and diabetes, e.g., with a DEXA scan and 
diabetes screening test (fasting blood glucose, glycosylated hemoglobin, or oral 
glucose tolerance test) within 2 years prior to the screening visit.  Whether or not 
to order these pre-screening tests (or to omit them at the risk of an uncompensated 
visit in the case of screen failure) will be left to the discretion of the local PI. 
b. Dalfampridine: Since most patients with progressive MS with EDSS 2.0-6.0 have 
some walking impairment, it follows that most will be candidates for treatment 
with dalfampridine (or other aminopyridine preparation).  While this is permitted 
within the study, starting or stopping dalfampridine (or other aminopyridine) 
during the course of the study should be avoided, as this may confound the 
ambulation outcome measures in the study.  It is recommended that for all 
patients, consideration of whether or not they should be treated with 
dalfampridine be done prior to enrollment.  For subjects interested in enrolling 
and who have not had a trial of dalfampridine (and are deemed an appropriate 
candidate for this medication), a trial of dalfampridine is recommended to see if 
they benefit from it.  Once the determination is made whether or not to continue 
dalfampridine, they may enroll in the study once they have been stable on (or off) 
dalfampridine/aminopyridine for 3 months. 
 
 
5.  Outcome measures 
 
A.  Ambulation 
 
Walking impairment is a signature characteristic of MS, and of progressive MS in 
particular.   Estimates of the prevalence of gait impairment in MS range from 
approximately 40-80%, and MS patients rate walking difficulties as one of the most 
burdensome aspects of the disease (20).  Multiple walking assessment methods have been 
developed and evaluated in MS, including the gait-specific measures included in the 
present study:  the 6MWT (21), the T25FW (22), the MSWS-12 (23) and the AI (24).   


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There is no clear "best" objective assessment of ambulation in MS.  The most commonly 
used metrics are the EDSS (an overall measure of MS-related disability that is heavily 
"weighted" toward walking ability) and the T25FW.  The T25FW is, as the name implies, 
a timed measurement of how fast a patient can safely walk 25 feet.  Thus, it is primarily a 
measure of walking speed.  In contrast, the 6MWT (a measure of the distance a subject 
can walk in 6 minutes) is a test of walking endurance.  While impairments in walking 
speed certainly may cause problems in daily living for MS patients (e.g. crossing the 
street, getting to the bathroom on time), impairments in walking endurance probably 
account for the majority of walking-related  functional limitations in MS.  Several studies 
have evaluated and compared these metrics, and found both to be valid and reliable (25, 
26).  These studies found high correlations between walking speed and walking distance, 
but recommended a test of walking distance such as 6MWT be included in intervention 
studies where ambulatory function in an important outcome (as in the present study) (25).  
The 6MWT is more likely to capture the effect of motor fatigue on walking ability than is 
the T25FW, and is likely less susceptible to floor effects from subjects with no (or mild) 
gait impairment (27). 
 
The literature contains much more data on T25FW than on 6MWT in MS patients.  In 
particular, there is no published data on the change in 6MTW in MS patients over time.  
Therefore, change in the T25FW will serve as the primary endpoint of the study.  
Multiple studies have found that a change of 20% from baseline T25FW is both reliably 
detectable and clinically meaningful (28-31).  The primary endpoint of this study will 
be the proportion of subjects in each treatment arm who show a 20% increase in 
T25FW at the last study visit, compared to baseline.  Changes in 6MWT, MSWS-12, 
and AI will be secondary endpoints. 
 
 
B.  Safety and Tolerability 
 
A key outcome measure of this phase II study is the safety and tolerability of pulsed 
ACTH compared to placebo.   Little background information on adverse effects of pulsed 
ACTH in MS is available.  A preliminary report of a one-year study (17) reported 
generally no increase in adverse effects in MS subjects receiving pulsed ACTH compared 
to pulsed MP, and fewer "psychiatric episodes" in the ACTH group.  Potential AEs of 
concern are primarily those related to corticotropic effects, i.e. common steroid-related 
AEs such as increased risk of infection, weight gain, glucose intolerance, osteoporosis, 
hypertension, fluid retention, electrolyte derangements, and mood or behavioral changes.  
 
Safety and tolerability of ACTH will be assessed in three ways:  via volunteered 
responses from subjects regarding AEs, by elicited responses regarding specific 
symptoms, and by laboratory and physical exam measures.  The advantage of volunteered 
(unsolicited) responses is that they allow unexpected AE's to be assessed and tend to 
highlight more serious or distressing AEs, while elicited responses have the advantage of 
more sensitive detection of specific AEs of interest (32).  The volunteered responses will 
be obtained by an investigator or study coordinator at each follow-up visit, asking the 


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subject "Have you had any medical problems since your last visit?"  Responses will be 
recorded on a log and severity will be rated according to the Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.03.  Subjects may also report AE's by 
phone, and these will be rated and logged in a similar manner.  Study personnel will 
contact subjects monthly (by phone, email, etc.) around the time of their scheduled study 
drug injections, to remind them of the injections and to check for any new AE.  If a 
phone-reported AE is deemed serious or possibly serious, an unscheduled visit will be 
arranged to allow the local investigator to assess the AE more fully (see section 7E, 
Unscheduled Study Visits).  Elicited responses will be assessed through a questionnaire 
that will explore insomnia, irritability, dyspepsia, injection pain, edema, dysgeusia, 
fatigue, vision, skin changes, and changes in menstruation.   
 
Physical exam and laboratory measures will include objective measurements of weight, blood 
pressure, skin changes, edema, myopathy, cataracts, glucose, electrolyte abnormalities, bone 
mineral density (DEXA) and hepatic toxicity.  
 
The following events are considered protocol-defined AEs and should be recorded on the AE 
log: 
 
1. Weight gain: 5% increase compared to baseline 
2. Increased blood pressure: increase of >20mm systolic or 10mm diastolic compared to 
baseline 
3. Increased A1c: absolute increase of 1% or greater from baseline (Screening visit value) 
that is sustained across 2 consecutive measures 
4. Hypokalemia: any potassium value below the lower limit of normal 
5. New Osteopenia (compared to Baseline): DEXA T score between -1 and -2.5 
6. Osteoporosis: DEXA T score less than -2.5 
7. A DEXA T score drop of ≥ -0.5 during the study 
 
As is typical, the study will not be powered based on safety and tolerability measures because 
AEs are anticipated to be rare and because the type and severity of AEs may be unpredictable.  
The main secondary endpoint for safety and tolerability will be a comparison of the 
number of serious adverse events (SAE) over the study period in the ACTH group versus 
the placebo group.  A SAE will be considered any event with a score equal or greater than 3 on 
the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.  AEs receiving a 
mild or moderate grade will also be compared between the two treatment groups. 
 
 
C.  Cognition 
 
Cognitive dysfunction is ubiquitous in MS, affecting an estimated 40-70% of patients 
(33), and is a major cause of disruption in daily and occupational function in MS patients 
(34).  The most common domains of cognitive impairment in MS are memory, 
processing speed, visuospatial functions, verbal abilities, sustained attention and 


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executive function (35).  The BRB-N is a set of five cognitive tests developed by 
National MS Society's Cognitive Function Study Group as a research tool to detect 
cognitive changes in MS patients and to evaluate the effect of treatment interventions on 
cognition (36).  The five neuropsychological tests comprising the BRB-N were chosen 
for their ability to assess the cognitive domains most frequently impaired in MS in a 
practical time period (20-30 minutes).  The BRB-N includes the Selective Reminding 
Test (SRT, a test of verbal learning and delayed recall), the 10/36 Spatial Recall Test 
(10/36, visuospatial learning and delayed recall), the Symbol Digit Modalities Test 
(SDMT, sustained attention and processing speed), the Paced Auditory Serial Addition 
Test (PASAT, sustained attention and processing speed) and Word List Generation task 
(WLG, verbal fluency). 
 
Relatively little published data exists on the evolution of BRB-N over time in progressive 
MS patients, but available data suggest that study durations longer than 2 years are 
needed to observe changes in cognition.  Huijbregts et al. (35) found stable BRB-N 
performance over 2 years in 30 SPMS and 25 PPMS patients.   Montalban and colleagues 
conducted a 2 year study of interferon β1b or placebo in PPMS, and administered the 
BRB-N at baseline, at 2 years, and at 5 years.  No change in any of the BRB-N tests was 
evident in the placebo group at 2 years (37), but at 5 years the placebo group showed 
significant deterioration in the SDMT, 10/36 and WLG (but not in the PASAT or SRT) 
(38). 
 
The tests will be administered according the BRB-N manual (36), including order of test 
administration, instructions to subjects, testing procedures, and scoring.  Because practice 
effects may occur with neuropsychological tests, one practice administration of the BRB-
N will be performed in each subject as recommended in the BRB-N manual.  The 
practice session will be performed either during the screening visit or, if the screening 
and baseline visits are combined, the BRB-N will be performed twice during the baseline 
visit, with the second BRB-N administration serving as the baseline.  The PASAT can be 
administered with either a 2-second or 3-second interval between successive digits; the 3-
second version will be used in this study.  Multiple versions of each test are provided 
with the BRB-N, to control for learning effects with repeated application of identical test 
material (15 versions each for SRT, 10/36, SDMT and WLG, and 2 versions for PASAT).  
These different versions are constructed to be equivalent, but some authors have found 
significantly different scores between different versions of certain tests (39).  We will 
administer the BRB-N variants sequentially (version 1 at the training session, version 2 at 
baseline, version 3 at year 1 follow-up visit, etc.) for the tests with 15 versions, and will 
alternate versions A and B on successive administration of the PASAT.  Applying the 
same versions to all subjects at each visit, combined with the randomized design, should 
control for confounding or bias due to any systematically different performance 
(difficulty) between the test versions, and prevents confounding due to learning effects. 
 
 
 
 
 


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D.  Vision 
 
Low-contrast visual acuity (LCVA) is a sensitive measure of visual impairment in MS 
patients (40) and has been recommended for incorporation into the Multiple Sclerosis 
Functional Composite (MSFC).  LCVA is correlated with retinal nerve fiber layer 
thickness as measured by OCT (41) (see section 5.F., below).  Visual acuity will be 
measured in each eye separately as well as binocularly, at three contrast levels (100%, 
2.5%, and 1.25%) using low-contrast Sloan letter charts (Precision Vision, LaSalle IL).  
For each measurement, the number of letters (maximum = 70) correctly identified will be 
recorded.  Changes in LCVA over the study, and correlation of LCVA measures with 
OCT measures, will be exploratory outcomes of the study. 
 
 
E.  Fatigue 
 
Fatigue is an extremely common symptom in MS patients, and often one of the most 
disabling.  Over 50% (and up to 90%) of MS patients cite fatigue as a significant problem 
(42).  The Fatigue Severity Scale (FSS) is a validated, patient-reported metric of fatigue 
symptoms that was specifically developed for MS and related disorders (43).  The FSS 
will be administered to all study subjects at baseline and at each annual follow-up.  The 
change in FSS from baseline to study end will be compared between treatment arms, as 
an exploratory endpoint.  Many MS patients are treated with stimulant medications (such 
as methylphenidate, modafinil, or amphetamine preparations) for fatigue symptoms, and 
such medications (and the timing of their dosing) could obviously affect FSS scores, as 
well as other study measures.  Accordingly, subjects will be asked not to take such 
stimulant medications on study visit days (although they will be advised to bring such 
medications with them, so that they may take them as needed after the study assessments 
are completed). 
 
 
F.  Global Measures of MS-related disability (EDSS and MSFC) 
 
The EDSS and the MSFC are the two most commonly used metrics for assessing neurologic 
disability in MS.  The EDSS is a 19-step ordinal scale between 0 and 10 based on exam findings 
or symptoms in 8 functional systems plus ambulation.  Despite some well-known limitations 
(e.g. only moderate intra- and inter-rater reliability, overweighting of ambulation, insensitivity to 
change at certain levels), it remains the gold standard for assessing disease and disability status 
in MS.  Most current clinical trials in MS evaluate "progression of disability" as an increase in 
EDSS score that is sustained across multiple measures.  Because higher EDSS scores rely more 
heavily on changes in ambulatory function and generally become less sensitive to change than 
lower scores, a larger "step" change from baseline EDSS is often required for lower baseline 
EDSS than for higher baseline EDSS in order to constitute progression of disability.  In the 
current study EDSS will be measured at screening and at annual follow-up visits for the three 
year study duration, by a neurologist or nurse practitioner certified in EDSS evaluation.  The 
same examiner will perform all EDSS evaluations in an individual subject, if possible.  Use of a 
backup examiner (if trained and certified in EDSS) will be permitted in cases where the primary 


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examiner is unavailable.  Progression of disability will be defined as an increase from baseline 
EDSS of ≥ 1.0 for baseline EDSS of 2.0-5.0, or an increase of 0.5 for baseline EDSS of 5.5-6.0.   
The proportion of subjects in each treatment arm who exhibit progression of disability will 
serve as a secondary endpoint.  Due to the limited number of EDSS assessments, an increase in 
EDSS score will not have to be "sustained" across multiple assessments in order to be considered 
evidence of disability progression. 
 
The MSFC (22, 44) was developed by a National MS Society task force on clinical 
outcomes in MS.  It consists of 3 objective measures (tests) covering three functional 
domains: leg function and ambulation (the T25FW), arm and hand function (the 9-hole 
Peg test, 9HP), and cognitive function (the PASAT).  The individual scores on each test 
are converted to Z-scores, and the Z-scores averaged into a single MSFC Z-score (44).  
Change in overall MSFC Z-score (and in each individual Z-score) over the course of 
the trial will be compared between treatment arms, and will constitute secondary 
endpoints.   
 
It should be noted that 1) the T25FW is utilized both as a stand-alone measure (and 
primary endpoint) and as a component of the MSFC, and 2) the PASAT is a component 
of both the MSFC and of the BRB-N (see section 5D, above).  At each annual follow-up 
visit, the MSFC and the PASAT will be administered once to each subject, with the 
single score or measurement for that visit contributing to all relevant metrics (i.e., the 
PASAT will not be administered once for the BRB-N and then again for the MSFC).  
Previous studies have found practice effects in the 9HP and PASAT, but not the 
T25FW(45, 46), with the practice effects stabilizing after the third administration.  
Accordingly, three practice sessions of the PASAT and 9HP will be administered prior to 
the baseline tests.  Since the PASAT is one of the components of the BRB-N, and one 
practice session of the entire BRB-N will be administered, two additional practice 
sessions of the PASAT will be administered at the screening or baseline visit.  The MSFC 
tests will be administered according to the MSFC manual (44), including test order, 
instructions to subjects, testing procedures, number of repetitions, and scoring. 
 
 
G.  Optical Coherence Tomography (OCT) 
 
Retinal nerve fiber layer (RNFL) thickness will be measured by OCT, an accurate and 
reproducible measure of the integrity of unmyelinated axons in the retina (47, 48).  RNFL 
thickness is reduced in MS patients compared to controls, and reduction in RNFL 
correlates with visual function impairment in MS patients (49).  The reduction in RNFL 
thickness is most prominent in eyes that have experienced a prior episode of optic neuritis 
(ON), but even eyes that have not suffered past episodes of ON show a reduction in 
RNFL compared to healthy controls (50).  This latter fact makes OCT an attractive 
candidate for monitoring neurodegenerative processes in MS, which may underlie the 
gradual neurologic decline in progressive forms of MS.  To date, limited longitudinal 
studies of OCT in progressive MS have been performed (51), but this remains a 
potentially very powerful surrogate marker for MS progression and the effect of 
treatments.  Recently, alternative OCT measures such as macular volume and the 


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12 
 
thickness of retinal layers other than the RNFL (e.g. the ganglion cell layer) have been 
shown to be abnormal in MS, and possibly to differentiate between the different MS 
phenotypes (52). 
 
Each subject will have OCT performed on each eye at baseline and then annually for 3 
years (total of 4 OCT per subject).   OCT will be performed on the Spectralis OCT 
system (Heidelberg Engineering, Germany) using the glaucoma protocol set.  If the study 
center's available Spectralis OCT system has the neurology-oriented "N-site" software, 
then the RNFL scan (see below) will be obtained twice, once using the glaucoma 
protocol set and once using the axonal (N-site) protocol set.  Pupillary dilation will not be 
routinely performed, as it is usually unnecessary for OCT (49).  If dilation is deemed 
necessary to achieve adequate OCT quality (e.g., due to cataract), the subject may be 
excluded from the OCT portion of the study.  Alternatively, dilation may be performed 
(with typical mydriatic eye drops) if the dilation and OCT are done after the other 
functional study assessments (e.g.  EDSS, MSFC, LCVA, BRB-N) during the study visit, 
or if dilation/OCT are done on a separate visit day within a +/- 2 week window of other 
efficacy measures.  In other words, pupillary dilation for OCT purposes will not be 
allowed to interfere with the other efficacy assessments that require vision for their 
performance.   
 
Up to three different scans will be performed on each eye at each visit, to assess RNFL thickness 
macular volume, and individual retinal layer thickness (ganglion cell layer, inner nuclear layer, 
etc).  The RNFL scan will be obtained twice (once using the glaucoma protocol and once using 
the axonal protocol) if the axonal protocol is available.  The axonal protocol (N-site) is optimized 
for detecting abnormalities in MS, and is thus the preferred method.  However, all of the study 
sites are not expected to have access to the axonal protocol, while all will have the glaucoma 
protocol available.  Therefore, we will obtain all scans on the glaucoma protocol (to ensure 
consistency of data), and acquire the axonal protocol RNFL scan as well when it is an option.  
The scans to be obtained are: 
 
i. 
RNFL scan (circle scan) – Standard settings for peripapillary RNFL with the Spectralis 
glaucoma protocol will be used:  12 degree (3.45 mm) circular scan manually centered on the 
optic disc, ART = 100, circle = 12°, 768 A-scans. 
 
ii. 
Macular volume scan (posterior pole scan) – The posterior pole scan from the glaucoma 
protocol set will be used, again using the standard settings:  30x25, 61 sections, 760 A-scans 
per section, distance between B-scans = 120 µm, ART = 9. 
 
iii. 
(optional) RNFL scan (circle scan) using N-site software – Standard settings for 
peripapillary RNFL with the Spectralis axonal protocol will be used:  12 degree (3.45 mm) 
circular scan manually centered on the optic disc, ART = 100, circle = 12°, 768 A-scans. 
For each scan, minimum quality score is 20 (with a goal quality score of ≥ 25).  If a quality score 
of ≥ 20 cannot be obtained, data from that scan will not be included for analysis.  The individual 
centers/technicians obtaining the OCT will evaluate only for quality of the OCT scans (i.e., no 


Version Date: 10.26.21 
13 
 
formal clinical interpretation of the OCT results will be performed.  The image alignment eye-
tracking system (TruTrack, Heidelberg Engineering, Germany) will be utilized throughout.   
 
Data submitted from each OCT session will include printouts of all RNFL scans, plus electronic 
files (.e2e format) containing each of the 2 (or 3) scans.   
 
If a study site does not have access to the Spectralis OCT system, a different spectral-domain 
high-resolution OCT system such as Cirrus HD-OCT (Zeiss) may be used as an alternative, with 
similar scans acquired (RNFL scan, macular volume/posterior pole). 
 
Change in thickness of the temporal quadrant peripapillary RNFL over the course of the 
study will be a secondary study endpoint.  Exploratory endpoints will include changes in 
macular volume and changes in other RNFL regions (e.g. superior, inferior, nasal, and global). 
 
 
6.  Statistical Issues and Data Analysis 
 
A.  Study Design 
 
The study design is a randomized, double-blind, placebo-controlled, multi-center, phase II 
clinical trial. 
 
B.  Sample Size Calculation 
 
The main objective of the study is to investigate the safety and tolerability of pulsed 
ACTH in progressive MS patients over three years.  The primary efficacy endpoint of the 
study is the proportion of subjects exhibiting a 20% increase (worsening) from baseline 
in the T25FW.  No baseline data are available regarding the rate at which a pooled 
population of progressive MS (i.e., SPMS, PPMS and/or PRMS) patients experience 20% 
increase in T25FW.  However, Bosma et al. (53) evaluated change over 2 years in all 
three components of the MSFC (T25FW, 9HP, and PASAT) in 191 PPMS patients, and 
found that 45% of patients showed a 20% or greater increase in T25FW.  This data was 
used as the basis for sample size considerations, with the following assumptions: 
 
The findings in PPMS patients (53) 
1.  will generalize to a mixed sample of any progressive MS phenotype. 
2. Extrapolated to a 3 year follow up period, 60% of progressive MS patients will show a 20% or 
greater increase in T25FW. 
Utilizing a significance level of 0.05 and equal sample sizes, 42 subjects per treatment arm 
would provide 80% power to detect a 50% difference in the proportion of subjects reaching the 
threshold of 20% worsening in T25FW (P1 = 0.6, P2 = 0.3, α = 0.05, β = 0.2, 2-sided test).  
Given the length of the study, we anticipate a dropout rate of up to 10-20% of randomized 
subjects.  To account for this possibility, a total sample size of 100 subjects (50 per treatment 
arm) will be randomized. 
 
 


Version Date: 10.26.21 
14 
 
C.  Randomization 
 
The study will utilize blocked randomization stratified by study center, with equal (1:1) 
allocation to the ACTH and control groups.   
 
 
D.  Blinding 
 
Study subjects, their referring physicians, the study monitor, and all study personnel who come 
in contact with study subjects (including site principal investigators, examining neurologists, 
study coordinators, nurses, and other study staff and their designated backups) will be blinded 
to treatment allocation.  One investigator who will not come in direct contact with study 
subjects (Dr. Parry) as well as the study statistician and other members of the Data Safety 
Monitoring Board (DSMB, see section 7F) will be unblinded, to allow for assessment of any 
safety concerns that may arise over the course of the study. 
 
 
E.  Data Analysis Plan 
 
Descriptive analyses of baseline characteristics and all outcome measures (primary and 
secondary) will include means with standard deviations or medians with ranges for 
continuous variables depending on the parametric or non-parametric distribution of the 
variables, and frequencies with percentages for categorical variables.  Between group 
(ACTH and placebo) comparisons of baseline characteristics and baseline outcome 
measures will be done using two sample t-tests or Wilcoxon rank sum tests for 
parametric and non-parametric continuous variables, respectively, and Chi-square tests 
or Fisher’s exact tests for categorical variables.  
 
Models will adjust for age, gender, and MS phenotype; EDSS and disease duration will 
be included as covariates if significant in preliminary models. Interactions between 
treatment group and MS phenotype will be tested in each model; if significant, 
treatment effect will be evaluated in models stratified by MS phenotype.  
The possibility of mid-study therapy regimen change for some subjects (see Exclusion 
criteria g. and h.) will be accounted for in analysis by running models with and without 
these subjects to explore the impact of these changes on analysis results. If results from 
the two models are consistent, all subjects will be included in the final model.  
There are multiple distinct outcomes of interest in this study; since each outcome 
measures a unique aspect of MS progression no adjustment for multiple comparisons is 
planned.  
 
 
Primary endpoint: 
 
Between group differences in the odds of a 20% or greater increase in T25FW, the 
primary outcome measure of clinical progression of MS, will be tested at 36 months 
using multiple logistic regression models adjusted for covariates. Generalized 


Version Date: 10.26.21 
15 
 
estimating equation (GEE) models will be used to test for between group differences in 
change over time in clinical progression (20% or greater increase in T25FW) adjusted 
for covariates. To test for between group differences in time to clinical progression 
distribution curves, Cox proportional hazards models (conditional on model 
assumptions being met) or Kaplan-Meier analysis will be used.    
 
 
Secondary endpoints: 
 
Safety and tolerability 
To evaluate safety and tolerability of ACTH, lists and descriptive statistics of adverse 
events, serious adverse event, and treatment compliance will be compiled and 
calculated for each group at each visit.  Fisher’s exact tests will be used to test for 
between group differences in specific adverse event rates, serious adverse event rates, 
and treatment compliance rates.  
 
Between group differences in mean changes in physical exam and laboratory measures 
(weight, blood pressure, HgbA1c, bone mineral density) will be tested using two-
sample t-tests. In addition, between group differences in the proportion of subjects with 
abnormal blood pressure, HgbA1C, electrolyte and bone mineral density levels will be 
tested using Chi-square tests or Fisher’s exact tests.  
 
Change in ambulation, cognition, and global measures of MS-related disability 
scores 
Between group differences in study endpoint mean of each of the secondary outcomes: 
change in ambulation (6MWT, MSWS-12, Hauser Ambulation Index), change in 
cognition (eight subtests of the five BRB-N tests), and change in MSFC z-scores will 
be tested using multiple linear regression models adjusted for baseline score and other 
covariates. Mixed model analysis of repeated measures, utilizing data collected at all 
time points, will be used to test for between group differences in change over time in 
mean secondary outcome measures adjusted for covariates. Between group differences 
in the odds of EDSS progression will be tested using multiple logistic regression 
models adjusted for other covariates. Generalized estimating equation (GEE) models 
will be used to test for between group differences in change over time in progression 
rates adjusted for other covariates. Cox proportional hazards models (conditional on 
model assumptions being met) or Kaplan-Meier analysis will be used to test for 
between group differences in time to EDSS progression.  
 
OCT Temporal Quadrant RNFL 
OCT temporal quadrant RNFL measurements from one eye per subject will be used for 
analysis purposes; randomly selected unless the patient has a history of optic neuritis in 
which case the unaffected eye will be selected. Between group differences in change in 
OCT temporal quadrant RNFL thickness will be tested using a multiple linear 
regression model adjusted for baseline thickness and other covariates. Multiple linear 
regression models will also be used to test for between group differences in three year 
rate of change adjusted for other covariates. Separate mixed model analyses of repeated 


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16 
 
measures will be used to test for between group differences in 1) change over time in 
RNFL thickness and 2) change over the 3 years in annualized rates of RNFL change.    
 
 
Exploratory endpoints 
 
Fatigue  
 
Between group differences in study endpoint mean FSS will be tested using a multiple 
linear regression model adjusted for baseline FSS score and other covariates. Mixed 
model analysis of repeated measures, utilizing data collected at all time points, will be 
used to test for between group differences in change over time in mean FSS adjusted 
for covariates.  
 
Other vision measures 
 
Multiple linear regression models will be used to test for between group differences in 
LCVA scores adjusted for other covariates.  Binocular LCVA scores will be used to test 
for a treatment effect on vision changes; monocular LCVA scores will be used for 
correlation with OCT measures (from the matching eye).   Generalized estimating 
equation (GEE) models will be used to test for between group differences in change 
over time in vision loss rates adjusted for other covariates. In addition correlation of 
LCVA with OCT measures (RNFL and macular volume) will be evaluated using 
Pearson correlation analysis (Spearman correlation will be used if measures have 
skewed distributions).  
 
Between group differences in mean OCT macular volume scan measures will be tested 
using multiple linear regression models adjusted for covariates. mixed model analyses 
of repeated measures will be used to test for between group differences in change over 
time in OCT macular volume measures.  
 
 
7.  Study Procedures 
 
A.  Schedule of study procedures: 
 
1. Symptoms questionnaire for subjective adverse events at baseline, 3, 6 and 12 months and 
then annually. 
2. Comprehensive metabolic panel (CMP) and hemoglobin A1C (HbgA1C) at screening, 6 and 
12 months, and then annually. 
3. EDSS and DEXA scan (both hips/femurs and lumbar spine) at screening and then annually. 
4. OCT at baseline and then annually. 
5. MSFC, T25FW, 6MWT, LCVA, MSWS-12, AI, FSS and BRB-N at baseline and then 
annually.   
6. Practice sessions (at screening visit:   
a. BRB-N - 1 practice session 
 


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17 
 
b. PASAT - 2 practice sessions (in addition to the one administered during BRB-N) 
c. 9HP - 3 practice sessions 
 
Table 1. Study Schedule 
 
 
V1 
Screen 
0 to -4 wks 
V2 
Baseline 
M0 
V3
*** 
M3 
V4 
M6 
 
V5 
 M12 
 
V6  
M18 
V7  
M24 
V8   
M30 
V9 
M36 
Informed Consent 
X 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
 
 
 
 
 
 
 
 
Injection Training 
 
X 
 
 
 
 
 
 
 
Blood Pressure 
 
X 
X 
X 
X 
X 
X 
X 
X 
Weight 
 
X 
X 
X 
X 
X 
X 
X 
X 
Safety Lab Testsa 
X 
 
 
X 
X 
 
X 
 
X 
Skin & Edema Assessment 
 
X 
X 
X 
X 
X 
X 
X 
X 
OCT 
 
X 
 
 
X 
 
X 
 
X 
LCVA 
 
X 
 
 
X 
 
X 
 
X 
EDSS 
X 
 
 
 
X 
 
X 
 
X 
Timed 25-Ft Walk 
 
X 
 
 
X 
 
X 
 
X 
9-Hole Peg Test 
XXX 
X 
 
 
X 
 
X 
 
X 
PASAT (apart from BRB-N) 
XX 
 
 
 
 
 
 
 
 
6 Minute Walk Test 
 
X 
 
 
X 
 
X 
 
X 
MS Walking Scale - 12 
 
X 
 
 
X 
 
X 
 
X 
Fatigue Severity Scale (FSS) 
 
X 
 
 
X 
 
X 
 
X 
Hauser Ambulation Index 
 
X 
 
 
X 
 
X 
 
X 
Brief Repeatable Battery 
X 
X 
 
 
X 
 
X 
 
X 
DEXA Scanb 
Xc 
 
 
 
X 
 
X 
 
X 
Randomization 
 
X 
 
 
 
 
 
 
 
Symptom Questionnaire 
 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medications 
 
X 
X 
X 
X 
X 
X 
X 
X 
Unsolicited Adverse Events 
 
 
X 
X 
X 
X 
X 
X 
X 
Dispense Study Drug 
 
X 
X 
X 
X 
X 
X 
X 
 
Return Drug Vials and Logs 
 
 
X 
X 
X 
X 
X 
X 
X 
 
a  Safety lab tests: comprehensive metabolic panel and hemoglobin A1C.  
b  Bilateral hips and lumbar spine  
c  DEXA scan may be omitted at the Screening Visit if subject provides results of DEXA scan done within 
the 3 months prior to the Screening Visit 
 


Version Date: 10.26.21 
18 
 
***  The month 3 visit is primarily a safety visit to assess AEs and to assess any 
difficulties subjects may be having with study drug injections.  No laboratory tests are 
done, and no physical exam other than the skin and edema assessment (which would be 
unlikely to yield abnormal findings at 3 months, since chronic steroid side effects would 
likely take longer to occur in the 3 day per month pulsed dosing).  For patients traveling a 
long distance to the study, this visit might be much more conveniently done by phone.  
While the preference is for the month 3 visit to be done on-site, it can (optionally) be 
done as a phone visit, e.g. for subjects who 1) are inconvenienced by coming in person 
for this visit, and 2) have prior experience with taking subcutaneous injections.  If this 
option is chosen, then 1) 6 months' worth of study drug (rather than 3) must be given out 
at the baseline visit, 2) no study drug dispensing or drug return will occur at the month 3 
visit, and 3) no skin and edema assessment will be done at the month 3 visit.    
 
 
B.  Treatment Administration: 
 
ACTH (Acthar gel) and placebo will be provided by the funding sponsor and distributed to 
individual sites.  The study medication will be self-administered at a dose of 80 units 
subcutaneously for 3 consecutive days every month for the duration of the study.  The dose will 
be reduced to 40 units if the full dose cannot be tolerated.  Specific training in the injection 
procedure will be done prior to the initial injection. 
 
C.  Study Staff 
 
Each study site will have a local principal investigator (Fargo, Dr. Scarberry; Minneapolis, Dr. 
Carpenter; Milwaukee, Dr. Khatri; other sites may be added in the future) who will oversee study 
operation at that site and be responsible for the acquisition and handling of study data according 
to the procedures outlined in this protocol.  Each site will utilize a study neurologist or neurology 
nurse practitioner certified in EDSS administration, who will perform the EDSS, review safety 
and tolerability data and report AEs and SAEs.  There will not be a separate "treating" and 
"examining" neurologist at each site.  A backup study neurologist may be designated, in case the 
primary study neurologist is unavailable for a scheduled visit.  Other study staff such as research 
coordinators or nurses may be assigned to assist in recruitment, scheduling, and study 
procedures.  Study coordinators/nurses may administer all study assessments except the EDSS 
and the physical examination (e.g., MSFC, BRB-N, 6MWT, MSWS-12, AI, LCVA, and subject-
reported AE assessments), as long as they have been specifically and adequately trained on 
administering these assessments.  Alternatively, the site study neurologist (or backup) may 
administer these assessments as well.  OCT and DEXA scans will be performed by operators 
trained in administering those tests.  A study monitor will be designated from the primary study 
site (University of Minnesota, Minneapolis) and will oversee data collection and management, as 
well as visit all  study sites to review compliance with study procedures. 
 
D.  Relapses 
 
Patients with certain forms of progressive MS (SPMS, PRMS) may experience acute disease 
relapses in addition to gradual neurologic decline.  MS relapses entail new or worsened 


Version Date: 10.26.21 
19 
 
neurologic symptoms that typically evolve over days, last for weeks, and gradually improve.  
They commonly manifest as focal deficits in sensory and/or motor function, visual disturbance, 
brainstem/cerebellar symptoms (such as vertigo, diplopia or ataxia), bladder or bowel symptoms, 
gait impairment, or fatigue.  Acute cognitive or behavioral symptoms are less common, but may 
occur.  Relapse symptoms may eventually resolve completely, partially, or not at all.  
 
This study is not designed to assess the effect of ACTH on MS relapses, but the occurrence of 
relapses could affect the study in several ways.  First, relapse symptoms could affect study 
measures of neurologic function/disability (T25FW, EDSS, etc. – any of the study metrics could 
be affected), either because the study visit occurred during the relapse or because the relapse 
resulted in incomplete recovery.    Second, relapse symptoms (or signs) could be reported (or 
interpreted by study investigators) as AEs.  Third, relapses are commonly treated with short 
courses of corticosteroids, and side effects from corticosteroid therapy could be mistaken for or 
confounded with AEs related to study medication.  While relapses are expected to be quite rare 
in the study population, due to these potential impacts on study measures it is important to 
identify the occurrence and timing of relapses and corticosteroid treatment in study subjects.  
This will be done via the following procedures: 
 
1. Subjects will be instructed to contact their treating neurologist (who may or may not be a study 
investigator) if they think they may be experiencing an MS relapse.   
2. Subjects will also be asked to notify their study contact (site study coordinator or investigator) to 
inform them of the possible relapse, including the nature of symptoms, date of symptom onset, 
presence of any concomitant medical illness (e.g. upper respiratory tract infection, urinary tract 
infection, recent surgery or trauma), and any other special circumstances.  The study coordinator 
will enter this information on the Potential Relapse case report form. 
3. Evaluation of the potential relapse will be done by, and at the discretion of, the subject’s treating 
neurologist. 
4. The subject will be asked to provide copies of the treating neurologist’s clinic notes and/or other 
medical records related to the possible relapse (e.g., MRI reports) to study staff. 
5. The local principal investigator will review the medical records and judge whether or not the 
subject experienced a relapse.  This will be recorded on the Potential Relapse case report form (as 
Relapse or Not Relapse).   
6. Treatment of the relapse or suspected relapse (e.g., with corticosteroids) will be allowed, at the 
discretion of the treating neurologist.  The dates, dose and formulation of treatment will be 
reported to the study coordinator and logged on the Potential Relapse case report form.   
 
E.  Unscheduled Study Visits 
 
Subjects will be asked to contact their study site if they develop new symptoms that are 
concerning to them.  The local study coordinator will record the reported symptoms on the 
Unsolicited AE Form, which will be reviewed by the local investigator.  An unscheduled study 
visit will occur if the local investigator deems these AEs as potentially serious, possibly related 
to study medication, and/or requiring in-person assessment.  If the reported symptoms are 
interpreted as mild and/or unrelated to study medication, the subject may be referred to their 
primary physician or advised to report back by phone with updates about symptom 


Version Date: 10.26.21 
20 
 
evolution/resolution.  Unscheduled visits will not be routinely performed for suspected MS 
relapse (see section 7D, Relapses), although they may occur in this situation if the reported 
symptoms are interpreted as a possible treatment-related AE.  Assessments/procedures 
performed at an unscheduled visit will include all of the assessments done at Visit 3 (see Table 
1) with the exception of study drug distribution; any further assessments and/or procedures (e.g. 
physical examination, other tests, referrals) will be done at the discretion of the local 
investigator. 
 
 
F.  Early Termination and Intent to Treat 
 
Once subjects are randomized, regardless of if or the length of time they have been on blinded 
treatment, they will be included in the efficacy (intent to treat) analysis if efficacy data are 
available (that is, if they have completed at least one annual follow-up visit).  Subjects who 
withdraw (e.g., due to side effects) prior to completing the Month 12 visit will be asked to return 
the study drug to the site, and to participate in annual phone calls (Months 12 and 24), and to 
return to the site for the final visit at Month 36.  Subjects who withdraw after completing the 
Month 12 visit will be asked to return the study drug to the site, and to complete the remaining 
annual study visits (i.e., Month 24 and Month 36) even though they are not receiving drug.  
Subjects are of course allowed to decline further participation, in which case they would be 
considered lost-to-follow-up.   
 
 
G. Data Safety Monitoring 
 
A DSMB will be formed and will consist of one MS specialist, one neurologist familiar with the 
evaluation and treatment of MS but not otherwise associated with the study, and the study 
biostatistician.  A DSMB chairperson will be chosen from one of the two neurologists on the 
DMSB. 
 
Safety data will be reviewed by the DSMB at 6 and 12 months and then annually, starting from 
the time the first subject receives a dose of study medication and ending at participant study 
completion (i.e., no active participants on study drug and enrollment closed).  Reports from all 
DSMB meetings will be forwarded to the Institutional Review Board (IRB).  Any SAEs or 
unexpected AE's reported at other times will be reviewed by the head of the DSMB and reported 
to other members of the DSMB if considered significant enough to warrant interim review by the 
full committee.  In the event of unanticipated SAEs that reflect new or increased risk to the 
subjects and are considered possibly related to the study medication or procedures (UPIRTSO) 
the funding sponsor and all study sites will be notified within 48 hours of the local investigator 
learning of the event.  The local IRB will be notified within that IRB’s policy timelines (e.g., the 
University of Minnesota IRB will be notified within 10 business days).  A detailed analysis of all 
AEs will be conducted at the end of the first year of the study.  The efficacy measures will also 
be analyzed annually throughout the study to see whether any signal of benefit is appearing.  
However, the study will be terminated only if there are unacceptable adverse events, not because 
of lack of any efficacy signals since it may take the entire 3 year duration of the study for any 


Version Date: 10.26.21 
21 
 
beneficial effect to become manifest.  Study termination due to safety concerns will be at the 
discretion of the DSMB; no pre-specified stopping rules will be used. 
 
 
8.  Cytokine sub-study 
 
There are multiple mechanisms by which melanocortins such as adrenocorticotropic hormone 
(ACTH) might alter the course of multiple sclerosis (MS) in a beneficial way (16, 54).  One such 
mechanism is altering the balance between pro-inflammatory and anti-inflammatory cytokines 
via direct immunomodulating effects of melanocortins on immune system cells.  A sub-study 
will be performed (at the University of Minnesota site only) to evaluate the change in plasma 
cytokine levels in subjects receiving ACTH compared to those receiving placebo, in order to 
better elucidate the possible mechanisms of ACTH in MS. 
 
Subjects enrolling in the main study at the University of Minnesota site will be invited to 
participate in the plasma cytokine sub-study as well.  Subjects who enroll in the sub-study will, 
at the annual study visits when they have blood drawn for safety blood tests, have additional 
blood tubes drawn for the cytokine analysis (2 EDTA tubes).  Tubes will be mixed, centrifuged, 
and then plasma aliquoted and stored at -80° C.   Leukocytes (buffy coat) will also be aliquoted 
and mixed with RNAlater (a reagent that stabilizes RNA for future possible analysis of gene 
expression) and stored at -80° C.  Leukocytes or whole blood samples will also be stored for 
possible future DNA analysis.  The potential future RNA and DNA analyses are not currently 
planned as part of the sub-study, and subjects may opt out of this aspect (i.e. choose not to have 
genetic material stored) in the consent form. 
Cytokine levels will be assessed with multiplex cytokine assays on the Luminex system, 
and will be performed by the Cytokine Reference Laboratory at the University of 
Minnesota.  Approximately 25-30 analytes (cytokines, chemokines, growth factors, etc) 
will be measured.  The current list of analytes planned for the study include:  Eotaxin, 
FGF-2, G-CSF, GM-CSF, IFNa2, IFNg, IL-1b, IL-1ra, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, 
IL-9, IL-10, IL-12(p70), IL-13, IL-15, IL-17, IP-10, MCP-1, MIP-1a,b, TNFa, VEGF, M-
CSF, and MIG.  Assays will be performed in batches of 40 samples (in duplicate) at a 
time; thus each "batch" would correspond to 10 subjects worth of samples (10 subjects x 
4 samples/subjects = 40 samples).  We anticipate the total number of subjects to be 
enrolled in the sub-study to be between 30 and 80.  Differences between the active 
(ACTH) and placebo groups for plasma levels of each analyte will be assessed with 
multiple linear regression models adjusted for covariates (e.g. age, gender, MS 
phenotype) and/or mixed model analyses of repeated measures. 
 
 
 
 
 
 
 


Version Date: 10.26.21 
22 
 
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Neurology. 60, 31-36 (2003). 
24. S. L. Hauser et al., Intensive immunosuppression in progressive multiple sclerosis. A 
randomized, three-arm study of high-dose intravenous cyclophosphamide, plasma 
exchange, and ACTH. N. Engl. J. Med. 308, 173-180 (1983). 
25. D. Gijbels et al., Which walking capacity tests to use in multiple sclerosis? A 
multicentre study providing the basis for a core set. Multiple Sclerosis Journal. 18, 364-
371 (2012). 
26. Y. Learmonth, D. Dlugonski, L. Pilutti, B. Sandroff, R. Motl, The reliability, 
precision and clinically meaningful change of walking assessments in multiple sclerosis. 
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multiple sclerosis clinical trials: current status and future prospects. Lancet Neurology. 
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28. E. L. J. Hoogervorst, N. F. Kalkers, G. R. Cutter, B. M. J. Uitdehaag, C. H. Polman, 
The patient's perception of a (reliable) change in the Multiple Sclerosis Functional 
Composite. Multiple Sclerosis Journal. 10, 55-60 (2004). 
29. M. Kaufman, D. Moyer, J. Norton, The significant change for the Timed 25-foot 
Walk in the multiple sclerosis functional composite. Multiple Sclerosis Journal. 6, 286-
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30. J. J. Kragt, van der Linden,F A H., J. M. Nielsen, B. M. J. Uitdehaag, C. H. Polman, 
Clinical impact of 20% worsening on Timed 25-foot Walk and 9-hole Peg Test in 
multiple sclerosis. Multiple Sclerosis Journal. 12, 594-598 (2006). 
31. J. Hobart, A. Blight, A. Goodman, F. Lynn, N. Putzki, Timed 25-foot walk: direct 
evidence that improving 20% or greater is clinically meaningful in MS. Neurology. 80, 
1509-1517 (2013). 
32. L. M. Friedman, C. D. Furberg, D. L. DeMets, Fundamentals of Clinical Trials , 
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construction and validation of percentile curves. Journal of Neurology, Neurosurgery and 
Psychiatry. 76, 744-749 (2005). 
34. S. M. Rao et al., Cognitive dysfunction in multiple sclerosis. II. Impact on 
employment and social functioning. Neurology. 41, 692-696 (1991). 
35. S. C. J. Huijbregts, N. Kalkers, L. M. J. de Sonneville, V. de Groot, C. Polman, 
Cognitive impairment and decline in different MS subtypes. J. Neurol. Sci. 245, 187-194 
(2006). 
36. S. Rao, A Manual for the Brief, Repeatable Battery of Neuropsychological Tests in 
Multiple Sclerosis. National Multiple Sclerosis Society.(1990). 
37. X. Montalban et al., A single-center, randomized, double-blind, placebo-controlled 
study of interferon beta-1b on primary progressive and transitional multiple sclerosis. 
Multiple Sclerosis Journal. 15, 1195-1205 (2009). 
38. C. Tur et al., Interferon Beta-1b for the treatment of primary progressive multiple 
sclerosis: five-year clinical trial follow-up. Arch. Neurol. 68, 1421-1427 (2011). 


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39. J. B. Boringa et al., The brief repeatable battery of neuropsychological tests: 
normative values allow application in multiple sclerosis clinical practice. Multiple 
Sclerosis Journal. 7, 263-267 (2001). 
40. M. L. Baier et al., Low-contrast letter acuity testing captures visual dysfunction in 
patients with multiple sclerosis. Neurology. 64, 992-995 (2005). 
41. J. B. Fisher et al., Relation of visual function to retinal nerve fiber layer thickness in 
multiple sclerosis. Ophthalmology. 113, 324-332 (2006). 
42. R. Bakshi et al., Fatigue in multiple sclerosis and its relationship to depression and 
neurologic disability. Multiple Sclerosis Journal. 6, 181-185 (2000). 
43. L. B. Krupp, N. G. LaRocca, J. Muir Nash, A. D. Steinberg, The fatigue severity 
scale. Application to patients with multiple sclerosis and systemic lupus erythematosus. 
Arch. Neurol. 46, 1121-1123 (1989). 
44. J. S. Fischer, A. J. Jak, J. E. Kniker, R. A. Rudick, G. Cutter., Multiple Sclerosis 
Functional Composite (MSFC) Administration and Scoring Manual (National Multiple 
Sclerosis Society, , 2001). 
45. J. A. Cohen et al., Use of the multiple sclerosis functional composite as an outcome 
measure in a phase 3 clinical trial. Arch. Neurol. 58, 961-967 (2001). 
46. A. Solari, D. Radice, L. Manneschi, L. Motti, E. Montanari, The multiple sclerosis 
functional composite: different practice effects in the three test components. J. Neurol. 
Sci. 228, 71-74 (2005). 
47. R. C. Sergott, Optical coherence tomography: measuring in-vivo axonal survival and 
neuroprotection in multiple sclerosis and optic neuritis. Curr. Opin. Ophthalmol. 16, 346-
350 (2005). 
48. E. Frohman et al., Optical coherence tomography in multiple sclerosis. Lancet 
Neurol. 5, 853-863 (2006). 
49. L. Talman et al., Longitudinal study of vision and retinal nerve fiber layer thickness 
in multiple sclerosis. Ann. Neurol. 67, 749-760 (2010). 
50. A. P. D. Henderson et al., An investigation of the retinal nerve fibre layer in 
progressive multiple sclerosis using optical coherence tomography. Brain. 131, 277-287 
(2008). 
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layer in progressive multiple sclerosis. J. Neurol. 257, 1083-1091 (2010). 


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26 
 
52. P. Albrecht et al., Degeneration of retinal layers in multiple sclerosis subtypes 
quantified by optical coherence tomography. Multiple Sclerosis Journal. 18, 1422-1429 
(2012). 
53. L. V. A. E. Bosma et al., Progression on the Multiple Sclerosis Functional Composite 
in multiple sclerosis: what is the optimal cut-off for the three components? Multiple 
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7, 83-96 (2014). 
 

ICF_001.pdf: 
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ACTH in Progressive MS
Version Date: 07.17.19
                                   Page 1 of 7
Consent Form
Study Title:
Treatment of progressive forms of Multiple Sclerosis with pulsed ACTH (Acthar gel)
Principal Investigator:
Adam Carpenter, MD
University of Minnesota, Department of Neurology
717 Delaware Street SE, Suite 246
Minneapolis, MN 55414
Introduction
You are invited to participate in a research study to examine how safe and effective ACTH (adrenocorticotropic 
hormone, Acthar gel) is in patients with progressive forms of Multiple Sclerosis (MS).  You were chosen as a 
possible participant because you have been diagnosed with Primary Progressive MS (PPMS), Secondary 
Progressive MS (SPMS), or Progressive Relapsing MS (PRMS).  This consent form describes the research study 
and what you may expect if you decide to participate.  Please read this consent form carefully and ask any 
questions you may have before you decide if you want to participate.  
This study is being conducted by Dr. Adam Carpenter at the University of Minnesota.  It is funded by Mallinckrodt 
Pharmaceuticals, the manufacturer of ACTH.  Approximately 100 people will participate in this study. 
Study Purpose
The purpose of this study is to investigate the safety and effectiveness of ACTH in progressive MS patients when 
it is administered on a pulsed schedule of injections on three consecutive days per month.  ACTH is approved by 
the US Food and Drug Administration (FDA) for the treatment of MS relapses.  In this study, we are looking at 
whether pulsed ACTH is safe and well-tolerated in progressive forms of MS, as well as whether or not it can slow 
the progression of MS.  ACTH is considered an “investigational drug” in this study, because it has not been 
approved specifically for this use by the FDA.
Study Procedures
Approximately 100 patients with PPMS, SPMS or RPMS will participate in this study at research sites in 
Minnesota and the Midwest.  If you choose to participate, you will be in the study for 3 years, and you will come to 
the Clinical Neuroscience Research Unit (CNRU) for up to 9 study visits.  You will be assigned by chance (like 
flipping a coin) to inject either 80 units of ACTH or placebo (an injection that contains no medicine).  You or a 
caregiver will administer the injection subcutaneously (under the skin) on 3 consecutive days per month.  Neither 
you nor the study team will know which treatment group you are in, although in an emergency the exact treatment 
you receive can be identified. Procedures for each visit are outlined below.  
Screening Visit 1 (-30 to -1 days)
During the screening phase, you will be screened for your eligibility to participate in the study.  Your medical history 
will be reviewed, and you will be asked about all medications you are currently taking.   You will also complete 
standard MS measures: Expanded Disability Status Scale (EDSS), the 9-hole peg test (9HP, arm and hand 
function), and the Brief Repeatable Battery (BRB), a collection of cognitive tests which includes the Paced Auditory 
Serial Addition Test (PASAT; attention and processing speed), the Selective Reminding Test (SRT, a test of verbal 
learning and recall), the 10/36 Spatial Recall Test (10/36, spatial learning and recall), the Symbol Digit Modalities 
Test (SDMT, attention and processing speed), the PASAT, and Word List Generation task (WLG, listing words 
based on a category or initial letter).  A blood sample (approximately 1 teaspoon) will be taken from a vein in your 
arm for standard safety lab tests to monitor your blood sugar, liver function, electrolytes, and kidney function.   
You will also have a bone mineral density (DEXA) test done on your hips and spine.  For this test, you will lie on 
an imaging table.  After you are positioned as necessary for the scan, a scan bar will pass over your body.   A 
beam of very low dose x-rays will pass through your body and will be measured by a detector.  It will take 
approximately 15 to 30 minutes.


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Baseline Visit 2 (Month 0)
The baseline visit will occur between 1 to 30 days after the Screening Visit.  This will be a very tiring and long study 
visit, possibly lasting 5-6 hours. If you take stimulant medications such as methylphenidate (Ritalin), 
dextroamphetamine (Adderall), modafinil (Provigil), you will be told to not take them before the visit.  You may bring 
them with you to take after the study procedures are done.  You should also bring along any assistive walking 
device that you use.
At this visit, your blood pressure and weight will be measured.  Several standard MS evaluations will be done, 
including the   6-minute walk test (6MWT), timed 25-foot walk (T25FW), 9 HPT, the BRB and Low Contrast Visual 
Acuity (LCVA – done 3 times, once for each eye and once with both eyes).  
You will have an eye exam called Optical Coherence Tomography (OCT), which measures the thickness of the 
retinal nerve fiber layer in your eyes.  You will have an OCT done on both eyes.  For this procedure, you will be 
seated in front of the OCT machine and rest your head on a support to keep it still.  The equipment will then scan 
your eye without touching it.  If it is necessary to dilate your eyes for this test, you may be excluded from the OCT 
portion of the study, unless it is able to be scheduled after the other visit procedures have been completed or on a 
different day (within 2 weeks of the study visit).  
If you meet the study entry criteria, you will be randomized at this visit to begin injections with either ACTH or 
placebo.  The study nurse will train you and/or your caregiver how to give the injection.  The study staff will call you 
every month to remind you which 3 days to take your study medication.  You will be dispensed study drug and 
study drug logs to take home. You will be asked to complete the logs by writing down what time you do the injections 
and any side effects you may notice.  You will be asked to bring empty drug vials and completed study drug logs 
with you to your next visit.   
Visits 3, 6 and 8 (Months 3, 18, and 30)
At these visits, your blood pressure and weight will be measured, your skin will be examined and you will be checked 
for any swelling, which is a possible side effect of the study drug.  You will be asked about any side effects you’ve 
had and the medications you are taking. You will return your empty drug vials and study drug logs, and will be 
dispensed drug logs and enough vials to last until your next study visit.  The study staff will call you each month to 
remind you which 3 days to take your study medication.
At the study doctor’s discretion, Visit 3 (Month 3) may be done over the telephone if traveling to the study site is a 
hardship for you, and if you have had previous experience with taking subcutaneous medications.
Visit 4 (Month 6)
The procedures for Visit 4 are the same as Visit 3, with the addition of a blood draw (1 teaspoon) for standard safety 
labs. You will return your empty drug vials and study drug logs, and will be dispensed drug logs and enough vials 
to last until your next study visit.  The study staff will call you each month to remind you which 3 days to take your 
study medication.
Visits 5, 7 and 9 (Months 12, 24 and 36)
These 3 visits will be the same as the baseline visit; they will be very tiring and long study visits, possibly lasting 
5-6 hours.  If you take stimulants, you will be told to not take them before the visit.  You may bring them with you to 
take after the study procedures are done.  You should also bring along any assistive walking device that you use.
You will return your empty drug vials and study drug logs, and will be dispensed drug logs and enough vials to last 
until your next study visit.  The study staff will call you each month to remind you which 3 days to take your study 
medication.
Potential Relapses
If you feel you are experiencing an MS relapse (new or worsening neurological symptoms lasting more than 24 
hours, you should contact your treating neurologist (who may or may not be associated with this study).  Please 
also notify the study nurse at 612.624.8431.  If you are seen by your neurologist for a possible relapse, we will ask 


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you to allow us to obtain copies of your neurologist’s clinic notes and/or other medical records related to the relapse 
(e.g., MRI scan).   The cost for visits to your treating neurologist and for any procedures or treatments s/he 
prescribes will be charged in the usual manner, to you or your insurance company.
Unscheduled Visits
If you have any new symptoms that are of concern to you, you are encouraged to contact the study nurse at 
612.624.8431. If the symptom is potentially serious and could possibly be related to the study drug, you will be 
asked to come to the CNRU for an unscheduled visit.  The procedures at this visit will be the same as those done 
for Visit 3. 
Study Schedule
V1
Screen
--30 days 
to -1 day
V2
Baseline
M0
V3
M3
V4
M6
V5
 M12
V6 
M18
V7 
M24
V8  
M30
V9
M36
Unsched
Visit
Informed Consent
X
Inclusion/Exclusion
X
Injection Training
X
Blood Pressure
X
X
X
X
X
X
X
X
X
Weight
X
X
X
X
X
X
X
X
X
Safety Lab Tests
X
X
X
X
X
Skin & Edema Assessment
X
X
X
X
X
X
X
X
X
OCT
X
X
X
X
LCVA
X
X
X
X
EDSS
X
X
X
X
Timed 25-Ft Walk
X
X
X
X
9-Hole Peg Test
X
X
X
X
X
PASAT (apart from BRB-N)
X
6 Minute Walk Test
X
X
X
X
MS Walking Scale - 12
X
X
X
X
Fatigue Severity Scale (FSS)
X
X
X
X
Hauser Ambulation Index
X
X
X
X
Brief Repeatable Battery
X
X
X
X
X
DEXA Scans
X
X
X
X
Randomization
X
Symptom Questionnaire
X
X
X
X
X
X
X
X
X
Concomitant Medications
X
X
X
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
Dispense Study Drug
X
X
X
X
X
X
X
Return Drug Vials and Logs
X
X
X
X
X
X
X


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Risks of Study Participation
Four of the study visits (Baseline, M12, M24, and M36) will be very long and may be physically difficult.  For 
instance, several of the MS evaluations which measure your walking ability may make you feel tired or exhausted. 
The 6MWT requires you to walk as far as you can in six minutes, while the EDSS requires you to walk for 500 
meters (about 5 blocks) or until you need to stop.  If you use stimulant medications, you will not be allowed to take 
your stimulants before the visits, but you can bring them with you and can take them after the study visit.  
Possible side effects of ACTH include: 
-
increased risk of getting an infection
-
adrenal insufficiency (which may include symptoms of weakness, skin color changes, weight loss, low 
blood pressure, and abdominal pain)
-
fluid retention
-
congestive heart failure
-
high blood pressure
-
low potassium levels
-
high blood sugar
-
muscle weakness
-
loss of muscle
-
loss of bone mass and increased fracture risk
-
stomach ulcer
-
stomach bleeding
-
pancreas swelling
-
stomach enlargement
-
increased risk of gastrointestinal perforation (a hole forms all the way through the stomach, bowel or small 
intestine)
-
poor wound healing
-
thin fragile skin
-
bruising
-
increased sweating
-
dizziness
-
headache
-
menstrual irregularities
-
eye disorders (e.g., blurred vision or seeing double), cataracts (clouding of lens), glaucoma (damage to 
the eye’s optic nerve which can lead to permanent vision loss)
-
allergies, allergic or sensitivity reactions 
-
psychiatric side effects such as euphoria (an extreme high or “up” feeling), insomnia (difficulty sleeping), 
irritability, mood swings, personality changes, visual and auditory hallucinations (seeing or hearing things 
that are not there), confusion, and severe depression.  If you experience any of these side effects, contact 
the study doctor immediately.
Because of the increased risk of infections, you should not receive live or live attenuated vaccines while you are 
in the study.
You may also experience injection site reactions, which include swelling, itching, redness and pain at the injection 
site.
ACTH and Pregnancy: Women who are pregnant, planning to become pregnant, or breastfeeding should not 
participate in this study, as ACTH could have negative effects on the fetus/baby.
Placebo: You will have a 50% chance of receiving placebo instead of active study drug.  However, you will still be 
allowed to take any FDA-approved treatment that you were using provided you started it at least 3 months before 
Visit 2 (Baseline).


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DEXA Scan: As part of this study, you will undergo one DEXA scan per year.  This procedure involves exposure 
to ionizing radiation.  The average amount of radiation that the average person would receive from this procedure 
is less than 0.3% of that received by natural sources of radiation by a Minnesota resident in one year (300mrem).
Blood Draw: The risks of drawing blood from a vein are minimal, and may include discomfort and slight bruising 
from the needle stick.  Occasional dizziness, fainting, bleeding, or infection may occur.  These risks will be 
minimized by clean and careful techniques.
OCT: There are no known risks associated with OCT.  If your eyes need to be dilated, they may be sensitive to 
light following the procedure.
The study may involve risks which are currently unforeseeable.  You will be informed of any new information that 
becomes available over the course of the study that may change your willingness to participate.
Benefits of Study Participation
There is no guarantee that you will receive any benefit from your participation in this study.  Your condition may 
improve, worsen, or remain the same.  The information obtained from this study may aid in the development of 
better treatments for progressive MS, which may improve the quality and/or prolong the lives of future patients.
Study Termination
Your participation in this study could be ended should any of the following occur:

You decide to discontinue treatment

You do not follow the directions of the study team

The study doctor decides the study is not in your best interest

You become pregnant or intend to become pregnant

The blinding is broken (if the study doctor has to find out whether you are receiving ACTH or placebo in 
order to treat a side effect or for any other reason)
Regardless of the duration of your participation in the trial, upon termination you will be asked to return all unused 
ACTH/placebo to the CNRU.  If you have been taking ACTH/placebo for a year or more, and you decide to 
withdraw from the study, we will ask you to continue to come in for the remaining annual study visits (Visit 7, 
Month 24, and Visit 9, Month 36), even though you will no longer be taking the study drug.  If you have been 
taking ACTH/placebo for less than a year, we will ask you to participate in annual phone calls (Months 12 and 
24), and to return to the site for the Month 36 study visit.  You do not have to agree to return for these visits.
Alternatives to Study Participation
You do not have to be in this study to be treated for your condition.  You may wish to discuss your treatment 
options with your doctor before you decide to participate.  There are currently no FDA-approved drugs for the 
treatment of PPMS.  Mitoxantrone is FDA-approved for SPMS and PRMS.  Certain patients with SPMS and 
PRMS continue to experience intermittent MS relapses ("attacks"), and in those cases MS medications such as 
interferon beta, glatiramer actetate, natalizumab, fingolimod, teriflunomide and dimethyl fumarate may be 
considered.
Study Costs/Compensation
You will not be compensated for your participation in this study.  All study procedures, study drug (ACTH or 
placebo), and parking for your study visits will be provided at no cost to you.  
If you experience an MS relapse during the study, you or your insurance carrier will be responsible for the cost of 
any medications used to treat the relapse.
Research Related Injury
In the event that this research activity results in an injury, treatment will be available, including first aid, emergency 
treatment and follow-up care as needed.  Care for such injuries will be billed in the ordinary manner, to you or your 
insurance company. If you think that you have suffered a research related injury, let the study physician know right 
away.


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                                   Page 6 of 7
Confidentiality
The records of this study will be kept private.  In any publications or presentations, we will not include any 
information that will make it possible to identify you as a subject.  Your record for the study, however, may be 
reviewed by representatives of the study funder, Mallinckrodt Pharmaceuticals, and by departments at the 
University with appropriate regulatory oversight.  A note indicating that you are participating in this study will be 
added to your medical records.  To these extents, confidentiality is not absolute.
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by US law.  This 
website will not include information that can identify you.  At most, the website will include a summary of the 
results.  You can search this website at any time.
Protected Health Information (PHI)
We are committed to respecting your privacy and keeping your personal information confidential. When choosing 
to take part in this study, you are giving us permission to use your personal health information that includes health 
information in your medical records and information that can identify you. For example, personal health information 
may include your name, address, phone number or social security number. Those persons who get your health 
information may not be required by Federal privacy laws (such as the Privacy Rule or what you may know as 
“HIPAA”) to protect it. Some of those persons may be able to share your information with others without your 
separate permission. Please read the separate HIPAA Authorization form that we have provided and discussed.
The results of this study may also be used for teaching, publications, or for presentation at scientific meetings.
Voluntary Nature of the Study
Participation in this study is voluntary.  Your decision whether or not to participate will not affect your current or 
future relations with the University or the University of Minnesota Medical Center, Fairview.  If you decide to 
participate, you are free to withdraw at any time without affecting those relationships.
Contacts and Questions
If you have questions about research appointments, the study, research results, or other concerns contact the 
researchers.  The researcher conducting this study is Adam Carpenter, M.D. You may ask any questions you have 
now, or if you have questions later, you may contact him at 612.624.6145.  You may also reach the study 
coordinator at 612.624.8431.
This research has been reviewed and approved by an Institutional Review Board (IRB) within the Human Research 
Protection Program (HRPP). To share feedback privately about your research experience, call the Research 
Participants’ Advocate Line: 612.625.1650 (Toll Free: 1.888.224.8636) or go to z.umn.edu/participants. You are 
encouraged to contact the HRPP if:

Your questions, concerns, or complaints are not being answered by the research team.

You cannot reach the research team.

You want to talk to someone besides the research team.

You have questions about your rights as a research participant.

You want to get information or provide input about this research.
The University of Minnesota HRPP may ask you to complete a survey about your experience as a research 
participant.  You do not have to complete the survey if you do not want to. If you do choose to complete the survey, 
your responses will be anonymous. If you are not asked to complete a survey, but you would like to share feedback, 
please contact the study team or the University of Minnesota HRPP).
You will be given a copy of this form to keep for your records.


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Statement of Consent
I have read the above information.  I have asked questions and have received answers.  I consent to participate in 
the study.
Participant’s Name (Print)
Participant’s Signature
Date
Name of Person Obtaining Consent
Signature of Person Obtaining Consent
Date