Adrenocorticotropic Hormone (ACTH) Effects on Myelination in Subjects With MS
Phase: PHASE4
Conditions: Multiple Sclerosis
Sponsor: Weill Medical College of Cornell University

 
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ACTH effects on myelination in MS patients  
 
 
 
 
 
 
 
 
 
 
 
 
 
Susan A. Gauthier, DO, MPH 
Judith Jaffe Multiple Sclerosis Center,  
Weill Cornell Medical College,  
1305 York Avenue, Suite Y217,  
New York, NY 10021 
 
 
 

 
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1 Hypotheses and Rationale for the Study: 
1.1 
Hypothesis/Hypotheses: 
Patients identified as having new enhancing lesions and treated with a course of ACTH at the time 
of initial MRI and then subsequently treated with monthly pulse doses of 3 days of ACTH 
treatment over one year will have a greater degree of remyelination as measured by myelin water 
fraction (MWF) as compared to those patients treated with one course of ACTH.  
1.2   Rationale for the study: 
MS is a chronic inflammatory disease of central nervous system characterized by focal T cell and 
macrophage infiltrates associated with demyelination. The primary innate immune cells in MS 
consist of infiltrating macrophages/monocytes and resident microglia. Cells of the innate 
immune system are effector cells that function to cause central nervous system (CNS) injury both 
through direct effects on neighboring cells, such as oligodendrocytes, and through generation of 
soluble proinflammatory mediators that have distant effects on cells, such as neurons.  The innate 
immune inflammatory is thus sufficient to explain focal injury and diffuse injury. In the majority 
of patients, MS begins as a relapsing-remitting course but eventually evolves to a state of 
progressive decline in disability. Focal inflammatory demyelinating lesions are the predominant 
pathological findings in the patients with relapsing disease whereas diffuse axonal injury with 
microglial activation has been found to be the hallmark of progressive disease [1]. Microglial 
activation itself occurs either as a response to CNS injury for example as in Wallerian 
degeneration, or in response to signals from other inflammatory cells including macrophages and 
lymphocytes.   
High dose corticosteroids (methylprednisolone) have been a mainstay of treatment for MS 
relapses and have been shown to shorten the time to recovery from relapses, presumably at least 
in part due to their anti-inflammatory effects. However, despite their anti-inflammatory 
properties, corticosteroids have been shown to impair and delay remyelination in animal models 
of MS [2, 3] and there is little clinical evidence of a longer-term beneficial effect. 
Adrenocorticotropic hormone (ACTH) gel, a long-acting formulation of the full sequence ACTH 
that includes other pro-opiomelanocortin (POMC) peptides, is considered an alternative to 
corticosteroids in the treatment of relapses (currently FDA approved for this indication).  ACTH 
gel exerts direct anti-inflammatory and immune-modulating effects within the CNS, specifically 
on infiltrating macrophages and resident microglia [4, 5] as well as protecting mature 
oligodendrocytes from inflammation-related damage and excitotoxicity [6].  These effects are 
mediated not only via induction of endogenous corticosteroid production but also via effects on 
melanocortin receptors [7].  

 
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Chronic dosing of corticosteroids, specifically high dose methylprednisolone, (doses varying 
from once monthly to multiple doses every couple months) have been studied and found to be 
well-tolerated, safe and of a benefit on clinical as well as on conventional MRI measures of 
disease activity [8-10].  The rationale for these studies was based upon a potential benefit of 
chronic anti-inflammatory treatment to promote repair and neuroprotection. Following this same 
rationale, however instead implementing ACTH based upon it effect on the melancortin 
receptors, we propose to study the benefit of monthly pulses of ACTH in a cohort of MS 
patients.  We are targeting patients with new enhancing lesions to determine if monthly exposure 
to ACTH will promote more robost endogenous remyelination in new lesions compared to a one-
time treatment course. We hypothesize that continued exposure to the anti-inflammatory effects 
of ACTH on new lesions would be superior to promoting remyelination as compared to a one-
time treatment course. Given that the majority of endogenous remyelination is felt to begin 
within months after lesion development [11] and likely to be most prominent in the few months 
following, a one year study is most likely sufficient to measure this process.      
 
T2 relaxometry is a MR imaging technique in which a series of T2-weighted images at different 
echo times are obtained and the contribution of water associated with myelin and other tissue 
compartments can be differentiated using T2 decay curve analysis [12].  The relative 
contribution of the myelin water, represented as the myelin water fraction (MWF), has been 
shown to highly correlate with histological myelin measurement in animal models [13] and ex-
vivo brain [14,15] and has been applied to MS patients [16].  The histological correlation of T2 
relaxometry with myelin content makes it an excellent candidate as a biomarker for myelin 
content and it has been found to be reproducible and sensitive marker to change over time [17-
20].  Through the application a multi-slice 2D T2prep spiral gradient echo (GRE) imaging, T2 
data can be efficiently acquired [21,22] and we have further optimized a 3D T2prep GRE 
sequence at 3T for which full brain coverage can be achieved within 10 minutes [23].  One of the 
main advantages of using T2 relaxometry and MWF as a surrogate for myelin over other 
advanced MR modalities lies in the T2 spectrum (the T2 decay curve analysis).  Both MWF and 
the extracellular T2 component (the intermediate peak) within the T2 spectrum) can increase 
with edema [24], thus once the extracellular pool stabilizes, we can ensure that any change in 
MWF is a true reflection of myelination.   
To validate this concept, we performed a pilot study, which included 10 patients with either new 
contrast enhancing lesions or new non-contrast enhancing lesions. A total of 27 lesions were 
followed longitudinally, 15 of which demonstrated contrast enhancement on the initial MRI. Using 
a paired t-test we showed that the intra/extracellular water peak shifted in contrast enhancing 

 
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lesions (p=0.044). Resolving edema presumably caused this shift. As expected, no significant shift 
in the intra/extracellular water peak was shown in non-contrast enhancing lesions. We then used 
the longitudinal change in the T2 extracellular peak as a control for resolving edema in a random 
effects model aimed at calculating true myelin water fraction change. Based on our model we 
determined that true MWF change in lesions was anything above 0.045 (p=0.0139). 7 out of 15 
contrast enhancing lesions showed true myelin water fraction change while no significant change 
was seen in non-contrast enhancing lesions.  
                                Example A  
 
 
                      Example B  
  
 
Example A is of a new contrast enhancing lesions in the left occipital region where there was a 
large shift in the extracellular peak and a large increase in MWF. Because of the relative resolution 
of the lesion seen on FLAIR, we presume this lesion is edematous. We saw a MWF increased of 
137%, but the extracellular peak was also shifted by 11 ms. In this example, the large increase in 
MWF is likely due in part to edema.   
Example B is a new contrast-enhancing lesion in the left periventricular region. This lesion 
demonstrated a 137% increase in MWF but no real shift in the EC peak. Therefore, the increase in 
MWF in this lesion likely represents true remyelination.  

 
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In conclusion, we were able to show that the extracellular water peak shifts in the face of 
edema, and the T2 spectrum can be used as a control for edema in early lesions. Using our model 
we were able to accurately detect myelin change. 
CITATION: Vargas W, Monohan E, Pandya S, Dayan M, Nguyen T, Ashish R, Gauthier S. 
Longitudinal Changes in Myelin Water Fraction in New Multiple Sclerosis Lesions. Neurology 
2014; 82: S44.005 
 
 
2 Specific Aims 
Specific aim #1: The primary objective of this study is to determine if monthly pulse doses of a 
three-day course ACTH (H.P. Acthar®) is more effective at recovering myelin at 12 months, as 
measured by MWF, in new multiple sclerosis lesions as compared to one course of treatment.   
 
Specific aim #2: The main secondary objective is to utilize every three-month MWF 
measurements to determine the peak time of remyelination in new multiple sclerosis lesions 
when followed over the course of 12 months.  
 
 
3 Study design 
 
3.1: Study Description 
This pilot study proposal is designed to perform a chronological measurement of MWF in new 
contrast-enhancing lesions in patients treated with ACTH during an acute exacerbation of MS.   
 
The treatment decision will be made by the patient’s MS treating physician as part of standard of 
care for MS patients having an with acute exacerbation. After the patient’s treating physician has 
recommended ACTH, the study will be offered to the patient and the consenting process will be 
initiated, as described in eIRB. If the patient agrees to participate and signs the consent and 
HIPAA forms, he/she will become a study subject and randomized to one of two treatment 
groups. The initial stage of the study is for all patients to receive the standard of care course of 
and ACTH and depending on the randomization, a patient may or may not receive additional 
monthly doses of ACTH. If the patient does not enroll into the study, ACTH will be prescribed 
as standard of care. Participation in this study will be offered to every eligible patient. Every 
physician in Judith Jaffe MS Center is an investigator for this study and will be discussing the 
study with their eligible patients. 
 
The initial course of ACTH (H.P. Acthar®) will be administered as recommended in the package 
insert, a subcutaneous daily dose of 80-120 units daily for 2-3 weeks.  However, as recommended 
in the package insert, the dosage may be individualized according to the medical condition of each 

 
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patient.  Therefore, the frequency and dose of the drug may be determined by considering the 
severity of the disease and the initial response of the patient.  The typical dosing for an MS 
exacerbation is 80units/day for 3-5 days and it is expected that this will be the initial dosing for 
the majority of the patients.   
MS patients enrolled in this study will be randomized into: 
Group A: 80units/day ACTH for 3-5 days (The dose could be adjusted based on the individual 
needs of the patients up to 80-120 units daily for 2-3 weeks.) 
 
Group B: 80units/day ACTH for 3-5 days (The dose could be adjusted based on the individual 
needs of the patients up to 80-120 units daily for 2-3 weeks.), followed by monthly 80 units/day 
ACTH for 3 days for 12 months of treatment. 
 
The Judith Jaffe Multiple Sclerosis Center currently has over 1000 patients in a clinical and MRI 
database.  Patients who have signed consent for the database will have their standard of care 
MRI scans monitored for new enhancing lesions; this will only have to be repeated if initial scan 
is not completed at our MS center with our current clinical protocol.  All RRMS patients with 
new enhancing lesions will be considered for the study and approached regarding participation 
Patients that are considered candidates and consent for the study, patients will then be 
randomized (1:1) to receive one course of ACTH followed by monthly pulses vs. receiving only 
one course of ACTH treatment. All patients will have follow-up MRI’s are 3 months, 6 months 
and 12 months post lesion onset for a total of 3 additional scans. If a patient is identified as 
having an enhancing lesion from MRI scan not obtained through our database, an additional scan 
will be obtained through the study and serve as the baseline MRI. All patients will receive the 
first course of ACTH within 4 weeks of new lesion detection.  
 
3.2: Study endpoints 
The primary endpoint of this study will be change in MWF within new enhancing lesions over 
the course of 12 months. The absolute change in lesion MWF (over our test-retest variability) 
between baseline and one year MRI’s will be calculated and compared between treatment 
groups. 
 
The main secondary end-point will be longitudinal assessment of MWF (every 3 months) to 
determine the dynamics of myelin change over 12 months, specifically to determine the timing 
of remyelination.  The advantage of T2 relaxometry is the ability to look at both the contribution 
of water within myelin bilayers (MWF) but also the water within the intra/extracellular 
compartment (the intermediate peak within the T2 spectrum).  This second peak (extracellular 
peak) can increase with edema, thus once the extracellular pool stabilizes, we can ensure that any 
change in myelin water fraction (MWF) is a true reflection of myelination.  
 
We will also explore a measurement called “absolute myelin content”.  Through this 
measurement, we can control for the increased edema associated with a new lesion, thus 
providing for a more accurate measure of true myelin change.  

 
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Additional secondary end points include measurement of the following clinical measurements: 
EDSS, and the following MRI measurements: change in T2 lesion volume, whole brain volume, 
and cortical volume.   
 
If patients in either arm have an additional relapse during the study, they will be removed from 
the study.  At that point patients are likely to change on-going treatment for their MS and based 
upon their treating physician, may require additional steroids (either ACTH or 
methylprednisolone)  
 
3.3 Inclusion and Exclusion Criteria: 
 
Inclusion criteria:  
Patients with RRMS or SPMS with new contrast-enhancing lesions who will start as part of their 
standard of care ACTH. 
 
Exclusion criteria: 
• Patients having received oral or IV corticosteroids within one month prior to initial scan 
demonstrating contrast enhancing lesion  
• Patients with known or new allergy to ACTH  
• Patients being treated with Natalizumab, Rituximab, and Cyclophosphamide 
• Patients unwilling to have serial MRI exams  
• Patients unable to undergo MRI imaging because of having an artificial heart valve, 
metal plate, pin, or other metallic objects in their body or is unable to complete all the 
MRI scans required for this study 
• Patients with acute or chronic renal disease in whom administration of gadolinium may 
pose risk of nephrogenic systemic fibrosis 
• Patients that are pregnant  
• Premenopausal woman not willing to use at least one form of contraception  
• Patients with a known history of diabetes mellitus 
• Progressive neurological disorder other than RRMS or SPMS 
• Clinically significant cardiovascular disease, including myocardial infarct within last 6 
months, unstable ischemic heart disease, congestive heart failure, or angina 
• Subjects on chronic steroid therapy for treatment of MS or other systematic disease 
• Subject currently has a significant medical condition (other than MS) including the 
following: neurological, psychiatric, metabolic, hepatic, renal, hematological, 
pulmonary, cardiovascular (including uncontrolled hypertension), gastrointestinal, 
urological disorder, or central nervous system (CNS) infection that would pose a risk to 
the subject if they were to participate in the study or that might confound the results of 
the study 
o Note: Active medical conditions that are minor or well-controlled are not 
exclusionary if, in the judgment of the Primary Investigator, they do not affect 
risk or the subject or the study results.  

 
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• Subject is unable to cooperate with any study procedures, unlikely to adhere to the study 
procedures and keep appointments, in the opinion of the Investigator, or was planning to 
relocate during the study 
 
 
3.4  Randomization procedure: 
Given this is a small pilot study and a chance that simple randomization would course all patients 
to fall within one treatment group we will randomize patients in permuted blocks. This 
randomization scheme consists of a sequence of blocks such that each block contains a pre-
specified number of treatment assignments in random order. The purpose of this is so that the 
randomization scheme is balanced at the completion of each block. Patients will be randomized 
after the consent is signed. 
 
3.5  Sample Size: 
We are proposing a pilot to study fifteen patients per study arm (for a total of 30 patients, 
includint ~ 10 screen failures) with new enhancing lesions over a 12 month time period.  The 
longitudinal dynamics of MWF have only been studied in a handful of patients and the effect of 
any specific steroid treatment has not been studied, thus we are unable to propose a proper 
calculated sample size.  However, from our preliminary longitudinal MWF lesion data, we are 
able to determine that at least 50% of new enhancing lesions show some signs of remyelination 
after initial acute treatment (methylprednisolone or ACTH).  If we were to perform a sample size 
based upon an assumption that repeated course of ACTH will show a 25% greater proportion of 
lesions showing signs of improvement, we would require approximately 53 lesions per arm. In 
order to achieve that goal, we would have to screen and enroll at least 50 patients per arm.  
Therefore we are proposing a small pilot study to gain more information regarding the potential 
benefit of repeated courses of ACTH to allow for a more accurate design of a larger clinical trial.  
In addition, we will focus our efforts toward patients with more than one lesion in an attempt to 
reach a goal of at least 25 lesions per arm.  We expect that repeated course of ACTH may 
profoundly affect the remyelination and hope to a much higher proportion of lesions showing 
repair.  Again, we are hopeful that information gained from this pilot study can help to accurately 
calculate sample sizes for larger clinical trials as well as gain insight into the potential benefit of 
ACTH on remyelination.   
 
 
3.6  Clinical visit schedule:  
Screening visits: Patients will be screened during standard of care clinical visits for multiple 
sclerosis.  If a patient had MRI within 2 weeks of visit and had new enhancing lesions, the 
patient will be asked to participate in the study.    

 
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Baseline visit: Baseline EDSS (if not obtained during screening visit), consent signed, schedule 
repeat MRI with and without contrast if screening MRI not completed as part of the Weill 
Cornell Multiple Sclerosis Center Clinical Protocol. Initiation of ACTH (H.P. Acthar®) course 
of therapy following visit (patient will do home therapy) after randomization.  
Visit 1: EDSS, safety evaluations, and initiation of monthly course of ACTH (H.P. Acthar®) in 
patients randomized to this arm.  
Visit 2: EDSS, safety evaluations.  
Visits 3, 4, 5: EDSS, safety evaluations, MRI with and without contrast  
Visit 6 (last visit): EDSS, safety evaluations, MRI with and without contrast.   
 
3.7  Study schema: 
 
Tests and 
Evaluations 
Time 
point: 
screening
/Baseline
- 
Visit 1 
(1 
month) 
Visit 2 
(2 
months) 
Visit 3 
(3 
months) 
Visit 4 
(6 
months) 
Visit 5 
(9 
months) 
Visit 6 
(12 
months-
end of 
study) 
Consent 
obtained 
X 
 
 
 
 
 
 
MS history and 
EDSS, safety 
evaluations 
X 
X 
X 
X 
X 
X 
X 
Randomization 
to treatment 
arm  
X 
 
 
 
 
 
 
MRI  
X 
 
 
X 
X 
X 
X 
 
4 Assessment and documentation of adverse events  
An AE is any physical or clinical worsening in symptoms or disease experienced by the patient at 
any time during the course of the study, whether or not it is considered related to study participation 

 
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or procedures. Multiple sclerosis symptoms that worsen during the course of the trial will be treated 
as AEs. AEs may also include complications that occur as a result of protocol-mandated 
procedures. 
 
ACTH Safety Background 
 
ACTH has been approved by the US Food and Drug Administration for treatment of MS 
relapses, however, we are proposing to use this drug on a monthly pulsed dosing (80mg for three 
days per month) schedule for one year.  A few trials have evaluated the longer-term clinical benefit 
and safety profile of ACTH pulse therapy in idiopathic glomerular diseases, such as nephrotic 
syndrome and focal segmental glomerulosclerosis (FSGS), as well as one pilot study in MS.  These 
studies had varying dosing schedules, some of which included a higher per month drug exposure 
as compared to our proposed study [26-30]. None of the studies reported severe-events related to 
ACTH and the adverse events were consistent with the expected common side effect profile listed 
on approved label. Based upon these studies, the adverse events between the two groups of patients 
proposed in this study should be similar.    
The studies are summarized below. 
• In an investigation of twenty-four patients with nephrotic syndrome from idiopathic 
FSGS, patients were treated with a median dose of 80 units injected subcutaneously 
twice weekly for up to 24 weeks [26].  ACTH gel provided a favorable safety profile 
with adverse events reported in 21 of 24 patients, most of which were mild and transient 
[26]. There were 52 typical steroid-related events (ranging from weight gain, mild 
elevation of BP, mood alteration) and no serious infections.  
• In an investigation of 15 subjects with resistant glomerular diseases treated with 80 
units of subcutaneous ACTH twice weekly for 6 months, no moderate to serious events 
or significant infections were reported with three of the 15 subjects reporting typical 
steroid-like adverse events (worsening glycemic control, weight gain, insomnia, mild 
elevation of BP and mild skin pigmentation changes) [28].  Importantly, no severe 
infections were reported.  
• An investigation of twenty-one patients with nephrotic syndrome treated with ACTH 
gel twice weekly for up to 12 months reported five patients with steroid-like adverse 
events (impaired blood glucose control, weight gain, and 1 patient showed evidence of 
accelerated bone loss on bone densitometry not observed prior to ACTH gel therapy) 
but no severe infections [27].  
• In a study of  23 nephrotic patients treated with an average of 25mg/week for a range 
of 5-11 months reported only similar steroid-related adverse events, all of which were 
mild [29]. 
In a pilot study in multiple sclerosis, monthly ACTH was compared to monthly IV 
methylprednisone (corticosteroid). Twelve subjects tolerated a regimen of 80 units of ACTH 
injected subcutaneously for three consecutive days once a month for 12 month [30]. The ACTH 
pulse therapy proved to have a favorable relapse and psychiatric side effect profile when compared 
to IV methylprednisolone as well as a lower number of adverse events. The study reported no 

 
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moderate to severe events. Psychiatric episodes only occurred in the IV methylprednisolone group 
and the ACTH group had a significantly stronger improvement in Mental Health Inventory. The 
ACTH treatment group had a lower number of infection incidence rate. When the two treatment 
groups were compared, they reported a similar amount of disease-related significant adverse 
events. 
 
Adverse events  
1. Common adverse reactions for H.P. Acthar Gel are similar to those of corticosteroids and 
include fluid retention, alteration in glucose tolerance, elevation in blood pressure, behavioral 
and mood changes, increased appetite, and weight gain.   
2. Severe and non-common adverse reactions: The adverse events of H.P. Acthar Gel are 
related primarily to its steroidogenic effects. Not all of the adverse events described below have 
been seen after treatment with H.P. Acthar Gel, but might be expected to occur. 
H.P. Acthar Gel may increase susceptibility to new infection and increase risk of 
exacerbation, dissemination, or reactivation of latent infections. Signs and symptoms of 
infection may be masked. 
Treatment with H.P. Acthar Gel can cause hypothalamic-pituitary-axis (HPA) 
suppression and Cushing’s syndrome. Suppression of the HPA may occur following 
prolonged therapy with the potential for adrenal insufficiency after withdrawal of the 
medication. Signs or symptoms of Cushing’s syndrome may occur during therapy but 
generally resolve after therapy is stopped.  
H.P. Acthar Gel can cause elevation of blood pressure, salt and water retention, and 
increased excretion of potassium and calcium.  
Live or attenuated vaccine to patients on immunosuppressive doses should not be 
administered. Killed or inactivated vaccines may be administered; however, the response 
to such vaccines can not be predicted. Other immunization procedures should be 
undertaken with caution in patients who are receiving H.P. Acthar Gel, especially when 
high doses are administered, because of the possible hazards of neurological 
complications and lack of antibody response.  
H.P. Acthar Gel often acts by masking symptoms of other diseases/disorders without 
altering the course of the other disease/disorder (monitor patients for signs of infection, 
abnormal cardiac function, hypertension, hyperglycemia, change in body weight, and 
fecal blood loss. Monitor patients for signs of other underlying disease/disorders that may 
be masked).  

 
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H.P. Acthar Gel can cause GI bleeding and gastric ulcer. There is also an increased risk 
for perforation in patients with certain gastrointestinal disorders. Signs of gastrointestinal 
perforation, such as peritoneal irritation, may be masked by the therapy.  
Use of H.P. Acthar Gel may be associated with central nervous system effects ranging 
from euphoria, insomnia, irritability, mood swings, personality changed, severe 
depression and psychosis. Existing emotional instability or psychotic tendencies may be 
aggravated.  
Patients with a comorbid disease may have that disease worsened. Symptoms of diabetes 
and myasthenia gravis may be worsened with treatment.  
Prolonged use of H.P. Acthar Gel may produce posterior subcapsular cataracts, glaucoma 
with possible damage to the optic nerves and may enhance the establishment of 
secondary ocular infections due to fungi and viruses.  
H.P. Acthar Gel is immunogenic. Prolonged administration of H.P. Acthar Gel may 
increase the risk of hypersensitivity reactions. Neutralizing antibodies with chronic 
administration may lead to a loss of endogenous ACTH activity.  
There is an enhanced effect in patients with hypothyroidism and in those with cirrhosis of 
the liver.  
Decrease in bone formation and an increase in bone resorption both through an effect on 
calcium regulation and inhibition of osteoblast function may occur. These, together with 
a decrease in the protein matrix of the bone (secondary to an increase in protein 
catabolism) and reduced sex hormone production, may lead to the development of 
osteoporosis.  Bone density should be monitored in patients on long term therapy.  
H.P. Acthar Gel has been shown to have an embryocidal effect. Women of child-bearing 
potential should use approved methods of birth-control while administering the drug.  
3. Adverse Reactions after Additional Postmarketing Experience  
A. The following adverse reactions associated with the use of H.P. Acthar Gel have been 
identified from the postmarketing experience with H.P. Acthar Gel.  
Allergic responses have presented as dizziness, nausea and shock. 
Necrotizing angitis and congestive heart failure.  
Skin thinning, facial erythema and increased sweating.  
Pancreatitis, abdominal distention and ulcerative esophagitis.  

 
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Headache, vertigo, subdural hematoma, intracranial hemorrhage. 
 
The adverse event collection period for this study begins at the baseline visit and will end after the 
last day of study medication. Patients discontinued from the study will be followed for at least 14 
days after the last day of the study medication. At each visit patients will be specifically asked for 
adverse events using the table below.  
 
All AEs, the onset and resolution dates, relationship to study drug, severity and seriousness will 
be documented. Based on the available information, the physician investigator will use the 
following guidelines to determine the relationship of any adverse event to the use of the study 
drug: 
Unrelated: No temporal association, or the cause has been identified, or study medication 
cannot be implicated 
Possible: Temporal association, but other etiologies are likely to be the cause; however, 
involvement of study mediation cannot be excluded 
Probable: Temporal association, other etiologies are possible, but unlikely. 
 
The severity of adverse events experienced during the course of the study will be assessed using a 
grading system: 
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental activities of daily living.  
Grade 3: Severe or medically significant but not immediately life-threatening AE; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care 
acitivies of daily living.  
Grade 4: Life-threatening consequences; urgent intervention indicated.  
Grade 5: Death related to AE 
 
Reference: Common Terminology Criteria for Adverse Events (NIH):  
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf 
Adverse events that occur during the study (from enrollment through the final visit), regardless of 
treatment group or relationship to the research, will be reported according to the policy of 
WCMC’s Office of Research Integrity and Assurance and Data Safety Monitoring Board.  
 
As per WCMC IRB reporting policy, only AE Grades 3, 4, and 5 will be reported to the IRB and 
DSMB.  
(http://weill.cornell.edu/research/rea_com/irb_adv.html 
 
 
All safety data will be reported to the WCMC DSMB. No efficacy interim analysis will be 
performed. Safety review will be done by the DSMB after the six-month visit of the first patient 
and then yearly. More frequent meetings or meetings ad-hoc could be organized if needed or 

 
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requested by the DSMB. The study does not have preset rules for discontinuation. Upon review of 
the data, the DSMB can recommend stopping the study at any time if appropriate. 
 
 

 
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