Double-blind, Placebo-controlled, Randomized Study of the Safety and Tolerability of Isoxsuprine HCL Combined With High Dose Steroid Treatment of Multiple Sclerosis (MS) Relapse
Phase: PHASE1
Conditions: Multiple Sclerosis
Sponsor: University of New Mexico

PROTOCOL TITLE: Double-blind, placebo-controlled, randomized study of the safety 
and tolerability of isoxsuprine HCL combined with high dose steroid treatment of 
multiple sclerosis (MS) relapse
Page 1 of 19
Version Date: 06/18/2020

PROTOCOL TITLE: Double-blind, placebo-controlled, randomized study of the safety 
and tolerability of isoxsuprine HCL combined with high dose steroid treatment of 
multiple sclerosis (MS) relapse
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Version Date: 06/18/2020
PROTOCOL TITLE:
Double-blind, placebo-controlled, randomized study of the safety and tolerability of 
isoxsuprine HCL combined with high dose steroid treatment of multiple sclerosis 
(MS) relapse
PRINCIPAL INVESTIGATOR:
Clotilde Hainline, MD,
1101 Yale Blvd., NE
Albuquerque, New Mexico 87131
ADMINISTRATIVE CONTACT:
Jacquelyn Morales
Research Coordinator
1101 Yale Blvd., NE
Albuquerque, New Mexico 87131
VERSION NUMBER:
Version 2.0
DATE:
18 June 2020
REGULATORY FRAMEWORK:
Please indicate all that apply:
DOD (Department of Defense)
DOE (Department of Energy)
DOJ (Department of Justice)
ED (Department of Education)
EPA (Environmental Protection Agency)
FDA (Food and Drug Administration)
HHS (Department of Health and Human Services)
VA
Other:      
Is this a clinical trial under ICH-GCP E6?   
 Yes   
 No
If yes, please confirm that the research team is familiar with and agrees to comply 
with the investigator requirements cited in ICH-GCP E6.  
 Yes   
 No 

PROTOCOL TITLE: Double-blind, placebo-controlled, randomized study of the safety 
and tolerability of isoxsuprine HCL combined with high dose steroid treatment of 
multiple sclerosis (MS) relapse
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Version Date: 06/18/2020
Table of Contents
1.
Objectives.....................................................................................................................4
2.
Background ..................................................................................................................4
3.
Study Design ................................................................................................................4
4.
Inclusion and Exclusion Criteria ..................................................................................4
5.
Number of Subjects......................................................................................................4
6.
Study Timelines............................................................................................................5
7.
Study Endpoints ...........................................................................................................5
8.
Research Setting...........................................................................................................5
9.
Resources Available.....................................................................................................5
10.
Prior Approvals.........................................................................................................6
11.
Multi-Site Research ..................................................................................................6
12.
Study Procedures ......................................................................................................7
13.
Data Analysis............................................................................................................8
14.
Provisions to Monitor the Data to Ensure the Safety of Subjects.............................8
15.
Withdrawal of Subjects.............................................................................................8
16.
Data Management/Confidentiality............................................................................9
17.
Data and Specimen Banking...................................................................................10
18.
Risks to Subjects.....................................................................................................11
19.
Potential Benefits to Subjects .................................................................................11
20.
Recruitment Methods..............................................................................................11
21.
Provisions to Protect the Privacy Interests of Subjects ..........................................12
22.
Economic Burden to Subjects.................................................................................12
23.
Compensation .........................................................................................................13
24.
Compensation for Research-Related Injury............................................................13
25.
Consent Process......................................................................................................13
26.
Documentation of Consent .....................................................................................16
27.
Study Test Results/Incidental Findings ..................................................................16
28.
Sharing Study Progress or Results with Subjects...................................................17
29.
Inclusion of Vulnerable Populations ......................................................................18
30.
Community-Based Participatory Research.............................................................19
31.
Research Involving American Indian/Native Populations .....................................19
32.
Transnational Research...........................................................................................19
33.
Drugs or Devices ....................................................................................................20
Checklist Section ...............................................................................................................21
34. Export Control…………………………………………………………………….22

PROTOCOL TITLE: Double-blind, placebo-controlled, randomized study of the safety 
and tolerability of isoxsuprine HCL combined with high dose steroid treatment of 
multiple sclerosis (MS) relapse
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Version Date: 06/18/2020
1. Objectives
Primary Objective
The primary objective of this study is to:

Assess the safety and tolerability of Isoxsuprine (ISX) in combination with 
high dose corticosteroids in subjects experiencing acute relapses due to 
multiple sclerosis.
The safety analysis population will include all randomized subjects who 
receive at least one dose of study drug.  Safety endpoints will be summarized 
by treatment group (ISX or placebo) from the time of the first does and 
include all available safety data.  No formal statistical testing will be done.
All adverse event data will be listed and will be summarized by treatment 
group.  Quantitative safety variables (vital signs) will be summarized at each 
visit by treatment group and changes from baseline will be summarized by 
treatment group at selected visits.
Secondary Objective
The secondary objective of this study is to:

Evaluate the potential efficacy of Isoxuprine as add-on treatment for 
improving neurological deficits in walking ability, visual acuity, and other 
associated symptoms of MS, including fatigue and cognitive dysfunction in 
this MS population experiencing a relapse.
The efficacy analyses will include all randomized and dosed subjects who 
provide Week 12 efficacy data.  The key secondary analysis will compare the 
changes in EDSS functional system scores most relevant to the relapse 
associated disability (e.g. pyramidal, visual, cerebellar).  Also walking speed 
and z-score from the Multiple Sclerosis Functional composite score (MSFC) 
from Baseline to Week 12 in the ISX group compared to the placebo group.
2. Background
Overview
Multiple sclerosis (MS) is a disease of the central nervous system (CNS) 
characterized by multifocal inflammation, demyelination, axonal injury and brain 
atrophy secondary to neurodegenerative changes. The prevalence of MS in the US is 
estimated to be 1,000,000 in the US with approximately 2,000 new cases diagnosed 
annually. MS occurs more often in women than men (2:1 ratio) with a mean age of 
onset in the US of approximately 33 years. The most common pattern of MS is 
termed relapsing MS (RMS) where patients experience acute exacerbations or 
episodes of worsening neurological function followed by partial or complete 
recovery. Relapses of MS can be associated with transient or permanent disability. 
For this reason, it is common to treat significant relapse symptoms with short pulses 
of high dose corticosteroids. Severe relapses involving vision loss, impaired 
ambulation or other disabling symptoms may recover more quickly with high dose 
corticosteroids given daily for 3 to 5 days. Evidence from preclinical stroke models 

PROTOCOL TITLE: Double-blind, placebo-controlled, randomized study of the safety 
and tolerability of isoxsuprine HCL combined with high dose steroid treatment of 
multiple sclerosis (MS) relapse
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and experimental allergic encephalomyelitis suggest that isoxsuprine hydrochloride 
may have neuroprotective activity and reduce disability in animal models. 
Isoxsuprine belongs to the group beta-agonists that cause vasodilation and has been 
used to treat problems resulting from poor blood circulation and, in certain women, to 
stop premature labor. Given its potential neuroprotective effects in CNS injury 
models, we propose to test it as a safe, tolerable add on treatment for acute relapses in 
patients with relapsing forms of MS. 
3. Study Design
Description
This is a proof of concept, randomized, double-blind, placebo-controlled, 2-arm, 
parallel group study of Isoxsuprine in MS subjects experiencing a typical relapse.
All subjects will have a documented diagnosis of relapsing MS or a clinically isolated 
syndrome by international criteria.  The relapse will be of sufficient severity that their 
physician recommends treatment with a high dose corticosteroid pulse.  All subjects 
will have a physical examination and history with questions on drug sensitivities.  
Subjects experiencing the onset of objective neurological deficits consistent with 
relapse within 7 days of randomization are eligible for screening for this study.  
Those currently on MS disease modifying therapy will have received a stable regimen 
of the medications for at least 30 days prior to screening and will continue the same 
doses and regimens for the duration of their study participation.
Consented subjects will be assessed for relapse criteria and those who meet study 
eligibility criteria and agree to be treated with a standard 3 to 5 day pulse of high dose 
corticosteroids, will be randomized with equal probability to 1 of 2 treatment groups:  
placebo capsule or active Isoxsuprine (ISX).  
The Screening Visit will take place within 7 days of relapse onset and within 48 hours 
of initiating high dose steroids. Subjects may start corticosteroids anytime during this 
7 day window. During the screening period, subjects will be assessed with the 
Expanded Disability Status Scale (EDSS), Multiple Sclerosis Functional Composite 
(MSFC), and cognitive testing prior to treatment with ISX or placebo (1:1 ratio). 
Safety Assessments during screening will include a physical exam, 
electrocardiogram, vital signs, weight and a urine pregnancy test for females of child 
bearing potential.  At 7 (± 1) days following the completion of the 5-day ISX dosing, 
subjects will be re-assessed with the EDSS.
Subjects will be evaluated for treatment response using the EDSS and other standard 
measures described below at visits 1, 4 and 12 weeks.
Study drug will be administered as one (1) 10 mg capsule, 3 times daily for 5 days in 
conjunction with concomitant dosing with high dose corticosteroids. This can be any 
accepted regimen, including daily iv methylprednisolone 1000 mg/day or 600mg oral 

PROTOCOL TITLE: Double-blind, placebo-controlled, randomized study of the safety 
and tolerability of isoxsuprine HCL combined with high dose steroid treatment of 
multiple sclerosis (MS) relapse
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prednisone two times a day at approximately 8AM and noon, with food, as typically 
provided by UNM MS Specialty Clinic
4. Inclusion and Exclusion Criteria
Inclusion Criteria
Subjects must meet all the following criteria for inclusion in the study at the 
Screening
Visit:
1. Subjects must be adequately informed and understand the nature and risks of the 
study and must be able to provide a signature and date on the ICF;
2. Male or female subjects between 18 and 50 years of age, inclusive;
3. Confirmed diagnosis of Multiple Sclerosis or Clinically Isolated Syndrome (CIS) 
suggestive of MS, according to the 2010 Revised McDonald criteria. 
4. On a stable regimen of medications taken specifically to treat MS for at least 30 
days prior to screening, and willing to continue the same doses and regimens for 
the duration of study participation;
5. New neurological disability consistent with MS relapse no longer than 7 days 
prior to screening;
6. Screen visit and randomization must occur within 48 hours of subject initiating 
steroid treatment.
7. Maximum EDSS score during screening of 6.5;
8. Sufficient ambulatory ability (ambulatory aids acceptable if used consistently) to 
complete two trials of the Timed 25 Foot Walk (T25FW) at the screening visit 
with the two trials completed within 5 minutes of each other in accordance with 
the specific instructions provided by the National MS Society Functional 
Composite Manual.
9. Subject must be willing to take a high dose steroid (600mg oral prednisone two 
times a day (bid).
10. Subjects must have a mean systolic blood pressure ≤ 160 and greater than 100 
mm Hg and a mean diastolic blood pressure of ≤ 100 and greater than 50 mm Hg 
determined by the average of 3 seated readings taken at least 5 minutes apart at 
the Screening Visit.
11. Subjects must be able to communicate effectively with study personnel. For this 
reason only English speaking subjects will be eligible for the study.
12. Subjects must be able and willing to follow all protocol requirements and study 
restrictions.
13. Subjects must be able and willing to return for all study visits.

PROTOCOL TITLE: Double-blind, placebo-controlled, randomized study of the safety 
and tolerability of isoxsuprine HCL combined with high dose steroid treatment of 
multiple sclerosis (MS) relapse
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Exclusion Criteria
Subjects are ineligible for study participation if they meet any of the following criteria at 
the Screening Visit:
1. Subject is from a vulnerable population, as defined by the US CFR Title 45, Part 
46, Section 46.111(b) and other local and national regulations, including but not 
limited to, employees (temporary, part-time, full time, etc) or a family member of 
the research staff conducting the study, or of the sponsor, or of the IRB.
2. Subject has only sensory, bowel/bladder, and/or cognitive symptoms of MS 
associated with the most recent relapse.
3. Subject has cognitive or behavioral impairment that in the opinion of the 
investigator would impair the ability of the subject to comply with study 
procedures.
4. Subject has any known contraindication(s) to the use of corticosteroids or 
isoxsuprine hydrochloride (ISX), including, but not limited to:
•
any current uncontrolled hypertension, primary adrenocortical 
insufficiency

Any current psychoses, infectious disease, or Cushing’s syndrome.

Any current congestive heart failure (defined as New York Heart 
Association (Functional Class III to IV).

Peptic ulcer (within 24 weeks prior to the Screening Visit).

Recent major surgery (within 24 weeks prior to the Screening Visit).

Use of tizanidine any time in the past 30 days. 
5. Subject has a clinically significant infection requiring intravenous administration 
of antibiotics and hospitalization prior to the Screening Visit.
6. Subject has poorly controlled type 1 or type 2 diabetes mellitus (prior diagnosis of 
gestational diabetes mellitus is not exclusionary
7. Received systemic steroids for a problem unrelated to the MS relapse within 30 
days prior to screening.
8. History of other neurological disease that, 'in the opinion of the Investigator, 
would affect motor function or cognition;
9. For patients with a history of Major Depressive Disorder, at risk for worsening 
depression due to steroids or the presence of active depressive symptoms 
sufficient, in the opinion of the investigator, to affect the subject's ability to 
complete study assessments, or which would not be in the subject's best Interest to 
participate in the study;
10. Presence of cognitive impairment sufficient, in the opinion of the investigator, to 
affect the subject's ability to complete study assessments, or which would not be 
In the subject's best interest to participate in the study;

PROTOCOL TITLE: Double-blind, placebo-controlled, randomized study of the safety 
and tolerability of isoxsuprine HCL combined with high dose steroid treatment of 
multiple sclerosis (MS) relapse
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11. History of sensory impairments (e.g., hearing, vision) that, In the opinion of the 
investigator, would impair the subject's ability to complete study assessments;
12. History of current alcohol or substance abuse or dependence;
13. History of myocardial infarction, or NYHA Functional Classification of Heart 
Failure Class 3 or 4 within 2 years prior to screening, or history of coronary artery 
disease and/or active angina pectoris;
14. Any clinically significant ECG abnormalities;;
15. Inability to swallow oral capsules, or a history of gastrointestinal malabsorption 
that would preclude the use of oral medication;
16. If female, is pregnant or lactating;
17. History of hypersensitivity or allergic reaction to any of the study drugs.
18. History of heavy use of tobacco/smoking
5. Number of Subjects
Approximate Number of Subjects
Target enrollment is 20 subjects equally randomized to ISX or matching placebo.
6. Study Timelines
Approximate Duration of Subject Participation
Subjects will participate in the study for a total of up to 12 weeks. Study visits include 
a screening/randomization visit with drug administered and safety and efficacy 
assessment visits at weeks 1 (7 days after completion of ISX dosing), 4 and 12 weeks.
7. Study Endpoints
Primary safety endpoints will be assessed using the following:

Individual GI symptoms

Adverse events (AEs)

Vital signs (temperature, respiratory rate, pulse, systolic and diastolic blood 
pressure)

Electrocardiogram (ECG) parameters (heart rate, RR, QT, QTcF, QTcB, PR, 
and QRS intervals)
Secondary efficacy endpoints will be assessed using the following:

Kurtzke Expanded Disability Status Scale (EDSS0

Timed 25-foot Walk (25FTW)

Symbol Digit Modality Test (SDMT)
8. Research Setting

PROTOCOL TITLE: Double-blind, placebo-controlled, randomized study of the safety 
and tolerability of isoxsuprine HCL combined with high dose steroid treatment of 
multiple sclerosis (MS) relapse
Page 9 of 19
Version Date: 06/18/2020
Aside from recruitment which will take place at the Clinical Neuroscience Center, 
MS Clinic, all research activities will be completed at the MS Specialty Clinic. The 
MS Specialty Clinic is located at 1101 Yale Blvd, NE, Albuquerque, NM 87131.
9. Prior Approvals
The following approvals are available and will be provided with study 
documentation: 

Departmental Review Form 

Drug Attachment for Isoxsuprine and matching placebo

IND Exemption Checklist
10.Study Procedures 
Screening Visit (Visit 1) Procedures/Assessments
The following procedures will be performed at the Screening Visit:
•
Informed consent.
•
Inclusion/exclusion criteria.
•
Medical and surgical history.
•
Demographics.
•
Physical examination.
•
EDSS.
•
Multiple Sclerosis Functional Composite (MSFC).
•
Cognitive Battery consisting of the Symbol Digit Modality test
•
Height and Weight.
•
Vital signs.
•
Urine pregnancy test.
•
Electrocardiogram (ECG) pre-dose.
•
Treat with oral prednisone (600 mg BID) if not already receiving 
corticosteroid pulse, which can be via Iv or Po route.
•
Adverse events and concomitant medications.
Randomization Visit (Visit 1) Procedures/Assessments
•
Initiate treatment with Isoxsuprine HCL (oral) Capsule 10mg or placebo.
•
1 hour monitoring post dose.
•
Vital signs.
•
Electrocardiogram (ECG) post dose.
•
Adverse events.
1 Week Post Treatment Safety Follow-Up Visit (Visit 2) Procedures/Assessments
The following procedures will be performed at this visit:
•
Physical examination.
•
EDSS.

PROTOCOL TITLE: Double-blind, placebo-controlled, randomized study of the safety 
and tolerability of isoxsuprine HCL combined with high dose steroid treatment of 
multiple sclerosis (MS) relapse
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•
Multiple Sclerosis Functional Composite (MSFC).
•
Vital signs.
•
Adverse events and concomitant medications.
4 Week Post Treatment Safety Follow-Up Visit (Visit 3) Procedures/Assessments
The following procedures will be performed at this visit:
•
Physical examination.
•
EDSS.
•
Multiple Sclerosis Functional Composite (MSFC).
•
Cognitive Battery (Symbol Digit Modality).
•
Vital signs.
•
Adverse events and concomitant medications.
12 Week Post Treatment Safety Follow-Up Visit (Visit 4) Procedures/Assessments
The following procedures will be performed at this visit:
•
Physical examination.
•
EDSS.
•
Multiple Sclerosis Functional Composite (MSFC).
•
Cognitive Battery (Symbol Digit Modality).
•
Vital signs.
•
Adverse events and concomitant medications.
Adverse Events
Adverse events will be recorded from signing of the ICF and followed by the investigator 
until the AE is resolved or stabilized. Any and all safety measures (which includes 
standard of care activities) should be provided by the study site to the subject. Any study 
site follow-up should be documented.
Medical History
Medical history will be obtained at the Screening Visit. Medical history will include a 
review of the following systems: general medical and surgical history. Historical and 
current medical conditions including date of last menstrual period for female subjects will 
be recorded.
Current Medical Conditions
At each visit after screening, subjects will be asked about any changes in medical 
conditions, specifically new medical conditions and worsening of existing medical 
conditions. Any changes since the Screening Visit will be recorded as AEs, as 
appropriate.
Physical Examination
A complete physical examination will be performed at all four study visits. The complete 
physical examination includes evaluation of the head, eyes, ears, nose, throat, neck 

PROTOCOL TITLE: Double-blind, placebo-controlled, randomized study of the safety 
and tolerability of isoxsuprine HCL combined with high dose steroid treatment of 
multiple sclerosis (MS) relapse
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(including thyroid), cardiovascular system, lungs, abdomen, neurological system not 
obtained with EDSS, skin, extremities and other conditions of note.
The findings of the physical examinations will be recorded. Any change from the 
Screening Visit physical examination that is considered clinically significant by the 
investigator will be recorded as an AE.
Electrocardiogram
A 12 lead ECG will be taken at visits baseline and 1 week, (pre and post dose for visit 1).
Height and Weight
Height and Weight will be collected at screening only. 
Vital Signs
Vital signs will be obtained after the subject has been seated for 5 minutes (minimum) 
and will include systolic and diastolic blood pressures, pulse rate, respiratory rate, and 
body temperature. Additionally, at the Screening/Randomization Visit, blood pressure 
will be measured at least 3 times, with 5 minutes between assessments after the subject 
has been seated for a minimum of 5 minutes prior to the initial blood pressure 
assessment. The date and time for all vital sign assessments will be recorded.
The investigator may perform additional unscheduled vital sign measurements to evaluate 
or manage a suspected AE. These unscheduled vital sign measurements should be 
obtained after the subject has been seated for at least 5 minutes, if possible. Unscheduled 
vital signs will be recorded.
Urine Pregnancy Tests
Urine pregnancy Tests will be completed at visit 1 on females of child bearing potential 
based on medical history obtained at screening visit.  
Symbol Digit Modality Test
SDMT has demonstrated sensitivity in detecting not only the presence of cognition 
impairment, but also changes in cognitive functioning over time and in response to 
treatment.  The SDMT is brief, easy to administer, and involves a simple substitution task 
that normal adults can easily perform. SDMT will be administered by a qualified 
examiner.
11.Withdrawal of Subjects
Subject Withdrawal
Subjects who discontinue, the reason for discontinuation will be recorded. A subject may 
be discontinued from the study for the following medical or administrative reasons:
•
Withdrawal by Subject.
•
Adverse Event.
•
Death.

PROTOCOL TITLE: Double-blind, placebo-controlled, randomized study of the safety 
and tolerability of isoxsuprine HCL combined with high dose steroid treatment of 
multiple sclerosis (MS) relapse
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•
Loss to Follow Up.
•
At PI discretion.
Treatment Discontinuation
On rare occasion, oral administration of the drug isoxsuprine has been associated with the 
occurrence of hypotension, tachycardia, chest pain, nausea, vomiting, dizziness,
abdominal distress, and severe rash. If rash appears, the drug will be discontinued.
Treatment with study drug should be discontinued if any of the following occur:
•
Development of accelerated hypertension (defined as systolic blood pressure ≥ 
180 and diastolic blood pressure ≥ 100 mm Hg) that cannot be managed by the 
adjustment of concomitant medications such as antihypertensive medications.
•
Development of symptomatic hypotension (defined as syncope or orthostatic 
lightheadedness) or  systolic blood pressure < 100 and diastolic blood pressure <  
50 mm Hg).
•
Development of congestive heart failure that cannot be managed by the 
adjustment of concomitant medications such as diuretics and antihypertensive 
medications.
•
Development of diabetic signs/symptoms or classic symptoms of hyperglycemia 
with random plasma glucose> 200 mg/dL).
•
Development of any other AE of at least moderate intensity and possibly, 
probably or definitely related to study drug that cannot be managed by the 
adjustment of concomitant medications.
12. Data Management/Confidentiality
Qualified Clinical Trial personnel will be the only ones that will carry out study 
procedures. MS Clinical Trial personnel will have access to study records. HIPPA 
Regulations will be strictly followed.
It is required that subjects be explicitly identified by a study number. This number is 
assigned at screening. A study number link is necessary in case of follow-up for 
accuracy and/or quality control. The link will be kept at least the duration of the 
study. 
All study data will be entered into a RedCAP data which maintained locally. Only the 
study id number is used in the database to identify study subjects. 
A subject identification log will be kept on-site, however, no copies will be made.
All records will be kept in a locked office at 1101 Yale Blvd NE.  Once the study has 
been closed the data will be stored for up to 3 years per regulations
13.Data and Specimen Banking
Not applicable. We will not be collecting any specimens or banking any data  for this 
study protocol.

PROTOCOL TITLE: Double-blind, placebo-controlled, randomized study of the safety 
and tolerability of isoxsuprine HCL combined with high dose steroid treatment of 
multiple sclerosis (MS) relapse
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14.Risks to Subjects
Along with its needed effects, isoxsuprine may cause some unwanted effects. Although 
not all of these side effects may occur, if they do occur they may need medical attention.
Check with your doctor as soon as possible if any of the following side effects occur 
while taking isoxsuprine:
Rare

Chest pain

dizziness or faintness (more common for injection)

fast heartbeat (more common for injection)

shortness of breath

skin rash
Some side effects of isoxsuprine may occur that usually do not need medical attention. 
These side effects may go away during treatment as your body adjusts to the medicine. 
Also, your health care professional may be able to tell you about ways to prevent or 
reduce some of these side effects. Check with your health care professional if any of the 
following side effects continue or are bothersome or if you have any questions about 
them:
Less Common

Nausea or vomiting (more common for injection)
Risks to patient confidentiality will be mitigated by good clinical practice procedures 
as outlined in the protocol. Part of this study is a standard of care treatment for MS 
relapse and only the addition of isoxsuprine or placebo is the subject of the research.
      All patients will be screened and excluded for pregnancy
      Careful examination and history will be taken to ascertain key inclusion and    
      exclusion criteria in order to minimize the probability and magnitude of risks.
15.Potential Benefits to Subjects
This is not an efficacy study.  The goal here is to study a reasonable number of MS 
patients in acute relapse who are receiving standard high dose steroid therapy. We 
will randomize 20 subjects to receive ISX or PBO and assess for any tolerability or 
safety issues as described in the protocol. Based on this pilot data, it may be 
reasonable to initiate a larger efficacy study. It is possible that ISX will in fact have 
neuroprotective properties in MS patients.  In that scenario, patients could attain some 
benefit to their future disability. Again, this is not an endpoint and the study is not 
powered to detect a clinical benefit. 
      
16.Recruitment Methods
Recruitment
Potential RRMS patients will be recruited and identified from the neurology clinic 
at the University of New Mexico Hospital. Once identified, the coordinator will 
contact the potential research patient to discuss the study with them. Once their 
interest is verified, a copy of the approved IRB consent is sent or given to the 
patient for their review. 

PROTOCOL TITLE: Double-blind, placebo-controlled, randomized study of the safety 
and tolerability of isoxsuprine HCL combined with high dose steroid treatment of 
multiple sclerosis (MS) relapse
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The coordinator will ask the patient to sign a release to obtain copies of their 
medical records for review. The coordinator will review the medical record prior 
to scheduling a screening visit. This is done so that if there is anything in the 
medical records which will exclude the potential research patient, this will be 
found prior to a screening scheduled visit. This preliminary review of the patient 
allows them to be deemed eligible to screen for the study. 
Subjects must be consented before any study screening tests or assessments are 
performed. At the time of consent, the subject will be enrolled into the study. 
The coordinator and/or study staff will document all screened candidates initially 
considered for inclusion in this study. If a subject is excluded from the study, the 
reasons for exclusion will be documented in the subject’s source documents and 
on the study screening log.
17.Provisions to Protect the Privacy Interests of Subjects
Protections for Subjects
The principal investigator and/or MS Clinical Trial personnel will approach the 
subject with specific details after they are referred to the clinic or are seen in the MS 
clinic. Only those study personnel will interact with the patient throughout the study.
All information is gathered and stored at 1101 Yale Blvd, NE for Dr. Hainline’s 
review, in case there are any safety issues that need to be addressed. 
From the beginning at the ICF process, all study activities are explained in terms the 
subject can understand and an opportunity is given for the subject to ask questions. 
This is continued throughout the study. At each visit a lot of time is given to the 
patient so that they understand the various procedures being done as a safety 
precaution. 
There is a lot of communication and the patient is always encouraged to ask questions 
either in clinic, at the research facility or via telephone. All of their questions will be 
answered with a level of compassion, as we understand this is for research.
18.Economic Burden to Subjects
Study Costs
This study will supply the study drug needed for treating the subject’s MS relapse 
while they participate, at no cost to the subject.  All of the required study 
procedures and activities that are above the standard of care will be covered by 
the UNM CTSC. will pay for all study-required procedures that are above and 
beyond standard of care. The subject’s health insurance company will be billed 
for the costs of tests that are not covered by the study. 
19.Compensation
The subjects will not be compensated for their participation in this study. 
20.Compensation for Research-Related Injury
Subject injury
If the subject experiences any unexpected symptoms or injury directly related to 
the study medication or study procedure which was properly performed in 

PROTOCOL TITLE: Double-blind, placebo-controlled, randomized study of the safety 
and tolerability of isoxsuprine HCL combined with high dose steroid treatment of 
multiple sclerosis (MS) relapse
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accordance with this protocol, all reasonable medical treatment will be provided 
by UNM HSC.  Study related injuries do not include injuries that result from 
subject own fault or intention.
21.Consent Process
Ethical Conduct of the Study
The study will be conducted in full compliance with applicable 
international, national and local regulatory requirements; FDA regulations 
including 21 CFR 314.106 and 312.120; and ICH guidelines for GCP and 
in accordance with the ethical principles that have their origins in the 
Declaration of Helsinki.
       Subject Information and Consent
The ICF must be approved by the IRB before any subject provides 
consent. 
At the Screening Visit, subjects will read the ICF and a Health Insurance 
Portability and Accountability Act (HIPAA) authorization form, after an 
explanation of the study. Before signing the ICF and the HIPAA 
authorization form, subjects will have an opportunity to discuss the 
contents of these forms with study site personnel.
Subjects must assent understanding of and voluntarily sign these forms in 
compliance with applicable GCP guidelines and 21 CFR, Parts 50 and 312 
(where applicable), before participating in any study-related procedures. 
Subjects will be made aware that they may withdraw from the study at any 
time. Subjects unable to give written informed consent must orally assent 
to the procedures and written informed consent must be obtained from a 
legally authorized representative in accordance with national and local 
laws.
The ICF must contain all applicable elements of informed consent and the 
mandatory statements as defined by national and local regulations 
including confidentiality. All versions of each subject's signed ICF will be 
kept on file by the site for possible inspection by regulatory authorities. 
Signed copies of the ICF and the HIPAA authorization form, if applicable, 
will be given to the subject.
If the subject withdraws consent and/or HIPAA authorization, the 
investigator will no longer disclose health information, unless it is needed 
to preserve the scientific integrity of the study.

Partial Waiver of HIPAA Authorization This study will seek a partial waiver 
of HIPAA authorization in order to review the medical records of current MS 
patients for screening procedures.

PROTOCOL TITLE: Double-blind, placebo-controlled, randomized study of the safety 
and tolerability of isoxsuprine HCL combined with high dose steroid treatment of 
multiple sclerosis (MS) relapse
Page 16 of 19
Version Date: 06/18/2020
22.Documentation of Consent
Consenting Process
The Principal Investigator or authorized representative reviews the ICF by 
discussing and or explaining study procedures, treatments, costs, potential 
benefits/risks involved, and the alternatives for care or treatment to the patient. The 
person obtaining consent is knowledgeable about the protocol and able to answer any 
questions. All study procedures are explained in terms the subject can understand and 
an opportunity is given for the subject to ask questions. The PI or authorized 
representative ensures the subject meets inclusion exclusion criteria. Expectations of 
subjects are reviewed. Special care is given to explaining the use and disclosure of the 
subject's protected health information. This is done before the informed consent is 
signed. The investigator documents this discussion in the patient's chart.
After the PI has explained the trial and determined the subject's interest level, the 
designated research staff or "person obtaining consent" will verify the subjects 
understanding of the study, ensuring the subject has adequate information in making 
the decision to participate in the clinical trial. After all questions are answered, both 
subject and PI or authorized representative sign ICF.
A copy of the fully executed and signed ICF is provided to the subject for their 
records. The original ICF will be kept in the subject’s study biner.
The full ICF process is completed prior to any study assessments and is documented 
in site's requisition form.
23.Study Test Results/Incidental Findings
Some diagnostic testing information will be given to the patient to include: Vitals, 
weight, Physical Exam. The patient will be given the information directly for them to 
share with their PCP.
24.Sharing Study Progress or Results with Subjects
Due to the length and the blinded nature of the study, there is no plans to share study 
progress or results with the study subjects at this time.
25.Inclusion of Vulnerable Populations
N/A This study does not seek to recruit participants from vulnerable populations. 
26.Drugs or Devices
Product Description
Isoxsuprine hydrochloride (ISX) 
Isoxsuprine hydrochloride structure

PROTOCOL TITLE: Double-blind, placebo-controlled, randomized study of the safety 
and tolerability of isoxsuprine HCL combined with high dose steroid treatment of 
multiple sclerosis (MS) relapse
Page 17 of 19
Version Date: 06/18/2020
Formulation and dosing: Compounded capsules with identical placebo, 10 mg by 
mouth 3 times per day for 5 days
Methods of Assigning Subjects to Treatment Groups
Subjects will be randomized 1:1 according to a computer-generated allocation scheme to 
receive either Isoxsuprine HCL 1 capsule 3 times daily for 5 days or matching placebo.
Emergency Identification of Investigational Medicinal Product
In case of an emergency during the study, when knowledge of the investigational product 
assignment is required for the medical management of an individual subject experiencing 
the emergency, the treatment blind for that subject may be broken by contacting the 
research pharmacy.  The investigator must also indicate in source documents that the 
blind was broken and provide the date, time, and reason for breaking the blind.
Dosing Procedures
The medication should be kept at room temperature and will be labeled according to all 
applicable national and local regulations.
The following treatments will be administered:
•
Treatment A: Isoxsuprine HCL 1 Capsule 3 times daily for 5 consecutive days, 
OR
•
Treatment B: Placebo 1 Capsule 3 times daily for 5 consecutive days.
The subject or clinic staff will administer the first dose of drug in the clinic under the 
supervision of study staff. The subject will remain in the clinic for at least 1 hour post-
dose to monitor for allergic or adverse reactions. Thereafter, all doses will be 
administered by the subject or the subject’s caregiver at home.
Subject Unblinding
The identity of the treatment assigned to individual subjects can be revealed in an 
emergency only. A subject’s treatment assignment should only be unblinded when 
knowledge of the treatment is essential for the safety of the subject
Storage of Clinical Supplies
Isoxsuprine HCL and placebo will be maintained in a temperature controlled, secure 
locked area with restricted access at the study site pharmacy.
Drug Accountability
Subjects will be asked to return all empty study medication containers at study visit week 
1 (Visit 2).  They will be asked if all study medication was taken as directed.
Safety Assessments and Procedures
The following safety assessments will be evaluated (see section 10): AEs, physical 
examinations, ECGs, vitals, weight, urine pregnancy tests and Concomitant Medications. 

PROTOCOL TITLE: Double-blind, placebo-controlled, randomized study of the safety 
and tolerability of isoxsuprine HCL combined with high dose steroid treatment of 
multiple sclerosis (MS) relapse
Page 18 of 19
Version Date: 06/18/2020
Michel Torbey, MD and Mark Unruh, MD to serve as a Data Safety Monitoring Board.  
They will have no connection to the study. On a quarterly basis, study progress and data 
will be submitted for review. Adverse events will be reported to the DSMB and IRB 
within 7 days and Serious Adverse Events within 24 hours.  The DSMB will help ensure 
patients safety and rights though out the study. The DSMB will have authority to provide 
recommendations on the conduct of the study, such as suspension of the study or advise 
on any potential protocol revisions.
IND Waiver Justification
This study proposes to use isoxsuprine HCl (ISX) in standard 10 mg tablets in subjects 
experiencing an acute relapse of multiple sclerosis. The rationale comes from strong 
preclinical observations that ISX had significant and novel neuroprotective action in 
ischemic stroke using a cell-based high-throughput screening (PLOS ONE, 1 May 2014,  
Volume 9 (5) e9676.). Isoxsuprine was identified as a top neuroprotectant among 1,200 
compounds in the Prestwick Chemical Library, which contains diverse, mostly FDA-
approved and off-patent compounds, and its neuroprotective function was confirmed in 
transient ischemic injury in animals. ISX has been used in the past for suppressing 
premature labor and for vascular dementia, since the drug is a beta-adrenergic agonist and 
vasodilator. These older indications are not used very often now but a typical dose was 
10mg by mouth 3 to 4 times per day.  In this tolerability and safety study we will use 
10mg tid as the dose, given for 5 consecutive days. The primary goal is to assess safety 
and tolerability in MS patients in a relapse, who are also receiving a short course of high 
dose steroids to shorten relapse recovery. These subjects are otherwise healthy and will 
not have significant other health issues. We do not anticipate adverse reactions to 
concomitant use of ISX and steroids. While ISX tends to lower blood pressure modestly, 
steroids tend to increase, essentially in offsetting directions. Subjects will be randomized 
to ISX 10mg tid x 5 days or matching placebo. They will initiate the ISX within 48 hours 
of starting steroids.

PROTOCOL TITLE: Double-blind, placebo-controlled, randomized study of the safety and 
tolerability of isoxsuprine HCL combined with high dose steroid treatment of multiple sclerosis 
(MS) relapse
Page 19 of 19
Version Date: 06/18/2020
Checklist Section
This section contains checklists to provide information on a variety of topics that require special 
determinations by the IRB.  Please complete all checklists relevant to your research.
I.
Waivers or Alterations of Consent, Assent, and HIPAA Authorization
Partial Waiver of HIPAA Authorization for Screening/Recruitment
Complete the following additional questions/attestations if the records you will 
review to identify potential subjects and/or determine eligibility include Protected 
Health Information (PHI).
1. Will you be recording any PHI when conducting the records review to identify 
potential subjects and/or determine eligibility?
 Yes. Describe: Only information found from potentially eligible subjects 
will be recorded. Information such as name, DOB, medical data, including 
laboratory test results, radiology and pathology results, information about 
other medical conditions that may affect their participation.
 No
2. If you answered “Yes” to question 6 above, please describe when you will 
destroy identifiers (must be the earliest opportunity consistent with the 
conduct of the research) or provide justification for why they must be 
retained:
This information will only be collected for potentially eligible participants. 
Subject will be consented and those found eligible will be and this information 
will become part of their study source documentation. Subjects found to be 
ineligible will have their reason for exclusion documented and this 
information will become part of their study source documentation. Those 
patients who do not sign consent will have their PHI destroyed upon their 
decline to participate.
3. The PHI accessed or recorded for identification/screening purposes will not be 
reused or disclosed to (shared with) any other person or entity, except as 
required by law, for authorized oversight of the research study, or for other 
research for which the use or disclosure of the PHI would be permitted under 
the Privacy Rule.
 True
 False