Conditions: Multiple Sclerosis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 2
Healthy volunteers: no

Brief summary:
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.

Evidence from preclinical stroke models and experimental allergic encephalomyelitis suggest that isoxsuprine hydrochloride may have neuroprotective activity and reduce disability in animal models. Given its potential neuroprotective effects in CNS injury models, the investigators propose to test it as a safe, tolerable add on treatment for acute relapses in patients with relapsing forms of MS.

Detailed 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.

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 prednisone two times a day at approximately 8AM and noon, with food, as typically provided by UNM MS Specialty Clinic.

Arms:
arm 1: Corticosteroid pulse of either daily iv methylprednisolone 1000 mg/day or 600mg oral prednisone two times a day at approximately 8AM and noon for 3 to 5 consecutive days and Isoxsuprine Hydrochloride one 10 mg Capsule 3 times daily for 5 consecutive days arm 2: Corticosteroid pulse of either daily iv methylprednisolone 1000 mg/day or 600mg oral prednisone two times a day at approximately 8AM and noon for 3 to 5 consecutive day and placebo one Capsule 3 times daily for 5 consecutive days

Interventions: intervention 1: Isoxsuprine Hydrochloride intervention 2: Placebo intervention 3: Corticosteroid
Intervention descriptions: intervention 1: Compounded Isoxsuprine hydrochloride capsules intervention 2: Identical microcrystalline cellulose placebo manufactured to mimic Isoxsuprine Hydrochloride 10 MG capsules intervention 3: This can be any accepted regimen, including daily iv methylprednisolone 1000 mg/day or 600mg oral prednisone two times a day at approximately 8AM and noon

Protocol document:
ICF_001.pdf: 
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Study D3RN
ICF Version Date: 18 June 2020
HRRC # 18-643
THE UNIVERSITY OF NEW MEXICO HEALTH SCIENCES CENTER 
CONSENT TO PARTICIPATE IN RESEARCH
Study 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
Protocol Number
D3RN Clinical Study Proposal
Principal Investigator (PI)
Clotilde Hainline, MD 
Name of Research Center
University of New Mexico
PI Phone Number
505-272-8905
PI Address
1101 Yale Blvd NE; Albuquerque, NM 87131
Introduction
You are being asked to participate in a research study being done by Clotilde Hainline 
MD, who is the Principal Investigator and associates, from the Department of 
Neurology. 
This consent form describes the research study to help you decide if you want to 
participate. Before agreeing to be in this study, it is important that you read this form, 
and the HIPAA Authorization. 
If you sign this form, it means that you agree to take part in this study. This form 
describes the study and what will happen if you are in the study. It also tells you about 
the risks and benefits of the study.
Please read this form carefully. You will be given ample time to read and review this 
form. You may discuss this study with family and friends. You will have an opportunity to 
ask the study staff about any of your questions or concerns regarding the research 
study. 
If you have a personal or primary care doctor, we suggest that you inform their office of 
your participation in this research study.
This consent form may contain words that you do not know. Please ask the study 
doctor, or the study staff to explain any words, or information that you do not clearly 
understand. 


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CTSC (Clinical & Translational Science Center) at UNM is funding this pilot study. 
When deciding to take part in a research study you should know:

The main goal of medical care is to help you.

The main goal of a research study is to gain information to help patients in the 
future. 

Parts of this study may involve medical care that is routine for you.  This routine 
care, known as standard care, is the treatment normally given for a certain 
condition or illness.

Being in this study does not replace your regular medical care.
This study was approved by The University of New Mexico Human Research Review 
Committee.  
You will be asked to sign and date this form, if you decide to be in this study; you will 
also get a copy of the form to keep, after you have signed. The signed and dated 
original will be given to the Investigator and will remain at the site with your file.
Purpose
The purpose of this study is to examine the safety and tolerability of Isoxsuprine (ISX) in 
combination with high dose oral prednisone in subjects experiencing acute relapses due 
to multiple sclerosis.  Studies of isoxsuprine done at this university in animals show that 
the drug can reduce damage to the brain caused by a stroke. This effect is referred to 
as neuroprotection (protecting the nervous system from injury). Since ISX is a safe, 
approved medication used in people for other reasons, we want to know if it might help 
people with MS who are having a relapse. Before we test the drug for any 
neuroprotective benefits, we need to show that it is tolerable and safe to take during an 
MS relapse that is also being treated with steroids.
Isoxsuprine hydrochloride (ISX), study medication, or study drug in this document is a 
compounded capsule with identical placebo, 10 mg by mouth 3 times per day for 5 
days.
This research study will use ISX and placebo. A placebo is an inactive treatment that 
looks the same as ISX, and is given the same way as ISX. The placebo has no active 
ingredients.  In this Informed Consent Form, the term “study drug” refers to either ISX or 
placebo.
You are being asked to be in this study because you are 18 years old or older; have a 
relapsing form of multiple sclerosis, and are currently having a relapse and willing to 


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take high dose oral prednisone (a corticosteroid).  About twenty people will be invited to 
take part in this study at the University of New Mexico.  
Study Requirements
The study doctor or study staff will review your current list of medications, supplements, 
and your medical history, to decide if there is anything that may prevent you from being 
in this study.
The study doctor, and staff will ensure for instance, that:

You are 18 years old or older

Your blood pressure is stable
You are expected to follow the directions of the study doctor, and the study staff as 
closely as you can. Some of these directions are:

Complete all required visits to the research center

Take the study drug as instructed by the study doctor

Give urine samples if you are a female of child bearing potential

Tell the study staff about all of the medicines you take during the study

Report all side effects and medical problems to the study doctor or the study staff

Not allow anyone else to use your study drugs

Inform the study doctor, or staff if you decide, you no longer wish to participate in 
the study. 
Study Restrictions
You should not participate in this study if you: 

Have a history of hypersensitivity or allergic reaction to any of the study 
drugs, prednisone or isoxsuprine. 

Poorly controlled type 1 or type 2 diabetes mellitus 

Have any known contraindication(s) to taking isoxsuprine hydrochloride 
(ISX), including, but not limited to:
o
any current uncontrolled hypertension, primary adrenal gland 
insufficiency
o
Any current psychoses, infectious disease, or Cushing’s syndrome. 
(Cushing’s syndrome is a diagnosis caused by overproduction of 
corticosteroid hormones by your adrenal gland. If you have this 
condition you will not be able to participate in this study.)
o
Any current congestive heart failure (defined as New York Heart 
Association (Functional Class III to IV).


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o
Peptic ulcer (within 24 weeks prior to the Screening Visit).
o
Recent major surgery

History of myocardial infarction (heart attack)

If female, is pregnant or breast feeding;

Chronic use of corticosteroids except low dose for asthma or related 
illnesses
Study Termination
Your participation in this study can be stopped by the study doctor or the Human 
Research Review Committee (HRRC), without your permission for any of the following 
reasons at any time:

If the study drug or procedures seem harmful to you;

If you do not follow directions for being in the study;

If it is discovered that you do not meet the study requirements;

If the study is canceled;

If you need treatment that is not allowed in the study;

If you become pregnant;

For other reasons that are unknown at this time.
If the study doctor stops you or you decide not to continue being in the study, all study 
data to that point will be reviewed.
What will happen if I decide to participate?
You must sign and date this Informed Consent Form before any tests and exams can 
be performed.
You will first complete a ‘Screening’ evaluation so that your doctor can check that you 
are suitable for the study. After being selected for the study, you will be randomly 
assigned (like flipping a coin) to receive high dose oral prednisone to treat your MS 
relapse plus one of the two following treatments:

Treatment A: Isoxsuprine HCL (ISX)1 Capsule 3 times per day  for 5 consecutive 
days, Or

Treatment B: Placebo 1 Capsule 3 times per day for 5 consecutive days.
You and your doctor will not know which treatment group you are in. You, or study staff 
will administer the first dose of study drug in the clinic under the supervision of study 
staff. You will remain in the clinic for at least 1 hour after taking the study drug so the 
study staff can monitor you for any allergic or anaphylactic reactions; afterwards, you or 
your caregiver will administer all doses at home.


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The study drug is supplied as a 10 mg capsule, to be taken three times daily for five 
days in addition to high dose corticosteroid 600mg twice a day (oral prednisone).  The 
study drug will be supplied to you by the study doctor.
This research study involves a Screening and Randomization visit; Weeks 1, 4, and 12 
(4 visits total). 
Screening Visit (Visit 1)
After signing the Informed Consent Form, you will have tests and procedures done, to 
determine if you are able to continue to take part in this research study.
At the first visit, screening tests and procedures will be done.  The study doctor will ask 
some questions about you, your general health, and your medical history. These tests 
do not guarantee that you will be able to take part in this research study; your 
participation in this study will depend on study guidelines.
The following procedures will be performed at your screening visit:

Review Eligibility Criteria; you must meet all eligibility criteria;

Vital signs (blood pressure taken 3 times, breathing rate, heart rate, and 
temperature), including height and weight;

Physical examination, which includes evaluation of your lungs, heart, abdomen, 
and extremities; 

Complete Memory and Physical Function Tests, and whether or not you are 
having any problems;

Perform 12 Lead Electrocardiogram (ECG) 
An ECG is a measurement of the electrical activity of your heart.

Neurological Exam

Review medications you are currently taking (concomitant medications).
Randomize (Visit 1)
Once screening procedures are completed, and you are found to be eligible to enter the 
study, you will be randomized to either group A or group B and the study doctor will ask 
you to either take oral prednisone (1,200 mg each day), for 3 to 5 days or to continue 
taking the prednisone already prescribed to you by your Neurologist.
The following procedures will be performed:

12-lead electrocardiogram (ECG) post dose;

Urine pregnancy test (if you are a woman who can become pregnant);

Study drug will be given, under the supervision of study staff, and you will be 
asked to remain in the clinic for observation for at least 1-hour thereafter;

Review adverse events (AEs), and concomitant medications.


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You must stay under supervision of the study staff for at least 1-hour after the first dose 
of study drug; you will be given study drug to take home afterwards to be taken three 
times daily for five days.
1 Week Post Treatment Safety Follow-Up Visit (Visit 2) Procedures/Assessments
The following procedures will be performed at this visit:
•
Physical examination;
•
Neurological exam;
•
Physical Function Tests;
•
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;
•
Neurological exam;
•
Complete Memory and Physical Function Tests;
•
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;
•
Neurological exam;
•
Complete Memory and Physical Function Tests;
•
Vital signs;
•
Adverse events and concomitant medications Adverse events and concomitant 
Study Drug Handling
You are only allowed to use ISX which should be kept at room temperature. 
It is your responsibility to:

Keep the study drug in a safe place;

Tell the study doctor, or study coordinator if any study drug is stolen, or lost;

Take study drug only as directed by the study doctor;

Stop anyone else from using the study drug meant for you.
How long will I be in this study?


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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 week 1 (7 days after completion of ISX dosing), week 4 and week 
12.
What are the risks or side effects of being in this study?
Risks are possible including side effects of study treatment and from tests done during 
the study. All medications can have side effects (adverse events) and there are always 
potential risks, discomfort and inconvenience associated with participation in a research 
study. This is why the physical examinations and other tests that you will undergo 
during this study are important.  If there are unwanted effects related to the study 
medication, they will be detected as early as possible and your Study Doctor can take 
steps to prevent you from harm.
You must tell the study doctor, or study staff about any side-effects you experience. If 
you do not tell the study doctor and study staff about the side effects, you may harm 
yourself by being in this study. Do not stop taking the study medication without first 
talking to your study doctor, even if you are experiencing side effects.
Taking a placebo may be similar to not taking any medication. Whether you are taking a 
placebo or taking ISX, your symptoms may stay the same or get worse. You will be 
allowed to continue taking your current treatment while you are participating in this 
study. The Prednisone tablets you will take are a standard high steroid dose commonly 
given to help speed recovery of your MS relapse symptoms as standard of care. 
Other possible side effects 
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


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
Nausea or vomiting (more common for injection)
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.
You should call the numbers provided or get medical help, if you have any of these or 
any other side effects during the study.
Reproductive Risks
Females 
Study drug taken during pregnancy may cause you to lose your unborn baby. 
Additionally, it is not known if the study drug can be in the mother’s breast milk.  
Therefore, you cannot be in this research study if:

You are pregnant ;

You are planning to become pregnant during the next couple of months;

You are breastfeeding. 
If you agree to be in this research study, and are able to get pregnant, you must take 
some steps to keep yourself from getting pregnant during the entire study.
You should use at least one method of birth control like the examples below:

Hormonal measures (birth control pills, contraceptive patch, contraceptive ring, 
injections);

Intrauterine device (IUD);
Double barrier method (condom plus diaphragm, condom or diaphragm plus 
spermicidal gel or foam);

Abstinence.


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If you have any questions about birth control, please ask the study doctor or study staff.
If you suffer any of these side effects (or any others not listed) or you think you are 
experiencing a side effect, during this study, please tell your study doctor immediately.
For your own safety, you must tell the study doctor the truth about your past and 
present health. You should also tell the study doctor about:
•
Disease and medical conditions;
•
Mental health conditions;
•
Allergies;
•
Medicines used during the study, including medicines you use that do not require 
a prescription (examples: Vitamins, aspirins, and herbal medicines).
If you are not truthful about your past or current health, you may be harmed by 
being in this study.
Unknown Risks
In addition to the risks of the study that are listed above, there may be other risks that 
are unknown and can’t be predicted. These risks may include allergic reactions or other 
side effects caused by mixing the study medication with other medicines or 
supplements you may be taking. 
If you have any concerns, you should tell the study doctor or study staff right away. 
Your safety will be closely monitored throughout the study.
What are the benefits to being in this study?
You may or may not benefit from participating in this study. ISX will not cure your 
multiple sclerosis but if you receive it in this study, it may lessen your MS symptoms and 
help you recover sooner or more completely from the relapse.  However, taking part in 
this clinical study might not benefit you in any way and the study drug may not help you. 
Your taking part may give more scientific information about ISX and its possible role in 
relapsing forms of multiple sclerosis. This information may help others in the future. You 
will have a 50:50 chance (like the flip of a coin) of receiving isoxsuprine or placebo. A 
computer will randomly assign you to receive either ISX or placebo and neither you nor 
the study staff or investigator will know what you have been given until the study is over.
What other choices do I have if I do not want to be in this study?
Corticosteroids like Prednisone are not considered effective long term treatments for 
MS but other treatments for MS are available. You may be on one of these now or might 
decide to start one after you complete this study. These treatments have been shown to 
be effective in reducing the number of relapses suffered by patients, in some cases 


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prolonging the time before a worsening in disability occurs. Relapses of MS do not have 
to be treated with Corticosteroids like Prednisone and recovery can occur naturally. 
However, it has been shown that the use of Corticosteroids can shorten the time to 
recovery or improvement. You may choose to receive the standard Prednisone dose 
alone without enrolling in the study. In this case the study doctor will write a prescription 
for you to take to your pharmacy.
The study doctor will be happy to discuss MS treatment options with you to help you 
determine if they are appropriate.  At the end of the study, you and your study doctor 
will discuss your future care options including any additional care you may need that is 
beyond what you would normally receive for your MS.
Being in this study is voluntary. This means you can decide if you do or do not want to 
be in the study. There will not be any penalty or loss of benefits or standard of care 
treatment to you if you decide not to take part or if you leave the study early. If you 
decide to be in this research study, you can stop participation at any time, as there is no 
penalty or loss of benefits for doing so.  If you want to withdraw from this study, please 
inform the study doctor. If you decide to leave the study early, there may be risks with 
this decision.  You should discuss these risks with your study doctor.  You may be 
asked to return to the clinic for tests.
How will my information be kept confidential?
We will take measures to protect your privacy and the security of all your personal 
information, but we cannot guarantee confidentiality of all study data. 
Your records will be identified by the study subject number (according to local law). 
Your name will not be used in any study reports, and these reports will be used for 
research purposes only.  UNM and its designee(s), the Human Research Review 
Committee (HRRC)and various government health agencies (such as the FDA) may 
inspect and/or copy your records of this study Information about your disease status 
and may be requested and reviewed on a regular basis after you have completed all 
visits in this study.  A copy of this consent form will be kept in your medical record.
Every effort will be made to keep your personal medical information confidential.  We 
cannot guarantee absolute confidentiality.  Your personal information may be disclosed, 
if required by law.  In addition, results from this study may be published.  In such a case, 
your identity will still be confidential, but the results of the study will be more widely 
distributed.
By signing this consent form, you are giving permission for this, as well as for 
processing and transferring your coded personal information relevant to this trial. You 
are also giving permission for processing of your coded personal information in a 
database. 


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You may use your rights under the local data protection law to access and correct your 
personal information or ask for it to be deleted. You can object to any further processing 
of your information by applying to the study doctor.
The study doctor may tell your family doctor about your taking part in the study and ask 
them for medical information about you
There is a risk of loss of confidentiality in research studies. Every effort will be made to 
protect you and your health information to the extent possible.
A description of this study clinical trial will be available on http://www.ClinicalTrials.gov
as required by U.S. Law. This Web site will not include information that can identify you. 
At most, the Web site will include a summary of results. You can search this website at 
any time.
What are the costs of taking part in this study?
This study will supply the study drug needed for treating your relapse while you 
participate, at no cost to you.  Many of the study tests (urine tests and ECG) and the 
steroid treatments are part of the standard evaluation and care for the treatment of your 
disease. UNM CTSC will pay for all study-required procedures that are above and 
beyond standard of care.  This includes the costs of study related tests that are not 
covered by your health insurance company.  Your health insurance company will be 
billed for the costs of these tests that are not covered by the study. The costs of those 
tests will be paid in the same way as if you were not part of this study. 
Will I be paid for taking part in this study?
You will not be compensated for your participation this study.
What will happen if I am injured or become sick because I took part in this study?
It is important that you follow carefully all the instructions given by the Study Doctor and 
his/her staff regarding this study.
If you become ill or are physically injured as a result of participation in this study, please 
contact the Study Doctor right away: Clotilde Hainline MD,  at (505) 272-3160, (505) 
272-0356 or (505) 272-2111; she will treat you or refer you for treatment.
If you are injured or become sick as a result of this study, the UNM HSC will provide you 
with emergency treatment.
If the study was done correctly and you were hurt by the study drug, UNMHSC will pay 
for all reasonable medical bills that your insurance company does not pay. UNMHSC 


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will only pay these bills if you received reasonable medical care. These are the only bills 
that UNMHSC will voluntarily pay.
UNMHSC will not pay your medical bills if:

you did not follow instructions,

your disease or the standard treatment of your disease caused your harm.
Contact the study staff if you think that being a subject in this study has caused you to 
be harmed. The study staff will tell you how you can get medical care for your problem.
You or your insurance company will be charged for continuing medical care and/or 
hospitalization required for any such injury or illness not related to the research study.
By signing this consent form, you will not give up any legal rights.
Study Contacts
You can call Dr. Clotilde Hainline at (505) 272-3160 or the research coordinator at (505) 
272-8905 from 8:00 AM to 4:30 PM Monday through Friday, if you feel that you are 
developing any undesirable or unwanted effect (adverse event), if you believe you have 
been injured as a result of receiving study drug, or if you have any questions about this 
study.  We will give you a card to carry with contact information and numbers in case of 
an emergency.
If you need to contact someone after business hours or on weekends, please call (505) 
272-2111 and ask for Dr. Clotilde Hainline or the faculty Neurologist on call.
If you have any questions about your rights as a research subject, questions about 
participation in the study, or complaints about the study, you may contact someone 
independent from the study at UNMHSC HRRC at (505) 272-1129. 
Whom can I call with questions or complaints about this study? 
If you have any questions, concerns or complaints at any time about the research study, 
Clotilde Hainline MD, or her associates will be glad to answer them at (505) 272-3160 
If you need to contact someone after business hours or on weekends, please call (505) 
272-2111 and ask for Dr. Hainline or the faculty Neurologist on call. 
If you would like to speak with someone other than the research team, you may call the 
UNMHSC HRRC at (505) 272-1129. 
Whom can I call with questions about my rights as a research subject?


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If you have questions regarding your rights as a research subject, you may call the 
UNMHSC HRRC at (505) 272-1129. The HRRC is a group of people from UNM and the 
community who provide independent oversight of safety and ethical issues related to 
research involving human subjects. For more information, you may also access the 
HRRC website at http://hsc.unm.edu/som/research/hrrc/.
Statement of Consent 
I have read the information in this consent form. I have had a chance to ask questions 
and my questions have been answered to my satisfaction. I voluntarily agree to be in 
this study until I decide otherwise. I do not give up any of my legal rights by signing this 
consent form. I will receive a copy of this signed document. 
Printed Name of Subject 
Signature of Subject 
Date
By signing below, I also authorize Dr. Clotilde Hainline or designee to contact me after 
the study ends to request additional information or to participate in additional studies 
that might be developed from the results of this study.
Printed Name of Subject 
Signature of Subject 
Date
Investigator/Designee: 
I have fully and carefully explained the study to the person named above in 
language he/she understands and confirm that, to the best of my knowledge, 
they clearly understand the nature, risks and benefits of taking part in this study.
I confirm that I gave them a chance to ask questions about the study and that I 
answered all the questions they asked correctly and to the best of my ability.
I confirm that they have not been forced into giving consent and that they have 
given their consent freely and voluntarily.
I confirm they have been given a copy of this information sheet and consent form.


Page 14 of 14
Study D3RN
ICF Version Date: 18 June 2020
HRRC # 18-643
Printed Name of Person Obtaining Consent:
Signature of Person Obtaining Consent:
Date

Prot_000.pdf: 
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
Page 2 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
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
Page 3 of 19
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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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.


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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
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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.


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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.


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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. 


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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 


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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