A Pilot Study Testing Benefits of Ursolic Acid (UA) as a Countermeasure To Myopenia and Insulin Resistance in Chronic Spinal Cord Injury (SCI)
Phase: PHASE2
Conditions: Spinal Cord Injuries, Tetraplegia, Paraplegia, Muscle Loss, Atrophy, Muscular, Insulin Resistance
Sponsor: University of Miami

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Protocol version 2.1 – Revised 05/01/2025
A Pilot Study Testing Benefits of Ursolic Acid (UA) as a 
Countermeasure To Myopenia and Insulin Resistance 
in Chronic SCI
Sponsor: 
W. Dalton Dietrich, Ph.D
ddietrich@med.miami.edu 
Office: (305) 243-2297
Fax: 305-243-3207
Principal Investigator: 
Mark S. Nash, Ph.D FACSM FASIA
mnash@med.miami.edu
Office: (305) 243-3628
Mobile: (954) 854-1950
Fax: 305 243-3215
Study Physician:
Alberto Martinez-Arizala, M.D., FAAN 
amartine@med.miami.edu 
Office: (305) 243-6732
Fax: 305-243-4678
Sub-Investigators:
Gregory Bigford, Ph.D
gbigford@med.miami.edu
Office: (305) 243-7122
Gary Farkas, Ph.D
gjf50@med.miami.edu
Office: (305) 243-4518
NCT Number:
 NCT05776862
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Protocol version 2.1 – Revised 05/01/2025
Table of Contents
1.
Protocol Signature Page...............................................................................................3
PRINCIPAL INVESTIGATOR SIGNATURE...................................................................3
2.
Protocol Title ...............................................................................................................4
3.
Objectives ....................................................................................................................4
Aim 1 ...........................................................................................................................4
Aim 2 ...........................................................................................................................4
4.
Study Endpoints...........................................................................................................4
5.
Background..................................................................................................................4
6.
Inclusion and Exclusion Criteria .................................................................................7
Inclusion Criteria .........................................................................................................7
Exclusion Criteria ........................................................................................................7
7.
Study Recruitment Methods ........................................................................................7
8.
Study Timelines...........................................................................................................7
9.
Product and Procedures ...............................................................................................8
10. Data and Specimen Banking......................................................................................14
11. Data Management......................................................................................................14
12. Confidentiality and Subject’s Data Safety.................................................................14
13. Provisions to Monitor the Data to Ensure the Safety of Subjects..............................15
14. Setting........................................................................................................................19
15. Resources Available ..................................................................................................19
16. Compensation for Research-Related Injury...............................................................19
17. Economic Burden to Subjects....................................................................................20
18. Consent Process.........................................................................................................20
19. REFERENCES: .........................................................................................................22
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1. Protocol Signature Page
PRINCIPAL INVESTIGATOR SIGNATURE
I have read this protocol and agree that it contains all necessary details for carrying out the 
study as described.  I will conduct this protocol as outlined herein, including all statements 
regarding confidentiality.  I will make a reasonable effort to complete the study within the 
time designated.  I will provide copies of the protocol and access to all information 
furnished by the Sponsor to study personnel under my supervision.  I will discuss this 
material with them to ensure that they are fully informed about the Investigational Product 
and the study.  I understand that the study may be terminated or enrollment suspended at 
any time by the Sponsor, with or without cause, or by me if it becomes necessary to protect 
the interests of the study patients.  Any supplemental information that may be added to this 
document is also confidential and proprietary to Sponsor and must be kept in confidence 
in the same manner as the contents of this protocol.
I agree to conduct this study in full accordance with all applicable regulations and Good 
Clinical Practice (GCP).
_____________________________                     _____________________________
Principal Investigator’s Signature                           Date of Signature (DD/MM/YYYY)
Mark S. Nash, Ph.D. FACSM, FASIA
Principal Investigator’s Name (Print) 
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Protocol version 2.1 – Revised 05/01/2025
2. Protocol Title  
A Pilot Study Testing Benefits of Ursolic Acid (UA) as a Countermeasure To 
Myopenia and Insulin Resistance in Chronic SCI 
3. Objectives
To address the need for an agent that maintains muscle mass and attenuates IR 
after SCI, we propose a ‘first-in-humans with SCI’ pilot trial that tests benefits of 
UA as a countermeasure to sarcopenia and IR. 
Aim 1 
•
To explore effects of UA administration on upper extremity lean mass and peak 
strength in persons with paraplegia.
Aim 2 
•
To test effects of UA administration in sedentary individuals with tetraplegia on 
whole body resting insulin sensitivity, glucose/insulin/inflammatory responses to 
an oral glucose challenge (OGTT), and whole-body lean mass.
4. Study Endpoints
Primary Outcome Measure(s):
1. Change in Muscle Mass Using Dual X-ray Absorptiometry (DXA) 
a.
Time Frame: Baseline, 12 weeks
2. Change in Peak Isokinetic Strength 
a.
Time Frame: Baseline, 12 weeks
3. Changes in Fasting Insulin Resistance (IR) 
a.
Time Frame: Baseline, 12 weeks
4. Changes in Glucose Disposal 
a.
Time Frame: Baseline, 12 weeks
5. Background
The multi-year COVID-19 pandemic has resulted in a decline of overall physical 
activity, life-satisfaction, and health within the spinal cord injured (SCI) 
community.1 During the pandemic, people with SCI have experienced health 
decay to a far greater extent than the general population, primarily due to 
profound social distancing, fears of social engagement and infection, and 
restrictions in exercise engagement.2 Even without social isolation and exercise 
restrictions, trauma to the spinal cord is typically associated with physical and 
metabolic disorders that have wide-ranging effects on almost all body systems.3 
Our works,4 and the works of other investigators5 have reported a level-of-injury 
dependent myopenia – i.e., clinically relevant muscle wasting – which is 
commonly observed following spinal cord injury (SCI), and ultimately 
compromises post-SCI function, metabolism, body composition, and health.  
Adjustments to body composition that accompany SCI-related myopenia include 
a decline of metabolically active muscle mass accompanying the loss of actively 
contracting muscle, which reduces whole body caloric expenditure and establishes 
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Protocol version 2.1 – Revised 05/01/2025
an environment in which substantial gains in whole body fat mass are reported 
within one year of SCI. Other myopenia-related co-morbid pathologies contribute 
to cardioendocrine disease clusters, that include insulin resistance (IR).4 This 
project addresses an overarching need for the community of spinal cord injured 
(SCI) individuals to maintain health and function throughout their lifespans. Left 
unresolved we can expect earlier functional decline and cardioendocrine 
morbidity in the SCI population. These risks also project onto the caregivers of 
those with SCI, who are also “living with an SCI” in the contemporary medical 
environment and are also struggling to recover from the COVID-19 pandemic.
Post-SCI Myopenia
Pathological changes in skeletal muscle have been extensively characterized in 
humans with SCI.5 Rapid loss of sublesional muscle mass is explained by a 48% 
reduction of cross-sectional muscle area occurring as early as 6-weeks following 
injury. Atrophy ranging from 30-60% of total body lean mass has also been 
reported, the extent of loss depending on the muscle-specific phenotype and both 
duration and severity of impairment. (Figure 1.) This muscle atrophy is 
accompanied by an adaptive fiber-type transformation from a slow-oxidative 
(Type I) to fast-glycolytic (Type II) myosin heavy-chain phenotype, with both 
Type I and II fiber atrophy contributing to overall muscular wasting. This shift in 
muscle phenotype also has known linkage with insulin resistance and progression 
of cardioendocrine medical complications.  Unfortunately, the maintenance or 
restoration of muscle mass and myosin phenotype following SCI has yet to be 
achieved by voluntary exercise or electrically-stimulated contractions of muscles 
located below the lesion level. Attempts to do so have also been dealt a significant 
blow by the multi-year COVID-19 pandemic, which has resulted in widespread 
social isolation for many people with SCI and exercise outreach programs. 
Outreach exercise programs using the Zoom platform have rushed in to fill this 
gap in needed physical activity.  However, the unintended yet widely reported 
consequences of COVID estrangement have challenged the ability of persons with 
SCI to preserve levels of fitness needed to sustain essential daily functions, and 
also offset their prevalent cardiometabolic disease (CMD) risks. These health 
risks are accompanied by ongoing delays in post-pandemic social reintegration, as 
fears of respiratory infection still pervade the SCI community, and in all 
expectation, will do so well into the future.
Cardiometabolic Pathology and Insulin Resistance
The loss of muscle mass after SCI has been associated with hastened trajectories 
pf all-cause cardiovascular diseases (CVD), which have emerged within the past 
decade as significant sources of morbidity and mortality for persons with spinal 
cord injuries (SCI).6 These trends forecast patterns of illness and death after SCI 
that increasingly resemble those of the non-disabled general population. Among 
these CVD risks is the increased hazard for cardiometabolic diseases (CMD), a 
clustering of interrelated prothrombotic and proinflammatory factors that confers 
health risks that are equivalent to either coronary artery disease or diabetes. 
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Protocol version 2.1 – Revised 05/01/2025
Notably, these risk equivalents may be experienced without actually having 
coronary disease or a clinical diagnosis of diabetes, making their occurrence an 
insidious health threat in need of focused early management.7
Ursolic Acid as a Countermeasure to Post-SCI Myopenia and Insulin Resistance 
Ursolic Acid – naturally occurring triterpene compound – is an herbal-like isolate 
obtained from the leaves of various plants (rosemary, marjoram, lavender, thyme, 
and organum), fruits (apple fruit peel), and berries. UA modulates several 
signaling pathways associated with the development of chronic diseases. Among 
confirmed benefits of UA administration are anti-inflammatory, anti-oxidant, anti-
obesity, anti-diabetic, cardioprotective, anti-skeletal muscle atrophy, and 
thermogenic effects. The mechanisms by which UA exerts these beneficial effects 
may involve regulation of insulin signaling in adipose tissue, as well as atrophy 
and metabolic signaling in skeletal muscles through the mTOR signaling 
pathway.8
Recent evidence suggests that the UA has beneficial effects on insulin resistance 
(IR) and related CMD health risks in persons without SCI, and also slows muscle 
wasting in instances of musculoskeletal disuse.8 Given that 60 percent of the SCI 
population has a metabolic profile with IR, and that obligatory sarcopenia occurs 
within the first year following SCI, UA may represent a novel countermeasure to 
health risks associated with COVID-related social isolation. 
Preclinical testing of UA following SCI 
Potential benefits of UA for persons with SCI are supported by our pre-clinical 
work in which UA but not a control compound, maintained muscle mass and 
muscle function in mice that had undergone experimental spinal cord contusion 
injuries.
In a pre-clinical study,9 we investigated UA as an agent affecting anabolic, 
metabolically-linked signaling pathways in muscle, and explored phenotypic 
outcomes in sublesional muscle following traumatic SCI. Our primary objectives 
were to examine following experimental SCI i. intracellular mTOR signaling, ii. 
The expression of related catabolic genes, and iii. The effects on these outcomes 
with UA treatment. We hypothesize that SCI would i. reduce growth pathways via 
mTOR signaling, ii. Increase the expression of catabolic genes, and iii. UA will 
attenuate these SCI-induced changes. In addition, we examined the effect of SCI 
on physical and functional measures, and whether UA-promoted signaling in 
muscle translated to improvements in these outcome measures. When examining 
effects of UA treatment on sublesional muscle mTOR signaling, catabolic genes, 
and functional deficits following severe SCI in mice we observed  that UA 
treatment significantly attenuated SCI-induced decreases in activated forms of 
mTOR, and signaling intermediates PI3K, AKT, and S6K, and the upregulation of 
catabolic genes including FOXO1, MAFbx, MURF-1, and PSMD11. In addition, 
UA treatment improved SCI-induced deficits in body and sublesional muscle 
mass, as well as functional outcomes related to muscle function, motor 
coordination, and strength. 
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These findings provided first evidence that UA treatment may be a potential 
therapeutic strategy to improve muscle specific pathological consequences of SCI.
6. Inclusion and Exclusion Criteria
Inclusion Criteria
•
18-65 years of age
•
Aim 1: Male and female individuals with paraplegia having chronic (≥ 1 
year) complete and incomplete (AIS A/B/C) injuries from T2-T8
•
Aim 2: Male and female individuals wi4.th chronic (≥ 1 year) complete 
and incomplete (AIS A/B/C) injuries from C4-C7 
Exclusion Criteria
•
Pregnant or planning to become pregnant
•
Women who are breastfeeding
Number of Subjects
•
Aim 1 will enroll up to 10 participants
•
Aim 2 will enroll up to 10 participants
7. Study Recruitment Methods
Recruitment will include IRB-approved flyers posted throughout the Christine E. 
Lynn Rehabilitation Center for the Miami Project to Cure Paralysis; social media; 
word-of-mouth at the Christine E. Lynn Rehabilitation Center for the Miami 
Project to Cure Paralysis; online advertisement using IRB-approved language 
from flyers, telephone or email contact for those individuals who have previously 
consented for contact in other studies. 
In addition, we will utilize the Miami Project to Cure Paralysis research registry 
of >3000 individuals with SCI who have expressed an interest in participating in 
research studies. The registry currently is composed mainly of individuals with 
traumatic SCI (89%) who are ≥18 years old. It includes men and women of 
different ages with SCI that differs by level, severity, duration, and cause. These 
individuals have completed and submitted a form that outlines their medical 
history. Their level of SCI and degree of completeness has also been evaluated. 
This registry often provides adequate subject enrollment for studies without the 
inherent expense and difficulty of coordinating recruitment at multiple sites.
8. Study Timelines
Participants that are eligible for Aim 1 will come to the research site (Miami 
Project) a total of up to 38 visits: 
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•
One day for consenting and screening assessments; Screening assessments 
may be completed on 2 separate visits to accommodate scheduling 
conflicts. This will add an additional day to the total visits
•
3 times a week for 12 weeks for exercise intervention; 
•
one day for post-study assessments.  
During this time, they will:
•
Take an oral 400mg (8 capsules – 4 in the morning/200mg and 4 at 
night/200mg) supplement of UA every day for 12 weeks.  
•
Drug accountability will occur every month and study staff will dispense 2 
bottle every month and collect all used or empty bottles
•
Pregnancy tests will occur monthly for females of child-bearing potential
•
Take part in an exercise program where you will perform strength-training 
exercises on one arm, 3 times a week, for 12 weeks. 
•
Complete pre and post intervention assessments (see section 8)
Participants that are eligible for Aim 2 will come to the research site (Miami 
Project) up to 4 visits: 
•
One day for consenting and screening assessments.  On this visit they will 
receive the first 2 bottles of the UA.  
•
2 monthly visits for drug accountability where study staff will dispense 2 
bottles every month and collect used or empty bottles; monthly pregnancy 
tests for females of child-bearing potential
•
One day for post study assessments
During this time, they will:
•
Take an oral 400mg (8 capsules – 4 in the morning/200mg and 4 at 
night/200mg) supplement of UA every day for 12 weeks
•
Complete pre and post intervention assessments (see section 8)
9. Product and Procedures
Ursolic Acid (UA)
UA will be sourced as Biotech Nutritions Ursolic Acid Gelatin Free Non-GMO 
capsules (i.e. form) ; 200mg (4 total capsules, 50mg each) taken twice daily by 
mouth with food and a non-alcohol-containing drink. UA is a non-Rx 
nutraceutical obtained without prescription. We will neither claim an FDA 
‘brand’ for the product, nor propose a new or extended indication for its use.
Manufacturer: Biotech Nutritions 
24875 Novi Road 865 
Novi MI 48376
Ph: 888 662 7001
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Protocol version 2.1 – Revised 05/01/2025
•
Aim 1: will couple UA administration at doses that increase muscle mass 
with strengthening exercise performed in one arm only. 
o
Subjects will receive 2 bottles of oral UA every month.  Subjects 
will be asked to take 400 mg or 8 capsules (4 in the 
morning/200mg and 4 at night/ 200mg) daily for 12-weeks 
o
Adherence to the UA intervention will be done once a month by 
study staff and will entail: 
▪
collection of used bottle(s)
▪
counting remaining capsules, if any
▪
calculation of compliance: [(days x 8) – capsules remaining
▪
and dispensing a new bottle(s).  
**Education regarding the importance of compliance to the dosing requirements will be 
part of the monthly drug accountability.  
*** Research Studies Subjects will be offered participation in other PM&R and Miami 
Project to Cure Paralysis studies for which they may be eligible. The possibility of dual 
enrollment or partial overlap of participation in more than one study is conceivable. This 
could result in duplication of required assessments subjects would need to complete. 
However, to simplify participation, reduce the number of visits to our research lab, and 
mitigate testing redundancy, we may apply test results completed for one study to another 
in those cases.
•
During this period, one upper limb (only), randomized by selection, will 
undergo exercise conditioning three times weekly using a strengthening 
program we have established to increase muscle mass and strength in 
people with SCI. The other arm will remain untrained as a control 
receiving the same whole body dose of UA. 
•
Lean mass will be examined before and after 12 weeks of treatment using 
dual-ray absorptiometry (DXA) and non-contrast CT scan of both arms, 
with the area of interest identified from the glenohumeral joint distally to 
the ulnar styloid. 
•
Peak isokinetic strength of both arms at 90 degrees of flexion will be 
tested in elbow flexion and extension on a Biodex dynamometer. 
•
Maximal inspiratory pressure will be measured with the Pro2 Fit device.
The co-primary outcomes will be lean mass and peak strength.
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•
Aim 2 subjects will: 
o
Subjects will receive 2 bottles of oral UA every month
o
Subjects will be asked to take 400 mg or 8 capsules (4 in the 
morning/200mg and 4 at night/ 200mg) daily for 12-weeks.
▪
Adherence to the UA intervention will be done once a 
month by study staff and will entail: 
•
collection of used bottle
•
counting remaining capsules, if any
•
calculation of compliance: [(days x 8) – capsules 
remaining]
•
and dispensing a new bottles.  
**Education regarding the importance of compliance to the dosing requirements will be 
part of the monthly drug accountability. 
 
*** Research Studies Subjects will be offered participation in other PM&R and Miami 
Project to Cure Paralysis studies for which they may be eligible. The possibility of dual 
enrollment or partial overlap of participation in more than one study is conceivable. This 
could result in duplication of required assessments subjects would need to complete. 
However, to simplify participation, reduce the number of visits to our research lab, and 
mitigate testing redundancy, we may apply test results completed for one study to another 
in those cases.
•
Whole body lean mass will be determined by DXA and CT scan before 
and after 12 weeks of treatment. 
•
Before and after the 12-week UA intervention an oral glucose tolerance 
test (OGTT: 75 g glucose as TrutolTM) will be administrated following an 
overnight fast. 
o
Bloods taken before glucose ingestion will be analyzed for 
glucose, insulin, and inflammatory biomarkers (TNF-alpha, IL-6, 
and CRP). 
o
Bloods will also be taken at 30-minute intervals for two hours. 
•
Maximal inspiratory pressure will be measured with the Pro2 Fit device.
Co-primary outcomes will be the fasting IR determined by the HOMA v2 model and 
the rates of glucose disposal defined by the area under the glucose challenge curve 
(AUC).
Dual X-ray Absorptiometry (DXA)*
The regional composition for Fat Free Mass (FFM), Fat Mass (FM), % FM, and 
Lean Mass (LM), in regions of interest including the trunk, arms, android, and 
gynoid regions will be measured by DXA as described by Gorgey et al., Spinal 
Cord 2018. Body composition will be measured by whole body scans using a GE 
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Protocol version 2.1 – Revised 05/01/2025
Lunar Prodigy Advance scanner (GE Lunar Inc., Madison, WI,USA). Transfer to 
the DXA scanner will be performed using either a ceiling lift or assisted self-
transfer with or without sliding board. Participants will be instructed to take off 
any metal, void their bladder, and dress in light clothes prior to transfer to the 
DXA table. Using the NHANES scanning method, both knees will be bound 
together using a large Velcro strap. Above the knee joints and each leg is placed 
in neutral position with the great toe facing upwards. Because of the difficulty in 
keeping the arms close to the body in large individuals or in cervical SCI, arms 
will be strapped near the body in the mid-prone position to ensure the total body 
is within the scanning field. The standard mode scan will be used with a radiation 
dose of 0.4 µGy. Scans are performed and analyzed by a certified DXA operator 
using current Lunar software. As part of quality assurance, the DXA scanner will 
be calibrated using a quality control phantom (L: 197.7, W: 60.1) according to the 
manufacturer guidelines for both short-term and long-term precision studies.
Non-contrast CT images (Structure)*
Computed tomography (CT) is a radiographic method that produces thin cross-
sectional high-resolution images that may better differentiate and measure 
volumes of fat and lean tissue when compared to DXA. For this pilot study, chest, 
abdominal and upper extremity/arm scans will be performed at UM/Sylvester 
Department of Radiology; these will be obtained pre- and post-intervention using 
a 128-slice multi-dimensional whole-body scanner before and after the 
intervention. Before the scan, subjects will have their upper extremities ranged. 
Images for upper extremities will be attained from the glenohumeral joint to the 
hand. All images will be analyzed at a separate workstation using TeraRecon 
iNtuition imaging software. 
Images are automatically segmented into adipose tissue, skeletal muscle, and 
bone/background based on location and their attenuation properties, with adipose 
having the lowest attenuation and bone/background having the highest attenuation. 
A CT attenuation range of -120 to -40 Hounsfield units (HU) will be used to 
encompass abdominopelvic adipose tissue, -190 to -30 HU will be used for intra 
muscular fat (IMF), and -29 to +150 HU will be used for skeletal muscle (needed 
for  IMF quantification). Cross-sectional area (CSA; cm2) will be automatically 
calculated by the software by summing the pixels of the tissue and multiplying it 
by the pixel surface area for each adipose tissue depot, while volume (cm3) 
computed by multiplying the CSA by the image slice thickness and inter-slice 
space. Visual distinction will be used to determine visceral adipose tissue (VAT), 
subcutaneous adipose tissue (SAT), muscle and bone based on the anatomical 
locations of the tissues and CSA and volumes will be summed together from 
consecutive slices. Total VAT mass and total SAT mass (in grams) will be the 
product of the total volume and fat density (0.9196 g/cm3). To account for muscle 
size, IMF CSA will be normalized to muscle CSA. The volume of IMF will be 
calculated as described above. All CT scans will be reviewed by a Radiologist.  
Subjects will be informed of any incidental abnormalities detected in the CT scans 
performed for this study and they will be referred to an appropriate provider. In 
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Protocol version 2.1 – Revised 05/01/2025
order to do a single scan of the upper limbs and abdominopelvic cavity, the chest 
will be included in the scan. It will also be reviewed for incidental findings. 
*Total effective dose of radiation for DXA and CT scans (total pre and post) is 
expected to be around 22 mSv (millisievert) or around 7 years worth of 
background radiation. 
Blood Analyte Testing
Subjects refraining from alcohol and caffeine ingestion starting 24 hours before 
testing will be studied in the postabsorptive state after a 10-hour overnight fast. 
Under antiseptic conditions, a 21-gauge Teflon catheter (Jelco) with multi-sample 
Luer connector will be inserted in a superficial arm vein by a State of Florida 
Certified Phlebotomist. The catheter is kept patent with sterile physiological 
(0.9%) saline. Blood samples obtained at rest and during the OGTT (taken at 30-
minute intervals for two hours) will be collected in NaF (glycolysis), clot lysis 
activator (serum), and citrated Vacutainer tubes, and then centrifuged at 8,000g 
for 30 minutes to isolate the serum. These isolates will be tested on a Roche Mira-
Cobas Automated Chemistry Analyzer (Roche Diagnostic Systems, Basel, 
Switzerland), as we have described.
Oral Glucose Tolerance Test (OGTT)
Baseline blood sample will be drawn (see to blood analyte for procedure details) 
after an overnight fast. Subjects will them be given Trutol glucose solution that 
contains seventy five (75) grams of glucose, similar in taste to a very sweet soda 
(usually orange flavor). Subjects will be instructed to complete ingestion within 
five (5) minutes. 
After drinking the Trutol, blood will be drawn at exactly 30 minute intervals for 
two hours. Blood collection process is detailed in the Blood Analyte Testing 
section.
Subjects must refrain from eating/drinking anything other than water for the 
duration of the test, approximately 2.5 hours.
Insulin Resistance
Insulin resistance will be computed using the Homeostatic Model of Mathews 
(HOMA; computer version v.2: 
[https://www.dtu.ox.ac.uk/homacalculator/download.php]) Criterion scores for 
normal, glucose intolerant, and insulin resistant were published by Nash, et al., 
Arch Phys Med Rehabil, 2016.
Strength 
Peak isokinetic forces generated during elbow flexion and elbow extension will 
be tested on a BiodexR dynamometer. Peak and average isokinetic forces will be 
tested through full range of flexion and extension.
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Protocol version 2.1 – Revised 05/01/2025
Maximal inspiratory pressure (MIP) is a surrogate measure of the strength of 
inspiratory muscles, primarily the diaphragm. Using the PRO2Fit device, each 
participant will be asked to perform up to 6 MIP maneuvers, with a goal of 
matching the highest two according to device or ATS guidelines. The participant 
will be seated for the test and will be instructed to exhale slowly and completely, 
seal lips firmly around the new mouthpiece, and then “pull in hard, like you are 
trying to suck up a thick milkshake.” Participants will rest for about one minute 
and then repeat the maneuvers. 
The PrO2 is a mobile connected device that measures inspiratory muscle 
performance and capacity.  The device has a removable mouthpiece that will be 
thoroughly hand washed (with soap and water) after each participant visit. In 
addition, we will use a single-use bacterial/viral filter (BVF) to provide additional 
protection for participants. Vitalograph’s BVFs provide an efficient hygiene 
solution giving better than 99.99% cross-contamination efficiency. The outer 
housing will be cleaned with alcohol or sani-wipes after each visit.
Pregnancy 
Urine pregnancy tests will be performed on all female subjects of childbearing 
potential.  The first test will be done at the first visit after the consent is signed 
and then every month for the duration of the study.
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Protocol version 2.1 – Revised 05/01/2025
10.
Data and Specimen Banking
•
Specimens – General – Whole blood will be assayed by the site laboratory 
(Diabetes Research Institute Biomarker and Immunoassay Laboratory and 
will be disposed of once analyzed. No residual samples will be banked. 
•
Electronic Data – All electronic files will be stored on password-protected 
computers at each center. Computer security is provided by data 
encryption, firewall protection, and backup on the Medical/Academic 
Center Servers. Only the PI and appropriately indicated study staff will 
have access to the data. 
•
 Data for the trial will be managed using a secure data repository system 
database (box or redcap), and through paper and pencil. Regulatory trial 
management may use the Complion INC e-regulatory system platform. All 
data collected will be entered into a secured data collection system.  All 
participating centers in this multi-site project will have access to the coded 
deidentified data collected as a part of the study.
11.
Data Management
Randomization 
•
For Aim 1, the dominant or non-dominant arm assigned to resistance 
exercise (versus non-exercise) will be randomized in equal numbers using 
the ‘RAND’ function in Microsoft Excel. 
•
No randomization is required for Aim 2.
Data analysis 
•
Will be performed using a repeated measures design corrected for multiple 
comparisons (Bonferroni) with co-primary outcomes for Aim 1 
of mass and strength, and Aim 2 for co-primary outcomes 
of IR and glucose disposal. Other outcomes will be considered 
exploratory. 
•
Non-parametric techniques will be used, or data transformed, if the data 
fail a test of normality or homogeneity of variance. 𝜶= 0.05 for all testing 
will represent the threshold value used to judge whether a test statistic is 
significant.
12. Confidentiality and Subject’s Data Safety
•
Physical/paper records will be stored in a locked room at the Miami 
Project (Christine E. Lynn Rehabilitation Center, 1611 NW 12th Ave, 2nd 
Floor) in a lockable file cabinet only accessible to study personnel in the. 
A security badge is needed to open the office door where data are stored. 
Access to Miami Project (Lynn Center 2nd Floor) is via a university-
issued hallway proximity card after passing a security guard located in the 
front lobby. 
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Protocol version 2.1 – Revised 05/01/2025
•
There are two types of electronic records, 1) source data and 2) pdf 
versions of all paper and electronic data.
o
Source electronic data will be stored in the original collection 
location. In addition, a copy of the electronic file may be stored on 
the Miami Project Server in a working group with restricted 
access. The Miami Project server is behind UM firewalls and is 
backed up electronically daily, with tapes of older copies archived 
off site in a fire/hurricane secure facility.
o
All electronic and paper source data will also be stored 
electronically as pdf’s in an electronic version of the participant’s 
folder. Paper source data will be scanned, and electronic source 
data will be saved as a pdf.  
•
Data Storage – Duration
o
Physical records will be kept for a minimum of 3 years after 
enrollment is closed and destroyed by shredding services provided 
to our center. Electronic records will be kept for a minimum of 5 
years after study closure. 
o
Source data will be maintained for 3 years after study closure – as 
mandated by UM IRB guidelines - and will then destroyed by a 
secure method, typically shredding using a university provider. All 
disposal of source data, hard copy records, and electronic records 
will meet or exceed all standards such as HIPAA, FDA Security 
Regulations
•
Data – Access
o
During execution of the study access to identifiable information or 
links to identifiable information will be restricted to study 
personnel. However, coded information will be accessible to study 
personnel and may be provided to non-study personnel on a limited 
basis to gain assistance with data entry, management, analyses, and 
interpretation.
•
Provisions to Protect the Privacy Interests of Subjects
o
To protect subject privacy, participant consent forms will be stored 
in a file that is separate from their source data. Records/source data 
(physical and electronic) will be identified by a numeric ID. 
Numerical code will be linked to participant names and contact 
info in a password protected electronic file solely accessible by the 
PI and authorized study personnel.  Linkage codes will be 
maintained until data analyses are completed. Once the data have 
been analyzed and published, the linkage codes will be destroyed.
13. Provisions to Monitor the Data to Ensure the Safety of 
Subjects
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Protocol version 2.1 – Revised 05/01/2025
•
Participants will be screened and approved for study participation by a 
trained staff member at each center, ensuring compliance with study 
inclusion/exclusion criteria. 
•
Testing will be performed at a medical-academic center that is located 
near an emergency room.
•
Security personnel who staff the Lynn Rehabilitation Cen are “first 
responders” and will follow standing policies and procedures for 
emergencies in the Center.
•
All study personnel at each center hold current CPR certificates.
•
An Independent Medical Monitor will receive reports of AEs and SAEs, 
as well as semiannual reports in study progress. IMM reports will be 
included in annual continuing reports to the IRB.
•
All phlebotomy will be performed by trained study staff holding a current 
certificate in the appropriate jurisdiction.
•
Emergency numbers are posted near all lab telephones. 
•
All serious adverse events and adverse events will be reported to the IRB 
within the mandated period as follows:
o
For any adverse event, the PI will immediately notify and consult 
with the Study Physician and come to an opinion as for the 
relatedness of the event and the study procedures as described in 
the protocol.
o
Adverse events will be evaluated by the Study Physician using the 
following criteria:
▪
Grade 1, Mild:  Awareness of symptom, but easily 
tolerated; usually transient requiring no special treatment; 
does not interfere with usual status or daily activities
▪
Grade 2, Moderate:  Might be ameliorated by simple 
therapeutic measures; may interfere with, but not keep the 
participant from performing usual daily care or 
participating in daily activities.
▪
Grade 3: Incapacitating event, inability to perform usual 
activities
▪
Grade 4, Life-threatening/Disabling:  Patient is at risk for 
death, or worsening disability or impairment as existed at 
the time of the event
•
For the first two grades, the Investigators will observe the participant and 
as necessary institute standard medical or therapeutic care. Repeated 
occurrence of Grade 1 and 2 events may be cause for notification of the 
IRB by the Investigators that stoppage is appropriate. The Investigators 
may take this action, and the IRB will be so notified.
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Protocol version 2.1 – Revised 05/01/2025
•
Grade 3 and 4 events will be individually evaluated. Any occurrence of 
Grade 3 and 4 events may be cause for notification of the IRB by the 
Investigators that stoppage is appropriate. The investigators may take this 
action, and the IRB will be so notified. Upon  a determination that the 
(S)AE was related to the protocol, the study will stop and undergo 
evaluation for continuation. 
Withdrawal of Subjects
Subjects may withdraw from the study without prejudice to medical treatment at 
the center or involvement in future studies at the discretion of the PI. The ICF 
advises students and employees of the rights with respect to study withdrawal. We 
may end a subject’s participation in the study if s/he experiences adverse effects or 
in case of an incidental pregnancy.  Subjects who experience AEs (nausea, bloating, 
for example) will be referred to the Study Physician for appropriate medical care 
and will have their dose decreased by 25% (total dose of 300mg or 3 capsulse in 
the morning plus 3 capsules at night).  This lower dose has been reported to be 
efficacious and may help alleviate the AEs. If symptoms do not improve after 1-2 
days, subjects will be withdrawn from the study.  Subjects that become upset by 
answering questions about their SCI will be referred to the Study Physician for 
appropriate medical care. Compliance to UA dosing will be calculated monthly and 
subjects who fall below the 80% adherence threshold will be withdrawn from the 
study. 
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Protocol version 2.1 – Revised 05/01/2025
Risks to Subjects
•
Subjects may become upset by having an investigator ask questions about 
their SCI. 
•
The risks of blood drawing include fainting, the occurrence of temporary 
discomfort and/or bruise at the site of puncture; rarely, infection or the 
formation of a small clot or swelling to the vein and surrounding area may 
occur. There may be slight discomfort in the arm or hand during the 
venipuncture. Occasionally, a small accumulation of blood (hematoma) 
may form at the point of insertion of the needle. This may result in a small 
lump that will disappear.  Occasionally, a small amount of bleeding may 
occur around the catheter site. On rare occasions, a local infection may 
occur around the venipuncture site.
•
You may find yourself becoming hungry when you fast to have your blood 
drawn.
•
Answering questions about your injury may make you feel nervous or 
upset. If you do not wish to answer a question, you can skip it and go to 
the next question.
•
DXA scans may cause anxiety and additional radiation exposure. 
Radiation exposure is less than two weeks of natural background radiation 
or like the exposure during a round-trip cross-country flight. 
•
CT Imaging may cause anxiety and an excess exposure to radiation.  
Exposure to low-levels of radiation does not cause immediate health 
effects, but can cause a small increase in the risk of cancer over a lifetime.  
•
MIP procedure is non-invasive and relatively quick procedure.  Subjects 
may feel the need to cough or may feel short of breath during or after the 
test.  On rare occasions, subjects can become lightheaded.
•
Muscle soreness from the exercise regimen that is part of this study is a 
possibility
•
Ursolic Acid - naturally occurring triterpene compound - is an herbal-like 
isolate obtained from the leaves of various plants (rosemary, marjoram, 
lavender, thyme, and organum), fruits (apple fruit peel), and berries.  
Some of the common side outcome
o
Nausea
o
Stomach distention or bloating
o
Trace quantities of blood within the urine
o
Skin rash
Small safety studies indicate UA is tolerable with mild to moderate side effects 10, 11, 12
In addition to these risks, this research may hurt you in ways that we do not yet know
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Protocol version 2.1 – Revised 05/01/2025
Potential Benefits to Subjects
Direct benefits are not promised. It is likely that participants in exercise groups 
will improve fitness and health and learn to lead a healthier lifestyle.
14. Setting
•
Consent will take place at the following sites:
o
The Miami Project to Cure Paralysis located at the Christine E. 
Lynn Rehabilitation Center on the University of Miami Miller 
School of Medicine Medical Campus. 
o
Blood samples will be analyzed in the Biomarker and 
Immunoassay Laboratory of the DRI (3rd. Floor).
15. Resources Available
•
Mark S. Nash, PhD is a Professor in the in the Department of Neurological 
Surgery and Physical Medicine and Rehabilitation, and a Principal 
Investigator (Applied Physiology Research) for the Miami Project.  He 
will serve as a Principal Investigator on the protocol and assessments, and 
will assist with data interpretation and dissemination; Product 
accountability.
•
Alberto Martinez, M.D.: He will serve as the study physician: primary 
responsibilities will be to assess potential AEs throughout the trial and 
determine reporting requirements.
•
Armando Mendez, PhD: He will oversee all lab testing involving subject 
samples
•
Gary Farkas, PhD: He will serve as a Sub-Investigator and will assist with 
protocol, assessments, data analysis and interpretation
•
David McMillan, PhD: Primarily responsible for outreach and participant 
recruitment.  He will assist with study assessments 
•
Patricia Graham, MS, CCRC: She will be responsible for regulatory 
management and will assist with the conduct of the study, including 
consenting, assessments, product dispensation and accountability.
•
Francisco Diaz: He is in charge of the lifestyle center at LRC.  He will 
assist with the exercise intervention. 
16. Compensation for Research-Related Injury
Details regarding research related injury compensation will be included in the FE 
agreement.  The following language was added to the ICF: You may be exposed to 
risk of injury from participation in this study. If injury occurs, treatment will in 
most cases be available. If you have insurance, your insurance company may or 
may not pay for these costs. If you do not have insurance, or if your insurance 
company refuses to pay, you will be expected to pay. Funds to compensate for 
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Protocol version 2.1 – Revised 05/01/2025
pain, expenses, lost wages and other damages caused by injury are not routinely 
available.
17. Economic Burden to Subjects
Subjects that sign consent and are eligible to participate will be reimbursed by 
check (sent by mail) after each completed visit.  
Group 1 (total $200): 
•
$50 for completing the first or screening visit
•
$150 ($50 every month) for completing the 12-week intervention (exercise 
and daily UA).
•
Re-dispensing of a new UA bottle will occur once a month at a scheduled 
visit
•
Monthly pregnancy tests for all women of child-bearing potential
•
$50 for completing the post-study assessments at the final visit
Group 2(total $200): 
•
$50 for completing the first or screening visit
•
$150 ($50 every month) for completing the 12 week intervention (daily 
UA)
•
Subjects will be required to return to the study site once a month for re-
dispensing of the UA.  
•
Monthly pregnancy tests for all women of child-bearing potential
•
$50 for completing the post-study assessments at the final visit
18. Consent Process
Consent will take place at each Center in a private office at the Miami Project to 
Cure Paralysis located at LRC, 2nd Floor.  We will abide all regulatory mandates 
and suggestions of the FDA ‘A Guide to Informed Consent - Information 
Sheet’  www.fda.gov/RegulatoryInformation/Guidances/ucm126431.htm
Before signing the ICF study subject candidates will be encouraged to share the 
ICF with family, a trusted family friend or their physician.  Subject candidates 
will be required to read the approved consent form. The person obtaining consent 
will ask several questions to assure they understand the study procedures and 
risks. A statement on the consent form will advise university employees that their 
participation (or failure to participate) will not affect their employment or 
academic status. The statement in the consent will advise individuals with spinal 
cord injury that their participation (or decision to not participate) will not 
influence their treatment or candidacy for other studies in any way. Individuals 
will be given the right to withdraw at any time without prejudice. 
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Protocol version 2.1 – Revised 05/01/2025
Process to Document Consent in Writing
•
Subjects will be presented with and asked to review the consent form. 
They will be queried whether they have any questions and if so, these 
questions will be addressed by the principal investigator or individual 
approved to obtain consent. Once the consent form is signed (subject may 
provide a mark if unable to sign), witnessed, and signed by the principal 
investigator (or other designated person obtaining consent) a copy of the 
consent will be provided so that the subject can review their rights. 
•
A copy of the consent will be provided so that the subject can review their 
rights at any time in future. The original copy of the ICF will be placed in 
the participant file and secured as described in section 21.b
Authorization for Use and Disclosure of Protected Health Information 
(HIPAA) 
Waiver of Authorization for access to medical record for subject 
identification/recruitment.
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Protocol version 2.1 – Revised 05/01/2025
19. REFERENCES:
1. McMillan, David W., et al. "Virtual Strategies for the Broad Delivery of High 
Intensity Exercise in Persons With Spinal Cord Injury: Ongoing Studies and 
Considerations for Implementation." Frontiers in Sports and Active Living (2021): 
214.
2. de Groot, Sonja, and Rachel E. Cowan. "Exercise for people with SCI: so important 
but difficult to achieve." Spinal Cord 59.1 (2021): 1-2.
3. McMillan DW, Nash MS, Gater Jr DR, Valderrábano RJ. Neurogenic obesity and 
skeletal pathology in spinal cord injury. Topics in Spinal Cord Injury Rehabilitation. 
2021;27(1):57-67.
4. Nash MS, Gater Jr DR. Cardiometabolic disease and dysfunction following spinal 
cord injury: origins and guideline-based countermeasures. Physical Medicine and 
Rehabilitation Clinics of North America. 2020 Aug 1;31(3):415-36.
5. Castro MJ, Apple Jr DF, Hillegass EA, Dudley GA. Influence of complete spinal 
cord injury on skeletal muscle cross-sectional area within the first 6 months of 
injury. European Journal of Applied Physiology and Occupational Physiology. 1999 
Aug;80(4):373-8.
6. Bauman WA, Nash MS. Endocrinology and metabolism of persons with spinal cord 
injury. In Spinal Cord Medicine: Third Edition 2018 Dec 28 (pp. 278-317). Springer 
Publishing Company.
7. Nash MS, Tractenberg RE, Mendez AJ, David M, Ljungberg IH, Tinsley EA, 
Burns-Drecq PA, Betancourt LF, Groah SL. Cardiometabolic syndrome in people 
with spinal cord injury/disease: guideline-derived and nonguideline risk components 
in a pooled sample. Archives of Physical Medicine and Rehabilitation. 2016 Oct 
1;97(10):1696-705.
8. Seo DY, Lee SR, Heo JW, No MH, Rhee BD, Ko KS, Kwak HB, Han J. Ursolic 
acid in health and disease. The Korean Journal of Physiology & Pharmacology. 
2018 May 1;22(3):235-48.
9. Bigford GE, Darr AJ, Bracchi-Ricard VC, Gao H, Nash MS, Bethea JR. Effects of 
Ursolic acid on sublesional muscle pathology in a contusion model of spinal cord 
injury. PloS one. 2018 Aug 29;13(8):e0203042.
10. Zhu Z, Qian Z, Yan Z, Zhao C, Wang H, Ying G, Xu C, Shi. A phase I 
pharmacokinetic study of ursolic acid nanoliposomes in healthy volunteers and 
patients with advanced solid tumors. Int J Nanomedicine. 2013;8(1):129-136
https://doi.org/10.2147/IJN.S38271
11. Xian-Huo Wang, Shi-Yong Zhou, Zheng-Zi Qian, Hui-Lai Zhang, Li-Hua Qiu 
(Master), Zheng Song (Master), Jing Zhao (Master), Ping Wang (Professor), Xi-
Shan Hao (Professor) & Hua-Qing Wang (Professor) (2013)Evaluation of toxicity 
and single-dose pharmacokinetics of intravenous ursolic acid liposomes in healthy 
adult volunteers and patients with advanced solid tumors, Expert Opinion on Drug 
Metabolism & Toxicology,9:2, 117-125, DOI: 10.1517/17425255.2013.738667
12. Zhengzi Qian, Xianhuo Wang, Zheng Song, Huilai Zhang, Shiyong Zhou, Jing 
Zhao, Huaqing Wang, "A Phase I Trial to Evaluate the Multiple-Dose Safety and 
Antitumor Activity of Ursolic Acid Liposomes in Subjects with Advanced Solid 
Tumors", BioMed Research International, vol. 2015, Article 
ID 809714, 7 pages, 2015.https://doi.org/10.1155/2015/809714
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