Brivaracetam to Reduce Neuropathic Pain in Chronic SCI: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial
Phase: PHASE3
Conditions: Spinal Cord Injuries, Neuropathic Pain
Sponsor: University of Minnesota

 
 
 
 
 
 
Department of Rehabilitation Medicine 
500 Boynton Health Services Bridge 
 
Medical School 
420 Delaware St SE, MMC 297 
 
 
Minneapolis, MN 55455 
 
 
 
 
 
Office: 612-625-2661 
 
 
Web: rehabmedicine.umn.edu 
 
Brivaracetam to Reduce Neuropathic Pain in Chronic SCI: A Randomized, 
Double-Blind, Placebo-Controlled Clinical Trial:  
Protocol and Statistical Analysis Plan Cover Page 
 
ClinicalTrials.gov ID NCT05639946 
 
Date April 15, 2024 
 

MEDICAL PROTOCOL (HRP-590) 
PROTOCOL TITLE: Brivaracetam to Reduce Neuropathic Pain in Chronic SCI: A 
Randomized, Double-Blind, Placebo-Controlled Clinical Trial  
VERSION DATE: v7.0 APR2024 
 
 
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Version 7.0 APR2024 
 
Template  Revised On: 6/2/2021 
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MEDICAL PROTOCOL (HRP-590) 
PROTOCOL TITLE: Brivaracetam to Reduce Neuropathic Pain in Chronic SCI: A 
Randomized, Double-Blind, Placebo-Controlled Clinical Trial  
VERSION DATE: v7.0 APR2024 
 
 
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MEDICAL PROTOCOL (HRP-590) 
PROTOCOL TITLE: Brivaracetam to Reduce Neuropathic Pain in Chronic SCI: A 
Randomized, Double-Blind, Placebo-Controlled Clinical Trial  
VERSION DATE: v7.0 APR2024 
 
 
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Version 7.0 APR2024 
 
Template  Revised On: 6/2/2021 
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MEDICAL PROTOCOL (HRP-590) 
PROTOCOL TITLE: Brivaracetam to Reduce Neuropathic Pain in Chronic SCI: A 
Randomized, Double-Blind, Placebo-Controlled Clinical Trial  
VERSION DATE: v7.0 APR2024 
 
 
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Version 7.0 APR2024 
 
Template  Revised On: 6/2/2021 
PROTOCOL COVER PAGE 
 
Protocol Title 
Brivaracetam to Reduce Neuropathic Pain in Chronic SCI: A 
Randomized, Double-Blind, Placebo-Controlled Clinical Trial 
Principal 
Investigator/Faculty 
Advisor 
Name: Ricardo Battaglino, PhD  
Telephone Number:  612-625-2661 
Email Address: rbattagl@umn.edu 
IND/IDE # (if 
applicable) 
150388 
IND/IDE Holder 
Leslie Morse, DO 
Investigational Drug 
Services # (if 
applicable) 
NA 
Version 
Number/Date: 
Version: v7.0 APR2024 

MEDICAL PROTOCOL (HRP-590) 
PROTOCOL TITLE: Brivaracetam to Reduce Neuropathic Pain in Chronic SCI: A 
Randomized, Double-Blind, Placebo-Controlled Clinical Trial  
VERSION DATE: v7.0 APR2024 
 
 
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Version 7.0 APR2024 
 
Template  Revised On: 6/2/2021 
REVISION HISTORY 
 
Revision # 
Version Date 
Summary of Changes 
Consent Change? 
1.1 
MAY2022 
Addressing pre-review comments 
Yes 
2.0 
SEP2022 
Fixed typos, added language 
about analysis of genomic 
sequencing, clarified 
compensation; added follow-up 
questionnaires 
Yes 
3.0  
NOV2022 
Enrollment numbers 
Yes 
4.0 
APR2023 
  Study duration; add bowel and 
bladder items; add PCL-5 and ACE-
Q 
Yes 
4.1 
 
Addressed reviewer comments: 
changed ramp-down to 2 weeks.  
 
5.0 
OCT2023 
Exclude vent dependent, increase 
drug timeline in cases of illness or 
other unexpected events, increase 
time between labs and baseline to 
6-weeks to reduce participant 
burden   
No 
6.0 
MAR2024 
Changing Leslie to a University of 
Miami collaborator, adding David 
Balsar, fixing typo in Pain Diary, 
adding disclaimer to ICF that 
participant may have difficulty 
swallowing the pill due to its size 
Yes 
7.0 
APR2024 
Per QA audit: Removing all 
mention of multisite study, adding 
unblinding language 
Yes 
 
 
 

MEDICAL PROTOCOL (HRP-590) 
PROTOCOL TITLE: Brivaracetam to Reduce Neuropathic Pain in Chronic SCI: A 
Randomized, Double-Blind, Placebo-Controlled Clinical Trial  
VERSION DATE: v7.0 APR2024 
 
 
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Table of Contents 
1.0 
Objectives ........................................................................................................ 11 
2.0 
Background ...................................................................................................... 11 
3.0 
Study Endpoints/Events/Outcomes .................................................................. 18 
4.0 
Study Intervention(s)/Investigational Agent(s) ................................................. 18 
5.0 
Procedures Involved ......................................................................................... 19 
6.0 
Data and Specimen Banking ............................................................................. 26 
7.0 
Sharing of Results with Participants ................................................................. 27 
8.0 
Study Population .............................................................................................. 28 
9.0 
Vulnerable Populations .................................................................................... 30 
10.0 Local Number of Participants ............................................................................ 32 
11.0 Local Recruitment Methods .............................................................................. 32 
12.0 Withdrawal of Participants ............................................................................... 35 
13.0 Risks to Participants ......................................................................................... 36 
14.0 Potential Benefits to Participants ..................................................................... 38 

MEDICAL PROTOCOL (HRP-590) 
PROTOCOL TITLE: Brivaracetam to Reduce Neuropathic Pain in Chronic SCI: A 
Randomized, Double-Blind, Placebo-Controlled Clinical Trial  
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15.0 Statistical Considerations ................................................................................. 38 
16.0 Health Information and Privacy Compliance ..................................................... 41 
17.0 Confidentiality .................................................................................................. 45 
18.0 Provisions to Monitor the Data to Ensure the Safety of Participants ................ 46 
19.0 Provisions to Protect the Privacy Interests of Participants ................................ 49 
20.0 Compensation for Research-Related Injury ...................................................... 50 
21.0 Consent Process ............................................................................................... 50 
22.0 Setting .............................................................................................................. 51 
23.0 Multi-Site Research .......................................................................................... 51 
24.0 Coordinating Center Research .......................................................................... 51 
25.0 Resources Available .......................................................................................... 52 
26.0 References ....................................................................................................... 52 
 
 

MEDICAL PROTOCOL (HRP-590) 
PROTOCOL TITLE: Brivaracetam to Reduce Neuropathic Pain in Chronic SCI: A 
Randomized, Double-Blind, Placebo-Controlled Clinical Trial  
VERSION DATE: v7.0 APR2024 
 
 
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ABBREVIATIONS/DEFINITIONS 
ACC 
Anterior Cingulate Cortex 
ACGME 
Accreditation Council for Graduate Medical Education  
ACIPAC 
Advanced Computational Image Processing and Analysis Center 
AHC-IS 
Academic Health Center’s Information System 
AI 
Artificial Intelligence 
ALFF 
Amplitude of Low Frequency Fluctuations 
ALT 
Alanine Transaminase 
ANOVA 
Analysis of Variance 
ART 
Artifact Detection Tools 
AST 
Aspartate Transaminase 
BID 
Bis in die (Twice a Day) 
BOLD 
(SIGNAL OF ALFF) 
BPI 
Modified Brief Pain Inventory 
BUN 
Blood Urine Analysis 
CDE 
Common Data Elements 
CHART-SF 
Craig Handicap Assessment and Reporting Technique 
CMRR 
Center for Magnetic Resonance Research 
CNS 
Central Nervous System 
Ct 
Cycle threshold 
CT 
Computed Tomography 
CTSI  
Clinical and Translational Science Institute 
DREZ 
Dorsal Root Entry Zone 
DWI 
Diffusion Weighted Imaging 
EPI 
Echo-Planar Imaging 
ERIS 
Enterprise Research Infrastructure and Systems 
FDA 
Food and Drug Administration 
FDR 
False Discovery Rate 
fMRI 
functional Magnetic Resonance Imaging 
GFR 
Glomerular Filtration Rate 
hCG 
human Chronic Gonadotropin 
HCP 
Health Care Professional 
HIPAA 
Health Insurance Portability and Accountability Act 
HPC 
High Performance Computing 
Hz  
Hertz 
ICA 
ICA-Based denoising 
IMMPACT       Initiative on Methods, Measurement, and Pain Assessment in Clinical 
Trials 

MEDICAL PROTOCOL (HRP-590) 
PROTOCOL TITLE: Brivaracetam to Reduce Neuropathic Pain in Chronic SCI: A 
Randomized, Double-Blind, Placebo-Controlled Clinical Trial  
VERSION DATE: v7.0 APR2024 
 
 
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IND 
Investigational New Drug Application 
INR 
International Normalized Ratio 
IPA 
Ingenuity Pathway Analysis 
IQRs 
Interquartile Ranges 
IRB 
Institutional Review Board 
iv 
intravenous 
LDAP 
Lightweight Directory Access Protocol 
MEMPRAGE Multi Echo Magnetization Prepared Rapid Acquisition Gradient Echo 
mg 
milligrams 
MGH 
Massachusetts General Hospital 
MI 
Motor Imagery 
miR-485 
microRNA 485  
miRNA 
MicroRNA 
MIT 
Massachusetts Institute of Technology 
mm 
millimeters 
MNI 
Montreal Neurological Institute  
MPRAGE 
Magnetization-Prepared Rapid Gradient-Echo 
MRI 
Magnetic Resonance Imaging 
N/A 
Not Applicable 
NIDRR              National Institute on Disability, Independent Living, and                             
Rehabilitation Research 
NIH 
National Institutes of Health 
PACS 
Picture Archive and Communication System 
PCP 
Primary Care Provider 
PET 
Positron Emission Tomography 
pFDR 
positive False Discovery Rate 
PHQ-9 
Patient Health Questionnaire-9 
PHS 
Partners Healthcare System 
PI 
Principal Investigator 
PMR 
Physical and Medicine Rehabilitation 
PNS 
Peripheral Nervous System 
PRO 
Patient Representative Organizations 
RC 
Research Information Services and Communications 
REDCap 
Research Electronic Data Capture 
RNA 
Ribonucleic Acid 
RNAse 
Ribonuclease 
ROI 
Region-of-Interest 
rsfMRI 
resting state functional Magnetic Resonance Imaging 

MEDICAL PROTOCOL (HRP-590) 
PROTOCOL TITLE: Brivaracetam to Reduce Neuropathic Pain in Chronic SCI: A 
Randomized, Double-Blind, Placebo-Controlled Clinical Trial  
VERSION DATE: v7.0 APR2024 
 
 
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SCI 
Spinal Cord Injury 
SDs 
Standard Deviations 
SG 
Substantia Gelatinosa 
Spm12 
Statistical Parametric Mapping-12 
SPM12 
Statistical Parametric Mapping 
SV2A 
Synaptic Vesicle Protein 2A 
SWLS 
Satisfaction with Life Scale 
T 
Tesla 
TID 
Three times a day 
TR 
Repetition Time 
VA 
Veterans Affairs 
VAS 
Visual Analog Scale 
VPN 
Virtual Private Network 
 
 

MEDICAL PROTOCOL (HRP-590) 
PROTOCOL TITLE: Brivaracetam to Reduce Neuropathic Pain in Chronic SCI: A 
Randomized, Double-Blind, Placebo-Controlled Clinical Trial  
VERSION DATE: v7.0 APR2024 
 
 
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Version 7.0 APR2024 
 
Template  Revised On: 6/2/2021 
1.0 
Objectives 
1.1 Purpose:  
Spinal cord injury (SCI) is associated with severe neuropathic pain that is 
often refractory to pharmacological intervention. Our preliminary data 
suggest brivaracetam is a mechanism-based pharmacological intervention 
for neuropathic pain in SCI. Based on our data and other reports in the 
literature, we hypothesize that SCI-related neuropathic pain occurs largely 
because of upregulation of synaptic vesicle protein 2A (SV2A) within the 
substantia gelatinosa of the injured spinal cord. We further hypothesize that, 
compared to placebo, brivaracetam treatment reduces severe below-level 
SCI neuropathic pain and increases parietal operculum (parts OP1/OP4) 
connectivity strength measured by resting-state functional Magnetic 
Resonance Imaging (rsfMRI). We also hypothesize that circulating miRNA-
485 levels may be associated with change in pain intensity due to 
brivaracetam treatment. To test these hypotheses, we will conduct a 
randomized, double-blind, placebo-controlled clinical trial to determine the 
efficacy of brivaracetam treatment for SCI-related neuropathic pain. We 
therefore propose the following: 
 
Specific Aims: 
Specific Aim 1: Determine whether a 7-week course of daily brivaracetam 
reduces below-level neuropathic pain in SCI. The objective of this aim is to 
assess efficacy of a 7-week course of brivaracetam to reduce neuropathic 
pain in men and women with SCI. We will assess change in pain intensity and 
related outcomes, including mood, satisfaction with life, and community 
integration. We will monitor drug adverse events and tolerability. 
Specific Aim 2: Determine whether a 7-week course of daily brivaracetam 
increases parietal operculum brain connectivity. The objective of this 
exploratory aim is to assess the effect of a 7-week course of brivaracetam 
treatment on parietal operculum activation and connectivity in SCI. We will 
assess changes in cortical activity of related pain perception regions and 
networks in the brain in response to brivaracetam treatment compared to 
placebo using rsfMRI and pain-related task-based fMRI. To achieve this aim, 
we will test the working hypothesis that brivaracetam increases parietal 
operculum activation and connectivity compared to placebo, using rsfMRI, 
task-based fMRI, and a validated image processing protocol. We will also 
examine changes in network connectivity and brain activity in the insula, 
because of its concurrent reported importance for neuropathic pain in SCI. 
We will assess the association between functional connectivity of the 
parietal operculum and the insula and change in pain intensity in response 
to brivaracetam treatment. 

MEDICAL PROTOCOL (HRP-590) 
PROTOCOL TITLE: Brivaracetam to Reduce Neuropathic Pain in Chronic SCI: A 
Randomized, Double-Blind, Placebo-Controlled Clinical Trial  
VERSION DATE: v7.0 APR2024 
 
 
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Version 7.0 APR2024 
 
Template  Revised On: 6/2/2021 
Specific Aim 3: Determine whether baseline microRNA-485 levels are 
associated with response to brivaracetam treatment. The objective of this 
exploratory aim is to assess microRNA expression as a potential predictive 
biomarker of response to brivaracetam treatment. To achieve this, we will 
test the working hypothesis that baseline circulating miR-485 levels predict 
change in pain intensity in response to brivaracetam treatment. To test this, 
we will use Next-Generation sequencing. We will assess miR-485 levels at 
baseline and after a three-month treatment course.  
 
2.0 
Background 
2.1 Significance of Research Question/Purpose:  
There is currently no effective pharmacological treatment for severe 
neuropathic pain in SCI. Identification of an oral medication that is effective, 
safe, and well tolerated would represent a major improvement in the clinical 
approach to neuropathic pain in SCI. Additionally, there are no validated 
predictive biomarkers of response to pharmacological therapy in 
neuropathic pain after SCI. This work is innovative as it seeks to develop a 
new, mechanism-based pharmacological intervention for neuropathic pain 
in SCI. Additionally, this project seeks to identify novel biomarkers of 
neuropathic pain and response to therapy. Development of a reliable, easy 
to measure biomarker that distinguishes responders from non-responders 
would dramatically improve clinical care for this condition. Successful 
completion of this work will rapidly lead to larger clinical trials testing drug 
efficacy and validating novel predictive biomarkers of treatment response. 
2.2 Preliminary Data:  
SCI is associated with a high prevalence of severe below-level neuropathic 
pain that is often refractory to therapeutic interventions. Our preliminary 
work demonstrates overexpression of the synaptic vesicle protein 2A (SV2A) 
in electrically hyperactive substantia gelatinosa surgical samples in patients 
with neuropathic pain. The FDA-approved antiepileptic drug brivaracetam 
targets and binds to the SV2A protein with greater binding affinity than other 
drugs targeting SV2A. We have used brivaracetam off-label for 
compassionate reasons in severe, refractory neuropathic pain with 
sustained pain relief. We have identified multiple brain networks altered in 
SCI and modulated by neuropathic pain. Neuropathic pain also increases 
local brain activity of the periaqueductal gray. miR-485 regulates presynaptic 
expression of SV2A as well as dendritic spine density and synapse 
morphology and function. Therefore, circulating miR-485 may be a 
mechanism-based predictive biomarker of response to therapies targeting 
the SV2A protein, including brivaracetam. These findings, paired with our 

MEDICAL PROTOCOL (HRP-590) 
PROTOCOL TITLE: Brivaracetam to Reduce Neuropathic Pain in Chronic SCI: A 
Randomized, Double-Blind, Placebo-Controlled Clinical Trial  
VERSION DATE: v7.0 APR2024 
 
 
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Template  Revised On: 6/2/2021 
preliminary data, suggest that reduced levels of miR-485 may contribute to 
the pathophysiology of SCI-induced neuropathic pain by disrupting normal 
levels of SV2A and neural network activity in nocioceptive neurons. 
Collectively, these findings provide the scientific rationale for the following 
hypotheses to be tested in this pilot clinical trial: compared to placebo, 
treatment with brivaracetam reduces severe below-level SCI neuropathic 
pain (Aim 1). We also hypothesize that either parieto-insular brain function 
(Aim 2) or circulating miRNA-485 (Aim 3) may be candidate predictive 
biomarkers of response to brivaracetam therapy. Collectively, the results of 
this pilot clinical trial will be used to design larger clinical trials to confirm 
these hypotheses. 
 
We performed extensive proteomic analyses of electrically hyperactive and 
normal substantia gelatinosa surgical samples using the SOMAscan platform 
[Shi et al., 2019]. These spinal cord samples were obtained from SCI patients 
with excruciating below-level neuropathic pain refractory to all 
pharmacological management, including Lyrica, Neurontin, and Oxycontin. 
Proteomic analyses of over 4000 proteins yielded 12 proteins substantially 
overexpressed in the electrically hyperactive tissue relative to the normal 
tissue, 5 of these 12 proteins markedly so. One of the 5 proteins found to be 
markedly overexpressed is the synaptic vesicle protein 2A (SV2A). This 
protein has been implicated in models of both partial and generalized 
epilepsy, and the drug brivaracetam (Briviact), which targets and binds SV2A, 
is used as an FDA approved drug to treat partial-onset seizures. 
Brivaracetam’s effectiveness at treating epileptiform neural activity is 
attributed to its selective SV2A binding and the binding affinity is 30 times 
greater than the SV2A agonists levetiracetam (Keppra) [Nicolas et al., 2016]. 
Clinical Success with Off-label treatment of SCI Neuropathic Pain with 
Brivaracetam. Because epileptiform-like neuronal hyperactivity and 
elevated SV2A expression is identified in the hyperactive substantia 
gelatinosa of our SCI patients with below-level neuropathic pain, we elected 
to treat 2 such patients with brivaracetam for compassionate reasons who 
had severe pain refractory to all medications, including opioids (e.g. 
Oxycontin), neuroleptics (e.g. Lyrica, Neurontin), and antidepressant 
medications (e.g. Cymbalta). These 2 patients were not candidates for our 
specialized pain surgery because of the risk surgery posed to neurologic 
function, although they did meet typical selection criteria. Both patients 
experienced sustained reduction in pain intensity. Patient 1 experienced a 
40% (2 point) reduction in average pain intensity and Patient 2 experienced 
a 66% (6 point) reduction in average pain intensity (figure). This clinical 

MEDICAL PROTOCOL (HRP-590) 
PROTOCOL TITLE: Brivaracetam to Reduce Neuropathic Pain in Chronic SCI: A 
Randomized, Double-Blind, Placebo-Controlled Clinical Trial  
VERSION DATE: v7.0 APR2024 
 
 
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Template  Revised On: 6/2/2021 
success provides the scientific rationale for the dosing and treatment 
duration to be tested in this pilot clinical trial. 
Resting State Brain Functional Connectivity and Neuropathic Pain. In our 
ongoing SCI studies, we observe that participants display a wide range of 
pain levels. As hypothesis-generating preliminary data for this pilot study, 
we evaluated how variations in neuropathic pain levels impact resting state 
functional connectivity after SCI. We studied 29 participants with chronic SCI 
(level C6 or lower) and 11 healthy control participants using 3T MR imaging. 
A high resolution structural (MPRAGE) dataset and two sets of 6-minute 
resting state EPI datasets (TR 3 sec) were collected in each participant. Prior 
to the neuroimaging session, participants rated their current pain levels on 
a 0 to 10 VAS scale. MRI data was analyzed using the SPM12 based Conn 
toolbox [Whitfield-Gabrieli and Nieto-Castanon, 2012] (Version 17f, Matlab 
R2018b). Preprocessing steps included realignment and unwarping, slice-
timing correction, ART based identification of outlier scans for scrubbing, 
segmentation and normalization to MNI space, and 8 mm smoothing. 
Denoising steps included scrubbing, aCompCor, ICA-based denoising, Global 
Regression, and 0.008 to 0.09 Hz band-pass filtering. Two main comparisons 
were evaluated: SCI participants versus uninjured controls, and the effect of 
concurrent pain ratings on rsfMRI measures. First, we evaluated region-of-
interest (ROI) based functional connectivity in a set of anatomically defined 
regions known to be impacted in SCI and neuropathic pain: the 
periaqueductal gray, the bilateral thalamus, the amygdala, the 
hippocampus, the insula, anterior cingulate, the precentral and the post-
central gyrus. Second, we evaluated, on a voxel-by-voxel basis, amplitude of 
low frequency fluctuations (ALFF) and intrinsic resting state functional 
connectivity. ALFF measures the total power of the BOLD signal within the 
low-frequency range between 0.01 and 0.1 Hz and is a measure of intensity 
of low frequency oscillations. Intrinsic resting state connectivity is a measure 
of how connected a voxel is to other voxels but does not provide information 
on the regions with which this voxel is connected. 
SCI participants reported an average VAS pain of 3.0 (±2.5), ranging from 0 
to 8, while uninjured control participants reported an average of 0.26 
(±0.64), ranging from 0 to 2. The difference in pain ratings was significant 
(p=0.00053).  
When considering differences between SCI and uninjured controls, we found 
increased connectivity in the following networks: right amygdala to the left 
posterior temporal fusiform cortex (pFDR =0.032), left hippocampus to the 
right frontal pole (pFDR =0.036) the right occipital fusiform gyrus (pFDR 
=0.025), the right temporal occipital fusiform gyrus (pFDR =0.036), and the 

MEDICAL PROTOCOL (HRP-590) 
PROTOCOL TITLE: Brivaracetam to Reduce Neuropathic Pain in Chronic SCI: A 
Randomized, Double-Blind, Placebo-Controlled Clinical Trial  
VERSION DATE: v7.0 APR2024 
 
 
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left cerebellum 6 (pFDR =0.036). We also found significantly increased 
regional brain activity (ALFF) in the paracingulate gyrus (pFDR=0.004).  
When considering differences based on the presence of neuropathic pain, 
we found decreased connectivity in the following networks: right thalamus 
to the left frontal operculum, (pFDR=0.0002) and left amygdala to the vermis 
of the cerebellum (pFDR=0.0001). We found increased connectivity in the 
left amygdala to cerebellum 3 (pFDR =0.0001). 
We considering pain rating as a continuous variable, we found a significant 
positive linear correlation between pain rating and intrinsic connectivity of 
the post-central gyrus in the somatosensory area of the torso and lower 
body (pFDR =0.003). We also found a significant positive linear correlation 
between pain rating and brain activity (ALFF) in the periaqueductal gray area 
(pFDR=0.0009).  
These preliminary findings suggest that SCI disrupts multiple brain networks, 
along with significant alteration of resting state function of the paracingulate 
gyrus. Pain may modulate some of these properties, and notably disrupts 
local brain activity of the periaqueductal gray. The frequency band of ALFF 
alterations are similar to those of calcium channels and astrocytes, 
consistent with findings in post-traumatic neuralgia [Alshelh et al., 2016]. 
Further, the primary somatosensory region representing the lower torso 
displayed an increase in intrinsic connectivity in parallel with increased pain 
ratings. This may be consistent with phantom limb like pain, or an increased 
processing of denervated lower body sensations. Collectively, this work 
demonstrates feasibility and our expertise with the proposed imaging 
methodology. ALFF has high test-retest reliability and is thus suitable for 
longitudinal evaluations [Zuo et al., 2010]. Based on these findings, we 
hypothesize that brivaracetam treatment will normalize pain-related 
changes identified above, with ALFF of the periaqueductal gray being the 
primary outcome. Therefore, these findings provide the scientific rationale 
for the fMRI studies proposed in Aim 2. 
2.3 Existing Literature:  
SCI Neuropathic Pain. Neuropathic pain in SCI is associated with decreased 
pain inhibitory capacity [Albu et al., 2015], and may cause extensive atrophy 
and reorganization of the CNS [Cragg et al., 2015]. Common pain descriptors 
used by patients with SCI neuropathic pain include sharp, burning, electric, 
stabbing, pins-and-needles sensations experienced in regions of anesthesia 
or hypesthesia. These pains are believed to be of central origin and are often 
referred to as central neuropathic pains. Pain experienced at the level of 
injury is referred to as at-level pain and that experienced more than 3 

MEDICAL PROTOCOL (HRP-590) 
PROTOCOL TITLE: Brivaracetam to Reduce Neuropathic Pain in Chronic SCI: A 
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dermatomes caudal to the level of injury as below-level pain. At-level and 
below-level neuropathic pains are believed to have different mechanisms of 
central mediation to brain pain centers. At-level pains are believed to 
originate substantially from electrically hyperactive neuronal activity in the 
substantia gelatinosa (SG) corresponding to classical somatic dermatomal 
innervation of the regions of pain experienced. These regions of neuronal 
hyperactivity are believed to be mediated through classical pain pathways, 
e.g. spinothalamic tracts, to brain pain centers. Below-level pains are 
believed to originate substantially from electrically hyperactive neurons in 
the substantia gelatinosa at the cord level of intermediolateral cell column 
end organ innervation of perceived pain regions, resulting in a novel 
somatotopic map of SG below-level pain generators. It is believed that these 
regions of neuronal hyperactivity are mediated wholly or in part through 
sympathetic nervous system pathways to brain pain centers. 
Dorsal root entry zone (DREZ) lesioning is a surgical method performed only 
at our center involving operative neurophysiological targeting and ablation 
of regions of hyperactive substantia gelatinosa that has met with excellent 
success at relieving severe below-level pains refractory to all forms of 
pharmacological management this surgical method, 85% of patients with 
severe below-level neuropathic pain refractory to all pharmacological 
management achieve essentially 100% pain relief. It is because of this 
excellent surgical outcome that an IRB study was approved, allowing biopsy 
of regions of electrically hyperactive substantia gelatinosa and subsequent 
proteomic analysis, in patients with severe SCI below-level neuropathic pain. 
Because regions of substantia gelatinosa with normal electrical activity are 
typically found intermixed with regions of hyperactivity, (these normal 
regions are typically destroyed in the process of ablation of regions of 
hyperactivity), biopsies of these normal regions are able to be obtained for 
proteomic comparison. 
SCI-related Changes in Resting State Brain Connectivity. Spinal cord injury 
(SCI) leads to rapid atrophy of the cord above the lesion and to alterations in 
brain structure and function. This is initiated by direct effects of spinal nerve 
damage and immediate secondary inflammatory responses. The central 
nervous system (CNS) changes continue via adaptive and maladaptive 
plasticity, persistent reactive microglia, and physiological consequences of 
living with paralysis. Recent studies indicate that the resting state 
sensorimotor network is disrupted after SCI [Hou et al., 2014] and that the 
development of chronic pain has a physiologic basis in altered brain 
structure and function. Specifically, individuals with SCI display decreased 
inter-hemispheric functional connectivity between the bilateral primary 

MEDICAL PROTOCOL (HRP-590) 
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sensorimotor cortex, as well as increased intra-hemispheric functional 
connectivity within the motor network. Further, Nictora et al [Nicotra et al., 
2006] found that people with SCI displayed enhanced responses within 
dorsal anterior cingulate cortex and periaqueductal gray during the 
processing of threat. After SCI, there are also rapid and extensive reductions 
in gray matter volume in the primary somatosensory cortex lower body, leg, 
and foot areas [Solstrand Dahlberg et al., 2018]. The degree of atrophy likely 
depends on the level and completeness of the lesion, the time since injury, 
and on the presence of pain, but there is disagreement as to how these 
factors may interact. In a longitudinal study over the first 12 months post 
SCI, Freund et al. found gray matter volume reductions in the leg area of the 
primary motor cortex, but not the somatosensory cortex [Freund et al., 
2013], and progressive reductions over time were observed in the thalamus, 
anterior cingulate, secondary somatosensory cortex (part of the parietal 
operculum), insula and pons [Ziegler et al., 2018]. Such changes in volume 
related quantitatively to sensory deficits, but there were no correlations 
between neuropathic pain and volumetric declines during the first year of 
injury. On the other hand, Jutzeler et al. reported reductions in anterior 
cingulate cortex (ACC), insula, secondary somatosensory cortex, and 
thalamus volume in SCI patients with and without neuropathic pain 
compared to controls. Neuropathic pain was associated with increases in 
ACC and primary motor cortex gray matter, as well as reductions in primary 
somatosensory cortex and thalamic gray matter [Jutzeler et al., 2016]. 
Although inconclusive, the above studies indicate that structural reductions 
rapidly occur in both cortical (sensorimotor cortex, ACC, insula) and 
subcortical (hippocampus, thalamus, pons) areas following SCI that seem to 
be influenced by time since injury and the clinical state (i.e. presence of 
neuropathic pain).  
microRNA and Neuropathic Pain. microRNAs (miRNA) have emerged as 
important biomarkers and molecular mediators in numerous physiological 
and pathological settings. miRNAs are short, non-coding single-stranded 
RNA molecules with the ability to exert post-transcriptional modulation of 
large sections of the genome by binding to regulatory gene elements and 
inhibiting the translation of many genes [Bartel, 2009; Lagos-Quintana et al., 
2001]. They bind to untranslated regions of genes with sometimes imperfect 
complementarity, which allows for one specific miRNA molecule to inhibit 
the translation of multiple genes. They are found in every human tissue and 
biofluid, are resistant to RNAse degradation and have the ability to cross the 
blood brain barrier making them an excellent choice as a biomarker for 
neuro-trauma related conditions, neuro-recovery, and response to various 
therapeutic interventions [Liu and Paroo, 2010]. 

MEDICAL PROTOCOL (HRP-590) 
PROTOCOL TITLE: Brivaracetam to Reduce Neuropathic Pain in Chronic SCI: A 
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Significant alterations in microRNAs expression (together with the resultant 
changes in protein expression) have been reported in both the affected 
tissues and in the blood from patients suffering from several pain conditions 
such as complex regional pain syndrome, cystitis-induced chronic pain and 
irritable bowel disorder. Spinal cord injury-induced neuropathic pain 
represents a significant clinical challenge that affects 20-77% of injured 
persons. Specific changes in protein expression in peripheral nociceptive and 
central neurons are thought to contribute to the development of hyper-
excitability which is at the basis of the genesis and persistence of chronic 
neuropathic pain [Gold and Gebhart, 2010]. Because SCI-induced 
neuropathic pain is mediated by, among other factors, neuronal protein 
expression, the process can potentially be regulated by miRNAs. Many 
studies have been conducted in rodent models of neuropathy investigating 
changes in miRNA expression both centrally and peripherally. Most of them 
have demonstrated dysregulation in numerous miRNAs [Bali et al., 2014; 
Genda et al., 2013; Wu et al., 2011]. In one particular study [Imai et al., 
2011], the authors found that a lesion in the periphery (sciatic nerve) caused 
downregulation of specific miRNA centrally (in post-synaptic neurons of 
nucleus accumbens). Furthermore, the authors proposed that these changes 
may be involved in the development of co-morbid conditions like anxiety 
and sleep disorders, typically associated with persistent pain stimuli. Despite 
some discrepancies in the literature of this emerging research field, there is 
a general consensus in that miRNA alterations that occur both in the CNS 
and the PNS mediate or are associated with neuropathic pain. 
The study of miRNA in neuropathic pain is a relatively new field of research. 
However, the significance of miRNA alterations in a variety of rodent pain 
models and in clinical conditions characterized by pain has been clearly 
established (there are more than 30 publications in 2019 alone). The 
majority of these studies have been conducted in animal models. However, 
a few studies also describe changes in miRNAs-signatures in complex 
regional pain syndrome [Orlova et al., 2011] and irritable bowel syndrome-
patients [Zhou et al., 2010]. There is evidence that a specific miRNA might 
play a role in the pathogenesis of neuropathic pain in SCI. miR-485 regulates 
presynaptic expression of SV2A and regulates dendritic spine density and 
synapse morphology and function [Cohen et al., 2011]. Synaptic plasticity is 
a homeostatic response essential to adapt neural circuit connectivity and 
excitation in response to neurotrauma. miRNA-485 expression is regulated 
in a number of neurological diseases and after brain trauma. For instance, 
miRNA-485 is down-regulated in Huntington disease [Packer et al., 2008], 
Alzheimer’s disease [Cogswell et al., 2008], and traumatic brain injury [Redell 
et al., 2009]. These disease studies, together with our findings that SV2A 

MEDICAL PROTOCOL (HRP-590) 
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expression is increased in individuals with neuropathic pain, suggest that 
decreased levels of miR-485 with corresponding increased levels of SV2A 
and neural network activity in nociceptive neurons may contribute to the 
pathophysiology of SCI-induced neuropathic pain.  
Because miR-485 regulates SV2A expression, the target of brivaracetam, we 
hypothesize that circulating miR-485 may be a valuable predictive biomarker 
of response to therapy. That is, we hypothesize that individuals with lower 
circulating miR485 levels may be less likely to respond to brivaracetam 
treatment for neuropathic pain than those with higher circulating miR485.  
miRNAs are promising molecules with potential use as prognostic and 
diagnostic biomarkers of neuropathic pain and also as predictive biomarkers 
to monitor the effect of treatments for neuropathic pain in humans. 
However, the lack of properly conducted clinical studies prevents the bench-
to-bedside translation of this knowledge to the clinical setting. This project 
aims to address these gaps by studying the role of miRNA in SCI neuropathic 
in humans as well as miRNA signatures as predictive biomarkers of response 
to brivaracetam therapy in SCI. This evidence provides the scientific rationale 
for the studies proposed in Aim 3. 
3.0 
Study Endpoints/Events/Outcomes 
Primary Endpoint/Event/Outcome:  
Our primary endpoint will be reduction in pain intensity assessed by the 
International Spinal Cord Injury Pain Data Set.  
 
Secondary Endpoint(s)/Event(s)/Outcome(s):  
Secondary outcomes include brain resting state and task based activity and 
functional connectivity and various psychosocial factors related to 
participants’ experiences with SCI, such as change in mood, satisfaction 
with life, community integration, sleep, self-efficacy, pain catastrophizing, 
perceived disability, and spasm frequency. 
4.0 
Study Intervention(s)/Investigational Agent(s) 
Description:  
Intervention: brivaracetam or placebo administration. Dr. Morse (Co-
I/study physician) currently holds an Investigational New Drug (IND) 
application for brivaracetam to treat severe neuropathic pain in individuals 
with SCI (IND # 150388). With regulatory support provided by UMN CTSI, 
we will submit this protocol to the FDA for review under the existing IND 
upon notification of funding. RxArtisans Pharmacy (Wayzata, MN) will 
FedEx the drug to the participant directly (study staff will send an email 
notification to the participant that the drug has been sent by overnight 

MEDICAL PROTOCOL (HRP-590) 
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mail) or to the designated contact at the enrolling site for distribution. To 
minimize wasting of drug, RxArtisans will dispense and ship prescriptions 
concurrent with the ramp-up schedule (weekly, biweekly, or as requested 
by study doctor). Participants will be asked to verify by phone or email 
receipt of study drug and initiation of the treatment course.  
Drug dosage will be individually titrated for each participant with a goal of 
100mg BID according to the following dose escalation protocol that we use 
clinically: 50mg BID for 1 week followed by 100mg BID for 28 days as 
tolerated. Participants will be allowed to reduce the dose of brivaracetam 
if they experience unacceptable side effects defined as increased 
somnolence according to routine clinical practice with other drugs in this 
class used for pain. Participants will be given an additional week to ramp 
up to 100mg BID, as needed. The 28-day treatment period might also be 
extended in the case of illness or other unanticipated event that impacts 
the ability to take the medication consistently. This will be determined on 
a case-by-case basis by the study team. The treatment course will be 
recorded and considered in analysis. A dose of 50mg BID or higher must be 
maintained to complete the trial. The study drug will be paid for by the 
study. 
Drug discontinuation at study completion will be done according to the 
following protocol we use clinically that will be initiated for 2 weeks 
following end of study testing (Visit 3): reduction to 50mg BID for 1 week 
followed by 50mg daily for 1 week. For those at the highest study tolerated 
dose of 50mg BID, the dose will be reduced to 50mg daily for 1 week and 
then stopped. At the end of the two-week ramp down, participants will 
mail any remaining pills and the empty pill bottle along with the 
medication diary using self-addressed and prepaid packaging. University of 
Minnesota Investigational Drug Services (IDS) will register the study, while 
Rx Artisans will be dispensing the drug. 
 
If a participant is admitted to the hospital for any reason during the 
course of the study, the participant or physician will notify the study 
coordinator or study PI using the phone number contained on the 
consent form or printed on the medication bottle. The PI/study 
coordinator will immediately notify the blinded study physician (Dr. 
Morse) who will contact the unblinded medical monitor (Dr. Stillman). 
The two will decide whether unblinding is warranted. If warranted, the 
medical monitor will access the unblinding key that is stored in a 
password-protected file that only he and the pharmacy can access. The 
medical monitor will follow up with the treating physician and provide 

MEDICAL PROTOCOL (HRP-590) 
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the drug information (i.e., placebo or study drug) within 30 minutes of 
notification. The process for emergent unblinding will be available 24 
hours a day, 7 days a week. 
 
At the beginning of the study, all participants are directed that if in this 
situation, they are to bring study medication to the hospital and inform 
the physician overseeing the hospital stay that they are taking a research-
related study drug. Further, the medical professional should assume that 
they are on the study drug. He/she may reach out for more information 
about the study drug.  
 
Drug/Device Handling:  
Brivaracetam or placebo will be compounded and dispensed by RxArtisans 
Inc. The active drug will be placed without modification into the 
appropriate  gelatin capsule. Each strength of active and placebo will have 
an identical capsule color and inactive ingredients (microcrystalline 
cellulose and silica gel). Study investigators will send a prescription to the 
pharmacy, and the pharmacy will dispense the appropriate study 
medicine. The study medicine will then be provided to research volunteers 
at UMN or via FedEx/courier delivery in the United States. Study staff will 
confirm with each participant by phone (or participant-preferred 
communication including email, text, etc.) that the drug was received. 
Biosafety: N/A  
Stem Cells: N/A 
Fetal Tissue: N/A 
 
5.0 
Procedures Involved 
Study Design: 
This is a randomized, double-blind, placebo-controlled clinical trial in 40 
adults at least 18 years of age with SCI. Participants who meet the eligibility 
criteria (described in Section 8.1) will be randomly assigned with a 1:1 ratio 
to active drug (escalating brivaracetam dose to 100 mg twice daily for four 
weeks) or placebo using a randomization schedule developed by our 
biostatistician. This is a simple computer generated 1:1 scheme that 
randomly assigns participants to arm C or arm D.  Study participants, 
research coordinators, and study personnel involved in outcomes 
assessments and analyses will all be masked to allocation. The drug will be 
provided by RxArtisans pharmacy in Wayzata, MN. The active and placebo 
capsules will have identical appearance and consistency. Treatment 
assignment will be known only to the investigational drug pharmacy 
(RxArtisans). We will register this trial at www.clinicaltrials.gov. 

MEDICAL PROTOCOL (HRP-590) 
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Study Procedures:  
Overview of study procedures/study interventions. This study involves 
research activities that occur in-person, over the phone, and via online 
REDCap surveys. Participants will also have the option to participate 
entirely remotely. In this circumstance, there will be no MRI scan nor blood 
draw for banking; instead, all required safety labs will be completed with 
the participant’s primary care physician and insurance will be charged and 
the participant will be responsible for any associated copays or costs. All 
research activities are summarized in Table 1 below and described in detail 
in the subsequent text.  
Screening: A phone screen will be administered to confirm basic eligibility 
criteria listed in Section 8.1 such as age, pain level, medication use, and 
other medical conditions. Study staff will also screen for MRI 
contraindications at that time with the Center for Magnetic Resonance 
Research (CMRR) pre-screening questionnaire (i.e., implanted medical 
devices or retained metal fragments). Eligible individuals will be required 
to receive medical clearance from their primary care provider within one 
month of (prior to) Visit 1, including physical exam, health history, and lab 
work to confirm normal renal function, absence of liver cirrhosis, and 
absence of pregnancy. While we will target obtaining lab work within 1 
month of baseline, labs up to 6-weeks prior to baseline will be accepted to 
reduce participant burden. Their insurance will be charged, and they will 
be responsible for any associated copays or costs. 
For participants who recently had comprehensive metabolic panel done, 
medical record review of lab results can replace new screening labs if the 
blood labs were completed within one month of (prior to) the scheduled 
baseline appointment. If the participant is seeing a provider in-system, the 
study coordinator will pull labs from the medical record. If the participant 
is not seeing a provider in-system, the study coordinator will instruct the 
participant’s physician to fax the lab report to the study coordinator. The 
instructions for faxing will be on the screening eligibility sheet the 
participant brings to their doctor’s appointment and available to be 
emailed for the participant upon request. 
 
Visit 1: This visit includes informed consent, randomization, a focused 
physical exam, and a mental health and health history screen. CDE-
recommended questionnaires relating to pain, mood, active suicidality, 
satisfaction with life, kinesiophobia, sleep quality, and community 
integration will also be administered.  

MEDICAL PROTOCOL (HRP-590) 
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Visit 2: This visit may be combined with Visit 1, if the participant prefers. 
Visit 2 includes an optional blood draw for batch analysis and an optional 
MRI scan; the optional MRI and optional blood draw are paid for by the 
study. Visits 1 and 2 can take place either at the study site or virtually, 
depending on participant preference. Those who choose to participate in 
the study virtually will not take part in the MRI or blood draw. For 
participants with contraindications to MRI, the MRI will not be completed.  
Once randomized, the 7-week  supply of study drug will be dispensed and 
mailed directly to participants to begin 7 weeks of active treatment or 
placebo, as described in Section 4.0. All participants will receive a 
medication diary to track study drug compliance and to record medication 
use.  
Weekly phone check-in: Masked data collectors will perform weekly check-
in calls to assess for medication-related adverse events (AEs). The data 
collector will also administer the Patient Health Questionnaire 9-item 
(PHQ-9) to assess for changes in mood and suicidality. A suicide protocol 
will be initiated if a participant endorses suicidality (see below). 
Participants will also report on their level of pain (rate highest, lowest, and 
average pain (0-10) that day). Reported AEs identified in these calls will be 
documented and immediately shared with the PI for review.  
Suicide Protocol: Endorsement of active suicidality on PHQ-9 will trigger 
the suicide protocol. Study staff will call 911 in the event of a psychological 
emergency noted during a phone call (credible report of intent to harm 
oneself). Study staff will first ask to speak to another adult in the 
household. If none is present or comes to call, study staff will call 911 and 
remain on the line until first responders arrive. In the event of a non-
emergent psychological situation (psychological distress in the absence of 
intent for self-harm), study staff will refer the participant to their PCP or 
the National Suicide Hotline (1-800-SUICIDE). In either case, study staff will 
notify the PI immediately.      
 
Visit 3: End of intervention assessments will be repeated 5 weeks after Visit 
2. This includes a focused physical exam, a mental health and health 
history screen, optional blood draw, optional MRI, and questionnaires 
relating to pain, mood, active suicidality, satisfaction with life, 
kinesiophobia, sleep quality, and community integration. Additionally, 
limited safety labs will be repeated (from pre-Visit 1) to confirm normal 
renal function, absence of liver cirrhosis, and absence of pregnancy in 
individuals of childbearing potential. The fasting blood draw and analysis 

MEDICAL PROTOCOL (HRP-590) 
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will occur either at the enrolling site or with the participant’s primary care 
provider, based on participant preference. Blood will be analyzed for blood 
urea nitrogen (BUN), creatinine, alanine transaminase (ALT), aspartate 
transaminase (AST), total bilirubin, albumin, GFR, calcium, corrected 
calcium, and human chorionic gonadotropin (hCG); urine hCG test will also 
be accepted. International normalized ratio (INR) will be collected at the 
discretion of the participant’s primary care provider if the participant is on 
anticoagulation or has abnormal liver function tests. People who are 
menopausal and have not had a menstrual period for at least 12 months, 
or people who have had a hysterectomy will not be required to take 
pregnancy tests. Results of the pregnancy test will be sent only to study 
staff. At the end of Visit 3, study staff will provide instruction for the first 
week of the two-week dose reduction period. Data collectors will continue 
weekly check-ins throughout the ramp down period and up until Visit 4. 
Data collectors will also remind the participant to return the remaining pills 
and pill bottle along with the medication diary using the pre-paid envelope 
provided by study staff. 
 
Visit 4: Visit 4 occurs 1 month following the end of study drug. Data 
collectors will assess for AEs, changes in mood and suicidality via the PHQ-
9, medications, and pain levels; surveys related to mood, satisfaction with 
life, community integration, fear of movement related to pain, and sleep 
will also be administered at this time.   
 
Our primary endpoint is reduction in pain intensity assessed by the 
International Spinal Cord Injury Pain Data Set. Secondary outcomes include 
reduction in opioid use, change in mood, satisfaction with life, community 
integration, brain resting-state functional connectivity, and task-based 
brain activation and connectivity, sleep, neuropathic pain, self-efficacy, 
pain catastrophizing, perceived disability, spasm frequency, and 
intervention expectations. The specific study measures are listed below:  
International Spinal Cord Injury Pain Data Set. This tool assesses average 
pain intensity in the last week using a 0-10 numerical rating scale. The 0-
10 numerical rating scale has been recommended by the IMMPACT 
consensus group for use in pain clinical trials [Dworkin et al., 2005] and by 
the 2006 NIDRR SCI Pain outcome measures consensus group. [Bryce et al., 
2007] This scale is recommended to standardize pain outcomes across 
studies. The International Spinal Cord Injury Pain Data Set also assesses 
dimensions of pain (i.e., intensity of pain, time of day, location, occurrence, 
etc.), and pain interference with mood, activity, and sleep. 

MEDICAL PROTOCOL (HRP-590) 
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Modified Brief Pain Inventory (BPI). The BPI is a short self-assessment 
questionnaire that provides information on various dimensions of pain 
including how pain developed, the types of pain a patient experiences, and 
time of day pain is experienced, as well as current ways of alleviating pain 
[Cleeland and Ryan, 1994]. The BPI also consists of the numeric pain rating 
scale, a simple 10-point scale (0 = ‘‘no pain’’, 10 = ‘‘pain as bad as you can 
imagine’’) measuring a patient’s worst pain and least pain, on average in 
the last 24h and at present time. The Brief Pain Inventory provides 
information on the intensity of pain (the sensory dimension) as well as the 
degree to which pain interferes with function (the reactive dimension). 
According to several previous studies on pain in spinal cord injury, the BPI 
is an effective measure [Bryce et al., 2007]. 
DN4 Assessment Tool. This is a 4-item assessment that characterizes 
neuropathic pain. 
Assessment of Mood with the Patient Health Questionnaire (PHQ-9). This 
is a 9-item scale that assesses patient quality of life through mental state. 
It identifies active suicidality [Kroenke et al., 2001]. It assists physicians in 
both diagnosing depression and determining a treatment route. It 
incorporates DSM-IV depression classifications and determines severity of 
depression [Bombardier et al., 2004; Graves and Bombardier, 2008; 
Kalpakjian et al., 2009; Krause et al., 2010]. 
 
Satisfaction with Life Scale (SWLS). This is a 5-item scale that assesses 
patient happiness with current quality of life [Diener et al., 1985]. It 
consists of a 1-7 Likert scale.  
Craig Handicap Assessment and Reporting Technique – Short Form 
(CHART-SF). This assessment is commonly used to provide an objective 
measure as to the degree by which a person with SCI remains with 
impairment or disability [Whiteneck et al., 1992]. It measures several 
domains including: the type and level of daily assistance needed on both a 
physical and cognitive level (i.e., personal care, hygiene, decision making, 
communicating with others); level of physical activity (ranging from travel 
to daily mobility); transportation needs how time is spent (i.e., 
employment, housekeeping, cooking, leisure activities); social interactions 
(including relatives, co-workers, and friends); and available financial 
resources. 
Posttraumatic Stress Symptoms (PTSS). The PTSD Checklist for DSM-5 (PCL-
5) is a 20-item self-report measure assessing symptoms of PTSD. 

MEDICAL PROTOCOL (HRP-590) 
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Participants rate how bothered they have been by each of the 20 items in 
the past month on a 5-point scale ranging from 0 (not at all) to 4 
(extremely). Scores range from 0-80, with higher scores indicating greater 
severity of PTSD symptoms. The PCL-5 is psychometrically sound in 
civilians and Veterans. 
Childhood Trauma. The Adverse Childhood Experiences Questionnaire 
(ACE-Q) is a 10-item measure to quantify instances of adverse or traumatic 
experiences that a person has had before the age of 18. The ACE-Q will be 
asked at baseline and screens for exposure to childhood psychological, 
physical, and sexual abuse as well as household dysfunction including 
domestic violence, substance use, and incarceration. 
Pittsburgh Sleep Quality Index. This is a 9-item scale that assesses sleep 
quality. 
Tampa Scale for Kinesiophobia. This is a 17-item scale that assesses fear of 
movement. 
 
Moorong Self-Efficacy Scale (MSES). This is a 16-item scale that assesses 
self-efficacy in performing functional activities of daily living individuals 
with SCI. 
Pain Catastrophizing Scale (PCS). This 13-item self-report measure is 
designed to assess catastrophic thinking related to pain among adults with 
or without chronic pain. 
Perceived Disability Index (PDI). This is a brief, self-report instrument 
developed to assess self-perception of disability. 
Penn Spasm Frequency Scale (PSFS). This is a self-report measure that 
assess a patient’s perception of spasticity frequency and severity following 
a spinal cord injury. 
 
Bladder and bowel function. Nine self-report items will assess current 
bladder and bowel functioning.  
 
Intervention Expectations. This self-report will assess what participants 
expect their outcomes to be during and after their participation in the 
study. 

MEDICAL PROTOCOL (HRP-590) 
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Study Expectancies. Participants respond to 24 items about how they think 
they will function 7 weeks from now in areas such as pain, sleep, 
participation, work, social activities, and sexual functioning.  
Concurrent Pain Medication Use. Although pain medications can confound 
the analgesic effects of brivaracetam, we consider it to be unethical to 
require participants to discontinue pharmacologic treatment for pain over 
the course of the study as a criterion for enrollment. In addition, to 
increase generalizability, it is important to recruit participants using pain 
medications. Therefore, we will record pain medication use over the 
course of the trial and consider this in the analysis. 
Pain Intensity and Medication Use Diary. We will monitor daily pain reports 
and patient medication throughout the course of the study using a Pain 
Intensity and Medication Use Diary. Participants will be asked to record 
daily pain ratings (highest pain 0-10, lowest pain 0-10, and average pain 0-
10) and any pain medication use. This diary will be started 1 week prior to 
drug treatment and maintained until completion of the study. 
Assessment of Brain Function with MRI. All scans will be performed on the 
same scanner for this study. We will use the Siemens 3-T Prisma multi-
band scanner. Prior to each scan, participants will be asked five questions 
regarding their pain now and over the last week as well as alcohol, caffeine, 
and tobacco use over the past 12 hours.  
1. Structural MRI acquisition: We will acquire a T1-weighted 
Magnetization-Prepared Rapid Acquisition with Gradient Echo 
(MPRAGE) image [Repetition Time (TR)=2.5s, Echo Time (TE)=4.5ms, 
0.8mm3 voxels], and a T2 weighted Sampling Perfection with 
Application optimized Contrasts using different flip angle Evolution 
(SPACE) image [TR=3.2s, TE=565ms, 0.8mm3 voxels]. We use special 
sequences for the scans to reduce the impact of head motion.  
 
2. Resting-state and task fMRI acquisition: The resting-state and task 
fMRI scans will be obtained with a T2*-weighted multiband echo 
planar acquisition tipped 30 degrees relative to the Anterior 
Commissure - Posterior Commissure (AC-PC) plane as determined by 
the auto-align software. This acquisition protocol is designed to 
measure whole-head BOLD-contrast with optimal temporal and spatial 
resolution, and to reduce signal dropout [TR=0.8s; TE=37ms; Flip 
Angle=55o; 72 slices; multiband factor 8; 2mm isotropic resolution]. We 
will use the Framewise Integrated Real-time MRI Monitoring (FIRMM) 

MEDICAL PROTOCOL (HRP-590) 
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Randomized, Double-Blind, Placebo-Controlled Clinical Trial  
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software to track head motion for each fMRI scan in real time. If visual 
inspection or FIRMM shows that image quality is substandard, the scan 
will be repeated immediately. After the MRI acquisition, a structured 
Quality Assurance (QA) process will occur within 72 hours to ensure 
that the data are of sufficient quality for subsequent analysis. Adhering 
to these QA procedures should result in over 95% usable data.  
 
i. Task 1: Mental body scan. Participants will be asked to focus with 
gentle, non-judgmental awareness on the sensations of the leg 
(that they experience having the most pain). In other words, they 
perform a gentle focused mental body scan and register any 
feelings of sensation in that limb. We alternate this task with rest 
periods. We chose Task 1 based on our previous study in adults 
with chronic low back pain showing OP1/OP4 and posterior 
parietal cortex activation after body awareness training during a 
similar task. Other brain imaging research showed that doing a 
mindful mental body scan significantly increases insula 
connectivity. 
ii. Task 2: Kinesthetic imagery of moving the limb. Participants will be 
asked to imagine the feeling of gently moving the painful leg (i.e., 
gentle non-judgmental awareness of any sensations during an 
imagined movement), alternated with rest. We chose this task 
based on tasks with mindfulness meditation showing insula and 
OP1/OP4 activation. 
iii. Task 3: Whole-body movement task. Participants will perform a 
kinesthetic imagery of a whole-body movement, in which the 
hands are moving away and closer to the body symmetrically with 
guided breathing after viewing a video demonstration of the 
movement. We chose task 3 based on studies that demonstrate 
substantial spatial overlap of areas activated during motor imagery 
vs. motor execution. Our prior studies showed OP1/OP4 and 
posterior parietal cortex activation during this task in adults with 
chronic low back pain. We showed stronger insula connectivity 
after CMR in adults with SCI/D. 
iv. Task 4: Sensory stimulation task of the pads of the big toes and 
thumbs with a towel. Participants will not be made aware of when 
stroking occurs and will be asked after the scan if they sensed any 
hand or foot stimulation and, if so, where exactly they felt the 
stimulation. 
v. Task 5: Finger tapping. The participant is instructed verbally to tap 
their right fingers 

MEDICAL PROTOCOL (HRP-590) 
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Randomized, Double-Blind, Placebo-Controlled Clinical Trial  
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vi. Task 6: Toe tapping. The participant is instructed verbally to tap 
their right foot. The task is alternated with rest. 
 
 
Table 1. Study Procedures 
Study Task 
Screening 
Visit 1b 
 
Visit 2b 
7-week 
intervention  
Visit 3c  
 (end of study 
testing) 
 
 Visit 4 c 
Screening Phone Survey 
X 
 
 
 
 
 
Consent/randomization 
 
X 
 
 
 
 
MRI Brain Scan (optional) 
 
 
X 
 
X 
 
Blood draw for biomarkers (optional) 
 
 
X 
 
X 
 
Physical health exam, health history 
screening 
 
X 
 
 
X 
 
Surveys 
 
X 
 
 
X 
Xc 
Dispense study drug 
 
 
X 
 
 
 
7-week drug intervention 
 
 
 
X 
 
 
Limited safety labs (blood draw, 
required) 
Xa 
 
 
 
X 
 
Pregnancy test (for women of child-
bearing potential) 
 
 
 
 
X 
 
Drug dose reduction protocol  
 
 
 
 
Xc 
 
Participant return remaining pills, 
bottle, and medication diary via mail 
 
 
 
 
Xc 
 
Adverse Events, PHQ-9, pain rating 
(highest, lowest, average) 
 
 
 
Assessed weeklyc 
 
PHQ-9: Patient Health Questionnaire 9-item 
aMedical clearance must be clinically obtained from participants’ primary care provider or other healthcare provider 
within 1 month prior to visit 1 
bVisits 1 and 2 may be combined for participant convenience  
cPerformed at the time of early withdrawal for those not completing the study 
 
Study drop criteria:  Participants will be removed from the study for safety 
reasons including drug intolerance, drug allergy, drug contraindications, 
development of depression, aggressive behavior, anxiety, or suicidality, or 
evidence of brivaracetam adverse events according to the manufacturer’s 
prescribing guide (package insert). Poor drug compliance will be recorded 
for consideration during the analysis but will not be cause for removal from 
this study.  In the case of drug intolerance, participants will reduce the drug 
dose under medical supervision of the PI until the drug can be safely 
discontinued.  
 

MEDICAL PROTOCOL (HRP-590) 
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Randomized, Double-Blind, Placebo-Controlled Clinical Trial  
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Study Duration:  
This is a 5-year study. Eligible participants will be enrolled throughout the 
duration of the study. It is anticipated that study enrollment goal will be 
met six months prior to study ending in year 5. Individual participant’s 
participation will approximately be 11 weeks from time of enrollment into 
the study. We anticipate the completion of all study procedures, including 
data analysis and results to report, will take approximately a year once the 
study has completed all data collection from study participants. 
 
Use of radiation: N/A 
 
Use of Center for Magnetic Resonance Research:  
All participants who consent to MRI testing will get a 3T structural and 
functional MRI scan at Visit 2 and after completion of the 7-week 
treatment course (Visit 3). They will use the changing room to change into 
scrubs according to the CMRR protocol.  
 
6.0 
Data and Specimen Banking 
6.1 Storage and Access:  
All data used for this project will be obtained after receiving informed 
consent from all participants. The research material collected in this project 
are in the form of: (1) magnetic resonance imaging (MRI) records, (2) 
standardized patient-rated questionnaires, clinical assessments, and (3) 
blood serum. 
Clinical data will be stored on Research Electronic Data Capture (REDCap), 
physical paper files will be kept in a locked file drawer in the study 
coordinator’s office, and on encrypted servers (Box). Participant 
confidentiality will be safeguarded by the use of password protected 
databases and locked file cabinets. Research records will be stripped of all 
identifying information, with keys identifying individual participants 
available only to the PI or selected designees. Further, access to identifiable 
private information from study participants will only be accessible to study-
related personnel who have met the training requirements for the 
responsible conduct of research, Good Clinical Practice, HIPAA, and data 
security, and who have completed all initial and annual study specific 
training. 
Blood samples will be collected at each enrolling site and stored locally in a 
-80 freezer at UMN. Blood samples will be labeled by ID number, type 
(plasma or serum), and date of draw. A password-protected tracking sheet 
will be used to link participants’ blood samples with identifiable information 

MEDICAL PROTOCOL (HRP-590) 
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Randomized, Double-Blind, Placebo-Controlled Clinical Trial  
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(i.e., date of birth).  This sheet will only be accessed by the IRB-approved 
study staff. 
At the baseline and final evaluation, we will draw 38 ml of blood (20 mL 
plasma, 18 mL serum) after an overnight fast and store it at -80° Celsius until 
batch processing in the lab of the PI. 
6.2 Data:  
All clinical assessments and standardized patient-rated questionnaires will 
be stored on Research Electronic Data Capture (REDCap) and on encrypted 
servers.  
Imaging of brain activation and connectivity (resting-state and task-based 
fMRI), will be preprocessed using the HCP preprocessing pipeline. MRI data 
will be stored in digital form on encrypted servers.  
We will bank blood serum and plasma for long-term storage. To minimize 
the risk of loss of privacy all records will be kept confidential and identified 
by study code only in the working databases. Blood samples will be stored 
without identifiers using only the study code.  
6.3 Release/Sharing:  
The results will be submitted for publication in scientific journals and 
presented at conferences. In case the scientific journals request the original 
database, the de-identified Excel file with scoring and codes will be shared 
on their protected databases. 
7.0 
Sharing of Results with Participants 
7.1 Sharing Results:  
No information will be provided to the participant unless the information 
indicates that the participant may be at risk for a serious illness known at the 
time of testing to be treatable. In that case, the study doctor will attempt to 
notify the participant. The research participant and their clinical care 
person(s) are responsible for further evaluation/follow-up in response to 
MRI incidental findings. Participants will be given the option to opt out of 
receiving any incidental findings. 
7.2 Sharing Genetic Results: N/A 
 
7.2.1 Disclosure of Results: N/A 
 
7.2.2 Returning Results to Participants: N/A 
 

MEDICAL PROTOCOL (HRP-590) 
PROTOCOL TITLE: Brivaracetam to Reduce Neuropathic Pain in Chronic SCI: A 
Randomized, Double-Blind, Placebo-Controlled Clinical Trial  
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Aggregate or individual results: N/A 
 
Laboratory results: N/A 
 
Plan for return of results to participants: N/A 
  
Types of results to be returned to participants: N/A 
 
7.2.3 Future analysis of genotypes: Future genome sequencing may be 
conducted but will not be used for clinical diagnosis and will not have any 
clinical utility.  
 
8.0 
Study Population 
Inclusion Criteria:  
 18 years of age or older 
 Injured for > 3 months 
 Completed inpatient rehabilitation and living in the community 
 Chronic sublesional neuropathic pain defined as persistent pain (VAS 
grade 3-10) for three months or more 
 For people of child-bearing potential: currently practicing an effective 
form of two types of birth control (defined as those, alone or in 
combination, that result in a low failure rate (i.e., less than 1% per year) 
when used consistently and correctly). 
 
Exclusion Criteria:  
 Progressive myelopathy secondary to posttraumatic cord tethering or 
syringomyelia 
 Active use of drugs known to interact with brivaracetam: rifampin, 
carbamazepine, sodium oxybate, buprenorphine, propoxyphene, 
levetiracetam, and phenytoin.  
 Brain injury or cognitive impairment limiting the ability to follow 
directions or provide informed consent 
 Pregnancy or lactation 
 Epilepsy or active treatment for seizure disorder 
 Past or current suicidality 
 Active treatment for psychiatric disease 
 Drug addiction 
 Moderate or heavy alcohol intake (up to four alcoholic drinks for men 
and three for women in any single day, and a maximum of 14 drinks for 
men and 7 drinks for women per week) 

MEDICAL PROTOCOL (HRP-590) 
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Randomized, Double-Blind, Placebo-Controlled Clinical Trial  
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 Hepatic cirrhosis, Child-Pugh grades A, B, and C  
 Impaired renal function (GFR<60ml/minute) 
 Contraindications to brivaracetam or pyrrolidine derivatives including 
allergy 
 Active clinically significant disease (e.g., renal, hepatic, neurological, 
cardiovascular, pulmonary, endocrine, psychiatric, hematologic, 
urologic, or other acute or chronic illness) that, in the opinion of the 
investigator, would make the patient an unsuitable candidate for this 
trial. 
 History of malabsorption or other gastrointestinal (GI) disease that 
may significantly alter the absorption of brivaracetam 
 Use of any investigational drug 30 days prior to enrollment in this study 
 Dependent on mechanical ventilation. 
 Use a gastrostomy tube (G-Tube) for feeding.  
 Enrollment in another clinical trial. 
 
People with contraindications to MRI including retained bullet fragments, 
noncompatible metal implants, and implanted devices such as non-MRI 
compatible baclofen pumps may still be eligible for the study; they will not 
participate in the MRI scans. 
 
Screening: 
A phone screen will be administered to confirm basic eligibility criteria 
listed in Section 8.1 such as age, pain level, medication use, and other 
medical conditions. For those that agree to have an MRI, we will screen 
participants for contra-indications for MRI compatibility with the CMRR 
pre-screening questionnaire. If participant meets basic eligibility 
requirements, we will request that they obtain medical clearance for study 
participation from their primary care provider or other medical 
professional, including collecting 3-4 tablespoons of blood for screening 
blood work (described in detail below) and completing a physical exam and 
health history. This must be conducted within 1 month (or up to 6-weeks) 
of Visit 1. The participant’s insurance will be charged, and they will be 
responsible for any associated copays or costs.   
The participant’s provider will send research staff the results via fax or 
email, or the participant may carry a hard copy to Visit 1. If a patient is part 
of the enrolling site’s system of care, their medical records will be accessed 
directly by research staff who have obtained the appropriate approvals 
(e.g., NERS approval).  

MEDICAL PROTOCOL (HRP-590) 
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Randomized, Double-Blind, Placebo-Controlled Clinical Trial  
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Screening bloodwork for hepatic cirrhosis, renal insufficiency, and 
pregnancy. Brivaracetam treatment is not safe for those who are pregnant, 
have hepatic cirrhosis, or kidney dysfunction. Therefore, to be medically 
cleared to enter the study, participants must complete a fasting blood 
draw through their primary care clinic for analysis of blood urea nitrogen 
(BUN), creatinine, alanine transaminase (ALT), aspartate transaminase 
(AST), total bilirubin, albumin, GFR, calcium, corrected calcium, and human 
chorionic gonadotropin (hCG); urine hCG test will also be accepted. 
International normalized ratio (INR) will be collected at the discretion of 
the participant’s primary care provider if the participant is on 
anticoagulation or has abnormal liver function tests. People who are 
menopausal and have not had a menstrual period for at least 12 months, 
or people who have had a hysterectomy will not be required to take 
pregnancy tests. We will use lab work performed clinically during any 
recent visit (within one month or up to 6-weeks of testing) for screening 
labs when available. Any participant found to have renal insufficiency 
(GFR<60ml/minute), hepatic cirrhosis, Child-Pugh grades A, B, and C, or 
pregnant (positive hCG) will be considered a screen fail and will not 
progress in the study. 
 
9.0 
Vulnerable Populations 
Vulnerable Populations:  
Population / Group 
Identify whether any of the 
following populations will be 
targeted, included (not necessarily 
targeted) or excluded from 
participation in the study.  
Children 
Excluded from Participation 
Pregnant women/fetuses/neonates 
Excluded from Participation 
Prisoners 
Excluded from Participation 
Adults lacking capacity to consent 
and/or adults with diminished 
capacity to consent, including, but 
not limited to, those with acute 
medical conditions, psychiatric 
disorders, neurologic disorders, 
developmental disorders, and 
behavioral disorders 
Excluded from Participation 

MEDICAL PROTOCOL (HRP-590) 
PROTOCOL TITLE: Brivaracetam to Reduce Neuropathic Pain in Chronic SCI: A 
Randomized, Double-Blind, Placebo-Controlled Clinical Trial  
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Non-English speakers 
Included/Allowed to Participate 
Those unable to read (illiterate) 
Included/Allowed to Participate 
Employees of the researcher 
Excluded from Participation 
Students of the researcher 
Excluded from Participation 
Undervalued or disenfranchised 
social group 
Included/Allowed to Participate 
Active members of the military 
(service members), DoD personnel 
(including civilian employees) 
Included/Allowed to Participate 
Individual or group that is 
approached for participation in 
research during a stressful situation 
such as emergency room setting, 
childbirth (labor), etc. 
Excluded from Participation 
Individual or group that is 
disadvantaged in the distribution of 
social goods and services such as 
income, housing, or healthcare. 
Included/Allowed to Participate 
Individual or group with a serious 
health condition for which there are 
no satisfactory standard treatments. 
Targeted Population 
Individual or group with a fear of 
negative consequences for not 
participating in the research (e.g. 
institutionalization, deportation, 
disclosure of stigmatizing behavior). 
Excluded from Participation 
Any other circumstance/dynamic 
that could increase vulnerability to 
coercion or exploitation that might 
influence consent to research or 
decision to continue in research. 
Excluded from Participation 
 
Additional Safeguards:  

MEDICAL PROTOCOL (HRP-590) 
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Randomized, Double-Blind, Placebo-Controlled Clinical Trial  
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This project aims to research an intervention that may help vulnerable 
adults with spinal cord injuries reduce severe neuropathic pain, a severe 
health condition. To provide additional safeguards to protect individuals 
that may be vulnerable we: 
 Will provide assurance of confidentiality, freedom to decline to 
participate, right to withdraw at any time without penalty. 
 Engaged the SCI community in the planning of this research. 
 We have assessed the permissibility of the physician-investigator 
to obtain consent for research. 
 We will emphasize the risks and demands of this study 
participation to potential participants. 
 We will provide short forms and a translator to individuals who 
are unable to read or speak in English.  
 Groups included in the research where participant status in the 
group might be unknown (incidental enrollment), as group status 
is not solicited by the research team (ex: military status, if study 
teams don't ask and it doesn't impact the research):  
The vulnerable population groups that are allowed to participate will not 
be identified and information will not be collected as to a patient’s 
vulnerable population status.  This research does not add risk to this group. 
 
10.0 Local Number of Participants 
Local Number of Participants to be Consented: 
We expect to screen 200 individuals to enroll 48 participants. We expect 
20% attrition, therefore we anticipate a total of 40 participants will 
complete the study. 
 
We anticipate enrolling a minimum of 12 participants and up to a 
maximum of 48 participants. 
 
11.0 Local Recruitment Methods 
Recruitment Process:  
The UMN healthcare system treats hundreds of patients with SCI each 
year. Given the large pool available for recruitment, we anticipate no 
difficulty in recruiting sufficient numbers of persons with SCI who meet the 
inclusion/exclusion criteria. Recruitment material will accurately reflect 
the study and will not be coercive. 
For self-referrals from recruitment materials: 

MEDICAL PROTOCOL (HRP-590) 
PROTOCOL TITLE: Brivaracetam to Reduce Neuropathic Pain in Chronic SCI: A 
Randomized, Double-Blind, Placebo-Controlled Clinical Trial  
VERSION DATE: v7.0 APR2024 
 
 
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Participants may self-refer if they become aware of the study through 
recruitment materials, clinicaltrials.gov (or similar websites), or word of 
mouth referrals. A study-specific webpage will be published. A link to a 
REDCap online survey will be shared for individuals to indicate their 
interest and preferred contact method. Participants will self-enter their 
contact information prior to consent for contact purposes only. 
Potential participants will be identified by Co-Investigators from patients 
under their care and their colleagues. Potential participants will be asked 
about their interest in the study at the time of a routine care visit. If 
interested, the patient will be given the choice to be approached by the 
investigator in person, over phone, or via e-mail, or have reach out to the 
investigator themselves.  A flyer or recruitment card about the study may 
be sent to potential participants, asking them to contact study staff if they 
are interested. 
Individuals who respond to the recruitment materials will complete a 
phone screen with study staff. If following the phone screen, the potential 
participant is eligible and interested, they will be required to seek medical 
clearance from their primary care physician, including a screening blood 
draw, one month prior to study Visit 1.  
 
Regional Healthcare Institutions: 
Contacts at regional healthcare institutions that have partnered with the 
University of Minnesota in previous SCI research will be made aware of this 
research, including the VA. Flyers and/or postcards/recruitment cards will 
be posted around campus, at the VA, on the UMN website (e.g., Brain Body 
Mind Lab website) and on social media with information about this study. 
Patient Representative Organizations (PRO): 
Recruitment information about this study will be provided to PRO’s that 
will include sample text and flyers so they may distribute information 
about this study to their participating community members living with SCI. 
PRO’s commonly use social media, newsletters, and share information at 
peer support groups to distribute information about the clinical trial.  
Targeted PRO’s will include but will not be limited to Get Up Stand Up to 
Cure Paralysis, Minnesota Spinal Cord Injury Association, and Morton Cure 
Paralysis.  
 
University of Minnesota Spinal Cord Injury Research Recruitment Registry:  
We will utilize the Spinal Cord Injury Research Recruitment Registry 
managed by the UMN Department of Rehabilitation Medicine to help 

MEDICAL PROTOCOL (HRP-590) 
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facilitate enrollment. We will filter individuals in the registry based on 
inclusion/exclusion criteria and contact them via email or phone about this 
research opportunity. 
 
Online Clinical Trial Registries:  
This clinical trial will be listed on www.clinicaltrials.gov, www.scitrials.org, 
and other similar websites that assist community members to find and 
contact information about clinical trials. 
 
Local Community Presentations:  
The study team may hold presentations (digital or in-person) about this 
research and other projects and research results which may inform 
community members about this clinical trial which may result in 
recruitment. 
 
Social Media:  
Digital media may be shared on different social media platforms to notify 
potential participants about the clinical trial and how to contact the study 
team. 
Fairview Recruitment Mailing and MyChart Messaging:  
We will work with Fairview Research Services to identify individuals with 
SCI in the system and send recruitment mailings through the mail and/or 
MyChart messages, pending approval from the Fairview Research 
Administration. Patients who have opted out of having their records used 
for research will not be included. 
 
Identification of Potential Participants:  
Participants will be identified from the clinical partnerships listed in section 
11.1. Study PI and physicians from our clinical partnerships will identify 
potential participants from their patient pools. These physicians have 
access to potential study participants’ medical records and knowledge of 
their health history. Study staff will conduct prescreening over the phone 
or in-person to confirm eligibility at each site. 
Approaching potential participants in clinic: 
Potential participants will be identified by the Co-Investigator (Dr. Leslie 
Morse) and her team from among patients under her team’s care and that 
of their colleagues who have legitimate access to their medical records. 
Through BPIC involvement, EPIC will be searched on the hits provided by 
BPIC. If eligible, a mailing will be sent out. 
 
Participants self-referred from recruitment materials: 

MEDICAL PROTOCOL (HRP-590) 
PROTOCOL TITLE: Brivaracetam to Reduce Neuropathic Pain in Chronic SCI: A 
Randomized, Double-Blind, Placebo-Controlled Clinical Trial  
VERSION DATE: v7.0 APR2024 
 
 
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Potential participants will self-identify in response to flyer announcements 
via professional associations or support groups/word to mouth or other 
means. 
 
We will use following approaches to identify participants through self-
referrals: 
 Postings on StudyFinder, a website managed by the UMN CTSI’s 
Recruitment Center 
 Postings on clinicaltrials.gov 
 Identification via UMNs Research Match, an electronic volunteer 
recruitment registry 
 Postings, flyers, or recruitment cards at the University of 
Minnesota and local rehabilitation centers; relevant websites and 
on professional social media sites (e.g., Facebook, Twitter). 
 
Recruitment Materials:  
The following recruitment materials will be used in this study: flyers or 
recruitment cards. 
 
Payment:  
Participants will receive up to $350 for their time, effort, and to assist with 
transportation. Participants will receive $150 after baseline testing (Visit 
2), $150 after end of study testing (Visit 3), and $50 after Visit 4. 
 
12.0 Withdrawal of Participants 
Withdrawal Circumstances:  
At any time after enrollment, a participant may be discontinued. Reasons 
for discontinuation of a participant from the study will include, but may 
not be limited to, the following: 
 The participant is found to be intolerant to a required study 
procedure at any time point 
 Failure of the participant to adhere to protocol requirements 
 Positive hGC for individuals of childbearing potential 
 The participant experiences a serious adverse experience at any time 
point  
 The participant develops an inter-current illness that would, in the 
judgment of the investigator, affect assessments of clinical status to 
a significant degree.  
 The participant enrolls in another investigational study 
 The participant requests to withdraw from the study 
 

MEDICAL PROTOCOL (HRP-590) 
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Randomized, Double-Blind, Placebo-Controlled Clinical Trial  
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Withdrawal Procedures:  
The PI and study physician will work closely with any participant wishing to 
withdraw from the study to ensure that the study drug is tapered 
appropriately and safely.  
Termination Procedures:  
Participation may be terminated due to drug intolerance or allergy and 
based on clinical judgement of the study team. All data collected will be 
retained and analyzed unless the participant specifically requests to have 
their data withdrawn from the analysis.  
 
13.0 Risks to Participants 
Foreseeable Risks:  
There is a risk of drug intolerance including allergy, suicidal behavior and 
ideation, somnolence and fatigue, psychotic symptoms, irritability, 
depression, loss of coordination/balance, constipation, aggressive 
behavior, and anxiety. All participants and caregivers will be educated to 
notify the PI or a health care provider if mood changes or suicidal behavior 
is observed.  There is the risk of lowered seizure threshold for rapid drug 
withdrawal without tapering. There is some discomfort with venipuncture 
and there is the possibility of swelling and bruising at the site. There is also 
a slight chance that individuals become dizzy or faint. There are potential 
risks of loss of privacy and confidentiality. All participants will be 
encouraged to contact study staff, or an investigator regarding any side 
effects or adverse events that occur. 
 
MRI  
MRI machines use a strong magnet and radiofrequency magnetic fields to 
take images of your body. The scanning process is similar to an x-ray or CT 
scan, but MRI does not use ionizing radiation (high-energy radiation that 
can potentially cause damage to DNA) like x-rays or CT scans. The risks 
associated with MRI scans are: 
o Projectiles:  Objects with magnetic properties can be pulled into 
the magnet and turn into projectiles. To minimize this risk, we 
ask that participants remove all metallic items (watches, cell 
phones, hair pins, etc.) prior to entering the scanner and by 
controlling access to the scanner.   
o Claustrophobia:  The scanner is a long narrow tube that may 
cause some people to feel claustrophobic.   
o Hearing Damage:  The noise generated by the operation of the 
scanner during a study is loud enough to cause hearing damage 

MEDICAL PROTOCOL (HRP-590) 
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if hearing protection is not worn. Hearing protection is required 
and is provided by the investigator.  
o Nerve Stimulation:  Some people experience localized tingling, 
twitching, or muscle contractions during MRI scans. We ask the 
participants to notify the investigator if this sensation is 
uncomfortable. 
o Disruption of Devices:  Some devices can be damaged by 
magnetic fields and should not be brought into the scanner 
room. This includes some implanted devices such as 
pacemakers, 
cochlear 
implants, 
insulin 
pumps, 
nerve 
stimulators, etc. If participants have any implanted device, they 
are asked to notify the investigator. 
o Heating of Devices:  The radiofrequency waves used in MRI can 
heat conductive materials. "The research team will utilize the 
CMRR Center’s screening tools and adhere to the screening SOP 
during enrollment of all research participants in this 
protocol.  The CMRR Center’s screening tools and SOP are IRB 
approved under the CMRR Center Grant (HSC# 1406M51205) 
and information regarding screening procedures is publicly 
available on the CMRR website (CMRR Policies / Procedures). 
 
Venipuncture 
There is some discomfort with venipuncture and there is the possibility of 
swelling, inflammation, and bruising at the site, and, in rare cases, the risk 
of infection. There is also a slight chance that individuals become dizzy or 
faint. All blood draws completed at the study site will be performed by a 
trained technician following standard clinical protocols to minimize risks.  
 
Risks Associated with Breach of Confidentiality 
There is a risk of breach of confidentiality. Multiple measures will be taken 
to minimize this risk. All information that could be used to identify a 
participant will be kept in a secure and locked space accessible only by the 
trained study coordinator and the principal investigator. All of these 
documents will be kept in locked file cabinets, in locked offices, at all times. 
Also kept secure and separate from other files will be the unique ID for 
each participant. Information collected will be stored on Box Secure 
Storage or REDCap. The computers used are password-protected and will 
only be used by trained study staff and for study purposes only. All blood 
samples are uniquely coded by number and are “de-identified.” Blood 
samples collected to test for biomarkers will be stored behind locked doors 
in on-site freezers for an indefinite period of time with only coded numbers 

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as the key to identity. The key to the codes will be available only to selected 
investigators. Participants wishing to withdraw their samples from the 
study may do so at any time by notifying the investigators in writing. There 
is also a small chance that, if participants engage in a videoconference 
through the Zoom for Healthcare platform, the Zoom session could be 
hacked.  
 
Participant monitoring  
Study staff will monitor and respond to reports regarding adverse events 
collected during sessions and on self-report questionnaires. Adverse 
events will also be assessed once per week throughout the study over the 
phone and entered into a REDCap form. Participants will also be instructed 
to contact the investigators and/or study staff if they experience a serious 
adverse event. If an event occurs, protocols for adverse event classification 
and reporting will be followed. 
 
Participant confidentiality  
Procedures are in place for maintaining the full confidentiality of all 
information collected. Participant confidentiality will be protected by 
securing all hard copy study files in locked filing cabinets. Electronic files 
containing personal identifiers will be stored on Box Secure Storage or 
REDCap. All study staff receive training on privacy standards for 
maintaining participant confidentiality. All published reports will be of 
summary nature and no individual participants will be identified beyond 
the investigative staff involved in the project. Electronic data management 
is described above (see ‘Data Coordination’). 
 
Reproduction Risks:  
Pregnancy  
We are excluding pregnant or lactating people from this study. 
 
Risks to Others: N/A 
 
14.0 Potential Benefits to Participants 
Potential Benefits:  
Because this study will be used to develop clinical trials for testing 
pharmacological interventions to treat neuropathic pain in SCI, there is a 
potential future benefit to the spinal cord population.  
 
15.0 Statistical Considerations 
15.1 Data Analysis Plan:  

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For Aim 1, the first step for each outcome variable (e.g., pain,) is an 
unadjusted comparison across the groups as randomized. Each of the 
outcome variables uses a pre-defined instrument which has both top and 
bottom boundaries. These bounds are, however, wide enough so that the 
first steps will ignore the boundaries. The first analysis in each case is an 
unadjusted analysis and will be done in two ways: (1) a t-test (assuming 
unequal variances) and (2) a rank-sum test to take advantage of the Mann-
Whitney score, which provides the probability that one group will have 
scores greater (less) than the other group. This statistic is the same as the c 
statistic widely used after logistic regression. The next step for each outcome 
is regression model with the main predictor being an indicator group. 
Standard covariates (e.g., demographics, and measures relevant to SCI such 
as severity and time since injury) will be included in the analysis. Robust 
estimator of the standard errors will be used. Predicted values will be 
checked to see whether any, and, if so, how many, are outside the 
boundaries of the measure used for that outcome. As a sensitivity analysis, 
regression models that recognize the boundaries will be used (e.g., fractional 
logistic regression or two-limit Tobit models). The main analysis will be 
Intention-to-Treat. 
 
For Aim 2, we will use the same analytic approach we have refined in our 2 
active rsfMRI studies and our ongoing task-based and rsfMRI study in adults 
with SCI and neuropathic pain.  
 
Structural Preprocessing: We will perform preprocessing using the latest 
containerized fMRI preprocessing pipeline (FMRIPREP) version with 
standardized Brain Imaging Data Structure (BIDS) formatted Neuroimaging 
Informatics Technology Initiative (NIFTI) data. Each T1-weighted (T1w) 
volume will be corrected for intensity non-uniformity (INU) using 
N4BiasFieldCorrection and skull-stripped using antsBrainExtraction.sh (using 
the OASIS template). Brain surfaces will be reconstructed using recon-all 
from FreeSurfer, and the brain mask estimated will be refined with a custom 
variation of the method to reconcile Advanced Normalization Tools (ANTs)-
derived and FreeSurfer-derived segmentations of the cortical gray-matter of 
Mindboggle. Spatial normalization to the International Consortium for Brain 
Mapping (ICBM) 152 Nonlinear Asymmetrical template will be performed 
through non-linear registration with the Registration tool of ANTs using 
brain-extracted versions of T1w volume and template. 
 
fMRI Preprocessing: We will perform preprocessing with the latest 

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containerized FMRIPREP85 version with standardized BIDS formatted NIFTI 
data. Functional data will be slice time corrected using 3dTshift from Analysis 
of Functional NeuroImages (AFNI) and motion corrected using mcflirt. This is 
followed by co-registration to the corresponding T1w using boundary-based 
registration with 9 degrees of freedom, using bbregister (FreeSurfer). 
Motion correcting transformations, field distortion correcting warp, BOLD-
to-T1w transformation and T1w-to-template (Montreal Neurological 
Institute, MNI) warp will be concatenated and applied in a single step using 
antsApplyTransforms 
(ANTs 
v2.1.0) 
using 
Lanczos 
interpolation. 
Physiological noise regressors will be extracted by applying CompCor. 
Principal components will be estimated for the two CompCor variants: 
temporal (tCompCor) and anatomical (aCompCor). Framewise displacement 
and DVARS90 will be calculated for each functional run using the 
implementation of Nipype. Independent Component Analysis (ICA)-based 
Automatic Removal Of Motion Artifacts (AROMA) will be used to generate 
aggressive noise regressors and to create a variant of data that is non-
aggressively denoised. 
 
For Aim 3, we will analyze miRNA expression profiles for raw cycle threshold 
(Ct) values using real-time Statminer software (Integromics, Inc) to identify 
significantly altered miRNAs. For relative quantification of miRNAs between 
placebo and brivaracetam-treated samples, the following steps will be 
performed in the Statminer software suite: quality control of biological 
replicates, filtering of miRNAs expression having Ct values below cycles and 
the detection of expression in all biological replicates of calibrator and 
target. Statistically significant miRNAs will be selected based on stringent 
parameters such as Benjamin-Hochberg FDR and data will be conservatively 
selected with adjusted p-values and p-value lower than 0.01 and 0.05, 
respectively. Functional pathway analysis of altered miRNAs and their 
association with genes related to reduction in neuropathic pain will be 
performed using Ingenuity Pathway Analysis (IPA) program (Ingenuity 
Systems Inc., Redwood City, CA). For clinical correlation analysis, data 
comparing changes in miRNA expression will be described as means with 
standard error of the mean. To analyze the differences between group 
means we will use analysis of variance after assessing for distribution and 
variance. We will use Games-Howell test for multiple comparisons. 
 
15.2 Power Analysis: 
We present power and sample size analysis for the primary endpoint; a 2-
point improvement in neuropathic pain intensity as assessed by the 

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International Spinal Cord Injury Pain Basic Dataset. We based our sample size 
calculation on variations in pain intensity observed in an ongoing clinical trial 
(DoD W81XWH-14-SCIRP-CTA, Morse PI). In this sample, average 
neuropathic pain intensity in 28 adults with SCI was 3.43+3.17. Based on this, 
a sample size of 20 per arm will have more than 80% power to detect a 
significant difference in pre-post changes of neurological pain between the 
two arms at a two-sided significance α level of 0.05. This sample size is 
sufficient to address the exploratory analyses proposed in Aims 2-3. 
 
15.3 Statistical Analysis: 
All statistical analyses will be conducted with Stata v. 1771 or SAS v.9.472 
assuming a 5% level of significance unless otherwise stated. Participant 
characteristics will be described using frequency counts and percentages 
(nominal variables) and means/standard deviations (SDs) or medians and 
interquartile ranges (IQRs) (continuous variables). Chi-square tests and t-
tests or rank-sum tests will be used to compare the subject characteristics 
between the treatment arms. 
Aim 2 statistical analysis 
FMRI data will be processed using the conn functional connectivity toolbox 
with established standardized controls for multiple comparisons (SPM family 
wise error correction methods). Data will undergo realignment, scrubbing, 
artifact detection, and CompCor denoising. Primary analyses will focus on 
OP1/OP4 and insula regions-of-interest for resting-state connectivity and 
exploratory multivariate pattern analyses. Task-based fMRI will undergo the 
same preprocessing pipeline and will be modeled with a general linear 
model. Within-group pre-post changes in task-based brain activation and 
resting-state connectivity will be tested using paired t-tests or Wilcoxon 
signed-rank tests.  
 
Between-group differences of pre-post changes in these measures will be 
tested using 2 sample t-tests or Mann-Whitney U tests. Mixed effects models 
with correlated errors will also be used to test the effect of CMR on brain 
imaging outcomes after adjusting for potential confounders, which will 
include the subject-level effect, time, group indicator, and time-by-group 
interaction as predictors, and age, race, and other covariates as appropriate. 
We will use False Discovery Rate (FDR) correction to control for the overall 
Type 1 errors for the voxel-level analyses. We will test the correlation 
between changes in brain function and clinical measures of sensory and 

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motor function using Pearson’s correlations coefficients with 95% 
confidence interval calculated based on Fisher’s Z transform. 
15.4 Data Integrity: 
Study staff will collect and store data. Data will be collected electronically or 
on paper forms. All electronic data will be stored on Box Secure Storage or 
REDCap. Paper forms will only be accessible by the study staff, trained study 
coordinator, and the principal investigator. All paper documents will be kept 
in locked file cabinets in locked offices at all times. Participant names, 
contact information, health history, and other information that can be 
traced back to the participant will be kept separately from data collected for 
the study. Personal information will be kept in a locked office and away from 
data or in a separate folder on Box Secure Storage. Protocol sheets used 
during data collection will only have the participant’s ID.  
 
 
 
Data integrity of the data acquisition will be tested at the time of acquisition. 
Both the MRI technician and the PI or study staff will be present to monitor 
the data in real life. 
 
All study records will be kept indefinitely after the study is closed. Research 
records will be stored in a manner to protect the confidentiality of 
participant information.  
 
Drs. Battaglino and Morse will review data monthly. They will be responsible 
for monitoring the completeness of all data and source documents as well 
as monitoring the informed consent procedures. Checklists and note pages 
are used to note any deviations or omissions from the protocols. Any 
deviation to the protocol that may have an effect on the safety or rights of 
the volunteer, or the integrity of the study will be promptly reported to the 
IRB. 
 
16.0 Health Information and Privacy Compliance 
16.1 
Select which of the following is applicable to your research: 
☐ My research does not require access to individual health information.   
☒ I am requesting that all research participants sign a HIPCO approved 
HIPAA Disclosure Authorization to participate in the research (either 
the standalone form or the combined consent and HIPAA 
Authorization). 
☐ I am requesting the IRB to approve a Waiver or an alteration of 
research participant authorization to participate in the research. 

MEDICAL PROTOCOL (HRP-590) 
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Appropriate Use for Research:  
 
 
Identify the source of Private Health Information you will be using for your 
research (Check all that apply)   
☐ I will use the Informatics Consulting Services (ICS) available through 
CTSI (also referred to as the University's Information Exchange (IE) or 
data shelter) to pull records for me 
☒ I will collect information directly from research participants. 
☐ I will use University services to access and retrieve records from the 
Bone Marrow Transplant (BMPT) database, also known as the HSCT 
(Hematopoietic Stem Cell Transplant) database. 
☒ I will pull records directly from EPIC. 
☐ I will retrieve record directly from axiUm / MiPACS 
☐ I will receive data from the Center for Medicare/Medicaid Services  
☐ I will receive a limited data set from another institution  
☒ Other.  Describe: 
A screening phone survey to determine eligibility will be completed and 
stored in paper format and/or in REDCap. After consent, a health survey 
will be collected in paper format and stored in the participants study file. 
16.2 
Explain how you will ensure that only records of patients who have 
agreed to have their information used for research will be reviewed. 
The team will access PHI for screening purposes according to institutional 
policies.  The team will access and record PHI for data collection only after 
receiving permission from each enrolled study participant. 
 
16.3 
Approximate number of records required for review: 60 
 
16.4 
Please describe how you will communicate with research participants 
during the course of this research.  Check all applicable boxes 
☐ This research involves record review only. There will be no 
communication with research participants. 
☐ Communication with research participants will take place in the course 
of treatment, through MyChart, or other similar forms of communication 
used with patients receiving treatment.  

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☒ Communication with research participants will take place outside of 
treatment settings. If this box is selected, please describe the type of 
communication and how it will be received by participants.  
We will conduct prescreening over the phone or in person in a private 
setting.  We will communicate regarding scheduling and other important 
study information via phone, text, Zoom for Healthcare, email, or written 
communication, based on participant preference. Our communication 
plan will be clearly presented in the consent form. 
16.5 
Explain how the research team has legitimate access to 
patients/potential participants: 
Each site’s PI and team will cover recruitment from all outpatient locations 
within their geographical catchment area. Only individuals who have opted 
in for research contact will be approached.  
 
Location(s) of storage, sharing and analysis of research data, including any 
links to research data (check all that apply).   
☐ In the data shelter of the Information Exchange (IE)  
 
☐ Store 
☐ Analyze 
☐ Share 
☐ In the Bone Marrow Transplant (BMT) database, also known as the 
HSCT (Hematopoietic Stem Cell Transplant) Database  
 
☐ Store 
☐ Analyze 
☐ Share 
☒ In REDCap (recap.ahc.umn.edu)  
 ☒ Store 
☒ Analyze 
☒ Share 
☐ In Qualtrics (qualtrics.umn.edu) 
 ☐ Store 
☐ Analyze 
☐ Share 
☒ In OnCore (oncore.umn.edu)  
 ☒ Store 
☒ Analyze 
☒ Share 
☒ In the University’s Box Secure Storage (box.umn.edu) 
 ☒ Store 
☒ Analyze 
☒ Share 
☐ In an AHC-IS supported server. Provide folder path, location of server 
and IT Support Contact: 
 ☐ Store 
☐ Analyze 
☐ Share 
☒ In an AHC-IS supported desktop or laptop.  

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Name 
UMN Device # 
Dr. Ricardo Battaglino  
20190593 
Nguyen Nguyen  
20230504 
Rob Wudlick  
20192649 
Brian DeVries 
20200957 
 
☒ Other: 
MSI (Minnesota SuperComputer Institute) to analyze the MRI Data in a 
secure way and share the data location in a secure way. This platform is 
needed because the MRI datafiles are very large. MRI data acquisition will 
not contain personal health information.   
Indicate if data will be collected, downloaded, accessed, shared, or stored 
using a server, desktop, laptop, external drive or mobile device (including a 
tablet computer such as an iPad or a smartform (iPhone or Android 
devices) that you have not already identified in the preceding questions 
☐I will use a server not previously listed to collect/download research data 
☐I will use a desktop or laptop not previously listed 
☐I will use an external hard drive or USB drive (“flash” or “thumb” drives) 
not previously listed  
☐I will use a mobile device such as a tablet or smartphone not previously 
listed 
16.6 Consultants. Vendors. Third Parties:  - 
LC Sciences 
We will send blood serum samples to LC Sciences (Houston, TX) to perform 
microRNA analysis (non-genomic analysis). LC Sciences will have access to 
de-identified data only. 
 
REDCap eConsent  
The informed consent form and HIPAA form will be signed with an 
eSignature using REDCap. The REDCap eConsent process is a 21 CFR Part 11 
compliant method for electronic signature capture. For more information on 
REDCap compliance, please visit:  
  
https://redcap.ahc.umn.edu/surveys/?s=3PT9FY73NC&topics___ec=1#ec 
 

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Links to identifiable data:  
The research data will be collected on RedCap and on the MRI. Those data 
will not contain personal identifiable information. Only the PIs and 
designated study staff will have a document that links the name with the 
code, which will be kept secure on the University Box secure storage. 
 
Sharing of Data with Research Team Members:  
Only deidentified data will be shared with team members. The PIs and 
clinical trial coordinators will have access to identifiable information for 
contact purposes.  
Storage and Disposal of Paper Documents:  
Documents will be stored in a secure closet behind secure doors in the PI 
and Co-PI’s offices and labs. Documents that need to be disposed will be 
disposed of in secure bins and then shredded. 
 
17.0 Confidentiality 
Data Security: 
Clinical data will be stored on Research Electronic Data Capture (REDCap) 
and on HIPAA protected encrypted servers. Participant confidentiality will 
be safeguarded by password protected databases and locked file cabinets. 
Research records will be stripped of identifying information, with keys 
identifying participants available only to the PI or selected study-related 
personnel who have met the necessary Responsible Conduct of Research, 
HIPAA, human participants, data security and study specific training 
requirements. Brain imaging will be acquired via standardized protocols. 
Brain imaging will be acquired via standardized protocols. MRI data 
acquisition will not contain personal health information. The MRI data will 
be stored in digital form on encrypted servers. 
 
Information about study participants will be kept confidential and 
managed according to the requirements of the Health Insurance 
Portability and Accountability Act of 1996 (HIPAA). Those regulations 
require a signed participant authorization informing the participant of the 
following:  
 What protected health information (PHI) will be collected from 
participants in this study  
 Who will have access to that information and why 
 Who will use or disclose that information 
 The rights of a research participant to revoke their authorization for 
use of their PHI.  
 

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In the event that a participant revokes authorization to collect or use PHI, 
the investigator, by regulation, retains the ability to use all information 
collected prior to the revocation of participant authorization. For 
participants that have revoked authorization to collect or use PHI, 
attempts should be made to obtain permission to collect at least vital 
status (i.e., that the participant is alive) at the end of their scheduled study 
period. 
 
Procedures are in place for maintaining the full confidentiality of all 
information collected. Participant confidentiality will be protected by 
securing all hard copy study files in locked filing cabinets. Electronic files 
containing personal identifiers will be stored on Box Secure Storage or 
REDCap. All study staff receive training on privacy standards for 
maintaining participant confidentiality. All published reports will be of 
summary nature and no individual participants will be identified beyond 
the investigative staff involved in the project.   
 
REDCap includes a complete suite of features to support HIPAA 
compliance, including a full audit trail, user-based privileges, and 
integration with the institutional LDAP server. The MySQL database and 
the web server will both be housed on secure servers operated by the 
UMN Academic Health Center’s Information Systems group (AHC-IS). The 
servers are in a physically secure location on campus and are backed up 
nightly, with the backups stored in accordance with the AHC-IS retention 
schedule of daily, weekly, and monthly tapes retained for 1 month, 3 
months, and 6 months, respectively. Weekly backup tapes are stored 
offsite. The AHC-IS servers provide a stable, secure, well-maintained, and 
high-capacity data storage environment, and both REDCap and MySQL are 
widely-used, powerful, reliable, well-supported systems. Access to the 
study's data in REDCap will be restricted to the members of the study team 
by username and password. 
 
The informed consent form and HIPAA form will be signed with an 
eSignature using REDCap. The REDCap eConsent process is a 21 CFR Part 
11 compliant method for electronic signature capture. For more 
information on REDCap compliance, please visit:  
 
https://redcap.ahc.umn.edu/surveys/?s=3PT9FY73NC&topics___ec=1#ec 
 
Data files will be stored locally at the UMN Department of Rehabilitation 
Medicine. All data are stored on a secure HIPAA protected PC, and on 
secure HIPAA protected servers (Box Secure Storage). Raw and processed 
brain imaging data are also stored by the biostatistician/brain imaging 

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analysis specialists responsible for brain analysis and are backed up 
weekly. 
 
Training: All study staff will be appropriately trained in data security. 
 
Authorization of access: Only designated IRB-approved staff will have 
access to the data. 
 
Password protection/encryption/physical controls: All data will be stored 
in REDCap/Box. 
 
Separation of Identifiers: Study staff will keep the mapping of identification 
code to the identity of the participant in a database protected by two-levels 
of password protection stored separately from the data on Box. 
 
18.0 Provisions to Monitor the Data to Ensure the Safety of Participants 
18.1 Data Integrity Monitoring.  
This trial will be conducted in compliance with this protocol, good clinical 
practice, and the applicable regulatory requirements. 
 
Study Oversight.  Continuous study oversight will be provided by the study’s 
PI, Dr. Ricardo Battaglino, Vice Chair of Research, Department of 
Rehabilitation Medicine, University of Minnesota (rbattagl@um.edu, 612-
625-2661),Co-I, Dr. Scott Falci, Swedish Medical Center, and Co-I/study 
physician, Dr. Leslie Morse, University of Miami collaborator. 
Plan for Data Management. Data will be collected electronically (imaging 
files) or on paper forms. All electronic data will be stored on Box Secure 
Storage or REDCap. Paper forms will only be accessible by the study staff, 
trained study coordinator, and the principal investigator. All these 
documents will be kept in locked file cabinets in locked offices at all times. 
Participant names, contact information, health history, and other 
information that can be traced back to the participant will be kept separately 
from data collected for the study. Protocol sheets used during data 
collection will only have the participant’s ID.  
MRI imaging data will be identified by study ID without personal identifiers 
and stored on the system drive behind the institutional firewall. All 
computers are password-protected and will only be used by trained study 
staff and for study purposes only.  

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All study records will be kept indefinitely after the study is closed. Research 
records will be stored in a manner to protect the confidentiality of 
participant information.  
18.2 Data Safety Monitoring 
Plan for Monitoring Safety. The safety environment of UMN participants will 
be overseen and monitored by PI, Dr. Battaglino, Co-I, Dr. Scott Falci, and Co-
I/study physician, Dr. Morse. We will monitor to assure that participants 
meet eligibility criteria; that the informed consent process is conducted 
appropriately, that the data will be collected and analyzed as specified in the 
protocol, that adverse events (defined below) are reviewed promptly and 
reported as required (detailed below), that dropouts are documented, and 
that primary and secondary endpoints are evaluated. According to the data 
safety-monitoring plan, study participation will be terminated immediately 
in the event of injury or increased morbidity (drug intolerance). Data and all 
procedures will be monitored at each measurement time point and monthly 
throughout the duration of the study to ensure the safety of participants.  
We will establish a Data Safety and Monitoring Board (DSMB) in accordance 
with NIDILRR and FDA guidance for clinical trial sponsors. UMN’s 
institutional CTSI will assist with identifying board members and assist with 
managing board activities. The DSMB will review safety and efficacy data 
following a recruitment pause after the first 20 participants are enrolled and 
will make recommendations regarding continuation or termination of the 
study. The DSMB will also meet and review safety data quarterly and as 
needed throughout the duration of the study. The safety environment of all 
participants will be overseen and monitored by Dr. Morse (study Co-I).  We 
will monitor to assure that participants meet eligibility criteria; that the 
informed consent process is conducted appropriately, that the data will be 
collected and analyzed as specified in the protocol, that adverse events are 
reviewed promptly and reported as required, that dropouts are 
documented, and that primary and secondary endpoints are evaluated. Data 
and all procedures will be monitored at each measurement time point and 
monthly throughout the duration of the study to ensure the safety of 
participants.  
Unblinded Study Physician/Medical Monitor. Our safety monitoring plan 
also includes an independent medical monitor: Dr. Michael Stillman (Thomas 
Jefferson University). Dr. Stillman will review all reported adverse events on 
a monthly basis and as needed with the PI, Dr. Battaglino and study 
physician, Dr. Morse, who will inform Dr. Stillman immediately of all study-
related unanticipated problems involving risk to volunteers or others, 
serious adverse events, and all volunteer deaths associated with the 

MEDICAL PROTOCOL (HRP-590) 
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protocol, and provide an unbiased written report of the event to the IRB and 
FDA. The medical monitor will comment on the outcomes of the event or 
problem, and in the case of a serious adverse event or death, comment on 
the relationship to participation in the study. The medical monitor will also 
indicate whether he concurs with the details of the report provided by the 
study investigator. Reports for events determined by either the investigator 
or medical monitor to be possibly or definitely related to participation, and 
reports of events resulting in death will be promptly forwarded to the IRB 
and FDA. 
Reporting Adverse Events. Anticipated adverse events (detailed above in 
13.0, Risks to Participants) will be identified while interviewing participants, 
during physical exams, and while reviewing laboratory results. Participants 
also will be directed to call study staff to report adverse events that may 
occur between these visits. All adverse events will be noted on the Adverse 
Events log form that will be kept in the participant’s file. Unanticipated 
adverse events and unanticipated serious adverse events (as defined in CFR 
Title 21), also will be identified during testing time points and through 
participant self-reporting between these visits. They will be noted on the 
Adverse Events Log and promptly brought to the attention of the study PI 
and study physician. 
Unanticipated serious adverse events will be reported within 5 working days 
to the IRB as required. 
Follow-up of Adverse Events. In the unlikely event that a participant is 
injured as a result of this research study, medical care, including emergency 
treatment will be provided.  
Assessment of Risk. This is a moderate risk pilot clinical study. As such, our 
safety monitoring plan will include a medical monitor: Dr. Michael Stillman. 
Drs. Battaglino and Morse will review all reported adverse events on a 
monthly basis with Dr. Stillman, the medical monitor. Additionally, Drs. 
Battaglino and Morse will inform Dr. Stillman immediately of all study-
related unanticipated problems involving risk to volunteers or others, 
serious adverse events, and all volunteer deaths associated with the 
protocol, and provide an unbiased written report of the event to the IRB.  
The medical monitor will comment on the outcomes of the event or 
problem, and in the case of a serious adverse event or death, comment on 
the relationship to participation in the study. The medical monitor will also 
indicate whether he concurs with the details of the report provided by the 
study investigator. Reports for events determined by either the investigator 
or medical monitor to be possibly or definitely related to participation, and 
reports of events resulting in death will be promptly forwarded to the IRB. 

MEDICAL PROTOCOL (HRP-590) 
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19.0 Provisions to Protect the Privacy Interests of Participants 
Protecting Privacy:  
Study staff will receive HIPAA and data security training to maintain 
participant confidentiality prior to the initiation of participant recruitment. 
Non-identifiable research related data will be directly entered by 
participants into REDCap. REDCap is a secure, web-based application 
designed to support data capture for research studies. Trained staff will 
double enter data from de-identified case report forms containing 
variables collected on questionnaires. All paper form files with personal 
identifiable information will be stored in locked filing cabinets. Electronic 
files containing personal identifiers will be stored on Box Secure Storage 
and REDCap. In the instance that participants engage in a study-related 
videoconference through the Zoom video-conferencing platform, Zoom 
does not have access to identifiable protected health information, and 
they protect and encrypt all audio, video, and screen-sharing data. Zoom 
sessions will not be recorded or maintained. All study staff will receive 
training on privacy standards for maintaining participant confidentiality. 
The informed consent form and the HIPAA form will be signed with 
eSignature using a REDCap form that is compliant with FDA Title 21 CFR 
Part 11. For more information on REDCap compliance, please visit:  
 
https://redcap.ahc.umn.edu/surveys/?s=3PT9FY73NC&topics___ec=1#ec 
 
Procedures are in place for maintaining the full confidentiality of all 
information collected. Participant confidentiality will be protected by 
securing all hard copy study files in locked filing cabinets. Electronic files 
containing personal identifiers will be stored on Box Secure Storage or 
REDCap. All study staff receive training on privacy standards for 
maintaining participant confidentiality. All published reports will be of 
summary nature and no individual participants will be identified beyond 
the investigative staff involved in the project. 
 
Access to Participants:  
Participants have been fully informed of the ways in which their data 
will/may be used during the informed consent process. The research team 
has been trained in conducting these conversations and the participants 
are also assessed for their understanding of consent prior to signing the 
consent form or initiating any study procedures. 
 
20.0 Compensation for Research-Related Injury 
Compensation for Research-Related Injury:  

MEDICAL PROTOCOL (HRP-590) 
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In the unlikely event that a participant is injured as a result of this research 
study, medical care, including emergency treatment will be provided. The 
participant’s insurance company may be billed for treatment. 
 
Contract Language: N/A 
 
21.0 Consent Process 
21.1 Consent Process (when consent will be obtained):  
Informed consent will be obtained by study staff electronically via REDCap, 
in person at the enrolling site, or a location convenient to the participant by 
study. For participants who meet the inclusion criteria, a qualified member 
of the study team will follow the informed consent process over Zoom, and 
the participant will provide consent through the REDCap eConsent form. 
Prior to obtaining consent, all participants will be given ample time to read 
the consent form and encouraged to ask questions. Potential participants 
will be reminded that participation is strictly voluntary and will not affect 
their current or future care at the enrolling site or any affiliated institute. 
Each participant will be told that they will be free to discontinue 
participation at any time, but that discontinuation of the drug must be done 
under medical supervision to ensure it is done safely. A copy of the signed 
informed consent form will be sent or given to the participant. Participants 
will be provided with Dr. Battaglino’s contact information if questions should 
arise during the course of the trial. Consent will be obtained only from the 
participant and we will not seek consent from legally authorized 
representatives. We will not enroll any participants unable to give consent 
due to altered mental capacity. We will not enroll children therefore will not 
obtain assent. 
21.2 Waiver or Alteration of Consent Process (when consent will not be 
obtained): N/A  
21.3 Waiver of Written/Signed Documentation of Consent (when written/signed 
consent will not be obtained): N/A 
21.4 Non-English speaking Participants:  
We will include enrollment of non-English speaking participants. We will 
provide a translator to interpret consent forms. The interpreters are trained 
and required to protect participant privacy. Additionally, PI Dr. Battaglino 
will also be available as needed to carry out study procedures in Spanish, 
correspond with Spanish-speaking participants, and provide Spanish-English 
translation. 

MEDICAL PROTOCOL (HRP-590) 
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21.5 Participants Who Are Not Yet Adults (infants, children, teenagers under 18 
years of age): N/A 
21.6 Cognitively Impaired Adults, or adults with fluctuating or diminished 
capacity to consent: N/A 
21.7 Adults Unable to Consent: N/A 
 
Permission: N/A 
 
Assent: N/A 
 
Dissent: N/A 
22.0 Setting 
Research Sites:  
University of Minnesota, Minneapolis, MN 
 
Mayo Clinic, Rochester, MN 
 
Regions Hospital, Saint Paul, MN 
 
 
Courage Kenny Rehabilitation Institute, Minneapolis, MN 
23.0 Multi-Site Research 
Study-Wide Recruitment Methods:  
 
Sites will draw on their clinical and community networks for recruitment, 
utilizing flyers and recruitment cards.  
 
 
Study-Wide Recruitment Materials:  
 
Recruitment flyers and cards will facilitate recruitment efforts.  
 
Communication Among Sites: 
Investigators, study coordinators, data managers, and data collectors from 
each site will have monthly or as needed calls to discuss matters of this 
study. Sites may contact other sites. Communication may be by phone, 
email, in person, fax, in person, or other forms of correspondence. 
 
Communication to Sites:  
Investigators, study coordinators, data managers, and data collectors from 
each site will have monthly or as needed calls to discuss matters of this 
consortium and this study. Sites may contact other sites. Communication 
may be in phone, email, in person, fax, in person, or other forms of 
correspondence. 
24.0 Coordinating Center Research: N/A 
 
25.0 Resources Available 
Resources Available:  

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Overview of MN Regional SCIMS Resources. Located within the rich scientific 
milieu of Minnesota’s “Medical Alley,” our research program leverages world-
class research infrastructure, core facilities, and one of the leading technology 
commercialization offices in the country. We will draw on this rich scientific 
environment to contribute to the national database, complete our proposed site-
specific and module projects, and contribute to module projects proposed by 
collaborating Model System centers. UMN ranks ninth among public universities 
in research spending, with more than $950 million in research expenditures in 
fiscal year 2019 and research awards of more than $860 million. Blue Ridge ranked 
the UMN Department of Rehabilitation Medicine fifth nationally based on NIH 
funding in 2020. At Mayo Clinic, total research and education funding in 2018 
exceeded $1.1 billion. In 2018, Mayo Clinic’s research programs generated 12,760 
active IRB-approved studies: 3,067 new human research studies, 5,268 active 
grants and contracts, and 9,725 research and review articles in peer-reviewed 
journals. 
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