Clinical trial NCT04379011
Conditions: Spinal Cord Injuries
Sponsor: University of Minnesota
Start date: 2021-02-01; Completion date: 2024-09-01
Enrollment: 24 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Spinal cord injury (SCI) is associated with severe neuropathic pain that is often refractory to all pharmacological intervention. Preliminary data suggest brivarecetum is a mechanism-based pharmacological intervention for neuropathic pain in SCI. This randomized, placebo-controlled pilot clinical trial will assess feasibility of a 3-month treatment course with brivarecetum.

Detailed description:
The investigations will assess changes in pain intensity and periaqueductal gray hyperactivity. Baseline periaqueductal gray hyperactivity and microRNA levels will be measured as potential biomarkers of response to treatment. These preliminary findings will be used to design larger clinical trials to establish efficacy of brivarecetum to treat neuropathic pain in SCI.

Arms: arm 1: Participants in this arm will receive the investigational drug, Brivaracetam. arm 2: Participants in this arm will receive a placebo.
Interventions: intervention 1: Brivaracetam intervention 2: Placebo
Intervention descriptions: intervention 1: Escalating brivaracetam dose to 150 mg twice daily for 3 months intervention 2: Placebo twice daily for 3 months

Protocol documents:
Prot_SAP_000.pdf: 
MEDICAL PROTOCOL (HRP-590) 
PROTOCOL TITLE: Brivaracetam to Reduce Neuropathic Pain in Chronic SCI: A 
Pilot Clinical Trial 
VERSION DATE: 03/18/2024 
 
 
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Template  Revised On: 6/2/2021 
ANCILLARY REVIEWS 
DO NOT DELETE.  Submit the completed checklist below with your protocol. 
Which ancillary reviews do I need and when do I need them? 
Refer to HRP-309 for more information about these ancillary reviews. 
Select yes or no 
Does your study… 
If yes… 
Impact on IRB 
Review 
☐ Yes 
No 
 
 
Include Gillette 
resources, staff or 
locations 
Gillette Scientific 
review and Gillette 
Research 
Administration 
approval is 
required.  Contact: 
research@gillettec
hildrens.com   
Required prior to 
IRB submission 
Yes 
☐ No 
Involve Epic, or 
Fairview patients, 
staff, locations, or 
resources? 
The Fairview 
ancillary review will 
be assigned to your 
study by IRB staff 
Contact: 
ancillaryreview@Fa
irview.org 
Approval must be 
received prior to 
IRB committee/ 
designated review.   
 
 
Consider seeking 
approval prior to 
IRB submission. 
 Yes 
☐ No 
Include evaluation 
of drugs, devices, 
biologics, tobacco, 
or dietary 
supplements or 
data subject to FDA 
inspection? 
The regulatory 
ancillary review will 
be assigned to your 
study by IRB staff 
Contact: 
medreg@umn.edu  
 
 
See: 
https://policy.umn.
edu/research/indid
e  
 Yes 
☐ No 
Require Scientific 
Review? Not sure?  
See guidance in the 
Investigator 
Manual (HRP-103). 
 
 
Documentation of 
scientific merit 
must be provided.   
Contact: 
hrpp@umn.edu  


MEDICAL PROTOCOL (HRP-590) 
PROTOCOL TITLE: Brivaracetam to Reduce Neuropathic Pain in Chronic SCI: A 
Pilot Clinical Trial 
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Relate to cancer 
patients, cancer 
treatments, cancer 
screening/preventi
on, or tobacco? 
Complete the CPRC 
application process.  
Contact: 
ccprc@umn.edu  
☐ Yes 
 No 
Include the use of 
radiation? 
(x-ray imaging, 
radiopharmaceutic
als, external beam 
or brachytherapy) 
Complete the 
AURPC Human Use 
Application and 
follow instructions 
on the form for 
submission to the 
AURPC committee. 
Contact: 
barmstro@umn.ed
u  
Approval from 
these committees 
must be received 
prior to IRB 
approval;  
 
 
These groups each 
have their own 
application 
process.  
 Yes 
☐ No 
Use the Center for 
Magnetic 
Resonance 
Research (CMRR) 
as a study location? 
Complete the 
CMRR pre-IRB 
ancillary review  
Contact: 
ande2445@umn.ed
u  
☐ Yes 
 No 
Include the use of 
recombinant or 
synthetic nucleic 
acids, toxins, or 
infectious agents? 
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application via 
eprotocol.umn.edu 
 
 
☐ Yes 
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Include the use of 
human fetal tissue, 
human embryos, or 
embryonic stem 
cells? 
Contact OBAO for 
submission 
instructions and 
guidance 
 Yes 
☐ No 
Include PHI or are 
you requesting a 
HIPAA waiver? 
If yes, HIPCO will 
conduct a review of 
this protocol. 
Contact: 
privacy@umn.edu  
☐ Yes 
 No 
Use data from the 
Information 
Exchange (IE)? 
The Information 
Exchange ancillary 
review will be 
assigned to your 
study by IRB staff 
Approval must be 
received prior to 
IRB approval. 
 
 


MEDICAL PROTOCOL (HRP-590) 
PROTOCOL TITLE: Brivaracetam to Reduce Neuropathic Pain in Chronic SCI: A 
Pilot Clinical Trial 
VERSION DATE: 03/18/2024 
 
 
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Contact: 
ics@umn.edu  
These groups do 
not have a 
separate 
application process 
but additional 
information from 
the study team 
may be required. 
 
 
☐ Yes 
 No 
Use the 
Biorepository and 
Laboratory Services 
to collect tissue for 
research? 
The BLS ancillary 
review will be 
assigned to your 
study by IRB staff. 
Contact: Jenny 
Pham 
Pham0435@umn.e
du 
☐ Yes 
 No 
Have a PI or study 
team member with 
a conflict of 
interest? 
The CoI ancillary 
review will be 
assigned to your 
study by IRB staff 
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becca002@umn.ed
u  
 Yes 
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registered on 
clinicaltrials.gov? 
If you select “No” in 
ETHOS, the 
clinicaltrials.gov 
ancillary review will 
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study by IRB staff 
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du  
 Yes 
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Require 
registration in 
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If you select “No” 
or “I Don’t Know” in 
ETHOS, the OnCore 
ancillary review will 
be assigned to your 
study by IRB staff 
Contact: 
oncore@umn.edu  
Does not affect IRB 
approval. 
 
 
  
 
 


MEDICAL PROTOCOL (HRP-590) 
PROTOCOL TITLE: Brivaracetam to Reduce Neuropathic Pain in Chronic SCI: A 
Pilot Clinical Trial 
VERSION DATE: 03/18/2024 
 
 
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PROTOCOL COVER PAGE 
 
Protocol Title 
Brivaracetam to Reduce Neuropathic Pain in Chronic SCI: A 
Pilot Clinical Trial 
Principal 
Investigator/Faculty 
Advisor 
Name: Dr. Ricardo Battaglino  
Telephone Number:  612-625-2661 
Email Address: rbattagl@umn.edu 
IND/IDE # (if 
applicable) 
150388 
IND/IDE Holder 
Leslie Morse 
Investigational Drug 
Services # (if 
applicable) 
NA 
Version 
Number/Date: 
Version: 8.0 / Date: 03/18/2024 


MEDICAL PROTOCOL (HRP-590) 
PROTOCOL TITLE: Brivaracetam to Reduce Neuropathic Pain in Chronic SCI: A 
Pilot Clinical Trial 
VERSION DATE: 03/18/2024 
 
 
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REVISION HISTORY 
 
Revision # 
Version Date 
Summary of Changes 
Consent Change? 
2.0 
11/1/2021 
• Increased medical 
clearance window 
• Add ancillary reviews 
• Add labwork, INR 
• Adding Study Specific 
Webpage 
• Adding EPIC medical record 
review 
• Clarified inclusion criteria 
• Adding new recruitment 
strategies 
• Changing monthly check ins 
to weekly 
• Add DN4 assessment tool 
Yes 
3.0 
01/25/2022 
• Allow for virtual 
participation 
• Allow for paper or 
electronic consent  
• Add off-campus option for 
end of study labs 
• End of study testing to 
occur prior to drug ramp 
down 
• Uniform formatting 
throughout document  
• Included previously added 
assessment tools 
description 
Yes 
4.0 
05/16/2022 
• Clarifying protocol is multi-
center pilot clinical trial 
(UMN, local site, and 
Swedish Medical 
Center/Craig Hospital, 
additional site) 
• Clarifying drug dosage and 
handling 
• Consent form updated to 
state Co-I COI. 
Yes 


MEDICAL PROTOCOL (HRP-590) 
PROTOCOL TITLE: Brivaracetam to Reduce Neuropathic Pain in Chronic SCI: A 
Pilot Clinical Trial 
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Revision # 
Version Date 
Summary of Changes 
Consent Change? 
4.1 
06/06/2022 
• Uniform compensation 
information described in 
consent form 
Yes 
5.0 
08/11/2022 
• Adding recruitment 
method with MyChart 
announcements 
• Removed Rebekah 
Summers listed device 
• Added Brian Devries listed 
device 
 
6.0 
09/22/2022 
• Adding Visit 4 with Long-
term follow up measures 
(1-month post medication 
cessation) 
              -CHART-SF 
             -PHQ-9 
             -DN4 
             -ISCI Pain Basic Data Set 
             -BPI 
             -PCS 
             -Penn SFS 
             -TSK 
             -PSQI 
             -Satisfaction with Life 
             -Moorong SES 
             -PDI 
Yes 
6.1 
09/26/2022 
• Adding $50 additional 
payment for Visit 4 
Yes 
7.0 
06/20/2023 
• Clarifying Section 18 to 
state that CTSI provides 
further monitoring for this 
study 
No 
8.0 
03/18/2024 
• Revise Ricardo Battaglino 
as Principal Investigator 
• Revise Leslie Morse as Co-I, 
University of Miami 
collaborator 
No (completed 
enrollment) 
 


MEDICAL PROTOCOL (HRP-590) 
PROTOCOL TITLE: Brivaracetam to Reduce Neuropathic Pain in Chronic SCI: A 
Pilot Clinical Trial 
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Table of Contents 
1.0 
Objectives ........................................................................................................ 12 
2.0 
Background ...................................................................................................... 12 
3.0 
Study Endpoints/Events/Outcomes .................................................................. 19 
4.0 
Study Intervention(s)/Investigational Agent(s) ................................................. 19 
5.0 
Procedures Involved ......................................................................................... 21 
6.0 
Data and Specimen Banking ............................................................................. 27 
7.0 
Sharing of Results with Participants ................................................................. 29 
8.0 
Study Population .............................................................................................. 29 
9.0 
Vulnerable Populations .................................................................................... 31 
10.0 Local Number of Participants ............................................................................ 34 
11.0 Local Recruitment Methods .............................................................................. 34 
12.0 Withdrawal of Participants ............................................................................... 37 
13.0 Risks to Participants ......................................................................................... 38 
14.0 Potential Benefits to Participants ..................................................................... 39 
15.0 Statistical Considerations ................................................................................. 39 
16.0 Health Information and Privacy Compliance ..................................................... 43 
17.0 Confidentiality .................................................................................................. 46 
18.0 Provisions to Monitor the Data to Ensure the Safety of Participants ................ 48 
19.0 Provisions to Protect the Privacy Interests of Participants ................................ 50 
20.0 Compensation for Research-Related Injury ...................................................... 51 


MEDICAL PROTOCOL (HRP-590) 
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21.0 Consent Process ............................................................................................... 52 
22.0 Setting .............................................................................................................. 53 
23.0 Multi-Site Research .......................................................................................... 53 
24.0 Coordinating Center Research .......................................................................... 54 
25.0 Resources Available .......................................................................................... 55 
26.0 References ....................................................................................................... 55 
 
 


MEDICAL PROTOCOL (HRP-590) 
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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) 
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Pilot Clinical Trial 
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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) 
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Pilot Clinical Trial 
VERSION DATE: 03/18/2024 
 
 
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rsfMRI 
resting state functional Magnetic Resonance Imaging 
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) 
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1.0 
Objectives 
1.1 Purpose:  
SCI is associated with severe neuropathic pain that is often refractory to all 
pharmacological intervention. Our preliminary data suggest brivaracetam is a 
mechanism-based pharmacological intervention for neuropathic pain in SCI. In 
this project we will conduct a randomized, placebo-controlled pilot clinical trial 
to assess feasibility of a 3-month treatment course with brivaracetam. We will 
assess changes in pain intensity and periaqueductal gray hyperactivity. We will 
assess baseline periaqueductal gray hyperactivity and microRNA levels as 
potential biomarkers of response to treatment. We will use these preliminary 
findings to design larger clinical trials to establish efficacy of brivaracetam to 
treat neuropathic pain in SCI. The pilot data are necessary to adequately power 
the larger clinical trial based on SCI-specific data for each outcome of interest. 
Here we will be able to present the scientific evidence base supporting the 
rationale for this project. 
 
Specific Aims: 
1. Specific Aim 1: Determine whether a 3-month course of daily brivaracetam is 
safe and effective at reducing severe below-level neuropathic pain after SCI. 
2. Specific Aim 2: Determine whether a 3-month course of daily brivaracetam 
decreases periaqueductal gray activity in SCI.  
3. Specific Aim 3: Determine whether baseline microRNA levels are associated 
with response to brivaracetam treatment. 
 
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 to establish drug efficacy and validate novel predictive 
biomarkers of response to therapy. 


MEDICAL PROTOCOL (HRP-590) 
PROTOCOL TITLE: Brivaracetam to Reduce Neuropathic Pain in Chronic SCI: A 
Pilot Clinical Trial 
VERSION DATE: 03/18/2024 
 
 
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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 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 with corresponding reduction in 
periaqueductal gray brain activity by rsfMRI (Aim 1). We also hypothesize that 
either periaqueductal gray brain activity or circulating miRNA-485 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 


MEDICAL PROTOCOL (HRP-590) 
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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 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. 


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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 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 


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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 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 (J Neurosurgery 
Spine 2002, 2018). 
 
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 (see appendix, J Neurosurgery Spine 2002, 2018). With 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 


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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 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, 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]. 


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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 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. 


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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 
3.1 
Primary Endpoint/Event/Outcome:  
Our primary endpoints will be 1) safety as determined by number of drug 
related adverse events and assessed through weekly adverse event 
screening by phone, and 2) efficacy as determined by reduction in pain 
intensity assessed by the Brief Pain Inventory. We will use the clinically 
meaningful reduction in Brief Pain Inventory score of 1 point or more as 
the definition of “drug response” in this study. 
 
3.2 
Secondary Endpoint(s)/Event(s)/Outcome(s):  
Secondary outcomes include brain resting state functional connectivity and 
various psychosocial factors related to participants’ experiences with SCI, 
such as change in mood, satisfaction with life, and community integration. 
 
4.0 
Study Intervention(s)/Investigational Agent(s) 
4.1 
Description:  
Intervention: brivaracetam or placebo administration. Because this is an 
off-label use of an FDA approved drug, we received an Investigational New 
Drug (IND) designation from the FDA for this study (IND Holder Morse, 
#150388).  RxArtisans Pharmacy (Wayzata, MN) will FedEx the drug to the 
participant directly or to the Rehabilitation Department Boynton Bridge, 
University of Minnesota (UMN) for distribution, and study staff will send an 
email notification that the drug has been sent by overnight mail. To 
minimize wasting of drug, RxArtisans will dispense and ship prescriptions 
for participants concurrent with the ramp-up schedule (weekly, biweekly, 
or as requested by study doctor). Once maximum dose is stabilized, 
RxArtisans will dispense and ship prescriptions monthly. Participants will be 


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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 X 2 weeks followed by 50mg TID X 2 weeks followed by 
100mg BID X for 48 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.   
In the case of intolerance at 50mg BID during dose escalation, the dose will 
be reduced to 25mg daily or 25mg BID. In the case of intolerance, the dose 
will be reduced down 1 step to last tolerated dose. For intolerance at 
100mg BID, the dose will be reduced to 50mg TID. For intolerance at 50mg 
TID, the dose will be reduced to 50mg BID. A dose of 50mg BID or higher 
must be maintained to complete the trial. 
Drug discontinuation at study completion will be done according to the 
following protocol we use clinically that will be initiated for 2 weeks after 
end of study testing:  Reduction to 50mg BID X 1 week followed by 50mg 
daily X 1 week.  For those at the highest study tolerated dose of 50mg BID, 
the dose will be reduced to 50mg daily X 1 week and then stopped.  At the 
end of study participants will be asked to mail empty bottles for pill counts 
with self-addressed and prepaid packaging, and will review the medication 
diaries via phone. We will use the clinically meaningful reduction in Brief 
Pain Inventory score of 1 point or more as the definition of “drug 
response” in this study. University of Minnesota Investigational Drug 
Services (IDS) will register the study, while Rx Artisans will be dispensing 
the drug. 
 
4.2 
Drug/Device Handling:  
Brivaracetam or placebo will be compounded and dispensed by Rx Artisans 
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 (25mg Purple, 50mg Green, 100mg Blue) 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 form including email, text, etc.) 
that the drug was received. 
 
4.3 
Biosafety: N/A  


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4.4 
Stem Cells: N/A 
4.5 
Fetal Tissue: N/A 
 
5.0 
Procedures Involved 
5.1 
Study Design: 
This is a multi-center randomized, double-blinded placebo-controlled pilot 
clinical trial.  Each site (Swedish Medical Center/Craig Hospital, UMN) will 
enroll and study 20 adults, 18 years of age and older with SCI. Dr. Ricardo 
Battaglino will serve as PI, and Dr. Leslie Morse will serve as Co-I at UMN 
(local site). MRI data analysis will be conducted by Dr. Clas Linnman 
(Harvard University). Dr. Linnman will receive a deidentified dataset and 
will have no human subject interactions. Research activities at the Swedish 
Medical Center/Craig Hospital will be conducted under a separate IRB 
protocol at Craig Hospital.  
 
Participants who meet the eligibility criteria will be randomly assigned to 
active drug (escalating brivaracetam dose to 100 mg twice daily for 3 
months) or placebo based on a randomization schedule developed by our 
biostatistician. This is a simple computer generated 1:1 scheme that 
randomly assigns participants to arm A or arm B.  Study participants, 
research coordinators, and study personnel involved in outcomes 
assessments and analyses will all be blinded. 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 pharmacies (RxArtisans). We have 
registered this pilot study with National Institutes of Health (NIH) clinical 
trials registry, www.clinicaltrials.gov (NCT04379011). The pilot data 
generated by this effort will be used to power a subsequent multi-center 
clinical trial. 
 
5.2 
Study Procedures:  
Overview of study procedures/study interventions.  All interventions and 
activities are summarized in Table 1 below and then described in detail in 
the subsequent text.  Potential participants will undergo an initial screening 
for eligibility based on the criteria below.  After giving informed consent, 
participants will be randomized. Eligible participants will be required to 
receive medical clearance from their primary care provider within one 
month of (prior to) the baseline appointment, including physical exam, 
health history, and lab work to confirm normal renal function, absence of 
liver cirrhosis, and absence of pregnancy.  


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Baseline testing includes a focused physical exam, mental health and 
health history, blood samples for batch analysis, and an MRI scan. These 
procedures can either take place 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. For participants 
who prefer not to undergo a research MRI, the MRI will be optional. 
Research blood banking will also be optional. 
Participants must see their primary care physician to determine if they are 
eligible to enroll in this study, including having their physician order lab 
work to confirm that they are not pregnant (for females/people of 
childbearing potential) and that their kidneys and liver function properly. 
Their insurance will be charged and they will be responsible for any 
associated copays or costs. The study drug, research banking lab, baseline 
and end-of-study physical examinations, and MRIs performed by the study 
will be paid for by the study.  
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. 
CDE-recommended questionnaires relating to pain, mood, active 
suicidality, satisfaction with life, kinesiophobia, sleep quality, and 
community integration will be administered. Participants will then begin 3 
months of active treatment (100 mg BID) or placebo. All participants will 
receive a medication diary to track study drug compliance and to record 
medication use. Blinded data collectors will perform weekly check-in calls 
to assess for medication-related adverse events including the PHQ-9 for 
changes in mood and suicidality. Reported AEs identified in these calls will 
be documented and immediately shared with the PI for review. 
End of study assessments will be repeated 3 months after baseline testing 
and again 1 month after cessation of study medication (active/placebo). 
Lab work will be repeated to confirm normal renal function, absence of 
liver cirrhosis, and absence of pregnancy in individuals of childbearing 
potential at the end of the study. Specimen collection and analysis will 
either occur at the Fairview Clinical Research Unit or with the participant’s 


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primary care provider, based on participant preference. Participants will 
receive $150 after baseline testing, $150 after end of study testing sessions 
and $50 after the 1-month post drug cessation follow-up to compensate 
them for their time and to assist with transportation.   
 
Our primary endpoints will be safety (# of drug related adverse events) and 
efficacy (reduction in pain intensity assessed by the Brief Pain Inventory).  
We will use the clinically meaningful reduction in Brief Pain Inventory score 
of 1 point or more as the definition of “drug response” in this study.  
Secondary outcomes include change in mood, satisfaction with life, 
community integration, and brain resting state functional connectivity.  All 
fMRI data will be deidentified and sent by secure server to Harvard Medical 
School for analysis by Dr. Linnman (consultant) as is done in our ongoing 
collaborative studies (Effects of Ekso-assisted gait training on Bone Health 
and Quality of Life: A Randomized Clinical Trial, PI Morse). 
 
Suicide Protocol:  Endorsement of active suicidality on PHQ-9 will trigger 
the suicide protocol.  911 will be called 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.      
 
Modified Brief Pain Inventory (BPI) – main outcome. 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 VAS 
Pain 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 
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]. 
 
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 1-10 


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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. 
 
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 simple Likert scale. 
 
 
 
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. 
 
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. 
 
DN4 Assessment Tool. This is a 4-item assessment that characterizes 
neuropathic pain. 
 


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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. 
 
Intervention Expectations. This self-report will assess what participants 
expect their outcomes to be during and after their participation in the 
study. 
 
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 Cortical Activity by Brain MRI. MRI scans of the brain will be 
performed for participants who are eligible and provide consent to MRI. 
Testing will be performed at baseline and end of study. We will use 3 Tesla 
Magnetic Resonance Imaging to collect i) brain structure (Multi Echo 
Magnetization Prepared Rapid Acquisition Gradient Echo, MEMPRAGE) ii) 
brain white matter integrity (Diffusion Weighted Imaging, DWI), iii) brain 
resting state functional connectivity (resting state functional Magnetic 
Resonance Imaging, rsfMRI), and iv) evoked responses to Motor Imagery 


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(MI). MI involves asking individuals to envision themselves executing motor 
actions, without actual execution, a task that activates the same or similar 
neural systems as the actual execution of motor actions.  
 
Limited safety labs for hepatic cirrhosis, renal insufficiency, and pregnancy. 
At the final study visit, participants will complete a fasting blood draw 
either at the Clinical Research Unit or through their primary care provider. 
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. INR will be collected at the discretion 
of the participant’s primary care provider if the participant is on 
anticoagulation or has abnormal LFTs. 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 the study staff by the CRU 
staff. 
 
Table 1. Study Procedures 
 
Study Task 
Pre-
Screen 
Visit 1* 
 
Visit 2* 
Visits 3 
(end of study 
testing) 
2 weeks drug 
dose 
reduction 
(after end of 
study testing) 
Visit 4 (long-
term follow-
up) 
Pre-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, surveys 
 
X 
 
X 
 
x 
Initiate intervention 
 
 
X 
 
 
 
Dispense 3-month drug supply 
 
 
X 
 
 
 
Reminder check-in: begin 2-week drug 
dose reduction protocol after end of 
study testing 
 
 
 
 
X 
 
Limited safety labs (blood draw, 
required) 
 
 
 
X 
 
 
Pill count/medication diary review 
 
 
 
 
X  
 
Pregnancy test (for women of child-
bearing potential) 
 
 
 
X 
 
 
Adverse Events 
Assessed weekly (phone) 
 
 
*Visits 1 and 2 may be combined for participant convenience  
 


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**Medical clearance must be clinically obtained from participants’ primary care provider or other 
healthcare provider within 1 month prior to visit 1 
 
 
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.  
 
5.3 
Study Duration:  
This is a 2-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 2. Individual participant’s 
participation will approximately be three months 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. 
 
5.4 
Use of radiation: N/A 
 
5.5 
Use of Center for Magnetic Resonance Research:  
All participants who consent to MRI testing will get a 3T structural and 
functional MRI scan at baseline and after completion of the 3-month 
treatment course. The scanning protocol will be standardized between the 
two testing sites.  We will collect i) brain structure (Multi Echo 
Magnetization Prepared Rapid Acquisition Gradient Echo, MEMPRAGE) ii) 
brain white matter integrity (Diffusion Weighted Imaging, DWI), iii) brain 
resting state functional connectivity (resting state functional Magnetic 
Resonance Imaging, rsfMRI), and iv) evoked responses to Motor Imagery 
(MI). MI involves asking individuals to envision themselves executing motor 
actions, without actual execution, a task that activates the same or similar 
neural systems as the actual execution of motor actions. 
 
6.0 
Data and Specimen Banking 
6.1 Storage and Access:  


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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 in the Fairview Clinical Research Unit (CRU), 
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 (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, quantitative proprioceptive recordings, 
standardized patient-rated questionnaires will be stored on Research 
Electronic Data Capture (REDCap) and on encrypted servers.  
Imaging of brain activation (fMRI), and brain networks via functional 
resting-state (functional connectivity), and task-based (effective 
connectivity) 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.  


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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, then the de-identified xls 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 
 
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: N/A 
 
8.0 
Study Population 
8.1 
Inclusion Criteria:  
• 18 years of age or older 
• Completed inpatient rehabilitation and living in the community 
• Ongoing severe below-level neuropathic pain (daily average 9/10 or 
10/10) 
• Tried and failed to achieve adequate pain relief with the use of other 
drugs (previous pain management drugs failed to decrease their pain 
below a self-reported level of 9 out of 10)  


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• 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). 
 
8.2 
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) 
• Hepatic cirrhosis, Child-Pugh grades A, B, and C  
• Impaired renal function 
• 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 
 
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. 
 


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8.3 
Screening: 
A prescreening checklist will be administered to confirm basic eligibility 
prior to consenting. This includes confirming age, pain level, medication 
use, implanted medical devices or retained metal fragments, and other 
medical conditions. 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 and 
completing a physical exam and health history. The participant’s insurance 
will be charged and they will be responsible for any associated copays or 
costs.   
The participant’s provider will provide UMN research staff with results via 
fax or email, or the participant may carry a hard copy. If the participant is a 
patient of Fairview, their medical records will be accessed directly by 
research staff who have obtained approval via the non-Fairview employed 
research staff (NERS) application process for conducting research tasks in 
Fairview facilities and systems.  
Screening for hepatic cirrhosis, renal insufficiency, and pregnancy. 
Brivaracetam treatment is not safe for those who are pregnant, have 
hepatic cirrhosis, or kidney dysfunction. Therefore, in order 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.  INR will be 
collected at the discretion of the participant’s primary care provider if the 
participant is on anticoagulation or has abnormal LFTs. The blood lab 
report and medical clearance form will be faxed from the medical provider 
to the study coordinator within one month of draw. 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 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 
9.1 
Vulnerable Populations:  


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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 
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 
Included/Allowed to Participate 


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social goods and services such as 
income, housing, or healthcare. 
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 
 
9.2 
Additional Safeguards:  
This project aims to research an intervention that may help vulnerable adults 
with spinal cord injuries with severe neuropathic pain, a severe health condition, 
and non-English speakers. 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 proposed 
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 consent 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. 


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10.0 Local Number of Participants 
10.1 
Local Number of Participants to be Consented: 
30 participants are expected to be screened. 20 participants will be 
enrolled at UMN. 
 
11.0 Local Recruitment Methods 
11.1 
Recruitment Process:  
We anticipate screening 30 individuals with SCI to recruit and enroll 20 
participants.  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: 
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 
(www.z.umn.edu/SCIPain). 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 the Co-Principal Investigators 
from among 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. The patient will be given the choice, if interested, to be 
approached by the investigator in person, over phone or e-mail or have 
them reach out to the investigator.  A flier or recruitment card about the 
study may be sent to potential participants, asking them to contact the 
study coordinator if they are interested. 
Individuals who respond to the recruitment materials will be taken through 
a phone screening questionnaire with the study coordinator. If following 
the phone screen, the potential participant is eligible and interested; the 
study coordinator will schedule the screening study visit. 
  
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 


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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 not limited to Get Up Stand Up to Cure 
Paralysis, Minnesota Spinal Cord Injury Association, and Morton Cure 
Paralysis.  
 
MN SCI Model System Members: Like above, participants may be told 
about this clinical trial by their clinicians and other personnel at healthcare 
centers (MHealth/Fairview, Allina Health Courage Kenny Rehabilitation 
Institute and HealthPartners/ Regions Hospital, Hennepin Healthcare, and 
Mayo Clinic) that specialize in the care and wellbeing of individuals with 
SCI. 
 
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 
facilitate enrollment. We will filter individuals in the registry based on 
inclusion/ exclusion criteria and contact them via email 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. 
 


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Fairview Recruitment Mailings: We will work with Fairview Research 
Recruitment Services to identify individuals with SCI in the overall MHealth 
Fairview Healthcare system and send recruitment MyChart 
announcements and recruitment mailings through the mail, pending 
approval from the Fairview Research Administration. Patients of Dr. Morse 
will be pre-screened using their medical chart and sent a letter in the mail 
if they meet eligibility criteria. Patients who have opted out of having their 
records used for research will not be included. 
 
11.2 
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. A study coordinator will contact individuals for 
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 principal investigator and co-
investigator (Dr. Ricardo Battaglino and Leslie Morse) and their team from 
among patients under Dr. Morse 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: 
Potential participants will self-identify in response to flyer announcements 
via professional associations or support groups/word to mouth or other 
means. 
 
Through BPIC involvement EPIC will be searched on the hits provided by 
BPIC. If eligible a mailing will be sent out. 
 
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 


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• 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). 
 
11.3 
Recruitment Materials:  
The following recruitment materials will be used in this study: flyers or  
recruitment cards. 
 
11.4 
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 1-month 
follow up testing (Visit 4). 
 
12.0 Withdrawal of Participants 
12.1 
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 
• 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 
 
12.2 
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.  
 
12.3 
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.  
 


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13.0 Risks to Participants 
13.1 
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 
are 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 the study coordinator, or an investigator regarding 
any side effects or adverse events that occur. 
 
MRI risks 
There are minimal risks or side effects of MRI testing for participants who do 
not have medical devices or implants.  These risks include magnetic objects 
being turned into projectiles by the MRI, claustrophobia in the scanner, and 
hearing damage if hearing protection is not worn in the scanner.   
 
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 at the UMN in the Fairview Clinical Research Unit (CRU), 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 secure and locked space with 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 code 
number 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 


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doors in on-site freezers for an indefinite period of time with only coded 
numbers as 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’). 
 
13.2 
Reproduction Risks:  
Pregnancy  
We are excluding pregnant or lactating people from this study. 
 
13.3 
Risks to Others: N/A 
 
14.0 Potential Benefits to Participants 
14.1 
Potential Benefits:  
Because this study will be used to develop clinical trials testing 
pharmacological interventions to treat neuropathic pain in SCI, there is a 
potential future benefit to the spinal cord population.  
 
15.0 Statistical Considerations 


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15.1 Data Analysis Plan:  
For aim 1, the main outcome variables of interest include various 
dimensions of pain, mood (PHQ-9), life satisfaction (SWLS), resting state 
brain connectivity, and community integration (CHART-SF) measured at 
baseline and again at 3-months of treatment. Of particular interest is 
whether there is a difference in pain reduction from baseline to end of 
study between the treatment and control groups; this will be analyzed in 
this pilot with linear regression including terms for group and time and the 
interaction of group by time. We note that many of these instruments have 
bounded scores and we will include analyses that recognize these (via, e.g., 
non- linearities or recognize the bounds such as Tobit regression) Further 
exploratory analyses will examine the relationships (correlations) between 
changes in pain and changes in mood, life satisfaction, resting state brain 
connectivity, and community integration using linear regression. 
 
For aim 2, we will use the same analytic approach we have refined in our 2 
active rsfMRI studies. MRI data will be analyzed using the SPM12 based 
Conn toolbox 3 (Version 17f, Matlab R2018b). Preprocessing steps include 
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 include 
scrubbing, aCompCor, ICA-based denoising, Global Regression, and 0.008 
to 0.09 Hz band-pass filtering). Three main comparisons will be evaluated: 
The effect of drug treatment on rsfMRI measures, the effect of pain 
intensity on rsfMRI measures (each via linear regression as in Aim 1), and 
the differences in rsfMRI measures between active drug responders and 
non-responders; this last will also be analyzed via linear regression; note, 
however, that this will be limited to those in the active group and people in 
the placebo group will not be included. First, we will evaluate 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 will evaluate, on a voxel-by-voxel basis, 
amplitude of low frequency fluctuations (ALFF) and intrinsic resting state 
functional connectivity. 
 
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 


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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 false discovery rate 
(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 proteins related to reduction 
in neuropathic pain will be performed using Ingenuity Pathway Analysis 
(IPA) program (Ingenuity Systems Inc., Redwood City, CA). This software 
compiles known interactions for relevant miRNAs potential/ targets from 
published literature.  This does not involve detection of genotypes, 
mutations, or chromosomal changes.  For clinical correlation analysis, data 
comparing changes in miRNA expression will be described as means with 
standard error of the mean. In order to analyze the differences between 
group means we will use analysis of variance (ANOVA) after the assessing 
for distribution and variance. Multiple comparisons will be performed using 
Games-Howell test.  
15.2 Power Analysis: 
Part of the goal of this pilot study is to obtain information that can be used 
for formal sample size estimation, including effect sizes and standard error 
estimates; therefore, analyses are included here that may not be included 
in a non-pilot follow-up (including the randomization analyses described 
below); further, some of the analyses here are exploratory to help in the 
design of a follow-up study. Also, (1) robust standard errors will be used in 
all cases to help guard against the effects of heteroskedasticity; (2) 
although there are a number of outcomes and, therefore, analyses, no 
adjustments for multiple comparisons will be made in this pilot study as the 
prime aim is not the level of statistical significance but rather the 
estimation of results needed for planning a follow-up. Of course, when 
disseminating our findings we will report the number of tests performed 
and the actual p-values so that readers can make their own adjustments if 
wanted. 
 
15.3 Statistical Analysis: 
All statistical analyses will be conducted with Stata v. 16 (Copyright 1985-
2019 StataCorp LLC, College Station, TX) or SAS v.9.4 (Copyright (c) 2002-
2012 by SAS Institute Inc., Cary, NC, USA) assuming a 5% level of 
significance unless otherwise stated. Participant characteristics will be 


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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 participant characteristics between the 
treatment arms.  
 
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. 
Collected data will have the participant’s identification code and some 
computer software used to collect data will have the date and time marked 
on the file. Protocol sheets used during data collection will only have the 
participant’s ID.  
 
Imaging data (MRI scan results) will be identified by study ID without 
personal identifiers and stored on the system drive behind the institutional 
firewall or on Box Secure Storage. Some institutions consider MRI of the 
brain to contain identifiers due to the presence of facial features.  We will 
not use software to mask facial features, therefore identifiable MRI data 
will be shared with Dr. Linnman for analysis.  All computers are password-
protected and will only be used by trained study staff and for study 
purposes only.  
 
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.  
 
Dr. Morse will review data monthly. She 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. 


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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. 
Appropriate Use for Research:  
 
 
16.2 
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 pre-screening phone survey will be completed and stored in paper 
format and REDCap to determine eligibility. After consent a health 
survey will be collected in paper format and stored in the participants 
study file. 
 
16.3 
Explain how you will ensure that only records of patients who have 
agreed to have their information used for research will be reviewed. 


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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. 
 
16.4 
Approximate number of records required for review: 25 
 
16.5 
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.  
☒ 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.  Our communication plan will be clearly presented in the 
consent form. 
 
16.6 
Explain how the research team has legitimate access to 
patients/potential participants: 
The PI and her team will cover recruitment from all outpatient locations 
within greater Minneapolis/Saint Paul area. We will also recruit with 
flyers and social media postings within the greater Minneapolis/Saint 
Paul area.  
 
16.7 
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)  


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 ☒ 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.  
Name 
UMN Device # 
Dr. Ricardo Battaglino  
20190593 
Dr. Leslie Morse 
20160309, 20190592 
Nguyen Nguyen  
20190734 
Rob Wudlick  
20192649 
Brian DeVries 
20200957 
 
☒ Other: 
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 
 


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16.8 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 
 
16.9 
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 PI/Co-PI will 
have a document that links the name with the code, which will be kept 
secure on the University Box secure storage. 
 
16.10 Sharing of Data with Research Team Members:  
Only deidentified data will be shared with team members. The PI and 
clinical trial coordinator will have access to identifiable information for 
contact purposes.  
 
16.11 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 
17.1 
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. 
MRI data acquisition will not contain personal health information. The MRI 


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data be stored in digital form behind institutional firewalls or on Box Secure 
Storage. 
 
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.  
 
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, 


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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 
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. Further monitoring 
will be completed by a CTSI monitor that will be assigned to the study. 
 
Study Oversight.  Continuous study oversight will be provided by the study 
PIs, Dr. Falci, Swedish Medical Center/Craig Hospital site PI, and Drs. 
Ricardo Battaglino and Leslie Morse, UMN site PI and Co-I, Department of 
Rehabilitation Medicine, University of Minnesota.  
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, 


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trained study coordinator, and the principal investigator. All of 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. Personal information will be 
kept in a locked office and away from data. Collected data will have the 
participant’s identification code and some computer software used to 
collect data will have the date and time marked on the file. 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.  
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 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.  
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. 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 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 


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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. 
Unanticipated serious adverse events will be reported within 5 working 
days to the UMN 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. 
Dr. Morse will review all reported adverse events on a monthly basis with 
Dr. Stillman, the medical monitor. Additionally, Dr. 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. 
 
19.0 Provisions to Protect the Privacy Interests of Participants 
19.1 
Protecting Privacy:  


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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. 
 
19.2 
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 
20.1 
Compensation for Research-Related Injury:  
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. 


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20.2 
Contract Language: N/A 
 
21.0 Consent Process 
21.1 Consent Process (when consent will be obtained):  
Informed consent will be obtained electronically via REDCap or in person at 
the CRU (or a location convenient to the participant) by study staff. 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 UMN or any affiliated institute. Each 
participant will be told that they will be free to discontinue participation in 
the experiment 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. Morse’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 English 
and Spanish speaking participants. We will provide a translator to 
interpreted consent forms. The interpreters are trained and required to 
protect participant privacy. Additionally, Co-I 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. 
 
21.5 Participants Who Are Not Yet Adults (infants, children, teenagers under 18 
years of age): N/A 


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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 
22.1 
Research Sites:  
University of Minnesota, Minneapolis 
 Department of Rehabilitation Medicine 
 Health Clinical Research Unit, Phillips-Wangensteen Building 
Craig Hospital/Swedish Medical Center, Englewood, CO 
 
23.0 Multi-Site Research 
23.1 
Study-Wide Number of Participants: 
20 enrolled participants. 30 screened participants. 
 
23.2 
Study-Wide Recruitment Methods:  
We anticipate screening 30 individuals with SCI to recruit and enroll 20 
participants across the 2 enrollment sites (Swedish Medical Center/Craig 
Hospital and University of Minnesota). The PI (Swedish Medical 
Center/Craig Hospital site) sees over 50 patients a year with severe 
sublesional neuropathic pain. Therefore, at Swedish Medical Center/Craig 
Hospital we will recruit potential participants from his clinical practice. The 
Department of Rehabilitation Medicine houses an ACGME-accredited, 12-
month SCI Medicine Fellowship program. This fellowship leverages 
collaborative relationships with all specialty hospitals in the greater 
Minneapolis area providing acute inpatient rehabilitation for spinal cord 
injury, including Fairview Acute Inpatient Center, Minneapolis VA Medical 
Center, Regions Hospital, and Courage Kenny Rehabilitation Institute. 
Therefore, we will recruit participants at the University of Minnesota from 
each of our SCI Medicine Fellowship clinical sites. We will also utilize local 
patient representative organizations by sharing posters and sample text for 
social media recruitment. The Rocky Mountain Regional Spinal Injury 
System at Craig Hospital provides comprehensive inpatient rehabilitation 
to over 200 newly injured individuals with SCI every year and continues to 
treat nearly 1,100 individuals with SCI annually in outpatient programs, 


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including Dr. Falci’s neuropathic pain clinic. Similarly, the University of 
Minneapolis SCI system of care treats over 200 newly injured individuals 
with SCI every 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. 
 
23.3 
Study-Wide Recruitment Materials:  
We will use flyers to recruit participants. 
 
23.4 
Communication Among Sites: 
The site PIs (Falci, Morse) will communicate in person daily with their 
local teams to discuss experimental design, data analysis, and all 
administrative responsibilities. The research team (all key personnel 
across the 2 sites) will meet virtually on a weekly basis to monitor project 
progress and to trouble-shoot. 
 
23.5 
Communication to Sites: 
Communication to sites will occur between the site PIs and study 
coordinators.  
 
24.0 Coordinating Center Research 
24.1 
Role:  
Dr. Morse will serve as PI for this proposal. As such, she will oversee 
implementation of all aspects of this proposal. Dr. Battaglino (UMN) will 
serve as co-investigator and will oversee the miRNA studies. Dr. Morse will 
oversee UMN recruitment, study coordination, data management, 
regulatory compliance, and dissemination activities. The UMN will serve as 
the statistical/data center for the study.  
 
24.2 
Responsibilities:  
Each PI will share research results with other co-investigators, key 
personnel, and consultants. Publication authorship will be based on the 
relative scientific contributions of the personnel. Each PI will be 
responsible for their own fiscal and research administration. 
 
24.3 
Oversight: 
Dr. Stillman will be the external medical monitor. As PI, Dr. Morse will 
oversee the study. 
 
24.4 
Collection and Management of Data:  
A REDCap database will be created. 
 


MEDICAL PROTOCOL (HRP-590) 
PROTOCOL TITLE: Brivaracetam to Reduce Neuropathic Pain in Chronic SCI: A 
Pilot Clinical Trial 
VERSION DATE: 03/18/2024 
 
 
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25.0 Resources Available 
Resources Available: The PI is eligible to serve as PI, has sufficient time to serve 
as PI, and will contribute 4% effort in both years to this project.  As such, she will 
oversee all aspects of this study.   
 
26.0 References 
Albu S, Gomez-Soriano J, Avila-Martin G, Taylor J. 2015. Deficient conditioned pain modulation after 
spinal cord injury correlates with clinical spontaneous pain measures. Pain 156:260-72. 
 
Alshelh Z, Di Pietro F, Youssef AM, Reeves JM, Macey PM, Vickers ER, Peck CC, Murray GM, 
Henderson LA. 2016. Chronic Neuropathic Pain: It's about the Rhythm. J Neurosci 36:1008-18. 
 
Bali KK, Hackenberg M, Lubin A, Kuner R, Devor M. 2014. Sources of individual variability: miRNAs 
that predispose to neuropathic pain identified using genome-wide sequencing. Mol Pain 10:22. 
 
Bartel DP. 2009. MicroRNAs: target recognition and regulatory functions. Cell 136:215-33. 
Bombardier CH, Richards JS, Krause JS, Tulsky D, Tate DG. 2004. Symptoms of major depression in 
people with spinal cord injury: implications for screening. Arch Phys Med Rehabil 85:1749-56. 
 
Bryce TN, Budh CN, Cardenas DD, Dijkers M, Felix ER, Finnerup NB, Kennedy P, Lundeberg T, 
Richards JS, Rintala DH, Siddall P, Widerstrom-Noga E. 2007. Pain after spinal cord injury: an evidence-
based review for clinical practice and research. Report of the National Institute on Disability and 
Rehabilitation Research Spinal Cord Injury Measures meeting. J Spinal Cord Med 30:421-40. 
 
Cleeland CS, Ryan KM. 1994. Pain assessment: global use of the Brief Pain Inventory. Ann Acad Med 
Singapore 23:129-38. 
 
Cogswell JP, Ward J, Taylor IA, Waters M, Shi Y, Cannon B, Kelnar K, Kemppainen J, Brown D, Chen C, 
Prinjha RK, Richardson JC, Saunders AM, Roses AD, Richards CA. 2008. Identification of miRNA 
changes in Alzheimer's disease brain and CSF yields putative biomarkers and insights into disease 
pathways. J Alzheimers Dis 14:27-41. 
 
Cohen JE, Lee PR, Chen S, Li W, Fields RD. 2011. MicroRNA regulation of homeostatic synaptic 
plasticity. Proc Natl Acad Sci U S A 108:11650-5. 
 
Cragg JJ, Noonan VK, Noreau L, Borisoff JF, Kramer JK. 2015. Neuropathic pain, depression, and 
cardiovascular disease: a national multicenter study. Neuroepidemiology 44:130-7. 
 
Diener E, Emmons RA, Larsen RJ, Griffin S. 1985. The Satisfaction With Life Scale. J Pers Assess 49:71-
5. 
 
Dworkin RH, Turk DC, Farrar JT, Haythornthwaite JA, Jensen MP, Katz NP, Kerns RD, Stucki G, Allen 
RR, Bellamy N, Carr DB, Chandler J, Cowan P, Dionne R, Galer BS, Hertz S, Jadad AR, Kramer LD, 
Manning DC, Martin S, McCormick CG, McDermott MP, McGrath P, Quessy S, Rappaport BA, Robbins 
W, Robinson JP, Rothman M, Royal MA, Simon L, Stauffer JW, Stein W, Tollett J, Wernicke J, Witter J, 
Immpact. 2005. Core outcome measures for chronic pain clinical trials: IMMPACT recommendations. Pain 
113:9-19. 
 


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PROTOCOL TITLE: Brivaracetam to Reduce Neuropathic Pain in Chronic SCI: A 
Pilot Clinical Trial 
VERSION DATE: 03/18/2024 
 
 
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Freund P, Weiskopf N, Ashburner J, Wolf K, Sutter R, Altmann DR, Friston K, Thompson A, Curt A. 
2013. MRI investigation of the sensorimotor cortex and the corticospinal tract after acute spinal cord 
injury: a prospective longitudinal study. Lancet Neurol 12:873-881. 
 
Genda Y, Arai M, Ishikawa M, Tanaka S, Okabe T, Sakamoto A. 2013. microRNA changes in the dorsal 
horn of the spinal cord of rats with chronic constriction injury: A TaqMan(R) Low Density Array study. Int 
J Mol Med 31:129-37. 
 
Gold MS, Gebhart GF. 2010. Nociceptor sensitization in pain pathogenesis. Nat Med 16:1248-57. 
 
Graves DE, Bombardier CH. 2008. Improving the efficiency of screening for major depression in people 
with spinal cord injury. J Spinal Cord Med 31:177-84. 
 
Hou JM, Sun TS, Xiang ZM, Zhang JZ, Zhang ZC, Zhao M, Zhong JF, Liu J, Zhang H, Liu HL, Yan RB, 
Li HT. 2014. Alterations of resting-state regional and network-level neural function after acute spinal cord 
injury. Neuroscience 277:446-54. 
 
Imai S, Saeki M, Yanase M, Horiuchi H, Abe M, Narita M, Kuzumaki N, Suzuki T, Narita M. 2011. 
Change in microRNAs associated with neuronal adaptive responses in the nucleus accumbens under 
neuropathic pain. J Neurosci 31:15294-9. 
 
Janz R, Sudhof TC. 1999. SV2C is a synaptic vesicle protein with an unusually restricted localization: 
anatomy of a synaptic vesicle protein family. Neuroscience 94:1279-90. 
 
Jutzeler CR, Huber E, Callaghan MF, Luechinger R, Curt A, Kramer JL, Freund P. 2016. Association of 
pain and CNS structural changes after spinal cord injury. Sci Rep 6:18534. 
 
Kalpakjian CZ, Toussaint LL, Albright KJ, Bombardier CH, Krause JK, Tate DG. 2009. Patient health 
Questionnaire-9 in spinal cord injury: an examination of factor structure as related to gender. J Spinal Cord 
Med 32:147-56. 
 
Krause JS, Reed KS, McArdle JJ. 2010. Prediction of somatic and non-somatic depressive symptoms 
between inpatient rehabilitation.  
 
Kroenke K, Spitzer RL, Williams JB. 2001. The PHQ-9: validity of a brief depression severity measure. J 
Gen Intern Med 16:606-13. 
 
Lagos-Quintana M, Rauhut R, Lendeckel W, Tuschl T. 2001. Identification of novel genes coding for small 
expressed RNAs. Science 294:853-8. 
 
Linnman C, Moulton EA, Barmettler G, Becerra L, Borsook D. 2012. Neuroimaging of the periaqueductal 
gray: state of the field. Neuroimage 60:505-22.Liu Q, Paroo Z. 2010. Biochemical principles of small RNA 
pathways. Annu Rev Biochem 79:295-319. 
 
Morse LR, Troy KL, Fang Y, Nguyen N, Battaglino R, Goldstein RF, Gupta R, Taylor JA. 2019. 
Combination Therapy With Zoledronic Acid and FES-Row Training Mitigates Bone Loss in Paralyzed 
Legs: Results of a Randomized Comparative Clinical Trial. JBMR Plus 3:e10167. 
 
Nicolas JM, Hannestad J, Holden D, Kervyn S, Nabulsi N, Tytgat D, Huang Y, Chanteux H, Staelens L, 
Matagne A, Mathy FX, Mercier J, Stockis A, Carson RE, Klitgaard H. 2016. Brivaracetam, a selective 


MEDICAL PROTOCOL (HRP-590) 
PROTOCOL TITLE: Brivaracetam to Reduce Neuropathic Pain in Chronic SCI: A 
Pilot Clinical Trial 
VERSION DATE: 03/18/2024 
 
 
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permeability and fast onset of action. Epilepsia 57:201-9. 
 
Nicotra A, Critchley HD, Mathias CJ, Dolan RJ. 2006. Emotional and autonomic consequences of spinal 
cord injury explored using functional brain imaging. Brain 129:718-28. 
 
Orlova IA, Alexander GM, Qureshi RA, Sacan A, Graziano A, Barrett JE, Schwartzman RJ, Ajit SK. 2011. 
MicroRNA modulation in complex regional pain syndrome. J Transl Med 9:195. 
 
Packer AN, Xing Y, Harper SQ, Jones L, Davidson BL. 2008. The bifunctional microRNA miR-9/miR-9* 
regulates REST and CoREST and is downregulated in Huntington's disease. J Neurosci 28:14341-6. 
 
Redell JB, Liu Y, Dash PK. 2009. Traumatic brain injury alters expression of hippocampal microRNAs: 
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Engelborghs S, De Roeck EE, Sleegers K, Frisoni GB, Blin O, Richardson JC, Bordet R, Molinuevo JL, 
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Ziegler G, Grabher P, Thompson A, Altmann D, Hupp M, Ashburner J, Friston K, Weiskopf N, Curt A, 
Freund P. 2018. Progressive neurodegeneration following spinal cord injury: Implications for clinical trials. 
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MP. 2010. The oscillating brain: complex and reliable. Neuroimage 49:1432-45. 

ICF_001.pdf: 
Approved for use by UMN IRB
Effective on 9/29/2022
IRB Study Number: STUDY00010959
Consent Form (includes HIPAA Authorization)
Page 1 of 16   
TEMPLATE LAST REVISED: 12/16/2019 (this ICF updated per template 11/01/2021)
Version Date: 6 09/26/2022
Title of Research Study: Brivaracetam to Reduce Neuropathic Pain in Chronic SCI: A Pilot 
Clinical Trial
Investigator Team Contact Information: 
For questions about research appointments, the research study, research results, or other 
concerns, call the study team at: 
University of Minnesota, Minneapolis 
Investigator Name: Dr. Leslie Morse, DO
Investigator Departmental Affiliation: Chair, 
Department of Rehabilitation Medicine, 
University of Minnesota 
Phone Number: 612-626-5957
Email Address: morsel@umn.edu 
Rehab Lab Study Staff
Phone Number: 612-301-3072
Email Address: rehablab@umn.edu
Supported By: This research is supported by the Craig H. Neilsen Foundation.  This trial is registered 
at the National Institutes of Health (NIH) clinical trials registry, www.clinicaltrials.gov (NCT04379011).
Financial Interest Disclosure:  The following disclosure is made to give you an opportunity to 
decide if this relationship will affect your willingness to participate in this research study:  Co-
Investigator Scott Falci, MD, has a patent application submitted for the use of Briviact in spinal cord 
injury neuropathic pain.
Key Information About This Research Study
The following is a short summary to help you decide whether or not to be a part of this research study. 
More detailed information is listed later on in this form. 
What is research?
Doctors and investigators are committed to your care and safety. There are important differences 
between research and treatment plans:
●
The goal of research is to learn new things in order to help groups of people in the future. 
Investigators learn things by following the same plan with a number of participants, so they do 
not usually make changes to the plan for individual research participants. You, as an individual, 
may or may not be helped by volunteering for a research study.  
●
The goal of clinical care is to help you get better or to improve your quality of life. Doctors can 
make changes to your clinical care plan as needed.
Research and clinical care are often combined. One purpose of this informed consent document is to 


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provide you clear information about the specific research activities of this study. 
Why am I being asked to take part in this research study?
We are asking you to take part in this research study because you have had a spinal cord injury and have 
severe nerve pain. 
What should I know about a research study?
●
Someone will explain this research study to you.
●
Whether or not you take part is up to you.
●
You can choose not to take part.
●
You can agree to take part and later change your mind.
●
Your decision will not be held against you.
●
You can ask all the questions you want before you decide.
●
We will inform you if new information becomes available, including any new neuropathic pain 
treatments that might affect your decision to participate in this study.
Why is this research being done?
Spinal cord injury can be associated with severe nerve pain that doesn’t respond well to treatments. In 
this study, we want to see if treatment with a drug called Brivaracetam can safely help control pain in 
patients with spinal cord injury. Brivaracetam is FDA-approved to treat epilepsy but is experimental 
when used for nerve pain associated with spinal cord injury. We also want to see what changes take 
place in your mood, brain, and genes when you take this drug, to help us design more research with this 
drug in the future. 
How long will the research last?
We expect that you will be in this research study for about 4 months. 
What will I need to do to participate?
You will be asked to provide blood samples, have two MRIs, fill out surveys, and take Brivaracetam or 
placebo (sugar pill) as instructed by the study team.  The study medication dose will be increased over 
the first 4 weeks of the study to a maximum dose of 100mg twice a day (morning and night).

For the first 2 weeks, we will ask you to take 50mg twice a day.

If you tolerate this well, we will ask you to increase the dose to 50mg three times a day for 2 
weeks.

If you tolerate this well, we will then ask you to increase the dose to 100mg twice a day for the 
rest of the study.
If at any point you do not tolerate the drug, we will ask you to reduce the dose to the last step that you 
tolerated well without symptoms.
If you have an implanted medical device (such as a baclofen pump, spinal cord stimulator or 


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Version Date: 6 09/26/2022
pacemaker), you may still be eligible for the study, but will not receive MRI scans.
If you do not wish to have an MRI, you may still be eligible for the study, but will not receive MRI scans.
If you do not wish to participate in baseline and end-of-study biomarker blood draws, you may still be 
eligible for the study, but will not take part in the blood banking.
You will be required to complete an end-of-study blood draw to evaluate your liver function for safety.
If you live out-of-area or are unable to travel to the University of Minnesota campus, you may still 
participate in the study. Your research appointments will be completed over the phone or zoom and you 
will complete the two required blood draws with your regular primary care provider who will then send 
us the results. You will not be able to take part in the MRI scans or optional blood banking activity.
More detailed information about the study procedures can be found under “What happens if I say yes, I 
want to be in this research?”
Is there any way that being in this study could be bad for me?
There are some potential risks to participating in this study, but we will minimize those risks as much as 
possible.
Risk of Brivaracetam Use:
Taking Brivaracetam may cause side effects. 
Common side effects are those experienced by at least 5% of adults taking Brivaracetam. These include: 
nausea/vomiting, somnolence/sedation, dizziness, fatigue.
Rarer side effects are experienced by less than 5% of adults taking Brivaracetam. These include: 

suicidal behavior or thoughts of self-harm

excess sleepiness 

psychotic symptoms (such as hearing voices, feeling paranoid, or feeling agitated)

irritability or changes in mood

loss of coordination or balance

constipation
If you experience any of these symptoms, please let us know.  We may recommend that you reduce the 
dose of medication that you are taking.  Many times this eliminates the symptoms. For instance, if you 
feel excessive sleepiness at 100mg twice a day (maximum study dose), we may recommend that you 
reduce the dose to 50mg three times a day.
Other rare but serious side effects also include:  

allergic reaction (shortness of breath, rash, swelling)

seizure when stopped abruptly without tapering


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You should stop using Brivaracetam and contact the study team at once if you have any of these serious 
side effects or allergic reactions (shortness of breath, rash, swelling) or thoughts of suicide or self-harm.  
The following medications that are not safe to take while you take Brivaracetam: rifampin, 
carbamazepine, buprenorphine, propoxyphene, levetiracetam, sodium oxybate, or phenytoin.  You are 
not eligible to participate in this study if you are taking one of these drugs.  You should let us know if you 
are considering starting one of these drugs so that we can safely stop Brivaracetam and remove you 
from the study. 
More detailed information about the risks of this study can be found under “What are the risks of this 
study?  Is there any way being in this study could be bad for me? (Detailed Risks)” and in the “What 
happens to the information collected for the research?” section.
Will being in this study help me in any way?
We cannot promise any benefits to you or others from your taking part in this research. However, 
possible benefits include a reduction in your nerve pain. 
What happens if I do not want to be in this research?
You do not have to participate in this research.  Instead of being in this research study, you may 
continue to receive your usual care for pain from your doctor.  This may include any pain medications or 
treatments that your doctor may recommend for your nerve pain. 
Detailed Information About This Research Study
The following is more detailed information about this study in addition to the information listed above.
How many people will be studied?
We expect about 20 people will complete this research study at our 2 enrollment sites (Swedish Medical 
Center/Craig Hospital and University of Minnesota). We expect about 40 people will complete the 
research study overall.
What happens if I say “Yes, I want to be in this research”?
If you decide you want to be in this research study, you will have 4 in-person study visits over four 
months. If you prefer, Visit 1 and Visit 2 can be combined for your convenience. You can expect the 
following procedures during your study visits listed below.  We may complete testing over a series of 
visits at each time point if this is more convenient for you. 
Obtain Medical Clearance 
Before you can start the study, you will need to see your primary care physician (your regular doctor) to 
obtain medical clearance. This visit must occur within one month of Visit 1. Your doctor will complete a 
physical exam, a health history, and collect 3-4 tablespoons of blood to confirm that you are not 
pregnant (for people of childbearing potential) and that your kidneys and liver function properly. Your 


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insurance will be charged for this visit and you will be responsible for any associated copays or costs, 
including any amount not covered by your insurance. We can provide you with a list of the required labs 
and we recommend that you contact your insurance in advance to see if you will have any costs 
associated with these tests.
If you are an M Health Fairview patient, we will pull the results directly from your electronic health 
record. If your doctor is not part of the M Health Fairview care system, we will ask that you or your 
doctor provide research staff with the results.
Visit 1
At your first study visit, the study will be explained to you, and you will be given a chance to ask 
questions.  A member of the study team will review the consent form with you. After you have enrolled 
in the study we will assign you randomly to one of 2 groups: the group that receives the active drug 
(Brivaracetam) or the group that receives a placebo (sugar pill).  There is a 50-50 chance that you will be 
assigned to one group or the other, similar to flipping a coin.  We will give you instructions on how to 
take the study drug and a drug diary for you to record your study drug use, your daily pain ratings, and 
any additional medications you may be taking.  
Additionally, once a week a member of our research team will call to ask you about any side effects you 
may be experiencing while taking the study drug.  This team member will not know if you are taking 
active drug or the placebo (sugar pill). You can complete this call via phone or Zoom.
Visit 2
At this visit:

You will have a Magnetic Resonance Imaging (MRI) scan of your brain. This activity is described 
in the section titled “MRI Scan” below.

You will fill out some surveys relating to pain, mood, satisfaction with life, and community 
integration.

If you choose to participate in the optional blood banking, we will collect about 3-4 tablespoons 
of blood for research purposes.  We will study potential biomarkers of pain in SCI, including 
microRNAs. MicroRNAs are small nucleic acids that control various cellular processes and may 
be involved in the production of pain.  We are not doing genetic analyses in this study.

You will have a physical exam and answer health questions.

RxArtisans Pharmacy will FedEx the drug to you and study staff will send an email notification 
that the drug has been sent by overnight mail.
Visit 3
This visit will take place about 3 months after Visit 2. This is your final study visit. At this visit:

You will have a second MRI. This activity is described in the section titled “MRI Scan” below.

You will fill out some surveys relating to pain, mood, satisfaction with life, and community 
integration.

If you choose to participate in the optional blood banking, we will collect about 3-4 tablespoons 
of blood for research purposes.  We will study potential biomarkers of pain in SCI, including 


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Version Date: 6 09/26/2022
microRNAs. MicroRNAs are small nucleic acids that control various cellular processes and may 
be involved in the production of pain.  We are not doing genetic analyses in this study.

You will have a physical exam and answer health questions.

You will have a fasting blood draw to assess your organ health. You have two options for this: 
you can either have your blood drawn at the Clinical Research Unit on the University of 
Minnesota campus OR you can return to your primary care provider (your regular doctor) to 
have your blood drawn and your doctor’s office will send us the test results. It is important for 
you to be aware that if you complete this activity with your own provider, your insurance will be 
charged for this visit and you will be responsible for any associated copays or costs, including 
any amount not covered by your insurance. If you choose to go this route, we recommend that 
you contact your insurance provider in advance so that you can know what to expect. If you 
complete your blood draw at the University of Minnesota research site, your blood draw and 
labs will be paid for by the study; there will be no cost to you. 

If you are of child-bearing potential, you will complete a urine pregnancy test.
Visit 4

You will fill out some surveys relating to pain, mood, satisfaction with life, and community 
integration.
2 weeks dose reduction after end of study testing

Someone from the study will call you to remind you to start reducing the dose of the study drug 
so that you can safely stop taking it when the study ends.  You will be instructed to take 1 pill 
twice a day for one week and then 1 pill once a day for 1 week and then stop taking it entirely.

You will be asked to mail empty bottles to RxArtisans Pharmacy for pill counts with self-
addressed, prepaid packaging we will provide for you.
MRI Scan:
(In-person participants only) 
If you agree to take part in the MRI scans and we have determined that an MRI scan will be safe for you 
(no contraindications to MRI), you will have a scan at Visit 2 and again at Visit 3. These visits will take 
place at the Center for Magnetic Resonance Research located on the East Bank of campus. 
In order to ensure your safety, we may ask you to undergo some additional safety screening measures 
such as a pregnancy test, x-ray, and completing a safety questionnaire. Additional information about 
MRI risks and safety measures can be found in the section titled “Risk of MRI Scans” below.
Prior to your MRI scan, we will ask you to remove any jewelry and removable metallic objects from your 
body. We will provide you with a pair of hospital scrubs to wear during your scan. 
The scanner is a very large tunnel. You will lie on your back on a narrow table that will slide you into the 
tunnel. We may ask you to imagine yourself performing tasks with your legs, such as walking or 
standing, or finger tapping for a few moments while you lie still during the MRI scan.
What are my responsibilities if I take part in this research?
If you take part in this research, you will be responsible for:


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
attending all study visits

taking study medication as instructed

telling the study team about any side effects that you experience
What happens if I say “Yes”, but I change my mind later?
If you take part in this research study, and want to leave, you should tell us.  Your choice not to be in this 
study will not negatively affect your right to any present or future medical care, your academic standing 
as a student, or your present or future employment.  
We will make sure that you stop the study safely.  We will also talk to you about follow-up care, if 
needed.   
If you decide to leave the research study, tell the study team about your decision. We may ask you to 
complete some evaluations at a final study visit. 
If you stop being in the research, information about you that has already been collected may not be 
removed from the study database. 
Can I be removed from the research?
It’s possible that we will have to ask you to leave the study before you finish it.  If this happens, we will 
tell you why.  We will also help arrange other care for you, if needed.
What are the risks of being in this study?  Is there any way being in this study could be 
bad for me? (Detailed Risks)
In addition to the risks of Brivaracetam described above, risks in this study include:
Risk of MRI Scans: 
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 Computed Tomography (CT) scan, but MRI does not use 
ionizing radiation (high-energy radiation that can potentially cause damage to deoxyribonucleic acid or 
DNA) like x-rays or CT scans. The risks associated with MRI scans are: 

Projectiles:  Objects with magnetic properties can be pulled into the magnet and turn into 
projectiles. To minimize this risk we ask that subjects remove all metallic items (watches, cell 
phones, hair pins, etc.) prior to entering the scanner and by controlling access to the scanner.  

Claustrophobia:  The scanner is a long narrow tube that may cause some people to feel 
claustrophobic.  

Hearing Damage:  The noise generated by the operation of the scanner during a study is loud 
enough to cause hearing damage if you do not wear hearing protection. Hearing protection is 
required and is provided by the investigator. 

Nerve Stimulation:  Some people experience localized tingling, twitching, or muscle contractions 
during MRI scans. This is expected, but if it is uncomfortable please notify the investigator.

Disruption of Devices:  Some devices can be damaged by magnetic fields and should not be 


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brought into the scanner room. This includes some implanted devices such as pacemakers, 
cochlear implants, insulin pumps, nerve stimulators, etc. If you have any implanted device notify 
the investigator.

Heating of Devices:  The radiofrequency waves used in MRI can heat conductive materials such 
as metal implants (screws, plates, rods, wires, artificial joints, etc.), certain tattoo inks, certain 
clothing fabrics, jewelry, medication patches, wigs, etc. You will be asked to remove these items 
if possible. If they cannot be removed you will be asked to provide more information to allow 
MRI staff to be able to make determination on the safety of proceeding with the scan. 
A thorough pre-scan questionnaire will allow us to minimize the risk of device disruption and heating. 
You will be in constant contact with the scanning operator and should notify the operator immediately, 
via the squeeze ball, if you notice anything unusual, become claustrophobic, think that your hearing 
protection is not adequate, or if you experience nerve stimulation that is uncomfortable.
In addition, there is a risk of unknown effects related to participation in MRI research.  Long-term effects 
of exposure to high magnetic fields are unknown.  Most people experience no short-term ill effects from 
the strong magnetic field, but some people report dizziness, mild nausea, headache, a metallic taste in 
their mouth, or sensations of flashing lights. These symptoms, if present, subside shortly after leaving 
the magnet. If any sensations experienced during participation cause discomfort or pain, notify the 
researcher right away and your participation will stop and you will be taken out of the magnetic field.
Risk of Blood Draws: 
The risk of infection during blood draw is low because we clean the skin first and use sterile techniques. 
There is a risk of pain and bruising. If this occurs, we expect it to be mild and to resolve in a day or two. 
Sometimes people feel faint or lightheaded during a blood draw.
Risk of Loss of Confidentiality: 
There is a small risk that your confidential medical information could be revealed or discovered by 
mistake. Information about you taking part in this study or the results of the research won’t be placed in 
your medical records. In addition, your samples and information will be coded and the key to the code 
will be kept in a separate, locked file. We won’t share or publish any information that will identify you. 
There is also a small chance that, if you engage in a videoconference through the Zoom for Healthcare 
platform, the Zoom session could be hacked. 
Will I receive any imaging results after an MRI?
The images or pictures created during this study are for research purposes only and are not intended to 
provide health care to you. However, if the results from the magnetic resonance imaging show 
something unusual in the pictures, a Radiologist trained in reading the pictures will look at them. The 
pictures will not contain any personal information except your age and pertinent medical history 
collected as part of the research. There will be no charge to you for having the Radiologist look at your 
pictures. The investigator in charge of this study will contact you if the recommendation of the 
Radiologist is to further investigate the unusual results of the pictures with your own physician. 
However, further medical follow up is not a part of this study and the study does not have funds set 


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aside for this purpose. Therefore, if the results do show something unusual, any medical follow up cost 
will be your responsibility and/or the responsibility of your health insurance carrier.
Will I know about any new information about the effects of MRIs on human health?
You will be told of any important new information that is learned during the course of this research 
study, which might affect your condition or your willingness to continue participation in this study.
Will it cost me anything to participate in this research study?
Prior to enrolling in the study, we ask that you see your primary care physician to determine if you are 
eligible, including having your physician order lab work to confirm that you are not pregnant (for people 
of childbearing potential) and that your kidneys and liver function properly. Your insurance will be 
charged for that visit and you may be responsible for any associated copays or costs. If your insurance 
does not cover this visit with your primary care provider and the associated lab work, you will be 
required to pay any uncovered amount out of pocket, up to the full cost of the visit. We recommend 
that you check with your insurance and your provider before scheduling your visit. 
The study drug, lab costs, physical examinations and MRIs performed for this study will be paid for by 
the study.   
You and your insurance company will be charged for the health care services that you would ordinarily 
be responsible to pay. In some cases, insurance will not pay for services ordinarily covered because 
these services are performed for a research study. You should check with your insurance to see what 
services will be covered by your insurance and what you will be responsible to pay.
If I take part in this research study, how will you protect my privacy?
During this research, identifiable information about your health will be collected.  In the rest of this 
section, we refer to this information simply as “health information”.  In general, under federal law, 
health information is private.  However, there are exceptions to this rule, and you should know who may 
be able to see, use, and share health information for research and why they may need to do so.
What happens to the information collected for the research, including my health 
information?
We try to limit the use and sharing of your information, including research study records, any medical 
records and any other information about you, to people who have a need for this information.  But we 
cannot promise complete confidentiality.  
Overview
If you participate in this study, your information, including your health information, will be used and 
shared for purposes of conducting this research.  As described later in this Consent Form, your 
information may also be used and shared for publishing and presenting the research results, future 
research, and any optional elements of the research you agree to in this Consent Form. If you sign this 


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Consent Form, you are giving us permission to use and share your health information for these 
purposes, and if we are using your medical records, you are giving permission to any health care 
providers who are treating you to share your medical records with us.  
Some people or groups who get your health information might not have to follow the same privacy rules 
that we follow and might use or share your health information without your permission in ways that are 
not described in this form.  For example, we understand that the sponsor of this study may use your 
health information to perform additional research on various products or conditions, to obtain 
regulatory approval of its products, to propose new products, and to oversee and improve its products’ 
performance.  We share your health information only when we must, and we ask anyone who receives it 
from us to take measures to protect your privacy.  The sponsor has agreed it will not contact you 
without your permission and will not use or share your information for any mailing or marketing list.  
However, once your information is shared outside of the UMN, we cannot control all the ways that 
others use or share it and cannot promise that it will remain private.
What health information will be made available?
Health information about you to be used and shared for the research includes those items checked by 
the research team below:
☒ Your medical records, which may include records from hospital and clinic visits, emergency room 
visits, immunizations, medical history and physical exams, medications, images and imaging reports, 
progress notes, psychological tests, EEG/EKG/ECHO reports, lab and pathology reports, dental records 
and/or financial records.  These records may be used and shared for as long as this research continues.
☒ Information collected as part of this research study, including research procedures, research visits, 
and any optional elements of the research you agree to, all as described in this Consent Form.  This 
information might not be part of your medical record, and may include things like responses to surveys 
and questionnaires, and information collected during research visits described in this Consent Form.
What about more sensitive health information?
Some health information is so sensitive that it requires your specific permission.  If this research study 
requires any of this sensitive information, the boxes below will be marked and you will be asked to initial 
to permit this information to be made available to the research team to use and share as described in 
this Consent Form.
☐ My drug & alcohol abuse, diagnosis & treatment records ______ (initial)
☐ My HIV/AIDS testing records  ______ (initial)
☐ My genetic testing records  ______ (initial)
☐ My mental health diagnosis/treatment records  ____ (initial)
☐ My sickle cell anemia records  _______ (initial)
Who will access and use my health information?
If you agree to participate in this study, your information will be shared with: 

The University of Minnesota research team and any institutions or individuals collaborating on 
the research with us. 


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
Others at the University of Minnesota and M Health/Fairview who provide support for the 
research or who oversee research (such as the Institutional Review Board or IRB which is the 
committee that provides ethical and regulatory oversight of research at the University, systems 
administrators and other technical and/or administrative support personnel, compliance and 
audit professionals (Such as the Quality Assurance Program of the Human Research Protection 
Program (HRPP)) , individuals involved in processing any compensation you may receive for your 
participation, and others); Department of Rehabilitation Medicine staff or UMN Clinical 
Research Unit staff involved in this study; Non-research staff at the Department of 
Rehabilitation Medicine or UMN Clinical Research Unit who need this information to do their 
jobs (such as for billing, or health care operations).

The Craig H. Neilsen Foundation (the sponsor of this study), and the people or groups it hires to 
help perform this research, as well as any affiliates, partners or agents of the sponsor(s) involved 
in the research, organizations funding the research, and any affiliates, partners or agents of the 
funding organization(s) involved in the research.

Organizations who provide accreditation and oversight for research and the research team, and 
others authorized by law to review the quality and safety of the research (such as U.S. 
government agencies like the Food and Drug Administration, the Office of Human Research 
Protections, the Office of Research Integrity, or government agencies in other countries); and a 
group that oversees the data (study information) and safety of this research.

Organizations that process any payments that may be made to you for participating in this 
study, and any other individuals or organizations specifically identified in this Consent Form.

In the instance that you engage in a study-related videoconference through the Zoom video-
conferencing platform, Zoom does not have access to identifiable protected health information 
(PHI) and they protect and encrypt all audio, video, and screen sharing data.  These Zoom 
sessions will not be recorded or maintained. 

People from organizations that provide independent accreditation and oversight of hospitals 
and research.

People or groups that we hire to do work for us, such as data storage companies, insurers, and 
lawyers.

Federal and state agencies (such as the Food and Drug Administration, the Department of 
Health and Human Services, the National Institutes of Health, and other US or foreign 
government bodies that oversee or review research).

Public health and safety authorities (for example, if we learn information that could mean harm 
to you, we may need to report this, as required by law).
Additional sharing of your information for mandatory reporting
If we learn about any of the following, we may be required or permitted by law or policy to report this 
information to authorities:

Current or ongoing child or vulnerable adult abuse or neglect;

Communicable, infectious or other diseases required to be reported under Minnesota’s 
Reportable Disease Rule;

Certain wounds or conditions required to be reported under other state or federal law; or


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
Excessive use of alcohol or use of controlled substances for non-medical reasons during 
pregnancy.
How will my information be used in publications and presentations?
We may publish the results of this research in scientific, medical, academic or other journals or reports, 
or present the results at conferences.  Information that makes it easy to identify you (such as your name 
and contact information, SSN and medical records number) will not be part of any publication or 
presentation.  If you have an extremely unique or rare condition that is not shared by many others, it is 
possible that some people may be able to determine your identity even without these identifiers.
What will be done with my data and specimens when this study is over?
We will use and may share data and/or specimens for future research. They may be shared with 
researchers/institutions outside of the UMN. This could include for profit companies. We will not ask for 
your consent before using or sharing them. We will remove identifiers from your data and/or 
specimens, which means that nobody who works with them for future research will know who you are.  
Therefore, you will not receive any results or financial benefit from future research done on your 
specimens or data. 
Because research is an ongoing process, we cannot give you an exact date when we will either destroy 
or stop using or sharing your health information.
The results of this research study may be published in a medical book or journal, or used to teach 
others.  However, your name or identifying information will not be used for these purposes without 
your specific permission.
Do I have to sign this Consent Form and give my permission to make my information, including my 
health information, available for use and sharing?
No, you do not have to sign this Consent Form.  But if you do not sign, you will not be able to participate 
in this research study.  Treatment available outside of the study, payment for such treatment, 
enrollment in health insurance plans and eligibility for benefits will not be impacted by your decision 
about signing this Consent Form.
Does my permission for making my health information available for use and sharing ever expire?
No, there is no expiration date.
May I cancel my permission for making my health information available for use and sharing?
Yes.  You may cancel your permission at any time by writing to the researcher at the address on the first 
page of this Consent Form.  If you cancel your permission, you will no longer be in the research study. 
You may also want to ask someone on the research team if canceling will affect any research related 
medical treatment.   If you cancel your permission, any health information about you that was already 
used and shared may continue to be used and shared for the research study and any optional elements 
of the study to which you agree in this Consent Form. 


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What happens to my health information after it is shared with others?
When we share your information with others as described in this Consent Form, privacy laws may no 
longer protect your information and there may be further sharing of your information.  
Will I be able to look at my records?
It is possible that the research team may not allow you to see the information collected for this study.   
However, you may access any information placed in your medical records after the study is complete.  
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. 
Law. This website will not include information that can identify you. At most, the website will include a 
summary of the results. You can search this website at any time
Will I receive research test results?
NO Results will be shared
Most tests done on samples in research studies are only for research and have no clear meaning for 
health care. The investigator(s) will not contact you or share your individual test results. 
Will anyone besides the study team be at my consent meeting?  
You may be asked by the study team for your permission for an auditor to observe your consent 
meeting. Observing the consent meeting is one way that the University of Minnesota makes sure that 
your rights as a research participant are protected. The auditor is there to observe the consent 
meeting, which will be carried out by the people on the study team. The auditor will not document any 
personal (e.g. name, date of birth) or confidential information about you. The auditor will not observe 
your consent meeting without your permission ahead of time.   
Whom do I contact if I have questions, concerns or feedback about my experience?
You can call us with your questions or concerns. Ask questions as often as you want. You can call us at 
612-301-3072, Monday through Friday, 8am-4:30pm or email at rehablab@umn.edu. Leslie Morse, DO 
is the person in charge of this study.  You can call her 612-626-5957 Monday through Friday 9am-5pm.
This research has been reviewed and approved by an IRB within the Human Research Protections 
Program (HRPP). To share feedback privately with the HRPP about your research experience, call the 
Research Participants’ Advocate Line at 612-625-1650  (Toll Free: 1-888-224-8636) or go to 
z.umn.edu/participants.  You are encouraged to contact the HRPP if: 
●
Your questions, concerns, or complaints are not being answered by the research team.
●
You cannot reach the research team.
●
You want to talk to someone besides the research team.
●
You have questions about your rights as a research participant.
●
You want to get information or provide input about this research.
Will I have a chance to provide feedback after the study is over? 
The HRPP may ask you to complete a survey that asks about your experience as a research participant. 


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You do not have to complete the survey if you do not want to. If you do choose to complete the survey, 
your responses will be anonymous.
If you are not asked to complete a survey, but you would like to share feedback, please contact the 
study team or the HRPP. See the “Investigator Contact Information” of this form for study team contact 
information and “Whom do I contact if I have questions, concerns or feedback about my experience?” of 
this form for HRPP contact information.
What happens if I am injured while participating in this research?
In the event that this research activity results in an injury, treatment will be available, including first aid, 
emergency treatment and follow-up care as needed.  Care for such injuries will be billed in the ordinary 
manner, to you or your insurance company.  If you think that you have suffered a research related injury 
and that you may be eligible for reimbursement of some medical care costs, let the study physicians 
know right away.
Will I be compensated for my participation? 
If you agree to take part in this research study, we will pay you up to $350 for your time, effort, and to 
assist with transportation. You will receive $150 after Visit 2, $150 after Visit 3 and $50 after Visit 4. 
Payment will be made using a pre-paid debit card called Greenphire ClinCard. It works like a bank debit
card. We will give you a debit card and each time you receive a payment for participation in this study,
the money will be added to the card after each completed visit. 
You may use this card at any store that accepts MasterCard or you can use a bank machine to remove
cash. However, there may be fees drawn against the balance of the card for cash withdrawals (ATM use) 
and inactivity (no use for 3 months). We will give you the ClinCard Frequently Asked Questions
information sheet that answers common questions about the debit card. You will also receive letters 
with additional information on how you can use this card and who to call if you have any questions. Be
sure to read these letters, including the cardholder agreement, for details about fees.
The debit card system is administered by an outside company. The company, Greenphire, will be given
your name. They will use this information only as part of the payment system. Your information will not 
be used for any other purposes and will not be given or sold to any other company. Greenphire will not 
receive any information about your health status or the study in which you are participating.


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Optional Elements:
MRI scans
In-person participants only
If you do not have any contraindications to MRI and you are able, do you agree to take part in the 
research MRIs?
▢ Yes      ▢ No        ▢ N/A
Participant Initials: ___________
Interest in blood sample banking
In-person participants only
Three to four tablespoons of blood samples will be collected in 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. If you are 
able, do you agree to let us store your blood samples and health information for future research related 
to nerve pain and spinal cord injury?
▢ Yes      ▢ No        ▢ N/A 
Participant Initials: ___________
Interest in future research
I would like to be contacted about future research studies that may interest me. 
Participant Initials: ___________
Signature Block for Capable Adult:
Your signature documents your permission to take part in this research.  You will be provided a copy of 
this signed document.
_______________________________________________      __________________
Signature of Participant                                                                   Date
_______________________________________________
Printed Name of Participant
_______________________________________________      __________________
Signature of Person Obtaining Consent                                       Date
_______________________________________________
Printed Name of Person Obtaining Consent


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For the Consent of Non-English Speaking Participants when an Interpreter is Used:
As someone who understands both English and the language spoken by the subject, I represent that the 
English version of the consent form was presented orally to the subject in the subject’s own language, 
and that the subject was given the opportunity to ask questions.
__________________________________________      __________________
Signature of Interpreter
Date
__________________________________________
Printed Name of Interpreter
OR: 
Statement from a Non-Interpreter:
As someone who understands both English and the language spoken by the subject, I represent that the 
English version of the consent form was presented orally to the subject in the subject’s own language, 
and that the subject was given the opportunity to ask questions.
__________________________________________      __________________
Signature of Individual
Date
__________________________________________ 
Printed Name of Individual
Witness to Consent of Subjects Who Cannot Read or Write or are Physically Unable to 
Talk or Write
Statement of Witness
I represent that the consent form was presented orally to the subject in the subject’s own language, that 
the subject was given the opportunity to ask questions, and that the subject has indicated their consent 
and authorization for participation by (check one box as applicable):
 Making their mark above
 Thumb print
_______________
____________________________________________________________________________________
Witness
Print Name
Date/Time