Topiramate as a Disease Modifying Therapy for Cryptogenic Sensory Peripheral Neuropathy in Metabolic Syndrome (CSPN)
Phase: PHASE2
Conditions: Cryptogenic Sensory Peripheral Neuropathy in Metabolic Syndrome
Sponsor: Virginia Commonwealth University

Topiramate as a Disease Modifying Therapy for CSPN  
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FULL PROTOCOL TITLE 
Topiramate as a disease modifying therapy for Cryptogenic Sensory Peripheral Neuropathy in 
Metabolic Syndrome (CSPN)  
 
Protocol Version: 8.0 
Protocol Date: 8/8/2018 
 
SHORT PROTOCOL TITLE 
The TopCSPN Study / Topiramate as a Disease Modifying Therapy for CSPN 
 
Protocol Principal Investigator (PPI); 
A. Gordon Smith, M.D. 
Professor and Chair of Neurology 
VCU Department of Neurology 
Virginia Commonwealth University 
 
Supported by: 
The National Institute of Neurological Disorders and Stroke (NINDS) 
U01NS095388 
  
Sponsor of IND/IDE: 
IND Exempt (IND 125823) 
 
 
 
 
 
 
 
 
 
The information contained herein is confidential and proprietary in nature, and will not be 
disclosed to any third party without written approval of authorized designee.  This document may 
be disclosed to the appropriate institutional review boards or to duly authorized representatives 
of the US Food and Drug Administration or a national regulatory authority under the condition that 
they maintain confidentiality. 
 
 

 
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TABLE OF CONTENTS 
 
INVESTIGATOR AGREEMENT.................................................................................................. 5 
1. 
STUDY OBJECTIVES ........................................................................................................... 9 
1.1. 
Primary Objectives ........................................................................................................... 9 
1.2. 
Secondary Objectives ..................................................................................................... 10 
2. 
BACKGROUND .................................................................................................................. 10 
2.1. 
Target Population ........................................................................................................... 10 
2.2. 
Study Timeline ............................................................................................................... 11 
2.3. 
Rationale......................................................................................................................... 11 
2.4. 
Supporting Data.............................................................................................................. 12 
3. 
STUDY DESIGN.................................................................................................................. 14 
4. 
SELECTION AND ENROLLMENT OF SUBJECTS ......................................................... 15 
4.1. 
Inclusion Criteria ............................................................................................................ 15 
4.2. 
Exclusion Criteria ........................................................................................................... 16 
4.3. 
Subject Withdrawal Criteria ........................................................................................... 17 
4.4. 
Study Enrollment Procedures ......................................................................................... 18 
4.4.1. 
Subject Recruitment and Retention ........................................................................ 18 
4.4.2. 
Screening Logs........................................................................................................ 18 
4.4.3. 
Informed Consent.................................................................................................... 19 
4.4.4. 
Assent ...................................................................................................................... 19 
4.4.5. 
Randomization/Treatment Assignment .................................................................. 19 
5. 
STUDY INTERVENTIONS/ STUDY DRUG ..................................................................... 20 
5.1. 
Study Drug and Dose Selection ..................................................................................... 20 
5.2. 
Dose selection ................................................................................................................ 20 
5.3. 
Formulation and Packaging ............................................................................................ 20 
5.3.1. 
Supplies and Dispensation ...................................................................................... 21 
5.3.2. 
Titration Schedule and Dose Adjustments .............................................................. 21 
5.4. 
Concomitant Interventions ............................................................................................. 22 
5.4.1. 
Prohibited Medications/Interventions ..................................................................... 22 
5.5. 
Subject Compliance........................................................................................................ 23 
6. 
STUDY PROCEDURES ...................................................................................................... 23 
6.1. 
Schedule of Assessments ............................................................................................... 23 
6.2. 
Visit 01 Screening (Day -30 to 0) .................................................................................. 23 
6.3. 
Re-screening ................................................................................................................... 24 
6.4. 
Visit 02 Baseline (Day 0) ............................................................................................... 25 
6.5. 
Visit 03 Week 16 (± 7 days) ........................................................................................... 26 
6.6. 
Visit 04 Week 32 (± 7 days) ........................................................................................... 27 
6.7. 
Visit 05 Week 48 (± 7 days) ........................................................................................... 28 
6.8. 
Visit 06 Week 64 (± 7 days) ........................................................................................... 28 
6.9. 
Visit 07 Week 80 (± 7 days) ........................................................................................... 29 
6.10. Visit 08 Week 96 Termination (± 7 days) ...................................................................... 30 
6.11. Visit 09 Safety Assessment ............................................................................................ 31 
6.12. Early Termination Visit (< 30 ± 7 days) ........................................................................ 31 
6.13. Early Termination and Premature Withdrawal .............................................................. 32 

 
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6.13.1. Premature Drug Discontinuation ............................................................................ 33 
6.13.2. Restarting Study Drug after Premature Drug Discontinuation ............................... 33 
6.13.3. Missed Doses .......................................................................................................... 33 
6.13.4. On Study/Off-Intervention Evaluations .................................................................. 33 
6.14. Off-Study Requirements ................................................................................................ 34 
6.15. Pregnancy ....................................................................................................................... 34 
6.16. Diabetes .......................................................................................................................... 34 
7. 
SPECIAL INSTRUCTIONS AND DEFINITIONS OF EVALUATIONS ................... 34 
7.1.1. 
Informed Consent.................................................................................................... 34 
7.1.2. 
Protocol Violations ................................................................................................. 34 
7.1.3. 
Medical History ...................................................................................................... 35 
7.1.4. 
Concomitant Medications/Treatments .................................................................... 35 
7.1.5. 
Physical Examination.............................................................................................. 35 
7.1.6. 
Vital Signs ............................................................................................................... 35 
7.1.7. 
Waist Circumference .............................................................................................. 35 
7.1.8. 
Electrocardiogram (ECG) ....................................................................................... 35 
7.1.9. 
Neuropathy Symptom Assessment ......................................................................... 36 
7.1.10. Utah Early Neuropathy Scale (UENS) ................................................................... 36 
7.1.11. Functional and Mobility Testing ............................................................................. 36 
7.1.12. Laboratory Evaluations ............................................................................................. 36 
7.1.14. Skin Biopsy ............................................................................................................... 38 
7.1.14.1. 
Distal Thigh Skin Biopsy ................................................................................ 39 
7.1.15. Columbia-Suicide Severity Rating Scale (C-SSRS) ............................................... 39 
7.1.16. The Norfolk Quality of Life – Diabetic Neuropathy (NQOL-DN) Scale ............... 39 
7.1.17. The Rapid Assessment of Physical Activity (RAPA) Survey ................................ 39 
7.1.18. Subject Adherence Assessments ............................................................................. 40 
7.1.19 Optional Tissue Banking............................................................................................ 40 
8. 
MANAGEMENT OF ADVERSE EVENTS ........................................................................ 40 
8.1. 
Pregnancy ....................................................................................................................... 42 
9. 
PROTOCOL AMENDMENTS AND STUDY TERMINATION ....................................... 42 
10. 
STATISTICAL CONSIDERATIONS............................................................................... 42 
10.1. Outcomes ........................................................................................................................ 47 
10.1.1. Primary Outcome (including definition) ................................................................. 47 
10.1.2. Secondary Outcome(s) ............................................................................................ 48 
10.1.3. Exploratory Outcomes ............................................................................................ 49 
10.2. Data Monitoring ............................................................................................................. 49 
11. 
DATA COLLECTION, SITE MONITORING, AND ADVERSE EXPERIENCE 
REPORTING ................................................................................................................................ 50 
11.1. Data Management .......................................................................................................... 50 
11.1.1. Registration ............................................................................................................. 50 
11.1.2. Data Entry ............................................................................................................... 51 
11.2. Role of Data Management.............................................................................................. 51 
11.3. Quality Assurance .......................................................................................................... 51 
11.3.1. Development of Monitoring Plan ........................................................................... 51 

 
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11.3.2. Site Monitoring Visits ............................................................................................. 52 
11.3.3. Laboratory Data Flow ............................................................................................. 52 
11.4. Adverse Experience Reporting....................................................................................... 52 
11.4.1. Definitions of Adverse Events, Suspected Adverse Drug Reactions & Serious 
Adverse Events ..................................................................................................................... 54 
11.4.1.1. 
Adverse Event Collection and Reporting .............................................................. 54 
11.4.1.2. 
Serious Adverse Events .......................................................................................... 55 
11.4.2. 
Assessment and Recording of Adverse Events .................................................. 56 
12. 
HUMAN SUBJECTS ........................................................................................................ 58 
12.1. Institutional Review Board (IRB) Review and Informed Consent ................................ 58 
12.2. Subject Confidentiality ................................................................................................... 58 
12.3. Study Modification/Discontinuation .............................................................................. 59 
13. 
PUBLICATION OF RESEARCH FINDINGS ................................................................. 59 
14. 
REFERENCES .................................................................................................................. 59 
15. 
Appendix A ........................................................................................................................ 66 
 
 
 
 

 
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INVESTIGATOR AGREEMENT 
 
I have read the foregoing protocol [version 8.0, dated 8/8/2018] and agree to conduct the study 
as described herein. 
By signing the protocol, the Investigator agrees to keep all information provided by the 
NeuroNEXT Network in strict confidence and to request the same from his/her staff and the 
Institutional Review Board. Study documents provided by the NeuroNEXT Network will be stored 
appropriately to ensure their confidentiality. The Investigator should not disclose such information 
to others without authorization, except to the extent necessary to conduct the study.  
 
 
 
 
 
______________________________________ 
_______________________ 
Investigator Signature 
Date 
______________________________________ 
Print Investigator’s Name 

 
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SIGNATURE PAGE 
Study Number:  
NN108 
 
Principal Investigator Approval: 
 
 Signature:                                                                                   Date: 
 Name: 
A. Gordon Smith, MD 
 
 
 
 
NeuroNEXT Clinical Coordinating Center Approval: 
 
Signature:                                                                                   Date: 
 Name: 
Merit Cudkowicz, MD 
 
 
 
 
NeuroNEXT Data Coordinating Center Approval: 
 
Signature:                                                                                   Date: 
Name: 
Christopher Coffey, PhD 
 
 
 
 
 
 
 
 
 
 
 
 

 
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LIST OF ACRONYMS, ABBREVIATIONS, AND DEFINITIONS OF TERMS  
 
6MWT  
 
6 Minute Walk Test 
ABC 
 
 
Activities-specific Balance Confidence 
AE 
 
 
Adverse Event 
ADA 
 
 
American Diabetes Association 
BMI 
 
 
Body Mass Index 
BMP 
 
 
Basic Metabolic Panel 
BPI-DN 
 
Brief Pain Inventory – Diabetic Neuropathy 
CCC 
 
 
Clinical Coordination Center 
CDE 
 
 
Common Data Elements 
CFR 
 
 
Code of Federal Regulations 
CIRB   
 
Central Institutional Review Board 
CRF 
 
 
Case report form 
CS 
 
 
Clinically Significant 
CSPN  
 
Cryptogenic Sensory Peripheral Neuropathy  
CSS PI 
 
Clinical Study Site PI 
C-SSRS 
 
Columbia-Suicide Severity Rating Scale 
DCC 
 
 
Data Coordination Center 
DOR  
 
Delegation of Responsibility 
DPP   
 
Diabetes Prevention Program 
DM 
 
 
Data Management 
DSMB  
 
Data Safety Monitoring Board 
ECG 
 
 
Electrocardiogram 
eCRF  
 
Electronic Case Report Form 
EDC 
 
 
Electronic data capture 
FDA      
 
Food and Drug Administration 
GCP 
 
 
Good Clinical Practice 
HIPAA  
 
Health Insurance Portability and Accountability Act 
ICF 
 
 
Informed Consent Form 
ICH 
 
 
International Conference on Harmonization  
IENFD   
 
Intraepidermal Nerve Fiber Density 
IGT  
 
 
Impaired Glucose Tolerance 
IGTN   
 
Impaired Glucose Tolerance Neuropathy 
IMM 
 
 
Independent Medical Monitor 
IRB 
 
 
Institutional Review Board 
IVRS  
 
Interactive Voice Response System 
IWRS  
 
Interactive Web Response System 
MedDRA 
 
Medical Dictionary for Regulatory Activities 
NCS 
 
 
Nerve Conduction Studies 
NCS 
 
 
Not Clinically Significant 
NINDS  
 
National Institute of Neurological Disorders and Stroke 
NQOL-DN 
 
Norfolk Quality of Life – Diabetic Neuropathy 
NIS-LL  
 
Neuropathy Impairment Scale Lower Limb 
NTSS-6 
 
Neuropathy Total Symptom Score – 6 
PPI 
 
 
Protocol Principal Investigator 
PLP 
 
 
Paraformaldehyde Lysine Phosphate 
PSC 
 
 
Protocol Steering Committee 

 
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QOL    
 
Quality of Life 
QUICKI 
 
Quantitative Insulin Sensitivity Check Index 
RAPA  
 
Rapid Assessment of Physical Activity 
SAE 
 
 
Serious adverse event 
SD 
 
 
Standard Deviation 
SOA   
 
Schedule of Activities 
TUG 
 
 
Timed Up and Go 
UENS  
 
Utah Early Neuropathy Scale 
 
 

 
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SYNOPSIS 
Title:  Topiramate as a Disease Modifying Therapy for Cryptogenic Sensory Peripheral 
Neuropathy in Metabolic Syndrome:  The “TopCSPN Study” 
 
Short Title:  The TopCSPN Study 
 
Primary Objective:  Determine if oral topiramate slows progression of CSPN using intraepidermal 
nerve fiber density (IENFD) as a primary measure of axon loss and the Norfolk Quality of Life –
Diabetic Neuropathy (NQOL-DN) as a measure of neuropathy related quality of Life. 
 
Secondary Objective:  Determine the patient focused clinical relevance of change in IENFD and 
other CSPN surrogate measures using measures of pain, QOL, balance and mobility.   
 
Design and Outcomes:  The TopCSPN study will consist of screening and baseline visits, safety 
and monitoring visits every 16 weeks, evaluation visits at 32 and 64 weeks, a 96-week end-of-
treatment visit, and a final safety assessment visit following termination of study drug.  Distal thigh 
IENFD and the NQOL-DN will serve as co-primary outcome measures. 
 
Interventions and Duration:  The proposed study is a 96-week double blind randomized placebo-
controlled trial of topiramate at a target dose of 100 mg daily (50 mg twice daily) as a potentially 
disease modifying therapy for cryptogenic sensory peripheral neuropathy (CSPN). Randomized 
participants will return to the clinic for follow up visits every 16 weeks.  Evaluation visits will occur 
at 0, 32, 64 and 96 weeks.  Enrollment will occur over a 48-week period.  Dropout is estimated to 
be 4% at 32 weeks, 8% at 64 weeks, and 12% at 96 weeks.  
 
Sample Size and Population:  After a screening period, a total of 125 male and female participants 
from 18 to 80 years of age, inclusive, will be enrolled into two treatment arms (topiramate 100 mg 
daily or matching placebo).  Enrollment will be stratified by body mass index (BMI). 
 
1. 
STUDY OBJECTIVES 
1.1. Primary Objectives 
The primary objective of this study is to determine if oral topiramate slows neuropathy progression 
and improves patient relevant outcomes. Change in Intraepidermal Nerve Fiber Density (IENFD) 
and in the validated Norfolk Quality of Life-Diabetic Neuropathy (NQOL-DN) scale will serve as 
co-primary endpoints. The study will be considered positive if there is significant treatment effect 
for both, or efficacy in one and noninferiority in the other (see the Go/No-Go section for details of 
the predefined algorithm).  
 
 
The primary objective is to determine if topiramate alters the natural history of progressive decline 
in Intraepidermal Nerve Fiber Density (IENFD) and improves neuropathy related quality of life. A 
positive signal for both primary outcome measures (Intraepidermal Nerve Fiber Density and 
Norfolk Quality of Life-Diabetic Neuropathy) would support additional study.  
Lack of improvement in either IENFD or NQOL-DN would indicate a Phase III trial of topiramate 

 
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as either a disease modifying or symptomatic agent for Cryptogenic Sensory Peripheral 
Neuropathy (CSPN) was not warranted.  A predefined detailed Go-No Go algorithm is provided 
in the statistical methods section.  If there is treatment efficacy in one endpoint and noninferiority 
in the other the trial will be considered possible.  
  
Pain, falls and reduced mobility due to distal sensory nerve injury reduce quality of life (QOL) in 
patients with Cryptogenic Sensory Peripheral Neuropathy (CSPN). The 47-item Norfolk Quality 
of Life –Diabetic Neuropathy (NQOL-DN) Scale is a validated neuropathy specific patient reported 
outcome measure developed following 1,000 structured patient interviews. The scale includes 
small fiber, large fiber, autonomic, symptoms, and activities of daily living subscores27.  The scale 
has been translated into 10 languages including Spanish40. The NQOL-DN captures symptoms 
related to diabetic neuropathy, which are in turn very similar to those experienced by CSPN 
patients. The NQOL-DN is responsive to change and significantly correlates with other clinical 
and confirmatory measures of neuropathy27 and has shown utility in both diabetic and familial 
amyloid polyneuropathy related to transthyretin mutations41. The mean total NQOL-DN among 
379 American and European patients with mild diabetic neuropathy was 27.3.  However, many 
patients with diabetes who do not have neuropathy answered affirmatively to a number of the 
general QOL questions.  Therefore, the NQOL-DN score for patients with moderate CSPN are 
expected to be much lower.  Inclusion criteria will require a NQOL-DN score of >9 in order to 
ensure some degree of baseline neuropathy related disability.28 This cutoff was selected following 
discussions with the scale’s developer. 
 
Cryptogenic Sensory Peripheral Neuropathy (CSPN) is clinically characterized by early injury to 
small unmyelinated axons, resulting in denervation of the epidermis (reflected in reduced 
Intraepidermal Nerve Fiber Density (IENFD) and positive sensory symptoms including pain. 
Measures of small fiber function typically decline before those reflecting large fibers42. These 
features make IENFD an appropriate objective measure of change in peripheral nerve integrity. 
IENFD is more sensitive than quantitative sensory testing or nerve conduction studies (NCS) in 
detection of idiopathic 43 and diabetic and prediabetic neuropathy10,44. IENFD is responsive to 
treatment and shows at least transient improvement with exercise intervention in patients with 
neuropathy associated with both diabetes and metabolic syndrome10,11.   
1.2. Secondary Objectives 
The secondary aim is to evaluate clinical meaning of change in Intraepidermal Nerve Fiber 
Density (IENFD), and examine the relative contribution of its change to improvement in clinically 
meaningful outcomes. 
 
2. 
BACKGROUND  
2.1. Target Population  
The target population is patients with Cryptogenic Sensory Peripheral Neuropathy (CSPN), also 
commonly referred to as idiopathic neuropathy.  Between 1/3 and 1/2 of patients with distal 

 
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symmetric polyneuropathy have no identifiable cause for neuropathy on detailed laboratory 
evaluation3,63.  As summarized in sections 2.3 and 2.4 there is an expanding body of data linking 
obesity and its metabolic consequences to CSPN risk.  Insulin resistance and glucose intolerance 
are present in up to 50% of CSPN patients2.  Metabolic syndrome (defined as three of the 
following: prediabetes/diabetes, central obesity, low HDL, elevated triglycerides, and 
hypertension) is observed in >80% of patients with CSPN with IGT, and over 50% of those with 
normal glucose tolerance. 
2.2. Study Timeline 
Once enrollment begins, the study will take approximately four years to complete.  A lead-in period 
of 32 weeks will be followed by the recruitment phase.  Recruitment is anticipated to take 48 
weeks from first subject enrolled. A total of 125 subjects will be randomized into the study.  All 
subjects will be followed for 96 weeks.  The last subject visit is anticipated to occur approximately 
144 weeks after first subject enrolled. Data cleaning and analysis will be completed within 16 
weeks following study closure.  
2.3. Rationale 
Peripheral neuropathy affects >10% of those over 40 years old 1, approximately half of whom 
have cryptogenic sensory peripheral neuropathy (CSPN), resulting in reduced quality of life (QOL) 
due to pain, sensory loss, imbalance, and fall related injuries. CSPN is a significant cause of 
patient morbidity, for which there exists no disease modifying therapy.  Clinically similar to early 
diabetic neuropathy, it is characterized by preferential injury to small axons, and frequently results 
in prominent sensory loss and neuropathic pain.  While the precise etiology of CSPN is unknown, 
and likely multifactorial, accumulating evidence indicates that obesity, dyslipidemia, and insulin 
resistance/prediabetes (metabolic syndrome) are linked to CSPN risk2.  Patients with CSPN have 
an elevated risk of metabolic syndrome3,4 and patients with prediabetes have an elevated risk of 
CSPN5.  Obesity and dyslipidemia also significantly increase the risk of neuropathy among 
diabetic patients6.  Animal models support the hypothesis that obesity and prediabetic levels of 
glucose dysregulation cause neuropathy7-9.    
 
Our previous studies show that exercise improves nerve regenerative capacity, results in 
increased intraepidermal nerve fiber density (IENFD) and improves pain among patients with 
CSPN and prediabetes 10. Together, these findings suggest CSPN is potentially reversible.   
However, lifestyle interventions are clinically limited by noncompliance and poor sustainability. 
While randomized clinical trials of strategies to treat metabolic syndrome in CSPN are lacking, 
the available data suggest aggressive management of metabolic syndrome components may be 
effective. The NINDS funded Impaired Glucose Tolerance Neuropathy (IGTN) study 
demonstrated that one year of diet counseling and exercise based on the protocol used in the 
Diabetes Prevention Program (DPP) resulted in improved IENFD and reduced pain among 
patients with CSPN and impaired glucose tolerance (IGT)10.  A similar study in patients with 
diabetic neuropathy found consistent results11.  The Steno-2 trial demonstrated that aggressive 
management of metabolic syndrome features resulted in a significantly reduced risk of autonomic 

 
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neuropathy compared to those treated conventionally12.  There was no impact on vibration 
sensation assessed using a biothesiometer, suggesting particularly robust therapeutic benefit for 
small diameter axons (the fiber population for which topiramate has shown promise).  Our 
preliminary data indicate aggressive exercise results in enhanced peripheral nerve regeneration 
capacity in metabolic syndrome patients.  Cumulatively, these data support the hypothesis that 
metabolic syndrome is linked to CSPN risk, and that aggressive management may be an effective 
strategy to enhance nerve regeneration and improve patient symptoms.  However, currently 
available lifestyle interventions are very difficult to employ in a clinical setting due to poor 
compliance and attrition from the necessary behavioral changes. Development of better 
pharmacologic approaches is a major priority.  
2.4. Supporting Data 
Topiramate is a promising therapeutic approach to CSPN. Clinical trials of this anticonvulsant 
agent in diabetic neuropathy suggest improvement in pain and QOL, but also in measures of 
peripheral nerve function including sensory testing and IENFD.13.  Topiramate has multiple 
potentially neuroprotective effects, including sodium channel inhibition, increased insulin 
sensitivity, and significant weight loss, which is greatest among obese patients 14,15.    It has been 
extensively studied for the treatment of epilepsy and migraine and is generally safe and well 
tolerated.  Several studies suggest a potential benefit for neuropathic pain associated with 
diabetic neuropathy.  The CAPSS-141 study enrolled 323 patients with painful neuropathy and 
found a significant improvement in pain severity, with a 50% response rate (>30% pain reduction) 
over 12 weeks compared to 34% for placebo (p<0.004)16. A 26-week open label extension study 
involving 225 participants demonstrated a durable treatment benefit17,18.  Three studies with 
similar design19,20, failed to demonstrate pain efficacy, but were limited by a high placebo response 
rate and use of a less specific visual analog pain outcome measure 21.  Small studies suggest 
topiramate therapy not only results in improved pain, but also improves QOL and preferentially 
impacts measures of small fiber function, including an increase in IENFD22,23. Data from animal 
models of diabetes also support its potential therapeutic efficacy24,25.  We hypothesize that 
topiramate will significantly slow the natural history of IENFD decline and will improve neuropathy 
specific QOL in patients with CSPN. 
 
Topiramate has multiple potential therapeutic mechanisms relevant to neuropathy.  It is 
associated with significant weight loss that may result in improved insulin resistance and reduction 
of overall metabolic risk for neuropathy.  There are currently 5 drugs available in the United States 
for long-term weight loss: orlistat, lorcaserin, phentermine-topiramate (Qysmia), naltrexone-
buproprion and liraglutide.  Mean weight loss varies from 4-9%, with phentermine-topiramate 
generally demonstrating the highest mean weight loss (8.6-9.3%), with 70% of treated patients 
experiencing >10% weight loss26. Topiramate monotherapy is associated with weight loss on par 
with other approved weight loss medications and greater than that observed in the IGTN Study 
and other studies of exercise and diet for neuropathy.  Obese diabetic patients treated with 
topiramate alone lost 6.6% of body weight over 11 months, most of which was lost in the first 5 
(5.5%) 27,28. A recent meta-analysis of topiramate trials found an average weight loss of 5.34 kg 

 
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among 3320 individuals (6.58 kg for those treated > 28 weeks)21.  The CAPSS-141 study of 
topiramate for diabetic neuropathy demonstrated a 2.6 kg weight loss over 12 weeks22, and a 5.2 
kg weight loss over 38 weeks in the open label extension23.  Weight loss was greatest in obese 
individuals.  Among 38 epilepsy patients treated with topiramate, there was a mean weight loss 
of 7.3% at one year.  Among those with a BMI of >30 kg/m2 the one-year weight loss was 11%. 
Weight loss at 3 months was associated with reduced caloric intake.  Afterwards, caloric intake 
returned to normal but weight loss continued, and ultimate weight loss was correlated with loss of 
body fat mass.  These data suggest weight loss is due to additional mechanisms other than 
appetite suppression29.  Topiramate leads to weight loss and reduced adiposity in rodent models 
and humans via decreased food intake and energy expenditure that is mediated by improved 
insulin and leptin signaling at the hypothalamic level30. Multiple studies demonstrate that 
topiramate improves insulin sensitivity independent of its weight loss effects30-32. Data from a high 
fat fed mouse model indicate improved insulin sensitivity is driven by uptake in adipose tissue, 
and blocked by intravenous tolbutamide, suggesting central nervous system uptake is necessary 
for this metabolic benefit19. In a high fat fed rat model, topiramate’s insulin sensitizing effects were 
in part mediated at the hepatic level by modulation of insulin receptor isoforms, increased 
adiponectin production and receptor expression, and lower TNF  levels20. As with neuropathy, 
animal models support its potential efficacy as a weight loss therapy, and also demonstrated 
improvement in insulin sensitivity that may be independent of weight loss effects30-33.   
 
Beyond improvement in weight and obesity-related metabolic consequences, topiramate inhibits 
voltage-gated sodium and calcium channels22,34.  There is evolving data linking changes in 
voltage-gated sodium channel function to CSPN, including a recent report of a high prevalence 
of SCN9A sequence variants in patients with otherwise idiopathic isolated small fiber 
involvement14,17. In these patients, with prominent neuropathic pain, sodium channel mutation 
leads to increased sensory axon irritability, suggesting a pharmacological role for sodium channel 
inhibition. It is likely that analogous acquired altered sodium channel function is linked to other 
forms of neuropathy, including diabetic and chemotherapy induced neuropathies35-37. Alterations 
in cellular excitability may both increase pain and lead to axon loss and progressive neuropathy38. 
Development of a well-tolerated small molecule approach to blockade of voltage gated sodium 
channels is a priority.  Topiramate has been shown to reduce peripheral nerve excitability, likely 
via inhibition of voltage gated sodium channels34,39.  While topiramate has multiple potential 
mechanisms of action (weight loss, improved insulin sensitivity, sodium channel modulation), the 
fact that each would be expected to have potential benefit in CSPN supports its further evaluation 
as a disease modifying therapy. 
 
While topiramate doses used in diabetic neuropathy trials have varied from 100-400 mg daily, 
data from two small trials suggest 100 mg/day is associated with improvement in both IENFD and 
neuropathy specific QOL assessed using the Norfolk Quality of Life –Diabetic Neuropathy (NQOL-
DN) scale.24,25.  Doses above 100mg daily are more likely to be associated with neuro-cognitive 
side effects.  A Cochrane review of the use of topiramate for headache suggests there is no 

 
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additional benefit to doses over 100 mg daily.  In light of the greater risk of side effects at doses 
over 100 mg daily, these data support selection of the 100 mg/day target dose. 
 
3. 
STUDY DESIGN 
This is a 96-week double blind randomized placebo-controlled trial of topiramate at a target dose 
of 100 mg daily (50 mg twice daily) as a potentially disease modifying therapy for CSPN.  After a 
screening period, a total of 125 male and female subjects from 18 to 80 years of age, inclusive, 
will be enrolled into two treatment arms (topiramate 100 mg daily or matching placebo). 
Randomized subjects will return to the clinic for follow up visits on a regular basis.  Enrollment will 
occur over a 48-week period.  All subjects will be followed for 96 weeks. 
 
The study will consist of screening and baseline visits, safety and monitoring visits every 16 
weeks, evaluation visits at 32, 64, and 96 weeks, and a final safety assessment visit following 
termination of study drug. The figure below displays the anticipated recruitment schedule and 
number of evaluable subjects at each visit, accounting for 12% dropout over 96 weeks. A 
Schedule of Assessments associated with each visit is provided at the end of the protocol in 
Appendix A.  
 
 
 
Participants will be seen for a screening visit, of which up to 30 days will be allotted to complete 
the screening assessments. After informed consent is obtained, the investigator will review 
inclusion/exclusion criteria with the participant, obtain a medical, family, and neurological history 
and perform a general medical and detailed neuromuscular physical examination including vital 
signs. Concomitant medications, including all nutritional, herbal and alternative therapies, will be 
recorded.  
 

 
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After meeting all entry criteria, participants who continue to meet all inclusion/exclusion criteria 
after screening will present to the clinic for the baseline visit.  The baseline visit will be performed 
within 30 days of the screening visit.  However, the investigator will review, date and initial the 
screening laboratory assessments to confirm participant eligibility for study participation prior to 
the baseline visit procedures. Therefore, adequate time must be provided for the laboratory 
results to be received from the central laboratory. The investigator or designee will again review 
the study inclusion/exclusion criteria and participant medical history, confirming that the 
participant meets criteria for study participation before randomization.  
 
Participants will be seen for safety and follow-up visits at 16, 48 and 80 weeks following the 
baseline visit. Participants will be seen for evaluation visits at 32, 64 and 96 weeks. All tests listed 
for the quarterly monitoring visits will be performed at each of these visits in addition to NCS, 
distal thigh skin biopsy for IENFD, functional and mobility testing, laboratory monitoring for 
metabolic status (fasting insulin and glucose, fasting lipid panel, hemoglobin A1c). The final study 
treatment visit will occur 96 weeks following baseline.  All assessments performed at the 
evaluation visits will take place.  The investigator will perform a complete physical examination.  
All study drug and study drug packages will be collected from the participant at this visit and a 
final assessment of study drug compliance will be calculated. A final safety visit will occur by 
telephone, or in person at the discretion of the site PI, 4 weeks (± 7 days) following the last dose 
of study drug. 
 
4. 
SELECTION AND ENROLLMENT OF SUBJECTS 
4.1. Inclusion Criteria 
1. Age 18-80  
2. Diagnosis 
of 
confirmed 
cryptogenic 
symptomatic 
distal 
symmetric 
peripheral 
polyneuropathy based on the Toronto consensus criteria for probable neuropathy (the 
presence of unequivocal signs and symptoms of neuropathy)45. 
3. Evidence of symptomatic neuropathy based on a screening visit NQOL-DN score of >9  
4. Metabolic syndrome based on modified ATPIII criteria, with a BMI ≥ 25 kg/m2 46 . Specific 
criteria require 3 of the following 6 to be present at the screening visit. 
o Waist circumference >102 cm for men, >88 cm for women 
o Serum triglycerides of > 150 mg/dl 
o HDL < 40 mg/dl for men, < 50 mg/dl for women  
o Those with either a normal HDL or TRG who are taking a lipid lowering medication 
for this purpose. 
o Blood pressure  130/85 mm Hg or use of anti-hypertension drug 
o Prediabetes based on American Diabetes Association (ADA) criteria at screening 
based on any one or more of the following:  fasting plasma glucose - 100 mg/dL to 
125 mg/dL (5.6 mmol/L to 6.9 mmol/L),  
2-hour glucose tolerance test - 140 mg/dL to 199 mg/dL (7.8 mmol/L to 11.0 

 
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mmol/L), or hemoglobin A1c between 5.7% and 6.4%. 
5. No current or prior history of therapy with topiramate.   
6. If female of child-bearing potential (i.e., not surgically sterile or post-menopausal defined 
as age > 51 years without menses for ≥ 2 years), negative serum pregnancy test at 
screening and negative urine pregnancy test at baseline visit. 
7. Women of child-bearing potential or men with sexual partners of childbearing potential be 
willing to use an acceptable method of birth control for the duration of the study and for 12 
weeks following completion of study drug therapy.  Acceptable methods of birth control 
include abstinence, oral contraceptives, the contraceptive patch, intra-uterine device, the 
contraceptive ring, and or barrier contraception such as condoms with spermicide.  
4.2. Exclusion Criteria 
1. CSS-PI clinical determination of an alternative cause for peripheral neuropathy (including 
but not limited to rheumatological disorders, Hepatitis B or C, Breast Cancer treated with 
neurotoxic chemotherapy within the past 15 years). All potential subjects will have 
screening neuropathy labs including assessment for diabetes (Hemoglobin A1c, oral 
glucose tolerance test), vitamin B12 level, and immunofixation47. 
2. Diagnosis of diabetes by history, or screening laboratory results including:  HgA1c ≥ 6.5%, 
fasting plasma glucose ≥ 126 mg/dL (7.0 mmol/L), or 2-hour oral glucose tolerance ≥ 200 
mg/dL (11.1 mmol/L).  Borderline screening labs can be repeated within two weeks with 
PPI approval. 
3. History of recurrent nephrolithiasis, a single episode of nephrolithiasis within one year prior 
to screening, or use of ongoing preventative treatment.  
4. Family history of a hereditary neuropathy in a first-degree relative.  
5. Severe neuropathy: Utah Early Neuropathy Score > 24 at screening 
6. Active foot ulceration or a history of a nontraumatic foot amputation. 
7. ECG with QTc more than 450 ms in men, or 470 ms in women.  
8. Current or planned therapeutic anticoagulation including coumadin or oral factor X or 
thrombin inhibitor therapy (anti-platelet agents are permissible).  
9. Chronic corticosteroid use excluding topical or inhaled treatment.  
10. Use of a carbonic anhydrase inhibitor (such as acetazolamide) due to risk of 
nephrolithiasis. 
11. Planned bariatric surgery 
12. Use of other weight loss medications. 
13. Use of scheduled opiates, or as needed opiate medications more than three times weekly.  
14. Use of topical capsaicin products within 16 weeks of screening or at any time on study. 
15. Medication change for neuropathy symptoms during the 8 weeks prior to screening; or 
anticipated change for the duration of study participation. 
16. Current use of an intrathecal pain pump or spinal cord stimulator.  
17. Screening laboratory creatinine ≥ 2.0 mg/dl. 
18. Severe edema, dermatologic or lower extremity condition that would increase risk of skin 
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19. Major depression, bipolar affective disorder, or other mental health disorders that are 
sufficiently severe to increase adverse event risk or impact neuropathy assessment in the 
opinion of the responsible site principal investigator. 
20. Current suicidal ideation within one year prior to the baseline visit as evidenced by 
answering “yes” to Questions 4 or 5 on the suicidal ideation portion of the Columbia-
Suicide Severity Rating Scale (C-SSRS). 
21. Ataxia sufficiently severe to represent an unacceptable fall risk in the opinion of the site 
principal investigator. 
22. A serious medical condition expected to dramatically shorten life span or prevent 
participation.  
23. Any clinically significant condition or illness, which, in the opinion of the CSS-PI, would 
pose a risk to the subject or might confound the study including metabolic acidosis, bone 
marrow suppression, blood dyscrasias, bleeding disorder, or closed angle glaucoma. 
24. History of alcohol or drug abuse within the past two years, or existing neuropathy related 
to past drug or alcohol abuse. 
25. History of malignancy within five years prior to study enrollment, except for adequately 
treated basal cell or squamous cell skin cancer or in situ cervical cancer. 
26. A history of epilepsy. 
27. An inability to understand or cooperate with the procedures of the study. 
28. Pregnant, or intending to become pregnant, or breastfeeding. 
 
ADA Diagnostic Criteria for Diabetes and Prediabetes 
Diagnosis 
Fasting Plasma Glucose 
2-Hour Oral Glucose 
Tolerance Test 
 
Hemoglobin 
A1C 
Normal 
< 100 mg/dL (5.6 mmol/L) 
 
< 140 mg/dL (7.8 mmol/L) 
< 5.7% 
Prediabetes 
100 mg/dL to 125 mg/dL 
(5.6 mmol/L to 6.9 mmol/L) 
 
140 mg/dL to 199 mg/dL (7.8 
mmol/L to 11.0 mmol/L) 
5.7% to 6.4% 
Diabetes 
(excluded) 
≥ 126 mg/dL (7.0 mmol/L) 
≥ 200 mg/dL (11.1 mmol/L) 
≥ 6.5% 
 
4.3. Subject Withdrawal Criteria 
A subject may discontinue study drug or withdraw from study participation at any time without 
bias for any of the following reasons: 
 
Administrative 
1. 
Withdrawal of consent by subject 
2. 
Request of Study Sponsor or Principal Investigator  
3. 
Request of primary care physician 
4. 
Pregnancy (must stop study drug) 

 
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5. 
Subject deemed lost to follow up/failure to return 
6. 
Early termination of study 
7. 
Other  
 
Adverse Event 
1. 
Worsening of the disease under study 
2. 
Worsening of pre-existing disease (other than disease under study) 
3. 
Intercurrent illness 
4. 
Death 
5. 
Major/clinically significant alteration in laboratory values after beginning study drug 
6. 
Prolonged QTc  
7. 
Active suicidal Ideation based on the C-SSRS  
8. 
Other adverse event 
 
4.4. Study Enrollment Procedures 
Subjects will be recruited from 14 NeuroNEXT sites and 1 non-NN site in the United States.  
Investigators will be responsible for obtaining written consent from each potential subject after 
adequate explanation of the purpose, study procedures, and any risks associated with the study.  
 
Treatment for each subject will be assigned by a randomized code. A block randomization 
scheme will be used to ensure approximately even distribution of subjects in treatment groups for 
each BMI strata. 
4.4.1. Subject Recruitment and Retention 
Subjects will be recruited from clinics at participating NeuroNEXT Network sites. Postings will be 
placed on selected website(s). Flyers about the study will be sent to community neurologists at 
NeuroNEXT clinical sites. Webinars will be conducted for subject recruitment as needed.  
Interested subjects will be contacted by the investigators or their staff and invited to participate. 
These recruitment strategies will include a mechanism by which the patients can provide their 
contact information. We will use the NeuroNEXT Recruitment and Retention Committee to identify 
recruitment strategies.  
4.4.2. Screening Logs 
All clinical sites will maintain screening logs documenting demographic information including age, 
gender, race and ethnicity, reasons for ineligibility at the screening visit, and reasons for non-
participation if eligible.  
 
Screening logs to document demographic information and reasons for ineligibility and non-
participation will be stored centrally at the NeuroNEXT Data Coordination Center. Information 
about screening failures and successes will be compiled and reviewed on a periodic basis so that 
feedback can be provided to sites. 

 
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Screening log data will be provided to the study team, de-identified and analyzed to determine 
the most successful routes for information dissemination and recruitment strategies for ongoing 
recruitment in this study and for future studies. The study team will work to identify any common 
reasons for screen failure that might be identified to consider amendments to the study to adjust 
inclusion/exclusion criteria if a large number of patients are screen failing for specific reasons that 
would not ultimately affect the study results if allowed. Likewise, reasons for non-enrollment will 
be tracked centrally. If there are recurring themes adjustments will be attempted to target this 
problem, as long as the adjustments do not affect the study conduct or data quality. 
4.4.3. Informed Consent 
Written informed consent will be obtained from each study participant before any study-specific 
procedures or assessments are done and after the aims, methods, anticipated benefits, and 
potential hazards are explained. The participant’s willingness to participate in the study will be 
documented in writing in a consent form approved by the NeuroNEXT Central Institutional Review 
Board (CIRB), which will be signed by the participant with the date of that signature indicated. 
The investigator will keep the original consent forms and a copy will be given to the participant. It 
will also be explained to the participant that they are free to refuse entry into the study and free to 
withdraw from the study at any time without prejudice to future treatment. Written and/or oral 
information about the study in a language understandable by the participant will be given to all 
participants. 
 
Informed consent will be obtained by licensed physician investigators only, who are trained on 
the study and delegated appropriately as being authorized to obtain consent. The site PI will 
typically be involved in explaining the study and will play a role during the consent process and 
answering any questions in conjunction with the coordinator, as well as overseeing that the 
process is carried out correctly.  
 
Optional DNA and tissue banking is planned for future research. Participants will consent to their 
preference for banking DNA and tissue separately.    
4.4.4. Assent 
Children (age less than 18) will not be allowed to participate in this study.  
4.4.5. Randomization/Treatment Assignment 
Randomization to study treatment (either topiramate or matching over- encapsulated placebo) will 
occur using an interactive web response system (IWRS).  Online randomization will follow 
confirmation of eligibility and completion of all required baseline procedures. Randomization 
codes will be constructed using random permuted blocks to assure balanced randomization over 
time with stratification by BMI. BMI of 30.0 will serve as stratification cutoffs reflecting anticipated 
median values.   
 

 
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Following randomization, subjects will be given a supply of study drug with instructions to take 
the study drug twice daily using a 2-week dose escalation schedule.  Subjects will titrate to two 
25mg tablets twice daily, or the maximally tolerated dose. 
 
5. 
STUDY INTERVENTIONS/ STUDY DRUG  
5.1. Study Drug and Dose Selection 
The intervention under study is oral topiramate, 100mg daily taken in two divided doses of 50mg.  
Matching placebo will be identical to topiramate in color, shape, and packaging.   
5.2. Dose selection 
Previous studies have evaluated topiramate as a potential therapy for pain associated with 
diabetic neuropathy with mixed results.  The dose in these trials varied from 100-400 mg 
daily22,23,64.  The objective of this study is to evaluate the potential efficacy of topiramate as a 
disease modifying therapy for CSPN associated with metabolic syndrome. Randomized trials in 
diabetic neuropathy have demonstrated that a dose of 100 mg/day is sufficient to improve both 
neuropathy associated QOL (as measured by NQOL-DN) and thigh IENFD 24,25, while side effects 
of decreased concentration or fatigue were more common at higher doses.  Similarly, a Cochrane 
review reported no additional benefit to doses over 100 mg daily in topiramate trials for 
headache65.  In light of the greater risk of side effects at doses over 100 mg daily, these data 
support selection of the 100 mg/day target dose. 
5.3. Formulation and Packaging 
Study drug, or matching placebo, will be provided in labeled packages with sufficient product for 
study subjects to take four capsules daily for 16 weeks, with sufficient overage in each package 
to allow for anticipated variation in visit scheduling.  Four 132-count bottles will be provided, 
permitting for 14 days of overage.  Each study test article packet will be labeled with the following 
information: 
 
 
Name of Sponsor 
 
Name and address of study drug distribution center 
 
Study number and IND number 
 
Unique drug package number 
 
Drug treatment label (each kit will list either 25 mg topiramate or placebo) 
 
Route of administration 
 
Quantity of dose unit 
 
Directions for use 
 
Storage conditions 
 
Space for investigator name, telephone, dispensing date and subject number 
 
Space for study subject identifier 
 
Label statement “Caution:  New Drug-Limited by federal law to investigational use” 

 
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Label statement “Caution:  Keep out of reach of children” 
5.3.1. Supplies and Dispensation 
Study drug supplies will be received by the site investigator or other authorized study personnel 
at the study site, managed and stored safely and properly, and kept in a secured location with 
restricted access.  Study staff with responsibility for drug management will keep accurate and 
complete records of study drug received by the site, dispensed to study subject, and used and 
returned by study subject.   
 
Study drug will be dispensed by appropriately qualified staff as designated by the investigator’s 
delegation of authority log.  Subjects will self-administer the study drug at home following the 
instructions provided to the subject at the study visit. The study site investigator will retain returned 
study drug, or study drug supplies not dispensed to subjects, until the sponsor provides written 
instructions for disposition.  
 
The study case report forms and source documents will include prompts to record study subject 
eligibility to receive study drug, study drug dispensed, dosing start date, dosing end date, missing 
doses, and study drug returned.    
5.3.2. Titration Schedule and Dose Adjustments 
 
 Subjects randomized to the topiramate arm will start 25mg topiramate once daily in the evening. 
On day 4 following randomization a morning dose of 25 mg will be added. On day 8 following 
randomization an addition 25 mg tablet will be added in the evening, and on day 12 a second 
morning dose will be added so that the subject will be taking a total of 50mg twice daily.  Subjects 
who experience an adverse event during the dose titration may continue at the highest tolerated 
dose for one week prior to an additional attempt to increase to the targeted dose.  Those who are 
tolerant of a lower dose but intolerant of the target dose will continue on the highest tolerated 
dose.  Results will be analyzed in an intent to treat fashion.  If a subject develops a treatment 
related adverse event, the dose may be lowered at the discretion of the site PI in order to establish 
a lower maximally tolerated dose.  Those who have an adverse event and are unable to continue 
medication will undergo a termination visit.    
 
In accordance with local regulatory requirements, the investigator, designated site staff, or head 
of the medical institution (where applicable) must document the amount of investigational product 
dispensed and/or administered to study subjects, the amount received from the central pharmacy, 
and the amount destroyed upon completion of the study. An investigator is responsible for 
ensuring product accountability records are maintained throughout the course of the study. The 
inventory will include details of topiramate received and dispensed to subjects, batch, and ID 
numbers. All unused capsules must be kept until reconciliation of delivery records with 
accountability logs by the monitor. After the monitor has performed accountability, the site will be 
instructed by the DCC or designee to either destroy the remaining study drug or return it to the 

 
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Central Pharmacy or manufacturer. An accounting must be made of any drug deliberately or 
accidentally destroyed. Discrepancies between the amount of topiramate received and dispensed 
drug must be reconciled. 
5.4. Concomitant Interventions 
The following are permissible as concomitant interventions for neuropathic pain related to CSPN 
if stable for 8 weeks prior to screening:  
• 
Gabapentin 
• 
Pregabalin 
• 
Tricyclic antidepressants 
• 
Duloxetine 
• 
Venlafaxine 
• 
Tramadol (200mg daily or less) 
• 
Topical lidocaine 
• 
Non-steroidal anti-inflammatory drugs 
 
The intent of the protocol is to keep allowable neuropathic pain agents and dosing unchanged 
for the duration of the study (8 weeks prior to screening through week 96).   
 
Marijuana, cannabinoids, and alpha lipoic acid (ALA) will be specified as neuropathic pain 
agents on the concomitant medication form. These products will not require dosing stability, but 
will be tracked to evaluate any potential impact on outcomes. 
 
If in the opinion of the site investigator, changes in the permissible neuropathic pain agents are 
required for the safety and/or well-being of the participant between baseline and week 96/ET, 
the change will be captured in EDC and reported to the PPI.  These participants will not be 
required to discontinue study medication or exit the study.  
 
5.4.1. Prohibited Medications/Interventions 
The following medications/interventions are exclusionary:  
• 
Therapeutic anticoagulations including coumadin or oral factor X or thrombin inhibitor 
therapy 
• 
Topical capsaicin 
• 
Oral prednisone 
• 
Carbonic anhydrase inhibitor (such as acetazolamide) 
• 
Weight loss medications 
• 
Neuropathic pain agents beyond first line agents  
• 
Scheduled opiates, or as needed opiate medications more than three times weekly 
• 
Intrathecal pain pump or spinal cord stimulator 
• 
Current or prior history of topiramate therapy 
 
 
 

 
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5.5. Subject Compliance 
At each study visit, the site Investigator and/or Study Coordinator will assess the subject’s 
compliance with the study requirements. This will include checks for protocol compliance, 
including use of study drug in order to assess the reliability of subject-generated data. Subjects 
who fail to comply with study requirements may be withdrawn from the study. 
 
A  serum topiramate level will be measured at baseline and weeks 32, 64, and 96 or ET to assess 
for compliance or potential crossover (e.g. a participant randomized to placebo taking off study 
prescription topiramate).  
 
Participants will be asked to hold their morning dose of study medication until after the blood draw 
at weeks 32, 64, 96/ET.  The date and time of last dose of study drug will be recorded.   If the 
participant does not hold the prior dose, the topiramate level should still be obtained.  These data 
will not be shared with the study team until after the study has closed. 
 
 
6. 
STUDY PROCEDURES 
6.1. Schedule of Assessments 
Recruitment will take place over 48 weeks. The study will consist of screening and baseline visits, 
safety and monitoring visits every 16 weeks, evaluation visits at 32, 64, and 96 weeks, and a final 
safety assessment visit or telephone assessment following termination of study drug. A Schedule 
of Assessments is provided in Appendix A.  
 
6.2. Visit 01 Screening (Day -30 to 0) 
Up to 30 days will be allotted to complete the screening assessments. Prior to any involvement in 
study related activities, the participant must sign and date a central Institutional Review Board 
(IRB) approved written informed consent form (ICF).  A copy of the signed and dated ICF must 
be given to the participant. Screening visit procedures may be performed over two consecutive 
days if scheduling constraints prohibit the completion of all study procedures in a single day. If 
screening procedures are completed over two days, the baseline visit will occur within 30 days of 
the last screening procedure completion.   
 
The following procedures will be performed at the screening visit (this visit may take approximately 
3 hours): 
• 
Obtain written informed consent from participant.  
• 
Review inclusion/exclusion criteria.  
• 
Obtain a medical, family, and neurological history to assess for possible exclusionary 
conditions. Medical histories should include baseline symptoms, ongoing illnesses, other 
chronic conditions, surgical history, review of currently used medications, as well as any 
other important information that may affect the conduct of the study. See section 7.1.3. 

 
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• 
Review concomitant medications, including all nutritional, herbal and alternative therapies. 
See section 7.1.4. 
• 
Administer the Norfolk Quality of Life-Diabetic Neuropathy scale (NQOL-DN). See section 
7.1.19. 
• 
Perform a general medical and detailed neuromuscular physical examination. See section 
7.1.5. 
• 
Perform vital sign measurements: blood pressure (systolic and diastolic), heart rate 
(beats/minute), and body temperature (°C). See section 7.1.6.  
• 
Record weight (kg), height (cm) and Body Mass Index (BMI). 
• 
Record waist circumference (cm). See section 7.1.7. 
• 
Perform a resting 12-Lead ECG. See section 7.1.8. 
• 
Collect blood samples for CBC, fasting basic metabolic panel, fasting insulin, fasting lipid 
panel, two-hour OGTT, HgbA1C, Vitamin B12, and serum immunofixation and serum 
pregnancy test (pregnancy test for women of child-bearing potential only). See section 
7.1.12. 
• 
Administer the Utah Early Neuropathy Scale (UENS). See section 7.1.10. 
• 
Perform clinical assessment for suicidal ideation with the Columbia-Suicide Severity 
Rating Scale (C-SSRS). See section 7.1.15. 
 
All clinical and laboratory evaluations, procedures related to inclusion/exclusion criteria, or 
assessments performed during treatment will be reviewed, initialed and dated by the Principal 
Investigator or the individual specifically designated by the investigator on the delegation of 
responsibility (DOR) log.   
 
6.3. Re-screening 
In the event a participant is originally found to be ineligible at the screening visit, but the 
investigator believes they may subsequently be eligible based on changes to the participant’s 
circumstances or the study protocol, the participant may return for another screening visit (re-
screening visit).  If the original screening visit was conducted greater than 90 days before the re-
screening visit, the re-screening visit will be treated the same as the original screening visit (see 
section 6.2).  
 
• 
If the original screening visit was conducted within 90 days prior to the re-screening visit, 
the following data may be re-used from the original screening visit: 
o Serum immunofixation 
o Two-hour OGTT  
o Vitamin B12 results 
o Resting 12-Lead ECG 
• 
If the original screening visit was conducted within 30 days prior to the re-screening visit, 
the following may be re-used from the original screening visit: 
o General medical and detailed neuromuscular physical examination results.  
o Vital sign measurements including blood pressure (systolic and diastolic), heart 
rate (beats/minute), and body temperature (°C).  

 
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o Weight (kg) and height (cm) measurements, and the calculated Body Mass Index 
(BMI). 
o Waist circumference (cm) measurement.  
o Blood sample results for CBC, fasting basic metabolic panel, fasting insulin, fasting 
lipid panel, two-hour OGTT, HgbA1C, Vitamin B12, and serum immunofixation and 
serum pregnancy test (pregnancy test for women of child-bearing potential only).  
o Utah Early Neuropathy Scale (UENS) results.  
o Columbia-Suicide Severity Rating Scale (C-SSRS) results. 
 
• 
The following procedures must be repeated regardless of timeframe between the original 
screening visit and re-screening visit: 
o Review inclusion/exclusion criteria.  
o Detailed medical, family, and neurological history to assess for possible 
exclusionary conditions.  
o Review concomitant medications, including all nutritional, herbal and alternative 
therapies.  
o Informed Consent 
• 
If a participant being rescreened had NCS performed as part of a prior screening visit, 
these data may be used for baseline data (assuming the participant proceeds to 
randomization) if the baseline visit occurs within 90 days of the original NCS performance 
date. 
All clinical and laboratory evaluations, procedures related to inclusion/exclusion criteria, or 
assessments performed during treatment will be reviewed, initialed and dated by the Principal 
Investigator or the individual specifically designated by the investigator on the delegation of 
responsibility (DOR) log.   
 
6.4. Visit 02 Baseline (Day 0) 
Participants who continue to meet all inclusion/exclusion criteria after screening will present to 
the clinic for the baseline visit. The baseline visit will be performed within 30 days of the screening 
visit. However, the investigator will review, date and initial the screening laboratory assessments 
to confirm participant eligibility for study participation prior to the baseline visit procedures. 
Therefore, adequate time must be provided for the laboratory results to be received from the 
central laboratory. The investigator or designee will again review the study inclusion/exclusion 
criteria and participant medical history, confirming that the participant meets criteria for study 
participation before randomization.  
 
The following procedures will be performed at the baseline visit (this visit may take about 4 hours): 
• 
Review Inclusion/Exclusion criteria.  
• 
Obtain a medical, family, and neurological history to assess for possible exclusionary 
conditions. Medical histories should include baseline symptoms, ongoing illnesses, other 
chronic conditions, surgical history, review of currently used medications, as well as any 
other important information that may affect the conduct of the study. See section 7.1.3. 

 
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• 
Review concomitant medications, including all nutritional, herbal and alternative therapies. 
See section 7.1.4. 
• 
Review interval medical history. 
• 
Review adverse events. 
• 
Perform vital sign measurements: blood pressure (systolic and diastolic), heart rate 
(beats/minute), and body temperature (°C). See section 7.1.6.   
• 
Record weight (kg) and Body Mass Index (BMI). 
• 
Perform an abbreviated Physical Examination, including visual field and fall risk 
assessment.  
• 
Perform Functional and Mobility testing (6MWT, TUG, ABC Scale). See section 7.1.11. 
• 
Perform nerve conduction studies. See section 7.1.13. 
• 
Perform distal thigh skin biopsy. See section 7.1.14. 
• 
Collect blood samples for routine hematology panel blood, basic metabolic panel, 
topiramate level and DNA analysis (OPTIONAL). See section 7.1.12.  
• 
Collect urine for a urine pregnancy test (pregnancy test for women of child-bearing 
potential only).  
• 
For women of childbearing potential and sexually active males, review acceptable birth 
control methods that must be used during the study.  
• 
Perform subject randomization via interactive voice response system (IVRS) and/or 
interactive web response system (IWRS). See section 4.4.5. 
• 
Dispense study drug. 
• 
Instruct subject about correct administration and titration of study drug. See section 5.3.2. 
• 
Instruct subject to bring unused study drug to each study visit, and to immediately report 
any AEs to the Investigator or Coordinator.  
• 
Administer the Neuropathy Total Symptom Score-6 (NTSS-6) to the subject. See section 
7.1.9. 
• 
Administer the Brief Pain Inventory – Diabetic Neuropathy (BPI-DN) BPI-DN. See section 
7.1.9. 
• 
Perform clinical assessment for suicide ideation with the Columbia-Suicide Severity Rating 
Scale (C-SSRS). See section 7.1.15. 
• 
Complete the Rapid Assessment of Physical Activity (RAPA) Survey.  See section 7.1.17. 
6.5. Visit 03 Week 16 (± 7 days) 
This safety follow-up visit will occur within ± 7 days of the targeted visit date. The following 
procedures will be performed at the Week 16 visit (this visit may take about 3 hours): 
• 
Review interval medical history.  
• 
Review adverse events. 
• 
Review concomitant medications, including all nutritional, herbal and alternative therapies. 
See section 7.1.4. 
• 
Perform vital sign measurements: blood pressure (systolic and diastolic), heart rate 
(beats/minute), and body temperature (°C). See section 7.1.6. 
• 
Record weight (kg) and Body Mass Index (BMI). 
• 
Record waist circumference (cm). See section 7.1.7.  
• 
Perform an Abbreviated Physical Examination including visual field examination and 
assessment for fall risk. 

 
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• 
Administer the Utah Early Neuropathy Scale (UENS). See section 7.1.10. 
• 
Collect blood samples for safety monitoring laboratory assessments including basic 
metabolic panel, CBC and serum pregnancy test (pregnancy test for women of child-
bearing potential only). (Refer to University of Rochester Medical Center Lab Manual for 
sample handling and processing requirements). See section 7.1.12. 
• 
Dispense study drug. 
• 
Perform study drug reconciliation and container collection. 
• 
Assess study drug compliance.  
• 
Administer the Neuropathy Total Symptom Score-6 (NTSS-6) to the subject. See section 
7.1.9. 
• 
Administer the Brief Pain Inventory – Diabetic Neuropathy (BPI-DN) BPI-DN. See section 
7.1.9. 
• 
Administer the Norfolk Quality of Life-Diabetic Neuropathy scale (NQOL-DN). See section 
7.1.19. 
• 
Perform clinical assessment for suicide ideation with the Columbia-Suicide Severity Rating 
Scale (C-SSRS). See section 7.1.15. 
 
6.6. Visit 04 Week 32 (± 7 days) 
The follow-up visit will take place within ± 7 days of the targeted visit date. The following 
procedures will be performed at the Week 32 evaluation visit (this visit may take about 4 hours): 
• 
Review interval medical history. 
• 
Review adverse events. 
• 
Review concomitant medications, including all nutritional, herbal and alternative therapies. 
See section 7.1.4. 
• 
Perform vital sign measurements: blood pressure (systolic and diastolic), heart rate 
(beats/minute), and body temperature (°C). See section 7.1.6. 
• 
Record weight (kg) and Body Mass Index (BMI). 
• 
Record waist circumference (cm). See section 7.1.7.  
• 
Perform an abbreviated Physical Examination, including visual field and fall risk 
assessment. 
• 
Administer the Utah Early Neuropathy Scale (UENS). See section 7.1.10. 
• 
Perform Nerve Conduction Studies (NCS). See section 7.1.13. 
• 
Perform distal thigh skin biopsy. See section 7.1.14.  
• 
Collect blood samples for OGTT, CBC, fasting basic metabolic panel, fasting insulin, 
fasting lipid panel, HgbA1C, topiramate level and serum pregnancy test for women of 
child-bearing potential only. See section 7.1.12. 
• 
Perform Functional and Mobility testing (6MWT, TUG, ABC Scale). See section 7.1.11. 
• 
Dispense study drug. 
• 
Perform study drug reconciliation and container collection. 
• 
Assess study drug compliance.  

 
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• 
Administer the Neuropathy Total Symptom Score-6 (NTSS-6) to the subject. See section 
7.1.9. 
• 
Administer the Brief Pain Inventory – Diabetic Neuropathy (BPI-DN) BPI-DN. See section 
7.1.9. 
Administer the Norfolk Quality of Life-Diabetic Neuropathy scale (NQOL-DN). See section 
7.1.19. 
• 
Perform clinical assessment for suicidal ideation with the Columbia-Suicide Severity 
Rating Scale (C-SSRS). See section 7.1.15. 
• 
Complete the Rapid Assessment of Physical Activity (RAPA) Survey.  See section 7.1.17. 
 
6.7. Visit 05 Week 48 (± 7 days) 
This safety follow-up visit will occur within ± 7 days of the targeted visit date. The following 
procedures will be performed at the Week 48 evaluation visit (this visit may take about 3 hours): 
• 
Review interval medical history. 
• 
Review adverse events. 
• 
Review concomitant medications, including all nutritional, herbal and alternative therapies. 
See section 7.1.4. 
• 
Perform vital sign measurements: blood pressure (systolic and diastolic), heart rate 
(beats/minute), and body temperature (°C). See section 7.1.6. 
• 
Record weight (kg) and Body Mass Index (BMI).  
• 
Record waist circumference (cm). See section 7.1.7.  
• 
Perform an abbreviated Physical Examination, including visual field and fall risk 
assessment. 
• 
Collect blood samples for safety monitoring laboratory assessments including basic 
metabolic panel, CBC and serum pregnancy test (pregnancy test for women of child-
bearing potential only). See section 7.1.12. 
• 
Dispense study drug. 
• 
Perform study drug reconciliation and container collection. 
• 
Assess study drug compliance.  
• 
Administer the Neuropathy Total Symptom Score-6 (NTSS-6) to the subject. See section 
7.1.9. 
• 
Administer the Brief Pain Inventory – Diabetic Neuropathy (BPI-DN) BPI-DN. See section 
7.1.9. 
• 
Administer the Utah Early Neuropathy Scale (UENS). See section 7.1.10. 
• 
Administer the Norfolk Quality of Life-Diabetic Neuropathy scale (NQOL-DN). See section 
7.1.19. 
• 
Perform clinical assessment for suicidal ideation with the Columbia-Suicide Severity 
Rating Scale (C-SSRS). See section 7.1.15. 
 
6.8. Visit 06 Week 64 (± 7 days) 
The follow-up visit will take place within ± 7 days of the targeted visit date. The following 
procedures will be performed at the Week 64 evaluation visit (this visit may take about 4 hours): 

 
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• 
Review interval medical history. 
• 
Review adverse events.  
• 
Review concomitant medications, including all nutritional, herbal and alternative therapies. 
See section 7.1.4. 
• 
Perform vital sign measurements: blood pressure (systolic and diastolic), heart rate 
(beats/minute), and body temperature (°C). See section 7.1.6. 
• 
Record weight (kg) and Body Mass Index (BMI). 
• 
Record waist circumference (cm). See section 7.1.7.  
• 
Perform an abbreviated Physical Examination, including visual field and fall risk 
assessment.  
• 
Administer the Utah Early Neuropathy Scale (UENS). See section 7.1.10. 
• 
Perform Functional and Mobility testing (6MWT, TUG, ABC Scale). See section 7.1.11.  
• 
Perform Nerve Conduction Studies (NCS). See section 7.1.13. 
• 
Perform distal thigh skin biopsy. See section 7.1.14. 
• 
Collect blood samples for OGTT, CBC, basic metabolic panel, fasting insulin, fasting 
lipid panel, HgbA1C, topiramate level and serum pregnancy test for women of child-
bearing potential only. See section 7.1.12. 
• 
Dispense study drug. 
• 
Perform study drug reconciliation and container collection. 
• 
Assess study drug compliance.  
• 
Administer the Neuropathy Total Symptom Score-6 (NTSS-6) to the subject. See section 
7.1.9. 
• 
Administer the Brief Pain Inventory – Diabetic Neuropathy (BPI-DN) BPI-DN. See section 
7.1.9. 
• 
Administer the Norfolk Quality of Life-Diabetic Neuropathy scale (NQOL-DN). See section 
7.1.19. 
• 
Perform clinical assessment for suicidal ideation with the Columbia-Suicide Severity 
Rating Scale (C-SSRS). See section 7.1.15. 
• 
Complete the Rapid Assessment of Physical Activity (RAPA) Survey.  See section 7.1.17. 
 
6.9. Visit 07 Week 80 (± 7 days) 
This safety follow-up visit will occur within ± 7 days of the targeted visit date. The following 
procedures will be performed at the Week 80 visit (this visit may take about 3 hours): 
• 
Review interval medical history. 
• 
Review adverse events. 
• 
Review concomitant medications, including all nutritional, herbal and alternative therapies. 
See section 7.1.4. 
• 
Perform vital sign measurements: blood pressure (systolic and diastolic), heart rate 
(beats/minute), and body temperature (°C). See section 7.1.6. 
• 
Record weight (kg) and Body Mass Index (BMI). 
• 
Record waist circumference (cm). See section 7.1.7.  
• 
Perform an abbreviated Physical Examination, including visual field and fall risk 
assessment.  
Administer the Utah Early Neuropathy Scale (UENS). See section 7.1.10. 

 
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• 
Collect blood samples for safety monitoring laboratory assessments including basic 
metabolic panel, CBC, and serum pregnancy test (pregnancy test for women of child-
bearing potential only). See section 7.1.12. 
• 
Dispense study drug. 
• 
Perform study drug reconciliation and container collection. 
• 
Assess study drug compliance.  
• 
Administer the Neuropathy Total Symptom Score-6 (NTSS-6) to the subject. See section 
7.1.9. 
• 
Administer the Brief Pain Inventory – Diabetic Neuropathy (BPI-DN) BPI-DN. See section 
7.1.9. 
• 
Administer the Norfolk Quality of Life-Diabetic Neuropathy scale (NQOL-DN). See section 
7.1.19. 
• 
Perform clinical assessment of suicidal ideation with the Columbia-Suicide Severity Rating 
Scale (C-SSRS). See section 7.1.15. 
6.10. Visit 08 Week 96 Termination (± 7 days) 
The final study treatment visit will occur 96 weeks following baseline.  All assessments performed 
at the evaluation visits will take place. The investigator will perform a complete physical 
examination. All study drug and study drug packages will be collected from the subject at this visit 
and a final assessment of study drug compliance will be calculated. The Week 96 visit will occur 
within ± 7 days of the targeted visit date. 
 
The following procedures will be performed at the Week 96 visit (this visit may take about 5 hours): 
• 
Review interval medical history.  
• 
Review adverse events.  
• 
Review concomitant medications, including all nutritional, herbal and alternative therapies. 
See section 7.1.4. 
• 
Perform vital sign measurements: blood pressure (systolic and diastolic), heart rate 
(beats/minute), and body temperature (°C). See section 7.1.6. 
• 
Record weight (kg) and Body Mass Index (BMI). 
• 
Record waist circumference (cm). See section 7.1.7.  
• 
Perform a general medical and detailed neuromuscular physical examination. See section 
7.1.5. 
• 
Administer the Utah Early Neuropathy Scale (UENS). See section 7.1.10. 
• 
Perform Functional and Mobility testing (6MWT, TUG, ABC Scale). See section 7.1.11.  
• 
Perform Nerve Conduction Studies (NCS). See section 7.1.13. 
• 
Perform distal thigh skin biopsy. See section 7.1.14. 
• 
Collect blood samples for fasting basic metabolic panel, CBC, fasting insulin, fasting lipid 
panel, two-hour OGTT, topiramate level and HgbA1C. See section 7.1.12. 
• 
Perform study drug reconciliation and container collection. 
• 
Assess study drug compliance.  
• 
Administer the Neuropathy Total Symptom Score-6 (NTSS-6) to the subject. See section 
7.1.9. 
• 
Administer the Brief Pain Inventory – Diabetic Neuropathy (BPI-DN) BPI-DN. See section 
7.1.9. 
• 
Administer the Norfolk Quality of Life-Diabetic Neuropathy scale (NQOL-DN). See section 
7.1.19. 

 
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• 
Perform clinical assessment for suicidal ideation with the Columbia-Suicide Severity 
Rating Scale (C-SSRS). See section 7.1.15. 
• 
Complete the Rapid Assessment of Physical Activity (RAPA) Survey.  See section 7.1.17. 
6.11. Visit 09 Safety Assessment 
A safety call or visit will occur 4 weeks  (+/- 7 days) following the last dose of study drug.  The 
following procedures will be performed at the safety assessment (this visit may take up to 2 hours). 
 
If the Site PI determines a Safety Call is appropriate for final safety assessment, the following 
information should be collected; 
 
• 
Review interval medical history. 
• 
Review adverse events. 
• 
Review concomitant medications, including all nutritional, herbal and alternative therapies. 
See section 7.1.4. 
 
If the Site PI determines a Safety Visit is required for either a final safety assessment or an 
unscheduled safety visit the following additional procedures can be performed (optional safety 
data based on clinical judgement of site PI): 
 
• 
Review interval medical history. 
• 
Review adverse events. 
• 
Review concomitant medications, including all nutritional, herbal and alternative therapies. 
See section 7.1.4. 
• 
Perform vital sign measurements: blood pressure (systolic and diastolic), heart rate 
(beats/minute), and body temperature (°C). See section 7.1.6. 
• 
Record weight (kg) and Body Mass Index (BMI). 
• 
Perform a general medical and detailed neuromuscular physical examination. See section 
7.1.5. 
• 
Collect blood samples for basic metabolic panel and CBC. See section 7.1.14.  
• 
Perform clinical assessment for suicidal ideation with the Columbia-Suicide Severity 
Rating Scale (C-SSRS). See section 7.1.15. 
6.12. Early Termination Visit (< 30 ± 7 days) 
The following procedures will be performed at the early termination visit (this visit may take about 
5 hours): 
• 
Review interval medical history. 
• 
Review adverse events. 
• 
Review concomitant medications, including all nutritional, herbal and alternative therapies. 
See section 7.1.4. 
• 
Perform vital sign measurements: blood pressure (systolic and diastolic), heart rate 
(beats/minute), and body temperature (°C). See section 7.1.6. 
• 
Record weight (kg) and Body Mass Index (BMI). 
• 
Record waist circumference (cm). See section 7.1.7.  
• 
Perform a general medical and detailed neuromuscular physical examination. See section 
7.1.5. 
• 
Perform Functional and Mobility testing (6MWT, TUG, ABC Scale). See section 7.1.11. 

 
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• 
Perform Nerve Conduction Studies (NCS). See section 7.1.13. 
• 
Perform distal thigh skin biopsy. See section 7.1.14.  
• 
Collect blood samples for fasting basin metabolic panel, CBC, fasting insulin, fasting lipid 
panel, topiramate level, two-hour OGTT and HgbA1C. See section 7.1.12. 
• 
Perform study drug reconciliation. 
• 
Administer the Neuropathy Total Symptom Score-6 (NTSS-6) to the subject. See section 
7.1.9. 
• 
Administer the Brief Pain Inventory – Diabetic Neuropathy (BPI-DN) BPI-DN. See section 
7.1.9. 
• 
Administer the Utah Early Neuropathy Scale (UENS). See section 7.1.10. 
• 
Administer the Norfolk Quality of Life-Diabetic Neuropathy scale (NQOL-DN). See section 
7.1.16. 
• 
Perform clinical assessment for suicidal ideation with the Columbia-Suicide Severity 
Rating Scale (C-SSRS). See section 7.1.15. 
• 
Complete the Rapid Assessment of Physical Activity (RAPA) Survey.  See section 7.1.17. 
6.13. Early Termination and Premature Withdrawal 
Subjects have the right to withdraw from the study at any time without prejudice.  The site 
Investigator may withdraw study drug from a subject in the study in the event of intercurrent 
illness, adverse events, other reasons concerning the health or well-being of the subject or other 
administrative reasons.  Early termination will be implemented in the case of emergency 
disclosure of drug treatment (i.e., unblinding). NOTE: All efforts should be made by study staff 
to encourage subjects to return for follow-up visit(s). If a subject withdraws consent from 
the study in writing, no further contact can be made.  
 
A subject may discontinue study medication for the following reasons: 
 
Administrative 
1. 
Withdrawal of consent 
2. 
Request of Sponsor or Principal Investigator 
3. 
Request of primary care physician 
4. 
Pregnancy 
5. 
Subject deemed lost to follow up/failure to return 
6. 
Termination of study 
7. 
Other  
 
Adverse Event  
1. 
Worsening of the disease under study 
2. 
Worsening of pre-existing disease (other than disease under study) 
3. 
Intercurrent illness 
4. 
Death 
5. 
Major/clinically significant alteration in laboratory values after beginning study drug 
6. 
Suicidality based on the C-SSRS 
7. 
Other adverse event 
 

 
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In the event a participant discontinues study medication for any reason, every effort should be 
made to complete the evaluation visits at week 32, 64, and 96. An early termination visit should 
be completed for all participants who are unable or unwilling to complete additional evaluation 
visits. If a subject is unable to return to the site, or refuses to complete all termination visit 
procedures, any reasonable study procedures to which the subject consents will be completed. 
 
Should a scheduled in-person visit be impossible, conduct as many of the verbal assessments as 
possible, with special emphasis on obtaining information on possible AEs, and arrange for return 
of study drug. Every effort will be made to determine the subject’s health status at withdrawal. 
 
Reasons for early termination of the subject prior to completion of the study must be stated 
in the CRF and in the site source documentation for all study subjects who were enrolled 
in the study.  The CCC and the IMM must be informed within 24 hours of all study subjects 
who are withdrawn due to an adverse event. 
 
6.13.1. Premature Drug Discontinuation 
Subjects who prematurely discontinue study drug will be questioned regarding reasons for 
discontinuation.  Subjects will be encouraged to restart study drug following the guidelines in 
section 6.12.2.  
 
6.13.2. Restarting Study Drug after Premature Drug Discontinuation 
Subjects who discontinue study drug for less than one week will be asked to restart at the prior 
dose.  Those who failed to take study drug for 1-7 days will be asked to restart at the previous 
dose.  Those not having taken study drug for 8-14 days will restart at half of the prior dose.  Those 
not having taken study drug for 15 days or more will restart the titration.  Those who discontinued 
due to an adverse event will restart at a dose lower than the maximally tolerated dose and titrate 
to that dose.  
 
6.13.3. Missed Doses 
Subjects who miss a dose will continue the planned dosing schedule and will not supplement the 
next dose with that which was missed.  
 
6.13.4. On Study/Off-Intervention Evaluations 
Every possible effort should be made by the site PI to encourage subjects who are no longer 
taking study drug to remain in the study.  They should explain that continued participation will 
teach us more about the natural history of CSPN progression, the impact of metabolic 
improvement and weight loss on CSPN, and the clinical relevance of IENFD and other surrogate 
measures of CSPN progression.  
 
When subjects decide to go off the study drug, it will be a reportable event and the project 
manager will discuss the reasons for this with site staff to learn the specifics in each case and 
provide advice on an individual basis about the best ways to keep the subject engaged in the 

 
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project. These subjects and their physicians will not be told whether they were given topiramate 
or placebo. 
 
6.14. Off-Study Requirements 
Adverse events will be followed up to 30 days after study completion (including early 
termination) or until the site Principal Investigator deems the condition to have resolved or the 
condition has stabilized (whichever occurs first).  
6.15. Pregnancy  
Women who become pregnant while in the study will have the study drug withdrawn immediately, 
will be asked to return for a final in-person evaluation, and will be followed according to adverse 
event reporting procedures until birth or conclusion. Generally, follow-up will not exceed 8 weeks 
following the estimated delivery date.  
6.16. Diabetes 
Patients who meet ADA criteria for diabetes at screening will be excluded.  Those who develop 
diabetes during the course of the study may continue in the study.  However, in the event a 
participant is found to have diabetes on follow up metabolic testing, their primary care provider 
will be notified. 
 
 
7. 
SPECIAL INSTRUCTIONS AND DEFINITIONS OF EVALUATIONS 
7.1.1. Informed Consent 
Written informed consent will be obtained from each participant before any study-specific 
procedures or assessments are performed and after the aims, methods, anticipated benefits, and 
potential hazards are explained. The participant’s willingness to participate in the study will be 
documented in writing in a consent form, approved by the NeuroNEXT CIRB, which will be signed 
by the participant with the date of that signature indicated. The investigator will keep the original 
consent forms and copies will be given to the participants. It will also be explained to the 
participants that they are free to refuse entry into the study and free to withdraw from the study at 
any time without prejudice to future treatment. Written and/or oral information about the study in 
a language understandable by the participant will be given to all participants. HIPAA guidelines 
for confidentiality and the principles of medical ethics will be adhered to during the study.  
 
7.1.2. Protocol Violations 
The site monitor is responsible for collection of all protocol deviations that occur during the course 
of the study to ensure proper reporting in the clinical study report.  
 
Generally, any activity that is not performed as outlined in the protocol should be categorized as 
a ‘Protocol Deviation’.  Missed visits and any procedures not performed (not attempted) for 
reasons other than illness, injury or progressive disability (i.e., subject is physically unable to 

 
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perform test) will be reported as protocol deviations. Procedures or visits not performed due to 
illness, injury or disability, including procedures that were attempted but failed (i.e., blood samples 
unable to be drawn after multiple attempts, or weight unable to be obtained due to subject 
immobility) will not be reported as protocol deviations. Deviations fall into two categories, ‘major’ 
and ‘minor’, and are defined as follows: 
 
Major: Any deviation that impacts safety, welfare, or rights of a study subject, or impacts the 
primary outcome of the study (safety assessments). Examples include: Informed Consent issues 
affecting a subject’s rights, Inclusion/Exclusion violations, Missed Assessments affecting safety 
endpoints, Study Drug Administration that affects a study endpoint or the subject’s welfare. A 
major deviation is also termed a protocol violation. 
 
Minor: Any deviation that does not fall within the above category. Examples include: out of 
window or missed study assessments that do not affect study endpoints or the subject’s welfare.  
 
7.1.3. Medical History 
A complete medical history including lifestyle questions (i.e., tobacco and alcohol use) will be 
obtained at screening and prior to randomization.  
 
7.1.4. Concomitant Medications/Treatments 
All concomitant medications must be recorded, including, but not limited to all vitamins, 
supplements, nutritional, herbal and alternative therapies. 
 
7.1.5. Physical Examination 
A general medical and detailed neuromuscular physical examination will be performed in order to 
exclude medical conditions precluding participation, and to confirm symptoms consistent with 
distal symmetric polyneuropathy. The neurological examination will include a baseline 
assessment of visual fields.  
 
7.1.6. Vital Signs 
Vital signs will be obtained after the subject has been sitting for five minutes.  Vital signs include 
blood pressure (systolic and diastolic), heart rate (beats/minute), and body temperature (°C). 
 
7.1.7. Waist Circumference 
Waist circumference will be measured in centimeters (cm) while standing.  Measurement will be 
performed at the level of the iliac crest after expiration. 
 
7.1.8. Electrocardiogram (ECG) 
An electrocardiogram (ECG) will be performed to exclude a baseline prolonged QTc interval. 
ECGs with QTc interval more than 430 ms in men, or 450 ms in women will be reviewed at each 

 
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site. Participants with QTc more than 450 ms in men, or 470 ms in women will be considered 
screen failures. Electrocardiogram’s are not required to be reviewed by the site cardiologist.  
7.1.9. Neuropathy Symptom Assessment 
Neuropathy Total Symptom Score -6 (NTSS-6) 53 is a brief inventory of neuropathy symptoms 
that has demonstrated reliability and validity in diabetic neuropathy.  
 
Brief Pain Inventory – Diabetic Neuropathy (BPI-DN) 54,55 is a validated pain inventory that 
assesses pain severity related to CSPN. 
 
7.1.10. Utah Early Neuropathy Scale (UENS) 
Utah Early Neuropathy Scale (UENS) 48 will be performed by the investigator to confirm diagnosis 
and exclude patients with severe neuropathy. 
 
7.1.11. Functional and Mobility Testing 
Functional and mobility testing, fitness and proactive balance will be assessed because balance 
and fall risk are major clinically relevant outcomes for patients with CSPN.   
o A 6-minute walk test (6MWT) will be performed on a standard course that will be used 
throughout the study.  The 6MWT has demonstrated reproducibility in obese participants56 
and has been shown to correlate with intermuscular adipose tissue, a depot of adipocytes 
related to insulin resistance and increased in patients with metabolic syndrome57.   
 
o A Timed up and Go (TUG) will be performed as a measure of proactive balance and 
fitness.  TUG times are normally distributed, resistant to ceiling effects58 and are reduced 
in patients with neuropathy in the setting of diabetes relative to control participants59.  
Among commonly employed fall risk assessments, the TUG had the highest diagnostic 
accuracy60. 
o The Activities-specific Balance Confidence (ABC) Scale.  The ABC scale is a self-
administered instrument assessing balance and gait confidence.89  
 
7.1.12. Laboratory Evaluations 
Clinical laboratory evaluations for the study will be analyzed by the NeuroNEXT central laboratory 
at the University of Rochester. Refer to the University of Rochester Medical Center Lab Manual 
for sample handling and processing requirements.  
 
The following laboratory assessments will be performed throughout the study: 
• 
Safety monitoring laboratory tests: 
o Complete Blood Count (CBC) 
o Basic Metabolic Panel (BMP) including Sodium, Potassium, Chloride, Carbon 
Dioxide, Urea Nitrogen, Glucose, Creatinine, Calcium, and Anion Gap (optional). 
o Hematology Panel 
o Serum Pregnancy Test (for women of child-bearing potential only) 
o Urine Pregnancy Test (for women of child-bearing potential only) 

 
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• 
Baseline metabolic monitoring laboratory tests. These are intended to assess the 
metabolic effects of therapy and to confirm the presence of metabolic syndrome for 
inclusion criteria and evaluation throughout the study: 
o Fasting Insulin  
o Fasting Lipid Panel including Cholesterol, Triglycerides, Calculated LDL 
Cholesterol, and HDL Cholesterol. 
o 2-hour Oral Glucose Tolerance Test (OGTT) using a 75g anhydrous dextrose oral 
load with the first blood draw (pre-dextrose) prior to 10 am. The second draw will 
be 2 hours post dextrose.  The subject will remain sedentary during the following 
two hours. 
o HgbA1C 
• 
Laboratory evaluation for additional causes for neuropathy: 
o Vitamin B12  
o Serum Immunofixation 
• 
Serum topiramate levels will be measured at Baseline and weeks 32, 64, and 96 (or ET) 
in order to assess for compliance and treatment crossover.  
 
Participants will be asked to hold their morning dose of study medication until after the 
blood draw at weeks 32, 64, 96/ET.  The date and time of last dose of study drug will be 
recorded.   If the participant does not hold the prior dose, the topiramate level should still 
be obtained.   
 
Topiramate laboratory kits, shipping materials, and requisitions will be provided by Utah.  
The sample will be obtained in a red collection tube with serum separated by centrifuge 
within 2 hours.   Serum will be placed in the transport vial and refrigerated prior to being 
placed on a cold pack for shipment.   The sample will be returned to Utah with the skin 
biopsy sample.  Samples should be received by Utah cool (not frozen).  The results will 
be made available to the DSMB. 
• 
DNA sample (OPTIONAL) 
DNA samples can be collected at Baseline using supplies provided by URMC.  Centrifuge 
the EDTA tube at 1500 RPM for 15 minutes.   The buffy coat will be transferred into 
cryovials and stored at -80C.  At the end of the enrollment period, sites will batch ship all 
the buffy coat samples to Utah with shipment kit and air bills provided. 
 
 
All clinical and laboratory evaluations, procedures related to inclusion/exclusion criteria, or 
assessments performed during treatment will be reviewed, initialed and dated by the Principal 
Investigator or the individual(s) specifically designated by the investigator on the DOR log. The 
Investigator must indicate if out of range lab values are Clinically Significant (CS) or Not Clinically 
Significant (NCS) on the lab report. 
 

 
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7.1.13. Nerve Conduction Studies  
Nerve conduction studies (NCS) will be performed at baseline and each evaluation visit. NCS will 
be performed on the left leg unless focal skin or orthopedic lesions preclude safe or accurate 
performance of NCS in this limb, in which case NCS will be performed on the right leg. NCS of 
the Sural sensory and Peroneal motor nerves with distal latency/conduction velocity, Peroneal 
motor conduction velocity in the leg segment (between the ankle and knee).   
 
Definition of CSPN:  For the purposes of CSPN diagnosis, an absent or low amplitude sural 
sensory response is required (as defined below).  
 
Detailed protocol:  NCS will be performed using standard techniques.  Unless there is a local 
process such as a skin lesion, prior traumatic injury, history of radiculopathy etc. Skin temperature 
must be maintained > 31°C.  Temperature should be recorded from the dorsal foot and 
documented.  T 
 
The sural sensory response will be performed in an antidromic fashion with stimulation 14 cm 
proximal to the recording electrode, which will be placed posterior to the lateral malleolus. 
Subsequently, two additional responses will be recorded using a sweep speed of 2 msec/division 
and an appropriate sensitivity setting.  Three responses will be averaged using the same sweep 
and gain settings, from which amplitude and distal latency will be derived.   
 
The peroneal motor response will be recorded from the EDB muscle with stimulation 9 cm 
proximally at the ankle, and at the level of the fibular head. Obtain a single waveform at each 
simulation site, marking the onset latencies and baseline to peak amplitudes.  The conduction 
velocity will be calculated. The minimal F wave latency will be measured using a sensitivity of 
200-500 uV/division and at least 10 stimuli. 
 
The waveforms will be uploaded to the central NCS laboratory at the University of Utah for 
immediate review.  This review will ensure adequate adherence to protocol (temperature, 
stimulation location, averaging) and technical quality (baseline stability, absence of artifact).  If 
after review, technical deficiencies are noted, the site will be notified and the selected NCS will 
be repeated51.   
 
 
7.1.14. Skin Biopsy 
 

 
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The left leg is the preferred site for skin biopsy.  The left lower extremity will be evaluated by study 
staff to rule out previous surgery at the hip or proximal to the knee. The site of biopsy should not 
have scarring, rash, burns, significant edema, or tattoos. If any of these conditions are present, 
the right leg should be similarly evaluated, and biopsied, if appropriate.   All biopsies should be 
performed from the same side throughout the study, unless reasonable justification is 
documented (ie: trauma or surgery to previously used side).  
 
A 3mm punch biopsy will be taken from the selected the biopsy site using local anesthesia 
(lidocaine with epinephrine) using standardized techniques.  The punch will be placed in fixative 
and shipped overnight courier to the Utah Cutaneous Nerve Laboratory, where the tissue will be 
processed and stained using PGP9.5 and intraepidermal nerve fiber density (IENFD) measured62. 
 
 
Details of the skin biopsy procedure, sample handling, processing and shipping are available in 
the reference manual for skin biopsy.  
 
 
7.1.14.1.  Distal Thigh Skin Biopsy 
 
A distal thigh skin biopsy is collected at the following visits: Baseline (Visit 02), Week 32 (Visit 
04), Week 64 (Visit 06), and Week 96 (Visit 08/Termination) and/or Early Termination.   
A 3mm punch biopsy will be taken from the distal, lateral thigh 10 cm distal to superior margin of 
the patella.    
 
Refer to the Reference Manual for skin punch biopsy.   
7.1.15. Columbia-Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS is a suicidal ideation rating scale. It measures a Subject’s degree of suicidal ideation 
on a scale ranging from wishing to be dead without an active plan to active suicidal ideation with 
a specific plan and intent to die. Only investigators who have been fully trained in the 
administration of the C-SSRS will assess subject suicidality. As part of training, investigators are 
prepared to respond to and manage instances in which patients express suicidal ideation or 
exhibit suicidal behavior. 
 
7.1.16. The Norfolk Quality of Life – Diabetic Neuropathy (NQOL-DN) Scale   
Patient reported neuropathy related QOL. The NQOL-DN is a validated neuropathy specific QOL 
measure.  Factor analysis has been used to group NQOL-DN items into 6 subscores: symptoms, 
autonomic, small fiber, large fiber, and activities of daily living27.   
 
7.1.17. The Rapid Assessment of Physical Activity (RAPA) Survey 
The RAPA is a validated patient reported survey that quantifies the intensity and frequency of 
aerobic and strength activity.90   The RAPA is included in order to assess the degree of exercise 

 
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and physical activity between the treatment groups.  This is important because intensive exercise 
programs may impact the natural history of CSPN associated with prediabetes. 
 
7.1.18. Subject Adherence Assessments 
At each study visit, the site Investigator and/or Study Coordinator will assess the subject’s 
compliance with the study requirements by performing study drug reconciliation and collecting 
study drug containers.  This will also include reviewing protocol compliance, including use of study 
drug and concomitant medications. If applicable, subjects who fail to comply with the study 
requirements may be removed from the study. 
 
The site Investigator and/or Study Coordinator will conduct monthly telephone calls between clinic 
visits (i.e.: between Baseline and Week 16 calls should occur at Week 4, Week 8, and Week 12) 
to encourage protocol compliance and enhance retention.   
 
7.1.19 Optional Tissue Banking 
 
DNA samples will be collected at Baseline using supplies provided by URMC.  Centrifuge the 
EDTA tube at 1500 RPM for 15 minutes.   The buffy coat will be transferred into cryovials provided 
by Utah and stored at -80C.  At the end of the enrollment period, sites will batch ship all the buffy 
coat samples to Utah with shipment kit and air bills provided. 
 
Skin biopsy tissue collected for IENFD testing for will be stored at the Utah Cutaneous Nerve Lab 
until study closure.  Samples from participants who consent to long-term tissue storage will be 
placed in long-term tissue banking and the rest will be destroyed. 
 
The DNA and tissue bank will be located in the laboratory of Rob Singleton, MD, at the University 
of Utah.   Participants can withdraw consent to bank their samples by notifying their CSS 
investigator.   Banking preferences will be entered into the EDC by the CSS staff.  At the end of 
the study, DNA or tissue in the bank will be destroyed if participants opt out of banking at any time 
during the study or do not mark and initial their preference on the consent form. 
 
 
 
8. 
MANAGEMENT OF ADVERSE EVENTS 
Extensive data regarding safety and adverse events are available from clinical trials of topiramate 
for epilepsy and episodic migraine. The dose of topiramate to be used in the TopCSPN Study is 
similar to that used for episodic migraine (50-200mg daily).  Adverse events observed in 
randomized trials for migraine will be summarized65.  Following this summary, potentially 
significant adverse events observed at higher doses will be listed.  
 
When topiramate must be discontinued for participant safety, the dose can be stopped 
immediately or titrated down  based on the clinical judgement of the site investigator.  
 
 

 
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Adverse Events Observed at 100 mg daily of topiramate: 
• 
Anorexia.  Loss of appetite is one of the mechanisms contributing to weight loss. Most 
commonly anorexia is mild.  In subjects complaining of intolerable anorexia, the dose will 
be tapered to the maximal tolerated dose. 
• 
Fatigue. Subjects complaining of intolerable fatigue will be asked to taper the dose to the 
maximum tolerated. 
• 
Memory Problems. Topirmate may cause confusion, psychomotor slowing, poor 
concentration, or memory loss.  These symptoms are more commonly observed with rapid 
dose escalation. Patients complaining of intolerable memory problems, or those observed 
to have cognitive dysfunction sufficiently significant to warrant dose modification in the 
opinion of the PI will taper their dose to that maximally tolerated. 
• 
Nausea. Subjects complaining of intolerable nausea will be asked to taper the dose to the 
maximum tolerated. 
• 
Paresthesias.  Paresthesias are typically mild and uncommonly lead to discontinuation.  
In the setting of this study, paresthesias may also be related to the underlying disease 
(CSPN), or nerve regeneration.  There are no data suggesting topiramate causes or 
worsens peripheral neuropathy.  Subjects experiencing increased paresthesias will be 
encouraged to continue to participate unless the symptom is severe enough in the opinion 
of the PI to warrant dose reduction.  
 
Potentially serious adverse events noted in the package insert include: 
• 
Glaucoma. Topiramate has been reported to cause acute myopia associated with 
secondary angle closure glaucoma. Symptoms typically occur within 1 month of initiating 
therapy, and include decreased visual acuity and ocular pain. Ophthalmologic findings can 
include myopia and ocular hyperemia (redness).  Mydriasis may or may not be present. 
Visual acuity will be assessed at each visit and subjects with reduced acuity, ocular pain, 
or ocular hyperemia will discontinue medication and be immediately referred for 
ophthalmologic examination. 
• 
Kidney stones. 1.5% of adults exposed to topiramate during its adjunctive epilepsy therapy 
development reported the occurrence of kidney stones, an incidence about 2 to 4 times 
greater than expected in a similar, untreated population. Carbonic anhydrase inhibitors 
(Topiramate, but also zonisamide, acetazolamide or dichlorphenamide) can promote 
stone formation by reducing urinary citrate excretion and by increasing urinary pH. 
• 
Metabolic acidosis. Hyperchloremic, non-anion gap, metabolic acidosis (i.e., decreased 
serum bicarbonate below the normal reference range in the absence of chronic respiratory 
alkalosis) is caused by renal bicarbonate loss due to the inhibitory effect of topiramate on 
carbonic anhydrase. Renal disease, severe respiratory disorders, status epilepticus, 
diarrhea, and ketogenic diet may increase this risk. Symptoms may include 
hyperventilation, fatigue, anorexia, or rarely cardiac arrhythmias or stupor. Serum 
electrolytes including bicarbonate will be measured at each study visit.  Subjects with a 
total bicarbonate of < 17 mEq/L and a > 5 mEq/L decrease from pretreatment will 
discontinue treatment. 
• 
Oligohidrosis (decreased sweating) and subsequent loss of temperature regulation with 
hyperthermia has been reported in adults, especially in combination with carbonic 
anhydrase inhibitors and anticholinergic medications.  Subjects complaining of significant 
reduction in sweating will taper medication to the maximum tolerated dose. 
• 
Visual field defects (independent of elevated intraocular pressure) have been reported in 
clinical trials and in postmarketing experience.  Visual fields will be assessed at each study 

 
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visit.  Patients observed to have new visual field abnormalities will be referred for 
ophthalmologic examination and medication will be discontinued. 
 
8.1. Pregnancy 
Pregnancy itself is not regarded as an AE unless there is a suspicion that the study drug may 
have interfered with the effectiveness of a contraceptive medication. However, the outcome of all 
pregnancies that occur during paternal or maternal exposure to study drug (spontaneous 
miscarriage, elective termination, normal birth or congenital abnormality) must be followed up and 
documented even after the subject has been withdrawn from the study. All reports of congenital 
abnormalities/birth defects are SAEs. Spontaneous miscarriages should also be reported and 
handled as SAEs. Elective abortions without complications should not be handled as AEs. All 
outcomes of pregnancy must be reported to the Coordination Center.  
 
 
9. 
PROTOCOL AMENDMENTS AND STUDY TERMINATION 
All revisions and/or amendments to this protocol must be approved in writing by the Sponsor and 
the CIRB. The Investigator will not make any changes to the conduct of the study or the protocol 
without first obtaining written approval from the Sponsor and the CIRB, except where necessary 
to eliminate an apparent immediate hazard to a study subject. 
The Sponsor and NeuroNEXT Network reserve the right to discontinue the study at a clinical study 
site(s) for safety or administrative reasons at any time. Should the study be terminated and/or the 
clinical study site closed for any reason, all documentation and study drug pertaining to the study 
must be returned to the Sponsor or its representative. 
 
 
10. STATISTICAL CONSIDERATIONS 
The NeuroNEXT Data Coordinating Center has developed a statistical analysis plan, in 
collaboration with the protocol principal investigator and protocol steering committee. 
 
a. General considerations. Univariate summaries will be provided for all randomized subjects and 
by treatment group. Transformations will be considered for continuous variables exhibiting 
substantial skewness. Analyses of topiramate’s effect will be conducted according to randomized 
treatment assignment in accordance with the intent-to-treat principle.  
 
b. Strategy for evaluating the Co-Primary Endpoints in Aim 1. Analyses of the effects of topiramate 
on the co-primary endpoints will be interpreted from two perspectives. From a scientific 
investigational perspective, IENFD and NQOL-DN will be viewed as representing separate 
outcome domains, and the hypotheses of treatment effects on these outcomes will be considered 
conceptually distinct. Because positive findings from this early-phase trial will be subjected to 
conformation in a subsequent pivotal trial, the scientific hypotheses of treatment effects on the 
conceptually distinct co-primary endpoints will be tested on a comparison-wise basis without 
multiple comparison adjustment in order to enhance statistical power 74,75. From a decision-

 
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theoretic perspective, the results of this early-phase clinical trial will be applied to determine 
whether to proceed to a larger pivotal trial with a definitive clinical endpoint. Proceeding to a full-
scale trial will be deemed appropriate if the present trial demonstrates that topiramate has a 
benefit based on either IENFD or NQOL-DN and does not have an adverse effect the other 
outcome. Because this choice represents a single decision point, a single global decision rule to 
control the risk of inappropriately proceeding to a full-scale trial will be applied. The analyses of 
the effect of topiramate on the IENFD and NQOL-DN as distinct endpoints are described first, 
followed by a global strategy for deciding whether to proceed to a full-scale trial.   
c. Analysis of Co-Primary Endpoints. We hypothesize that topiramate will reduce the rate of 
deterioration of IENFD over the full follow-up period. Hence the primary analysis of the IENFD will 
compare the mean IENFD slope between the treatment and control groups under a longitudinal 
model with fixed effects for baseline IENFD, age, baseline BMI randomization stratification group, 
follow-up time (as a continuous variable), and the interaction between treatment assignment and 
follow-up time. Inclusion of baseline IENFD as a covariate will increase statistical power in a 
similar fashion as adjustment for the baseline level of the outcome in a conventional analysis of 
covariance. Expressed mathematically, the longitudinal model for IENFD is: Yit = α0 + Yi0 β0 + Age 
β1 + [BMI Group] β2 + Yi0 × timeij × β3 + Ti β4 + timeit β5 + Ti × timeit β6 + εit, Var()=Σ,  i = 1, 2, .., N, 
t = 0, 1, 2, 3, where Yit denotes the IENFD measurement for patient i at visit t, with t = 0 
representing the baseline visit so that Yi0 is the baseline IENFD, Ti denotes the randomized 
treatment group for the ith patient (with Ti = 1 for the topiramate group, and Ti = 0 for the control 
group), timeit denotes the time of the tth IENFD measurement for patient i, Ti × timeit denotes the 
treatment by time interaction, and the εit denote residuals of the IENFD measurements which are 
assumed to be normally distributed with a covariance matrix Σ which is described below. The 
coefficient β6 represents the effect of the topirimate treatment on the mean IENFD slope over 
time.  We will use a general unstructured covariance model for Σ 76so that the full model 
represents a special case of the linear mixed model 76,77 that allows for all possible correlations 
among the residuals among the IENFD measurements. When the number of time points is small 
relative to the number of subjects as is the case for IENFD in this proposal, the general 
unstructured covariance model is widely used in randomized trials because it provides essentially 
identical statistical power to that obtained under less general covariance models while avoiding 
the need for post-hoc modifications to satisfy modeling assumptions76. Estimates of the model 
coefficients and standard errors will be obtained by restricted maximum likelihood estimation 
(RMLE)78.  
 
Topiramate may have direct effects on QOL that are independent of CSPN progression and 
which may occur shortly after treatment initiation, as well as longer term effects that result from 
effects of topiramate on neuropathy progression. Accordingly, the primary analysis of the NQOL-
DN will compare the total mean change in the NQOL-DN from baseline to 2 years between the 
treatment and control groups under a longitudinal model that includes linear spline terms to allow 
separate mean slopes during the first 12 weeks after randomization and from 12 weeks to the 
end of follow-up.  Age, baseline BMI group and baseline NQOL-DN will be treated as a covariates 
to increase statistical power. In addition to the primary comparison of the total mean change in 

 
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the NQOL-DN to 2 years, linear contrasts will be constructed to estimate the effect of the treatment 
on the early change in the NQOL-DN to 16 weeks, and on the longer-term NQOL-DN slope after 
16 weeks. Expressed mathematically, the mixed effects model for the NQOL-DN is: Yit = α0 + Yi0 
β0 + Age β1 + [BMI Group] β2 + Yi0 timloit β3 + Yi0 timhiit β4 + Ti β5 + timloit β6 + timhiit β7 + Ti × timloit 
β8 + Ti × timhiit β9 + εit,   Var(it)=Σ,  i = 1, 2, .., N, t = 0, 1, 2, …, 6, where Yit denotes the NQOL-DN 
measurement of the ith patient at visit t, timloit = min(0, timeit – 16 weeks) and timhiit = max(0, timeit 
– 16 weeks) represent linear spline terms in follow-up time, and the remaining terms are 
analogous to those defined in the model for the IENFD described above. Accounting for separate 
slopes in the first 16 weeks and the subsequent 80 weeks, the primary linear contrast defining 
the treatment effect on the mean change to 2 years is 4 × β8 + 20 × β9. Due to the relatively large 
number (6) of follow-up measurement times for the NQOL-DN, an unstructured covariance model 
may lead to inefficient estimation76, and a relatively parsimonious covariance model will be used 
to limit the number of unknown parameters to be estimated76. Standard covariance models to be 
considered include models with random intercepts and slopes combined with an autoregressive 
or Toeplitz covariance matrix for the residuals around the underlying trajectories79-81. The 
covariance model will be selected from a pre-specified collection of potential models by comparing 
BIC statistics under maximum likelihood estimation81. After selection of the covariance model, 
final statistical inferences will be performed using restricted maximum likelihood estimation as in 
the analyses of the IENFD outcome.    
 
d. Missing Data. Because statistical inference is based on restricted maximal likelihood (REML) 
estimation, the longitudinal analyses described above will remain unbiased in the presence of 
missing data which follows a missing at random mechanism82; sensitivity analyses will be 
conducted using multiple imputation of missing data83 under imputation models which incorporate 
auxiliary variables to account for predictors of missingness and/or the variables being analyzed 
beyond those in the analytic model.  
 
e. Statistical Power for Separate Analyses of the Co-Primary Endpoints. Statistical power for 
IENFD was estimated by first fitting a mixed effects model to the first 2 years of follow-up for 116 
subjects from the Utah Diabetic Neuropathy Study natural history cohort with baseline MNSI ≥ 3, 
indicating the presence of neuropathy symptoms.  This cohort, as described in the preliminary 
data, excluded patients with longstanding neuropathy and is thus appropriate given the 
phenotypic similarity with CSPN. This analysis yielded variance components for IENFD 
trajectories over time and within-subject residuals. A design matrix was then constructed for the 
planned measurement schedule for the topiramate trial with IENFD measurements at baseline 
and weeks 32, 64 and 96 but with 4% loss-to-follow-up every 32 weeks for a total 12% loss-to-
follow-up over 96 weeks. Using this design matrix and the variance components estimated from 
the preliminary data, 125 randomized subjects will provide 80% power with 2-sided α=0.05 to 
detect a difference in mean IENFD slope between the treatment and control groups of 0.47 
fibers/mm/year. An effect of 0.47 fibers/mm/year represents a reduction in the mean slope from -
0.68 fibers/mm/year observed in our preliminary data to -0.21 fibers/mm/year. This projected 
effect size is conservative given preliminary data that successful intervention may result in 

 
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improvement in IENFD rather than just slowing of its rate of decline10,12,13.  Statistical power for 
the NQOL-DN was estimated based on an assumed SD for change in the NQOL-DN score over 
2 years of 16.4 points, which conservatively allows for a 10% higher SD than the SD of 14.9 points 
reported for the change in the NQOL-DN in Boyd et al24. If the correlation between baseline and 
follow-up assessments is ≤ 0.60, 125 subjects with 12% loss to follow-up will provide 80% power 
with 2-sided α=0.05 to detect a mean difference of 7.9 points between the treatment and control 
groups over 96 weeks after adjustment for the baseline NQOL-DN. This represents a difference 
of 4.0 points per year. This power calculation is conservative, as the multiple repeated QOL 
measurements in the study design will provide greater precision than the simplified ANCOVA 
based on a single follow-up time considered in this power calculation.  
 
f. Decision for proceeding to a full-scale trial (“Go/No-Go” Algorithm). A full-scale trial will be 
justified if topiramate is demonstrated to be superior to placebo for either IENFD or NQOL-DN, 
and non-inferior for both of these outcomes. We estimated non-inferiority margins of up to 0.50 
fibers/mm/year for the IENFD slope and up to an average of 5 points per year for the NQOL-DN. 
A failure to proceed to the full-scale trial would be problematic if there is a treatment benefit of 
0.50 fibers/mm/year for the IENFD or of an average of 5.0 points per year for the NQOL-DN and 
the treatment does not have an adverse effect on the other outcome. Based on these conditions, 
the following global decision rule was developed: Proceed to the full scale trial if either: 
1. The comparison of randomized groups favors topiramate by at least 0.30 fibers/mm/yr for 
IENFD and favors the placebo by no more than 2.70 points per year for the NQOL-DN, or  
2. The comparison of randomized groups favors topiramate by at least 2.97 points per year for 
the NQOL-DN & favors the placebo by no more than 0.22 fibers/mm/yr for the IENFD. 
  
Given the previously stated assumptions for the analyses of IENFD and NQOL-DN as separate 
endpoints, and assuming a Pearson R of -0.30 between the IENFD and QOL-DN based on Boyd 
et al24, numerical integration of the bivariate normal distribution implies that this global decision 
rule has a Type 1 error ≤ 5% for an inappropriate recommendation to proceed to a full scale trial 
given inferiority for at least on outcome or absence of superiority for both outcomes, and Type 2 
error ≤ 18% for failure to recommend proceeding to the full scale trial when the stated criteria for 
superiority of at least 1 outcome and non-inferiority for both outcomes are satisfied. 
 
g. Secondary outcomes. Treatment effects on continuous secondary outcomes which are either 
approximately normally distributed or can be transformed to approximate normality will be 
analyzed using linear mixed effect models similar to those described for IENFD and NQOL-DN. 
Generalized linear mixed models with outcome models appropriate to each outcome variable will 
be applied for ordered categorical outcomes measured at the scheduled follow-up visits and for 
continuous outcomes that cannot be transformed to achieve approximate normality. The 
treatment effect on the rate of falls will be estimated using negative binomial regression.  
 
g. Evaluation of the clinical meaning of IENFD change. A major secondary objective of the 
TopCSPN study is to explore the clinical meaning of change in IENFD. TOPIRAMATE may 

 
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potentially affect NQOL-DN and other clinical endpoints (e.g., balance, fall risk) through direct 
effects that are independent of neuropathy progression (IENFD), or through indirect effects, which 
are mediated through a pathway that incorporates effects of the treatment on neuropathy 
progression based on IENFD. Using this conceptual framework, mechanistic information will be 
obtained from three types of analyses:  
M1) Evaluation of the profile of treatment effects on the QOL-DN and other clinical endpoints 
in comparison to the treatment effect on the IENFD,    
M2) Evaluation of regression coefficients relating changes in the QOL-DN and other clinical 
endpoints to the IENFD slope, controlling for treatment assignment, 
M3) Evaluation of the “proportion of the treatment effect explained by the IENFD”84 for the 
QOL-DN and other clinical endpoints.  
 
If the treatment does not affect NQOL-DN or another clinical endpoint, the M1 and M2 analyses 
will provide understanding of the null effect of the treatment. The evaluation of the profile of 
treatment effects in M1 will be performed by plotting the estimated treatment effects on each 
outcome with their 95% confidence intervals. Treatment effects on continuous and categorical 
variables will be estimated using linear or generalized linear mixed models analogous to those 
described in Aim 1; the treatment effect on the rate of falls will be analyzed using negative binomial 
regression. Concordant effects for IENFD and a particular clinical endpoint will suggest possible 
mediation of the treatment effect on the clinical endpoint through IENFD, whereas discordant 
effects will suggest IENFD did not play a major role (i.e. was not clinically relevant). Bootstrap 
resampling will be used to provide 95% confidence limits for ratios of treatment effects on IENFD 
vs. effects on the clinical endpoints.  
 
The treatment effect estimates in the M1 analyses represent direct comparisons of 
randomized groups, and hence are not subject to confounding due to the randomized trial design. 
This is not the case for the M2 and M3 analyses, as confounding factors that jointly influence both 
the intermediate variables and the NQOL-DN or other clinical endpoints will lead to biased 
estimates85.  Failure to recognize this issue has led to confusion in prior applications of path 
analysis for evaluation of mediating factors86. Thus, we will seek to identify and control for baseline 
and follow-up factors that may potentially influence both IENFD and NQOL-DN or other clinical 
endpoints in the M2 and M3 analyses.87   
 
The regression coefficients of the IENFD slope in the M2 analyses will provide information 
concerning the clinical interpretation of the IENFD slope by characterizing the difference in the 
96-week change in the NQOL-DN associated with a given difference in the IENFD slope.  These 
analyses will be carried out using a joint mixed effects model in which the NQOL-DN will be 
assumed to be related to the underlying random IENFD slopes.  We have experience fitting similar 
joint models using the SAS procedure NLMIXED88.  In the M3 analyses, the proportion of 
treatment effect explained (PTE) by the IENFD slope on the NQOL-DN will be obtained by first 
estimating the total effect of the treatment on change in the NQOL-DN to 96 weeks with 
adjustment for potential confounders but not the IENFD slope using a mixed effects model as 

 
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described in Aim 1, and then estimating the treatment effect on the change in the NQOL-DN that 
remains after controlling for the IENFD slope in a joint mixed effects model which adjusts for the 
IENFD slope in addition to the baseline confounders. The PTE by IENFD will be estimated by 
subtracting the ratio of the adjusted vs. unadjusted treatment effects from 1, and a 95% 
confidence interval constructed using bootstrap resampling. Similar analyses will be used to 
estimate the regression coefficients of the IENFD slope (for the M2 analyses) and the PTEs 
associated with IENFD (for the M3 analyses) for other clinical endpoints. To gain further insight 
into the effects of the topiramate intervention on different components of quality of life, the M2 
and M3 analyses will be repeated for the five individual subscales of the NQOL-DN. 
 
10.1. 
Outcomes 
10.1.1. Primary Outcome (including definition) 
IENFD and the validated NQOL-DN will serve as co-primary outcome measures. Rationale: The 
choice of endpoint measures is innovative, and validation of both measures as potential endpoints 
for use in a future Phase III trial is a major secondary objective of the current proposal. Most 
diabetic neuropathy trials use nerve conduction studies and clinical examination scales [e.g. the 
Neuropathy Impairment Scale Lower Limb (NIS-LL)] as primary outcome measures.  However, 
these measures are unresponsive to change in early neuropathy66 and their patient-based clinical 
meaning has not been established.  Current criteria for the minimal clinically important difference 
in nerve conduction parameters are based on expert opinion from nearly 25 years ago67.  IENFD 
was selected as an objective measure of axonal integrity.  NQOL-DN was chosen as a validated 
neuropathy specific measure of patient reported function and QOL. 
 
The Norfolk Quality of Life – Diabetic Neuropathy (NQOL-DN) scale:  IENFD provides an essential 
objective biomarker of axon structure but the patient focused clinical meaning of change in IENFD 
has yet to be conclusively determined.  Therefore, incorporation of a validated measure of patient 
symptoms and function is necessary.  Neuropathy clinical trials should assess the impact of 
therapy on patient function and QOL.  Pain, sensory loss, imbalance, falls and reduced mobility 
combine to reduce QOL.  The NQOL-DN captures the full spectrum of DPN related symptoms. 
Data from over 1000 structured clinical interviews was reviewed for content validity in an iterative 
multispecialty process in order to develop the instrument 27. 47 Items inventory DPN symptoms 
and their impact on function and activities of daily living. The NQOL-DN accurately distinguishes 
patients with and without DPN, and correlates significantly with other DPN measures27. The 
NQOL-DN is responsive to change. In an 18-week double blind crossover trial of ruboxistaurin, 
topiramate and placebo, total NQOL-DN improved significantly with both topiramate (12.2+/-2.76) 
and ruboxistaurin (-9.6+/-4.1) but not placebo (-5.6+/- 3.5)24. Topiramate reduces pain, and in a 
small clinical study was associated with increased IENFD over 18 weeks25, suggesting an effect 
on small axons. By inhibiting protein kinas C-beta, Ruboxistaurin is thought to inhibit 
microvascular injury. Factor analysis has been used to group NQOL-DN items into 6 subscores: 
symptoms, autonomic, small fiber, large fiber, and activities of daily living. These different 
subdomains were differentially responsive to ruboxistaurin and topiramate. Topiramate treatment 

 
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was associated with a significant improvement in the small fiber and symptom subscores, which 
in turn significantly correlated with change in IENFD24. By contrast, ruboxistaurin significantly 
improved only the large fiber subscore. These results suggest NQOL-DN subscores are 
physiologically valid measures that reflect different peripheral nerve populations.  NQOL-DN will 
serve as the co-primary outcome measure.   
 
Intraepidermal nerve fiber density:  Both CSPN and early diabetic neuropathy frequently result in 
loss of small unmyelinated axons before loss of larger myelinated fibers.  NCS evaluate 
myelinated axons, but are not affected by loss of small lightly myelinated or unmyelinated axons.  
While unmyelinated axons may be particularly vulnerable to metabolic stress, they are also more 
plastic than myelinated fibers, and have more robust regenerative capacity68.  Thus a validated 
biomarker of small fiber integrity would be a preferred endpoint in a CSPN clinical trial.  IENFD 
directly reflects nociceptive axons, has demonstrated reliability equivalent to nerve conduction 
velocity69, and age and gender specific normative data are available52.  Epidermal axons are 
capable of regeneration in surgical and chemical axotomy models70,71, and small studies suggest 
IENFD improves following intervention for diabetic neuropathy11 and idiopathic  
neuropathy in the setting of prediabetes 10.  A small open label trial of topiramate in diabetic 
neuropathy demonstrated improved IENFD and microvascular reactivity25 and a small 
randomized trial of topiramate versus ruboxistuarin or placebo demonstrated improvement in 
IENFD and the Total Neuropathy Score72 among the topiramate treated participants24.   
 
10.1.2. Secondary Outcome(s) 
Secondary outcome measures will include measures of neuropathy symptoms and signs, function 
and mobility, nerve conduction studies, and metabolic assessment.   
i. Neuropathy symptoms: 
1.  NTSS653 
3.  Brief Pain Inventory – Diabetic Neuropathy (BPI-DN) 54 
ii. Neuropathy signs:   
 
 
1.  Utah Early Neuropathy Scale48 
 
iii. Function and mobility 
1.  6-minute walk test (6MWT) 56  
 
2.  Timed up and Go (TUG) 58  
3.  ABC Scale.  
iv.Nerve conduction studies including Sural sensory amplitude and distal 
latency/conduction velocity, and Peroneal motor amplitude, distal latency, conduction 
velocity between the knee and ankle as described above. 
v. Metabolic assessment: 
• 
Height, weight, BMI, waist circumference 
• 
Fasting glucose and insulin with calculation of the “quantitative insulin 
sensitivity check index” (QUICKI)73 
• 
Hemoglobin A1c 
• 
Fasting lipid panel 

 
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10.1.3. Exploratory Outcomes 
Mechanistic Studies: This study is not designed to conclusively elucidate the precise mechanisms 
underlying topiramate’s potential efficacy for CSPN (weight loss and resultant metabolic 
improvement, Na channel inhibition), but will include biomarkers specific to these putative 
mechanisms. DNA will be banked from subjects who agree to the optional DNA sample collection.  
Once blind has been broken, the genes for voltage gated sodium channels of greatest relevance 
to peripheral nerve function (SCN2A, 3A, 4A, 8A, 9A and 10A) will be sequenced in subsets of 
subjects with the greatest and least clinical improvement in order to examine for sequence 
variants associated with topiramate responsiveness.  The relationship between baseline weight 
and metabolic parameters, and their improvement, and response to therapy will also be explored.  
Insulin sensitivity will be assessed using an indirect surrogate index (e.g. the QUICKI)73. 
 
10.2. Data Monitoring 
All aspects of the study will be monitored by qualified individuals designated by the sponsor.  
Monitoring will be conducted according to Good Clinical Practice and applicable government 
regulations.  The investigator agrees to allow monitors access to the clinical supplies, dispensing 
and storage areas, and to the clinical files of the study subjects, and, if requested, agrees to assist 
the monitors. 
 
Safety monitoring will include careful assessment and appropriate reporting of adverse events.  
Medical monitoring will include contemporaneous assessment of serious adverse events. 
 
The monitoring of subject safety and data quality will follow the NINDS Guidelines for Data and 
Safety Monitoring in Clinical Trials.  A Data and Safety Monitoring Board (DSMB) appointed by 
the NIH/NINDS will meet at 24-week intervals (or as determined by the NINDS) to review partially 
unblinded study data provided by the study statistician.  This committee will monitor rates of 
adverse events and endpoints in the trial and will monitor the performance of the trial. The 
frequency and format of DSMB meetings, reports, and guidelines for interim analysis will be 
agreed upon prior to study subject enrollment. 
 
The Protocol PI will appoint an Independent Medical Monitor (IMM) to review all adverse events, 
in a blinded fashion, on a periodic basis. In addition, the IMM will review all events that meet the 
regulatory definition of a Serious Adverse Event, upon receipt of notification via the Electronic 
Data Capture (EDC) system.    
An adverse event (AE) is any unfavorable and unintended sign (including a clinically significant 
abnormal laboratory finding, for example), symptom, or disease temporally associated with a 
study, use of a drug product or device whether or not considered related to the drug product or 
device. The FDA, Office of Human Research Protection (OHRP), and NeuroNEXT CIRB 
requirements for reporting AEs will be followed. Subjects will be monitored for AEs from the time 
they sign consent until 30 days following permanent discontinuation of study drug. Adverse 
events during the screening phase (from the time the subject signs consent until they are randomized) 
shall only include events related to study procedures, i.e. infection of skin biopsy site. 

 
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At that point, all ongoing AEs will be followed to resolution, but no new AEs will be recorded. The 
IMM/DSMB will review cumulative AEs; the frequency of this review will be determined by the 
IMM/DSMB in conjunction with the Protocol PI. 
 
Each Clinical Study Site Investigator and research team (co-Investigators, research nurse, clinical 
trial coordinator) are responsible for identifying and reporting AEs and determining the relationship 
of the event to the study drug/study procedures.  Aggregate reports blinded by treatment group, 
detailed by severity, attribution (expected or unexpected), and relationship to the study drug/study 
procedures, will be available from the DCC for review by the IMM. A separate report detailing 
protocol compliance will also be available monthly from the DCC for review by the Protocol PI, 
who will provide feedback to individual sites as needed. The Protocol Steering Committee (PSC) 
will advise the Protocol PI as to whether the protocol or informed consent document requires 
revision based on these reports.  
 
 
11. DATA COLLECTION, SITE MONITORING, AND ADVERSE EXPERIENCE REPORTING 
11.1. Data Management 
Site personnel will collect, transcribe, correct, and transmit the data onto source documents, 
CRFs, and other forms used to report, track and record clinical research data.  The DCC will 
monitor clinical sites to ensure compliance with data management requirements and Good 
Clinical Practices. The DCC is responsible for developing, testing, and managing clinical data 
management activities, as required, at the study sites, the CCC, and at the DCC. 
 
The general NINDS Common Data Elements (CDE) will be used to construct data collection 
forms. All study data will be collected via systems created in collaboration with the DCC and will 
comply with all applicable guidelines regarding patient confidentiality and data integrity. 
 
11.1.1. Registration 
Registration of subjects on this protocol will employ an interactive data system in which the clinical 
study site will attest to the subject’s eligibility as per protocol criteria and obtain appropriate 
informed consent. NeuroNEXT CIRB approval for the protocol must be on file at the DCC before 
accrual can occur from the clinical study site. 
 
The DCC will use a system of coded identifiers to protect subject confidentiality.  When the subject 
is registered to participate in the study using the DCC-provided web-based registration, the 
system will assign a subject ID number. The unique ID code will include a protocol ID, a site ID, 
and a unique subject ID.  To confirm the correct subject ID, the data entry system will require a 
second entry of the unique subject ID and compare for consistency.  In this fashion, no personal 
identifiers would be accessible to the DCC and the data will be collected on the correctly identified 
subject.  

 
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11.1.2. Data Entry 
Data entry will occur at the enrolling clinical study sites. Data quality assurance and analyses will 
be performed by the DCC.  The DCC, located at the University of Iowa, will coordinate all data 
and statistical services for the study, as well as on-site monitoring for all participating clinical study 
sites. 
 
Data collection for this study will be accomplished with online electronic case report forms.  Using 
encrypted communication links, online forms will be developed that contain the requisite data 
fields.   
 
11.2. Role of Data Management 
Data Management (DM) is the development, execution and supervision of plans, policies, 
programs, and practices that control, protect, deliver, and enhance the value of data and 
information assets. 
 
All data will be managed in compliance with NeuroNEXT policies, and applicable Sponsor and 
regulatory requirements. The DCC will instruct site personnel to collect, transcribe, correct, and 
transmit the data onto source documents, CRFs, and other forms used to report, track and record 
clinical research data.  The DCC will monitor clinical sites to ensure compliance with data 
management requirements and Good Clinical Practices. The DCC is responsible for developing, 
testing, and managing clinical data management activities, as required, at the clinical study sites 
(CSS), the CCC, and at the DCC. 
 
The DCC is responsible for all aspects of clinical data management, and for properly instructing 
key study personnel (including the CCC, the CSS, and DCC staff) on how to collect, transcribe, 
correct and transmit the data onto CRFs or other data collection forms and logs. 
 
The DCC is responsible for establishing procedures to ensure that clinical data management 
activities occur as required at the CCC, the CSS, and at the DCC. 
11.3. Quality Assurance 
By signing this protocol, the Sponsor and Investigator agree to be responsible for implementing 
and maintaining quality control and quality assurance systems with written standard operating 
procedures (SOPs) to ensure that studies are conducted and data are generated, documented, 
and reported in compliance with the protocol, accepted standards of GCP, and all applicable 
federal, state, and local laws, rules and regulations relating to the conduct of the clinical study. 
11.3.1. Development of Monitoring Plan 
Onsite monitoring visits will be conducted by DCC monitors according to a pre-defined Monitoring 
Plan.  The monitoring plan will detail the frequency of on-site visits, the study data to be monitored, 
the review of any regulatory files, drug and supplies accountability (if applicable), documentation 
of the on-site visit, and the resolution process for data errors that are discovered during the visits.   

 
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All participating clinical study sites will be monitored at least once after a study initiation visit and 
all sites will have a close-out visit for each protocol.  One on-site monitoring visit is anticipated for 
each clinical study site per year.  All subjects will be monitored for inclusion and exclusion criteria, 
informed consent procedures, and adverse events.  A certain percentage of data is also 
monitored/ source data verified against the data entered into the study database.  The monitoring 
plan will include flexibility to revise the frequency of visits or data monitored depending on clinical 
study site or study related issues. 
11.3.2. Site Monitoring Visits 
On-site monitoring visits will be conducted by DCC monitors according to a pre-defined monitoring 
plan for each protocol.  The goal of on-site monitoring is to analyze (review) the data as it is 
collected, to check the validity and integrity of the data, to verify source documentation, to ensure 
protection of human subjects, and to ensure protocol compliance with federal regulations.  During 
the monitoring visit, the monitor assesses the overall status of the study, staff, and facilities to 
determine whether the study is being conducted per protocol and in compliance with regulatory 
requirements.  The monitor also conducts a CRF review that includes checks of all adverse event 
documentation, verifies the presence of all critical correspondence and records related to 
investigational products and clinical supplies (if applicable), and determines if protocol violations 
have occurred and are documented properly.  After the monitoring visit, the monitor documents 
the results of the monitoring visit and completes a post-visit monitoring letter that conveys any 
issues discovered during the visit and the need for data corrections, if appropriate.  Drug and 
supplies accountability may also be monitored during the site visit.  The DCC will work closely 
with the CCC to monitor and document drug distribution from the manufacturers to the clinical 
study sites (CSS).  Each CSS will be provided with a drug accountability log which will be reviewed 
by the DCC monitors and reconciled with distribution logs. At the study closeout visit, the monitors 
confirm that appropriate data have been reviewed, source documentation has been verified, and 
all required documents are present in the Study Regulatory File. 
11.3.3. Laboratory Data Flow 
Safety Monitoring Labs: The DCC will provide laboratories with online forms and/or electronic 
data exchange mechanisms - depending on their capabilities and needs - to enter, update and 
obtain relevant data. When a blood or urine sample has been obtained, the clinical study site 
study coordinator will send the sample (subject ID, site ID, and protocol ID numbers will be used) 
to the University of Rochester central laboratory. Results will be sent via a secure system to 
University of Rochester laboratory with no individual-identifying information on the report. The 
laboratory will electronically communicate the test results to the respective clinical study sites in 
a secure manner.  The laboratory will also transfer test results electronically to the DCC. 
 
11.4. Adverse Experience Reporting 
The adverse event (AE) definitions and reporting procedures provided in this protocol comply with 
all applicable United States Food and Drug Administration (FDA) regulations and International 
Conference on Harmonization (ICH) guidelines.  The Site Investigator will carefully monitor each 

 
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subject throughout the study for possible adverse events.  All AEs will be documented on CRFs 
designed specifically for this purpose.  It is important to report all AEs, especially those that result 
in permanent discontinuation of the investigational product being studied, whether serious or non-
serious. 
Each clinical study site’s Principal Investigator and research team are responsible for identifying 
adverse events and reporting them through the DCC Online Adverse Event Reporting System.  
Investigators are also responsible for complying with NeuroNEXT CIRB’s reporting requirements 
for all safety reports.  Copies of each report and documentation of IRB notification and receipt will 
be kept in the investigator’s study file.  
 
An adverse event is defined as: “…an unfavorable and unintended sign, symptom, or disease 
associated with a subject’s participation in this research trial.” 
 
Serious adverse events include those events that: “result in death; are life-threatening; require 
inpatient hospitalization or prolongation of existing hospitalization; create persistent or significant 
disability/incapacity, or a congenital anomaly/birth defects.”  
 
Unexpected adverse event is defined as any adverse experience…the specificity or severity of 
which is not consistent with the risks described in the protocol.  
 
Expected adverse events are those that are known to be associated with or have the potential to 
arise as a consequence of participation in the study. 
 
On-line Adverse Event Reporting System  
Upon entry of a serious adverse event by a site investigator, the DCC Online Adverse Event 
Reporting System will immediately notify the Independent Medical Monitor (IMM).   
 
Within 24 hours (of learning of the event), investigators must report any Serious Adverse Event 
(SAE) Investigators must report all other AEs within 5 working days/7 calendar days (of learning 
of the event). 
 
Serious adverse events: The site investigator determines causality (definitely not related, probably 
not related, possibly related, probably related, definitely related) of the adverse event. The IMM 
will review the SAE report.  The IMM may request further information if necessary.  The Online 
Adverse Event Reporting System maintains audit trails and stores data (and data updated) and 
communication related to any adverse event in the study. The IMM may determine that the 
Serious Adverse Event requires expedited reporting to the FDA.  The DCC will prepare a 
Medwatch safety report for submission to the FDA.  If warranted, the IMM will notify the DSMB 
chair.  The DSMB may suggest changes to the protocol or consent form to the Study Chair as a 
consequence of adverse events.  
 

 
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Non-serious adverse events: Non-serious adverse events that are reported to or observed by the 
investigator or a member of his research team will be submitted to the DCC in a timely fashion 
(within 5 working days). The events will be presented in tabular form and given to the IMM on a 
quarterly basis or as requested. Local site investigators are also required to fulfill all reporting 
requirements of their local institutions. 
 
The DCC will prepare aggregate reports of all adverse events (serious/not serious, 
expected/unexpected and relationship to study drug) for the IMM and the DSMB on a quarterly 
basis or as requested. In addition, all adverse events will be coded using the MedDRA system. A 
separate report detailing protocol compliance will also be available from the DCC for DSMB and/or 
site review monthly or as requested. The research team will then evaluate whether the protocol 
or informed consent document requires revision based on the reports.  
11.4.1. Definitions of Adverse Events, Suspected Adverse Drug Reactions & Serious 
Adverse Events 
11.4.1.1. Adverse Event Collection and Reporting 
 
Subjects will be monitored for AEs from the time they sign consent until 30 days following 
permanent discontinuation of study drug. Adverse events during the screening phase (from the 
time the subject signs consent until they are randomized) shall only include events related to 
study procedures, i.e. infection of skin biopsy site.   If not related to study procedures, any new 
or worsened medical conditions reported during the screening process will be recorded in 
medical  history. 
An adverse event (AE) is any unfavorable and unintended sign (including a clinically significant 
abnormal laboratory finding, for example), symptom, or disease temporally associated with a 
study, use of a drug product or device whether or not considered related to the drug product or 
device.  
 
Adverse drug reactions (ADR) are all noxious and unintended responses to a medicinal product 
related to any dose.  The phrase “responses to a medicinal product” means that a causal 
relationship between a medicinal product and an adverse event is at least a reasonable possibility, 
i.e., the relationship cannot be ruled out.  Therefore, a subset of AEs can be classified as 
suspected ADRs, if there is a causal relationship to the medicinal product. 
 
Examples of adverse events include: new conditions, worsening of pre-existing conditions, 
clinically significant abnormal physical examination signs (i.e. skin rash, peripheral edema, etc), 
or clinically significant abnormal test results (i.e. lab values or vital signs), with the exception of 
outcome measure results, which are not being recorded as adverse events in this trial (they are 
being collected, but analyzed separately).  
 
Stable chronic conditions (i.e., diabetes, arthritis) that are present prior to the start of the study 
and do not worsen during the trial are NOT considered adverse events. Chronic conditions that 

 
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occur more frequently (for intermittent conditions) or with greater severity, would be considered 
as worsened and therefore would be recorded as adverse events. 
 
Adverse events are generally detected in two ways: 
 
 
Clinical → symptoms reported by the subject or signs detected on examination. 
 
Ancillary Tests → abnormalities of vital signs, laboratory tests, and other diagnostic procedures 
(other than the outcome measures: the results of which are not being captured as AEs). 
 
If discernible at the time of completing the AE log, a specific disease or syndrome rather than 
individual associated signs and symptoms should be identified by the Site Investigator and 
recorded on the AE log.  However, if an observed or reported sign, symptom, or clinically 
significant laboratory anomaly is not considered by the Site Investigator to be a component of a 
specific disease or syndrome, then it should be recorded as a separate AE on the AE log.  
Clinically significant laboratory abnormalities, such as those that require intervention, are those 
that are identified as such by the Site Investigator. 
 
An unexpected adverse event is any adverse event, the specificity or severity of which is not 
consistent with the current Investigators Brochure or package insert or described in the protocol.  
An unexpected, suspected adverse drug reaction is any unexpected adverse event that, in the 
opinion of the Site Investigator or Sponsor, there is a reasonable possibility that the investigational 
product caused the event. 
 
11.4.1.2.  Serious Adverse Events 
A serious adverse event (SAE) is defined as an adverse event that meets any of the following 
criteria: 
1. Results in death. 
2. Is life threatening: that is, poses an immediate risk of death as the event occurred. 
a. This serious criterion applies if the study subject, in the view of the Site Investigator or 
Sponsor, is at immediate risk of death from the AE as it occurs.  It does not apply if an 
AE hypothetically might have caused death if it were more severe. 
3. Requires inpatient hospitalization or prolongation of existing hospitalization. 
a. Hospitalization for an elective procedure (including elective PEG tube/g-tube/feeding 
tube placement) or a routinely scheduled treatment is not an SAE by this criterion 
because an elective or scheduled “procedure” or a “treatment” is not an untoward 
medical occurrence. 
4. Results in persistent or significant disability or incapacity. 
a. This serious criterion applies if the “disability” caused by the reported AE results in a 
substantial disruption of the subject’s ability to carry out normal life functions. 
5. Results in congenital anomaly or birth defect in the offspring of the subject (whether the 
subject is male or female).   

 
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6. Necessitates medical or surgical intervention to preclude permanent impairment of a body 
function or permanent damage to a body structure. 
7. Important medical events that may not result in death, are not life-threatening, or do not 
require hospitalization may also be considered SAEs when, based upon appropriate medical 
judgment, may jeopardize the subject and may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition.  Examples of such medical events include 
blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse. 
 
An inpatient hospital admission in the absence of a precipitating, treatment-emergent, clinical 
adverse event may meet criteria for "seriousness" but is not an adverse experience, and will 
therefore, not be considered an SAE.  An example of this would include a social admission 
(subject admitted for other reasons than medical, e.g., lives far from the hospital, has no place to 
sleep). 
 
A serious, suspected adverse drug reaction is an SAE that, in the opinion of the Site Investigator 
or Sponsor, suggests a reasonable possibility that the investigational product caused the event. 
 
The Site Investigator is responsible for classifying adverse events as serious or non-serious. 
 
11.4.2. Assessment and Recording of Adverse Events 
This study will utilize the CTCAE version 4.0 coding system for adverse event recording.  Adverse 
events reported using CTCAE will be recoded into MedDRA terms by the DCC. 
 
Assessment of Adverse Events 
At each visit (including telephone interviews), the subject will be asked “Have you had any 
problems or symptoms since your last visit?” in order to determine the occurrence of adverse 
events. If the subject reports an adverse event, the Investigator will determine: 
 
1. Type of event 
2. Date of onset and resolution (duration) 
3. Severity (mild, moderate, severe) 
4. Seriousness (does the event meet the above definition for an SAE) 
5. Causality, relation to investigational product and disease 
6. Action taken regarding investigational product 
7. Outcome 
 
Relatedness of Adverse Event to Investigational Product 
The relationship of the AE to the investigational product should be specified by the Site 
Investigator, using the following definitions: 
 

 
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1. Not Related: Concomitant illness, accident or event with no reasonable association with 
treatment. 
2. Unlikely: The reaction has little or no temporal sequence from administration of the 
investigational product, and/or a more likely alternative etiology exists. 
3. Possibly Related: The reaction follows a reasonably temporal sequence from administration of 
the investigational product and follows a known response pattern to the suspected 
investigational product; the reaction could have been produced by the investigational product 
or could have been produced by the subject’s clinical state or by other modes of therapy 
administered to the subject. (suspected ADR) 
4. Probably Related: The reaction follows a reasonably temporal sequence from administration 
of investigational product; is confirmed by discontinuation of the investigational product or by 
re-challenge; and cannot be reasonably explained by the known characteristics of the subject’s 
clinical state. (suspected ADR) 
5. Definitely Related: The reaction follows a reasonable temporal sequence from administration 
of investigational product; that follows a known or expected response pattern to the 
investigational product; and that is confirmed by improvement on stopping or reducing the 
dosage of the investigational product, and reappearance of the reaction on repeated exposure. 
(suspected ADR) 
 
Recording of Adverse Events 
All clinical adverse events are recorded in the Adverse Event (AE) Log in the subject’s study 
binder. The site should fill out the AE Log and enter the AE information into the online Adverse 
Event Reporting System within 5 working days of the site learning of a new AE or receiving an 
update on an existing AE.   
 
Please Note: Serious Adverse Events (SAEs) must be reported to the NeuroNEXT Data 
Coordinating Center within 24 hours of the site learning of the SAE.  
 
Entries on the AE Log (and into the online Adverse Event Reporting System) will include the 
following: name and severity of the event, the date of onset, the date of resolution, relationship to 
investigational product, action taken, and primary outcome of event. 
 
Adverse Events and Serious Adverse Events - Reportable Events 
The following are considered reportable events and must be reported to the NeuroNEXT Data 
Coordinating Center within 24 hours of the site being notified of the event.  
 
• 
All events that meet the above criteria for Serious Adverse Events (SAEs) 
 
All occurrences of Serious Adverse Events (SAEs) must be reported within 24 hours of discovery 
of the event.   All other Adverse Events (AEs) must be reported within 5 business days/7 calendar 
days (of discovery of the event). 

 
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Adverse Event Data Management System (AEDAMS) 
Upon entry of a serious adverse event by a clinical site, the DCC Online Adverse Event Reporting 
System will immediately notify the IMM. If warranted, the IMM will notify the DSMB chair.  
 
Serious adverse events: The site investigator determines causality (definitely not related, probably 
not related, possibly related, probably related, definitely related) of the adverse event. The IMM 
will review the SAE report.  The IMM may request further information if necessary.  The DSMB 
may suggest changes to the protocol or consent form to the Project PI as a consequence of 
adverse events. The Online Adverse Event Reporting System maintains audit trails and stores 
data (and data updated) and communication related to any adverse event in the study.  
 
Non-serious adverse events: Non-serious adverse events that are reported to or observed by the 
investigator or a member of his research team will be submitted to the DCC within 5 working days. 
The events will be presented in tabular form and given to the IMM on a quarterly basis or as 
requested. Local site investigators are also required to fulfill all reporting requirements of their 
local institutions. 
 
The DCC will prepare aggregate reports of all adverse events (serious/not serious and expected, 
unexpected) for the DSMB.  
 
12. HUMAN SUBJECTS 
Documented approval from the NeuroNEXT CIRB will be obtained for all participating centers 
prior to clinical trial start, according to ICH GCP, local laws, regulations and organization. When 
necessary, an extension, amendment or renewal of the CIRB approval must be obtained. 
Evidence of training in responsible conduct of research shall be on file for each CSS PI and co-
investigator. 
12.1. Institutional Review Board (IRB) Review and Informed Consent 
This protocol and the informed consent document (Appendix A) and any subsequent 
modifications will be reviewed and approved by the NeuroNEXT CIRB responsible for oversight 
of the study.  A signed consent form, approved by the NeuroNEXT CIRB, will be obtained from 
the subject.   The consent form will describe the purpose of the study, the procedures to be 
followed, and the risks and benefits of participation.  A copy of the consent form will be given to 
the subject and this fact will be documented in the subject’s record. 
12.2. Subject Confidentiality 
All laboratory specimens, evaluation forms, reports, video recordings, and other records that leave 
the clinical study site will be identified only by the study specific Subject Identification Number 
(SID) to maintain subject confidentiality.  All records will be kept in a locked file cabinet.  All 
computer entry and networking programs will be done using study specific SIDs only.  Clinical 

 
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information will not be released without written permission of the subject, except as necessary for 
monitoring by CIRB, the FDA, the NINDS, the OHRP, the sponsor, or the sponsor’s designee. 
 
12.3. Study Modification/Discontinuation 
The study may be modified or discontinued at any time by the CIRB, the NINDS, the sponsor, the 
OHRP, the FDA, or other government agencies as part of their duties to ensure that research 
subjects are protected. 
13. PUBLICATION OF RESEARCH FINDINGS 
Publication of the results of this trial will be governed by the policies of the NeuroNEXT Network 
and procedures developed by the NeuroNEXT Data Sharing and Publication Committee.  Any 
presentation, abstract, or manuscript will be made available for review by the sponsor and the 
NINDS prior to submission. 
 
14. REFERENCES 
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Smith AG. Impaired glucose tolerance and metabolic syndrome in idiopathic 
neuropathy. Journal of the Peripheral nervous system: JPNS. 2012 May;17 Suppl 
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Smith AG, Singleton JR. The diagnostic yield of a standardized approach to idiopathic 
sensory-predominant neuropathy. Arch. Intern. Med. 2004 May 10;164(9):1021–5.  
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Singleton JR, Smith AG, Bromberg MB. Painful sensory polyneuropathy associated 
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Ziegler D, Rathmann W, Dickhaus T, Meisinger C, Mielck A, KORA Study Group. 
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Smith AG, Singleton JR. Obesity and hyperlipidemia are risk factors for early diabetic 
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Vincent AM, Hinder LM, Pop-Busui R, Feldman EL. Hyperlipidemia: a new 
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15. Appendix A  
Schedule of Assessments:  Topiramate as a Disease Modifying Therapy for CSPN 
Tests and Evaluations1 
Screening  
Baseline 
W16 
W32 
W48 
W64 
W80 
W96 
Safety 
Assessment 
Early 
Termination 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
ET 
Telephone Calls 2 
 
X²  
X² 
X² 
X² 
X² 
X² 
 
 
 
Informed Consent 
X 
  
  
  
  
  
  
  
  
  
Inclusion/exclusion criteria 
X 
X 
  
  
  
  
  
  
  
  
Medical History 
X 
  
  
  
  
  
  
  
  
  
Complete Physical Examination 
X 
  
  
  
  
  
  
 X 
X  
 X 
Abbreviation physical Examination 
(including visual field and fall risk 
assessment) 
  
X 
X 
X 
X 
X 
X 
 
 
 
Interval Medical History 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs (including height3, weight, and 
BMI) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Waist Circumference 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Nerve Conduction Studies 
 
X  
  
X 
  
X 
  
X 
  
X 
Distal Thigh Skin Biopsy 
  
X 
  
X 
  
X 
  
X 
  
X 
Topiramate Level 
 
X 
 
X 
 
X 
 
X 
 
X 
Serum B12 and immunofixation 
X 
 
 
 
 
 
 
 
 
 
Fasting glucose4, insulin, and lipid panel, 
and hemoglobin A1c 
X 
  
  
X 
  
X 
  
X 
  
X 
2-HR oral glucose tolerance test 
X 
  
  
X 
  
X 
  
X 
  
X 
Basic metabolic panel and complete blood 
count 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum pregnancy test 
X 
  
X 
X 
X 
X 
X 
  
  
  
                                                 
1 Baseline visit will occur within 30 days of screening. All follow-up visits must occur within ± 7 days. 
2 Study coordinators will call each subject at least once per month to encourage participation and minimize dropout risk. 
3 Height at screening visit only. 
4 Fasting glucose is the pre-glucola/dextrose sample for the OGTT (gray top). 

 
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Urine pregnancy test 
  
X 
  
  
  
  
  
  
  
  
Functional and mobility testing (6MWT, 
TUG, ABC Scale) 
  
X 
  
X 
  
X 
  
X 
  
X 
Randomization 
  
X 
  
  
  
  
  
  
  
  
Study drug dispensing 
  
X 
X 
X 
X 
X 
X 
  
  
  
Study drug reconciliation 
  
  
X 
X 
X 
X 
X 
X 
  
X  
Neuropathy symptom scales (NTSS-6, BPI-
DN) 
  
X 
X 
X 
X 
X 
X 
X 
 
X 
NQOL-DN 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
UENS 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
C-SSRS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
RAPA 
 
X 
 
X 
 
X 
 
X 
 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse event review 
 X5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECG 
X 
 
 
 
 
 
 
 
 
 
DNA sample 
  
X 
  
  
  
  
  
  
  
  
 
 
 
                                                 
5 AEs to be collected at screening only for events related to study procedures (e.g., skin biopsy)