Clinical trial NCT02607254
Conditions: Idiopathic Small Fiber Neuropathy
Sponsor: Johns Hopkins University
Start date: 2015-09-01; Completion date: 2018-07-01
Enrollment: 11 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to assess safety and efficacy of treatment with pregabalin in patients with idiopathic small fiber neuropathy proven by skin biopsy.This is an enriched enrollment randomized withdrawal study that comprises 4 phases: a screening and selection phase, a washout period from previous pain medication for enriched enrollment, an 8 week single blind pregabalin treatment phase; and a 4 week randomized withdrawal phase.

Detailed description:
Patients who show any increase in their pain intensity score during the washout phase will be eligible for the single blind pregabalin treatment phase. Patients who respond to pregabalin, with at least 1 point improvement in neuropathic pain from baseline at the end of the single blind pregabalin treatment phase and meeting all other study requirements are considered eligible for participation in the withdrawal phase. These eligible patients are randomly assigned (1:1) to continue pregabalin or to be switched to placebo for a comparison of pregabalin efficacy and safety. Patients who have a worsening of average pain relative to the last week of the single blind pregabalin treatment period by more than one point and average pain level \> =4 will be considered to have a loss of therapeutic response (LTR).

Arms: arm 1: All patients will be initially treated with pregabalin in a single blind fashion arm 2: After finishing the treatment phase, some patients will be randomized to the placebo or continue on pregabalin for the 4 weeks of withdrawal phase.
Interventions: intervention 1: Pregabalin intervention 2: Placebo
Intervention descriptions: intervention 1: Pregabalin will be given to the patients, starting at 75 mg BID and increased weekly to reach 225 mg BID for 8 weeks. During withdrawal phase, dose of pregabalin will be kept the same for patients who are randomized to the pregabalin withdrawal group. intervention 2: Placebo will be given to the patients that are randomized to placebo during withdrawal phase.

Protocol documents:
Prot_SAP_000.pdf: 
 
TITLE: Efficacy and Safety of Pregabalin in Treatment of Neuropathic Pain in Patients with Idiopathic 
Small Fiber Neuropathy 
 
NCT02607254 
 
PI: Mohammad Khoshnoodi, M.D 
 
Date: February 20, 2017 
 
 
 


2 | P a g e  
 
Contents 
 
1. INTRODUCTION ...............................................................................................................................5 
1.1. Indication .......................................................................................................................................... 5 
1.2. Background and Rationale ................................................................................................................. 5 
2. STUDY OBJECTIVES AND ENDPOINTS .....................................................................................8 
2.1. Objectives ......................................................................................................................................... 8 
2.2. Endpoints .......................................................................................................................................... 8 
3. STUDY DESIGN .................................................................................................................................9 
4. SUBJECT SELECTION ..................................................................................................................10 
4.1. Inclusion Criteria ............................................................................................................................ 10 
4.2. Exclusion Criteria .......................................................................................................................... 11 
4.3. Randomization Criteria ................................................................................................................. 13 
4.4. Life Style Guidelines ..................................................................................................................... 13 
5. STUDY TREATMENTS ...................................................................................................................13 
5.1. Allocation to Treatment ................................................................................................................ 15 
5.2. Breaking the Blind ......................................................................................................................... 15 
5.3. Drug Supplies ................................................................................................................................ 15 
5.3.1. Formulation and Packaging .................................................................................................. 15 
5.3.2. Preparation and Dispensing ................................................................................................. 16 
6. STUDY PROCEDURES ..................................................................................................................21 
6.2. Treatment Phase .......................................................................................................................... 22 
6.2.1. Visit 2 – Clinic Visit ................................................................................................................ 22 
6.2.6. Visits 7 (at Weeks 14) – Clinic Visits .................................................................................. 24 
6.3. Subject Withdrawal ....................................................................................................................... 24 
7. ASSESSMENTS ...............................................................................................................................25 
7.1. Intra-epidermal Nerve Fiber (IENF) Biopsy ............................................................................... 25 
7.2. Efficacy Assessments ................................................................................................................... 25 
7.2.1. Daily IVRS Diary ..................................................................................................................... 25 
7.3. Other Assessments....................................................................................................................... 26 
7.3.1. Small Fiber Neuropathy – Symptom Inventory Questionnaire (SFN-SIQ) .................... 26 


3 | P a g e  
 
7.3.2. Brief Pain Inventory-Short Form (BPI-sf) ........................................................................... 27 
7.3.3. Sleep Score from the Daily Sleep Diary (NRS-Sleep) ..................................................... 27 
7.3.4. Patient Global Impression of Change (PGIC) ................................................................... 27 
7.3.5. EuroQol-5D (EQ-5D) ............................................................................................................ 27 
7.4. Safety Assessments ..................................................................................................................... 28 
7.4.1. Laboratory Assessments ...................................................................................................... 28 
7.4.2. Physical and Neurological Examination ............................................................................. 29 
7.4.3. Neurological Examination ..................................................................................................... 30 
7.4.4. Vital Signs ............................................................................................................................... 31 
7.5. Suicidality Assessment ................................................................................................................. 31 
7.5.1. Patient Health Questionnaire-8 (PHQ) ............................................................................... 31 
7.5.2. Columbia Suicidal Severity Rating Scale(C-SSRS) ......................................................... 31 
8. ADVERSE EVENT REPORTING ..................................................................................................32 
8.1. Adverse Events ............................................................................................................................. 32 
8.2. Reporting Period ........................................................................................................................... 32 
8.3. Definition of an Adverse Event .................................................................................................... 32 
8.4. Abnormal Test Findings ............................................................................................................... 33 
8.5. Serious Adverse Events ............................................................................................................... 33 
8.5.1. Potential Cases of Drug-Induced Liver Injury .................................................................... 34 
8.6. Hospitalization ............................................................................................................................... 34 
8.7. Severity Assessment .................................................................................................................... 36 
8.8. Causality Assessment .................................................................................................................. 36 
8.9. Withdrawal Due to Adverse Events ............................................................................................ 36 
8.10. Eliciting Adverse Event Information ......................................................................................... 36 
8.11. Reporting Requirements ............................................................................................................ 37 
8.11.1. Serious Adverse Event Reporting Requirements ........................................................... 37 
8.11.2. Non-Serious Adverse Event Reporting Requirements ................................................... 37 
8.11.3. Sponsor Reporting Requirements to Regulatory Authorities ........................................ 37 
9. DATA ANALYSIS/STATISTICAL METHODS ............................................................................37 
9.1. Sample Size Determination ......................................................................................................... 37 
9.1.1. Analysis of Primary Endpoint ............................................................................................... 38 
9.1.2. Analysis of Secondary Endpoints ........................................................................................ 38 


4 | P a g e  
 
9.2. Safety Analysis .............................................................................................................................. 38 
10. QUALITY CONTROL AND QUALITY ASSURANCE ..............................................................38 
11. DATA HANDLING AND RECORD KEEPING ..........................................................................38 
11.1. Case Report Forms/Electronic Data Record .......................................................................... 38 
11.2. Record Retention ........................................................................................................................ 39 
12. ETHICS ............................................................................................................................................39 
12.1. Institutional Review Board (IRB) ............................................................................................... 39 
12.2. Ethical Conduct of the Study ..................................................................................................... 39 
12.3. Subject Information and Consent ............................................................................................. 39 
13. DEFINITION OF END OF TRIAL .................................................................................................40 
14. SPONSOR DISCONTINUATION CRITERIA .............................................................................40 
15. PUBLICATION OF STUDY RESULTS .......................................................................................40 
16. REFERENCES ................................................................................................................................40 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


5 | P a g e  
 
1. INTRODUCTION 
1.1. Indication 
The purpose of this study is to assess safety and efficacy of treatment with pregabalin in 
patients with idiopathic small fiber neuropathy proven by skin biopsy. 
1.2. Background and Rationale 
Pregabalin is an alpha-2-delta (a2d) ligand that has analgesic, anxiolytic, and anticonvulsant 
activity.  It has demonstrated anti-nociceptive activity in animal models of neuropathic pain and 
in patients with painful diabetic painful neuropathy (DPN),post-herpetic neuralgia (PHN), and 
fibromyalgia.  Pregabalin (Lyrica) is approved for the treatment of neuropathic pain in the 
European Union and Canada, and for the management of neuropathic pain associated with 
DPN and PHN in the United States and South Africa.  Pregabalin has been shown to be an 
effective treatment for other indications, including generalized anxiety disorder, and central 
neuropathic pain associated with spinal cord injury. 
Small fiber neuropathy is a sub-type of sensory neuropathies that predominantly affects the 
small unmyelinated fibers. Small fiber neuropathy has been defined as “peripheral neuropathy 
manifest by paresthesias with findings of small-fiber dysfunction on neurologic examination”[1]. 
Paresthesia is often painful in these patients and signs of involvement of large fibers are absent 
or minimal. Patients typically present with positive sensory symptoms, including tingling, 
burning, shooting pain, or aching. The pain is often worse at night and may interfere with sleep. 
Patients may also have negative symptoms, including numbness, feeling of tightness around 
the feet, and coldness. Symptoms are usually distal and length-dependent [2]. The exam 
findings often include a reduction in sensitivity to pain and temperature along with normal 
strength, proprioception, and tendon reflexes.   
Diagnostic electrophysiologic studies are often performed in patients with suspected small fiber 
neuropathy to rule out the presence of large fiber neuropathy. The routine nerve conduction 
studies are often normal [3]. Skin biopsy with quantification of epidermal nerve fibers and sweat 
glands is an effective way to diagnose small fiber neuropathy[4].Quantitation of epidermal nerve 
fibers has a positive predictive value of 75% and a negative predictive value of 90%, with a 
diagnostic efficiency of 88% for patients with sensory neuropathies[5].The sensitivity (74–90%) 
and specificity (64–90%) of skin biopsy for diagnosis of small fiber neuropathy is 
high[6].Therefore, consensus guidelines have recommended skin biopsy as preferred method to 
establish diagnosis of small fiber neuropathy[7]. IENFD is an unbiased pathological measure of 
c-fiber nociceptors that is increasingly used as an outcome measure in human clinical trials. 
These fibers express TRPV1 and therefore are important in pain perception and painless 
injuries. In cross sectional studies IENFD is reduced in many neuropathic populations including 
people with HIV infection, diabetes, Fabry disease and genetic amyloid. In some instances 
morphological changes of nerve fibers such as large swellings have been associated with 
subsequent nerve fiber loss. Decreases or loss of IENFD has been correlated with increases in 
heat pain and cold thresholds. IENFD correlates with unmyelinated nerve fiber counts derived 
from electron microscopy studies of sural nerve biopsies and led to an editorial in Neurology 


6 | P a g e  
 
that concluded that skin biopsies should replace sural nerve biopsies in patients with normal 
nerve conduction test results. Epidermal nerve fibers are affected early in the course of most 
peripheral neuropathies compared to large myelinated nerve fibers. This is postulated to 
represent the increased metabolic demands that small unmyelinated nerve fibers are under to 
maintain a membrane potential. Thus a reduction in IENFD is often the only objective evidence 
of neuropathy in patients with early HIV-associated sensory neuropathy or early diabetic 
neuropathy.  IENFD also offers a confirmatory documentation that a patient with painful feet 
actually has a peripheral neuropathy and not another condition that could mimic neuropathy.  
Skin biopsy has been instrumental in defining a population of patients with painful peripheral 
neuropathy and relatively normal examinations and no known etiology for their neuropathy. 
Such patients are often labeled as having idiopathic small fiber neuropathy and typically 
complain of numbness, burning pain, paresthesias, or allodynia in the feet, usually with 
cutaneous sensory loss but with an otherwise normal neurologic examination. Small fiber 
neuropathy remains idiopathic in large number of patients despite extensive laboratory testing, 
especially in adults over 60 years old[8]. Diabetes, impaired glucose tolerance test, alcohol, 
Sjogren syndrome, medications, toxins, HIV infection, amyloidosis, Tangier disease, and 
Fabry’s disease are among identifiable causes of small fiber neuropathy. The incidence and 
prevalence of small fiber neuropathy is not well known. One study from Netherlands suggested 
an overall minimum incidence over of 11.73 cases/100,000/year and an overall minimum 
prevalence of 52.95 cases/100,000 [9].  
Small fiber neuropathy has been shown to have a detrimental effect on quality of life and to be a 
major source of disability [10]. Bakkers et al reported that idiopathic small fiber neuropathy can 
be as disabling as neuropathy caused by diabetes mellitus or other forms of small fiber 
neuropathy with an identifiable cause. Patients with small fiber neuropathy have ongoing, 
sometimes excruciating pain and experience continuous difficulty dealing with the 
consequences of their illness, causing severe reduction in all aspects of quality of life. A study of 
100 patients diagnosed with idiopathic small fiber neuropathy showed that these patients 
experience moderate to severe pain, which negatively impacts health status, function, and 
productivity, and leads to substantial direct and indirect costs [11]. 
Treatment of idiopathic small fiber neuropathy is mostly symptomatic. Unfortunately, there is no 
direct evidence for treating idiopathic small fiber neuropathy and most of the medications 
currently used are based on the assumption that evidence from small fiber neuropathy due to 
diabetes, HIV or other causes can be generalized to idiopathic cases [12]. However, studies in 
the past have shown that this generalization is not always successful, as we learned that some 
medications that are useful in diabetic induced small fiber neuropathy are not that effective for 
cases caused by HIV infection [13].  
Pregabalin has been used for treatment of painful small fiber neuropathy caused by diabetes. 
Multiple studies have shown safety and efficacy of pregabalin in controlling pain in patients with 
diabetic neuropathy. However, very few of these studies have patients with skin biopsy proven 
small fiber neuropathy. In a study of 157 patients with neuropathic pain from various etiologies 
(diabetes, HIV, post-trauma, etc), Gilron et al used an enriched enrollment protocol [14, 15] to 


7 | P a g e  
 
study the effect of pregabalin on pain score and reported a modest but significant effect. Only 8 
patients in their treatment group had idiopathic small fiber neuropathy and they did not use skin 
biopsy to confirm the diagnosis [16]. In a double-blinded randomized control trial of pregabalin in 
HIV-induced painful small fiber neuropathy, pregabalin was well tolerated but was not superior 
to placebo in pain control [17]. In a meta-analysis of 11 randomized controlled trial of pregabalin 
in treatment of neuropathic pain in elderly patients, the drug was shown to be effective and safe 
with dizziness, somnolence, peripheral edema, asthenia, dry mouth, weight gain, and infections 
being most common side effects [18]. However, they did not report the number of patients with 
idiopathic small fiber neuropathy. 
Since idiopathic small fiber neuropathy is a relatively common and disabling disorder, there is a 
need to develop treatment strategies and identify medications that can ameliorate pain, improve 
function and quality of life. Currently, there is no evidence regarding best treatment options for 
idiopathic small fiber neuropathy. Additionally, most of the studies that have examined the 
efficacy of various treatment options including Pregabalin on neuropathic pain did not use an 
objective and quantitative measure of small fiber neuropathy such as skin biopsy to select their 
study subjects. This might create a dilutional effect on the efficacy measures since some of the 
included subjects might have pain that is not originated from a neuropathic process. Since 
pregabalin has been shown to be a cost effective treatment for some types of small fiber 
neuropathy such as diabetic neuropathy [19] and improves quality of life [20], it would be a 
valuable therapeutic option for idiopathic small fiber neuropathy if proven effective. However, 
there is no study directly examining the effect of pregabalin on idiopathic, skin biopsy proven 
small fiber neuropathy. Therefore, we aim to study the effect of pregabalin on pain control 
specifically in a group of patients with idiopathic small fiber neuropathy proven by skin biopsy in 
a partially enriched enrollment plan. This design would allow us to improve upon previous 
studies in several aspects. Using skin biopsy as inclusion criteria would prevent recruitment of 
patients that might have non-neuropathic pain and therefore confound the data. Using a partial 
enrichment plan would help us to exclude patients who are non-respondent to treatment and 
increase the power of study.   
Enriched enrollment with randomized withdrawal design is recommended by The Initiative on 
Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT), comprising experts 
in the design and evaluation of treatments for chronic pain, in efficacy studies (Dworkin, et al 
2010). Patients exhibiting a response to treatment for neuropathic pain defined as a 30% or 
greater reduction in neuropathic pain from baseline (and mean NRS pain intensity <=7) will be 
randomized in this study if they have met all inclusion and no exclusion criteria.  The 30% pain 
reduction criteria is consistent with publications which characterize this as substantial 
improvement in pain (Dworkin et al, 2008; Farrar, et al 2001) and with evidence that enrichment 
based on this response criteria is consistent with good assay sensitivity in a neuropathic pain 
population (Hewitt 2011).  Durability of effect (ie, time to efficacy failure) will be assessed in the 
randomized withdrawal phase of the study by using the time to efficacy failure definition of the 
first 3 days of at least 30% increase in pain intensity relative to final maintenance week of single 
blind treatment phase and mean 24 hour pain intensity level >4.0 (or discontinuation due to lack 
of efficacy).  


8 | P a g e  
 
The safety and tolerability of pregabalin has been examined several clinical studies.  Pregabalin 
has been or is currently being investigated in over 102 clinical controlled and uncontrolled 
Phase 2/3 studies.  These studies have been conducted in 3 different therapy areas: pain, 
epilepsy, and psychiatric indications (anxiety disorders and acute mania). In the controlled 
studies, doses of 50 to 600 mg/day of pregabalin administered in 2 or 3 divided doses per day 
were evaluated for efficacy and safety. The most common adverse events reported are 
dizziness (30%), somnolence (18%), headache (12%), and weight increase (10%).   
2. STUDY OBJECTIVES AND ENDPOINTS 
2.1. Objectives 
Primary Objective:  
To evaluate the efficacy of pregabalin (150-600 mg/day, flexibly administered BID) compared 
with placebo for the treatment of pain associated with idiopathic distal symmetrical small fiber 
peripheral neuropathy. 
Secondary Objectives:  
1. To evaluate the efficacy of pregabalin compared with placebo on  global assessment of 
treatment ; 
2. To evaluate the efficacy of pregabalin compared with placebo on  quality of life ; 
3. To explore the relationship between proteomics and lipidomics profile and treatment 
response; 
4. To explore the relationship between metabolite profile and treatment response;  
5. To assess the safety and tolerability of pregabalin.  
2.2. Endpoints 
Primary Efficacy Endpoint  
Mean endpoint 24-h average pain intensity based on pain intensity scores after 12 weeks 
maintenance treatment phase. 
Secondary Measures and Efficacy Endpoints 
1. Brief Pain Inventory (BPI-sf); 
2. Daily Sleep Interference Rating Scale (SIRS);  
3. Patient Global Impression of Change (PGIC); 
4. EuroQoL 5-Dimensions (EQ-5D);  
5. Small Fiber Neuropathy Symptom Inventory Questionnaire (SFN-SIQ); 


9 | P a g e  
 
6. Proteomics, lipidomics and metabolite exploratory analysis for treatment response. 
Safety and other Diagnostic Assessments 
 
Adverse events monitoring; 
 
Physical exam/Neurological exam; 
 
Vital signs; 
 
Suicidality Assessment (C-SSRS). 
3. STUDY DESIGN 
This enriched enrollment randomized withdrawal study comprises 4 phases: a screening and 
selection phase, a 2-4 weeks washout period from previous pain medication for enriched 
enrollment, an 8 week single-blind pregabalin treatment phase; and a 4 week randomized 
withdrawal phase. Patients who show any increase in their pain intensity score during the 
washout phase will be eligible for the single blind pregabalin treatment phase. Patients who 
respond to pregabalin, with at least 1 point improvement in neuropathic pain from baseline at 
the end of the single-blind pregabalin treatment phase and meeting all other study requirements 
are considered eligible for participation in the withdrawal phase.  These eligible patients are 
randomly assigned (1:1) to continue pregabalin or to be switched to placebo for a comparison of 
pregabalin efficacy and safety. Patients who have a worsening of average pain relative to the 
last week of the single blind pregabalin treatment period by more than one point and average 
pain level > =4 will be considered to have a loss of therapeutic response (LTR). 
 
 
 
Pregabalin SB Treatment 
 
150-600 mg/day* 
Matching Placebo 
Pregabalin (at optimized dose) 
Withdrawal Phase 
(4 weeks Fixed Dose)
Single Blind Phase  
8 Weeks 
 
(Dose Optimization 4 
wks; fixed dose 4 wks) 
 Washout 
period 
 
Primary Endpoint:  
 
Taper 
1 wk 
Week 
1 
2 
3 
4 
5 
10 
 
14 
6 
1 
2 
3 
4 
8 
 
12 
*Low creatinine clearance patients: 150-300 mg/day
-1 
Visit 
Randomize Lyrica 
Responders (30% 
Pain Response) and 
mean  pain level <7.0 


10 | P a g e  
 
4. SUBJECT SELECTION 
This study can fulfill its objectives only if appropriate subjects are enrolled.  The following 
eligibility criteria are designed to select subjects for whom protocol treatment is considered 
appropriate.  All relevant medical and non-medical conditions should be taken into consideration 
when deciding whether this protocol is suitable for a particular subject.  
4.1. Inclusion Criteria 
Subject eligibility should be reviewed and documented by an appropriately qualified member of 
the investigator’s study team before subjects are included in the study. 
Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the 
study: 
1. Evidence of a personally signed and dated informed consent document indicating that 
the subject (or a legal representative) has been informed of all pertinent aspects of the 
study; 
2. Subjects who are willing and able to comply with scheduled visits, treatment plan, 
laboratory tests, and other study procedures and are able to read and participate in all 
study assessments; 
3. Subjects with idiopathic predominate-small fiber neuropathic pain based on medical 
history, neurological examination, and punch biopsy results. Diagnosis of small fiber 
neuropathy is based on presence of at least 2 of the following symptoms, one of the 
following signs and abnormalities in skin biopsy consistent with small fiber neuropathy. 
Idiopathic small fiber neuropathy is defined as ruling out presence of diabetes, HIV 
infection and other conditions listed in exclusion criteria;  
a.  Symptoms:  
 
Burning pain in feet   
 
Numbness  
 
Tingling (pins and needles)  
 
Hypersensitive to touch, heat, or cold 
 
b. Signs 
 
Allodynia (mechanical brush) 
 
Diminished perception of pain with pinprick  
 
Hyperalgesia to pin prick 
 
Diminished temperature sensation (cold or heat) 


11 | P a g e  
 
4. Subject must have chronic peripheral neuropathic pain consistent with predominately 
small fiber neuropathy. Pain history indicates that pain started in the feet or legs and has 
been present for more than 3 months; 
5. A score >3  and <8 on Pain intensity scale for pain in prior week at first visit;  
6. Show increase in pain intensity scores during the 2 weeks of wash off period; 
7. Age older than 18 years; 
4.2. Exclusion Criteria 
Subjects presenting with any of the following will not be included in the study:   
1. Subjects with large-fiber predominant neuropathy defined as sural SNAP amplitude 
less than 6 µv or Peroneal CMPA recorded at EDB of less than 1 mV; 
2. Subjects with peripheral neuropathic pain secondary to specific etiologies including  
HIV infection, trigeminal neuralgia (TGN), carpal tunnel syndrome (CTS), toxic 
neuropathy 
(e.g. 
chemotherapy 
exposure), 
paraneoplastic 
neuropathy, 
monogamopathy, inflammatory neuropathy, celiac disease, systemic lupus, peripheral 
vascular disease, connective tissue disorders, hepatitis C, Fabry disease, and 
diabetes;   
3. Subjects with uncontrolled thyroid or B12 disorders (subjects with a history of thyroid 
or B12 disorders currently taking replacement therapy with normal screening values 
are allowed);  
4. Subjects with pain due to Complex Regional Pain Syndrome (CRPS, Type I or 
Type II);  
 
5. Subjects with skin conditions in the affected area that in the judgment of the 
investigator could interfere with evaluation of neuropathic pain condition; 
 
6. Pain that is not present in both feet/legs (ie, pain is not bilateral); 
 
7. Patients with only negative symptoms defined as numbness without clear evidence of 
spontaneous pain either constant or episodic; 
 
8. Subjects with pain that is not present every day (chronic) or where pain description 
does not have a classic stocking distribution per the clinical assessment with clinician 
(pain may vary in severity during the day); 
 
9. Subjects with other pain that may confound assessment or self-evaluation of the 
peripheral neuropathic pain such as back pain, radicular pain, and fibromyalgia; 
 
 


12 | P a g e  
 
10. Subjects who have failed pregabalin treatment due to lack of efficacy with an adequate 
course of therapy (doses greater than 150 mg/day for at least 4 week), have 
hypersensitivity or intolerance to pregabalin or gabapentin, or participated in a 
pregabalin clinical trial at any time.  Subjects that have failed to respond to more than 
3 drug treatment trials of adequate dose/duration; 
 
11. Any subject considered at risk of suicide or self-harm based on investigator judgment 
and/or the details of a risk assessment; 
 
12. Use of prohibited medications in the absence of appropriate washout periods; 
 
13. Subjects with any clinically unstable cardiovascular (including a myocardial infarction 
in the 3 months prior to Visit 1), hematological, autoimmune, endocrine, renal, hepatic 
(including chronic hepatitis B, hepatitis B within the past 3 months or ALT or AST > 3X 
ULN), respiratory, or gastrointestinal disease; epilepsy, symptomatic peripheral 
vascular disease including intermittent claudication, pernicious anemia, untreated 
hypothyroidism, venous insufficiency, spinal stenosis, or HIV infection; 
 
14. Other severe acute or chronic medical or psychiatric condition or laboratory 
abnormality that may increase the risk associated with study participation or 
investigational product administration or may interfere with compliance or the 
interpretation of study results and, in the judgment of the investigator, would make the 
subject inappropriate for entry into this study;  
  
15. Subjects who have had a diagnosis of malignancy other than basal cell carcinoma or 
carcinoma in situ of the cervix within the past 5 years;  
 
16. Subjects with creatinine clearance (CLcr) 60 mL/min (estimated prior to Visit 2 from 
serum creatinine obtained at Visit 1, body weight, age, and gender using the Cockcroft 
and Gault equation;; Subjects who have an estimated CLcr 60 mL/min by this 
screening method may have their CLcr measured, at the investigator’s discretion, with 
a 24-hour urine collection performed at the central laboratory.  If this 24-hour urine 
CLcr is >60 mL/min, the subject may be eligible.  Subjects on dialysis are not eligible; 
 
17. Subjects with a current  diagnosis (DSM-IV-TR) of current  major depression, history of 
bipolar diagnosis, or any diagnosis of a psychotic disorder;  
 
18. History of known analgesic or illicit drug abuse within 12 months of first visit; 
 
19. Patients that meet the DSM-IV criteria for alcohol abuse or dependence in the last two 
years; 
 
 


13 | P a g e  
 
20. Subjects with pending Worker’s Compensation, Worker’s Compensation, civil litigation 
or disability claims pertinent to the subject’s based upon trauma; current involvement 
in out-of-court settlements for claims pertinent to subject’s trauma;  
 
21. Participation in other interventional studies within 28 days before the current study 
begins and/or during study participation;  
 
22. Pregnant females; breastfeeding females. 
 
4.3. Randomization Criteria 
A list of allowed and disallowed concomitant pain medication is provided in sections 5.3.7 and 
5.3.8. If patients is on any of the disallowed pain medications, this medication will be 
discontinued during the washout phase with an appropriate taper schedule based on the 
clinician judgment. Subjects must meet the following criteria after the washout period to be 
randomized for single-blind pregabalin treatment phase: 
1.  Subjects must have worsening in neuropathic pain from baseline to the end of washout 
phase. 
2.  Subjects must have an average pain score <or = 8 in the final week of washout phase. 
Subjects must meet the following criteria after the single-blind pregabalin treatment phase to be 
randomized for withdrawal phase: 
1. Subjects must have response to treatment defined as at least one point decrease in pain 
intensity score at the end of the single-blind pregabalin treatment phase. 
 
4.4. Life Style Guidelines 
Subjects should not initiate or alter an exercise regimen during the study, as this could influence 
efficacy results based on the pain scale scores. 
Subjects should not modify stable medication regimens, and should not have surgery or 
interventional medical procedures for the duration of the study. 
Female patients at child bearing age must be informed that pregabalin is a category C 
medication for pregnancy which means that a risk cannot be ruled out and therefore use of an 
effective birth control method is recommended.  
5. STUDY TREATMENTS 
During the screening phase, the medication history of the subjects who are eligible for the study 
based on meeting the inclusion and exclusion criteria will be reviewed. The current pain 
medications of the subjects will be categorized into allowed and disallowed medications (see 
sections 5.3.7 and 5.3.8 for a complete list of these medications). If patient is on any of the 


14 | P a g e  
 
disallowed neuropathic pain medication such as gabapentin, these medications will be 
discontinued during the washout phase. A written instruction will be provided to the patient on 
how to discontinue the medication during the washout phase. Patient will complete a daily pain 
diary during this phase. Patient can continue to take the allowed pain medications but no 
change in dose or frequency is permitted. At the end of the washout period which is at least 14 
days and might be longer based on the type of medication being discontinued, patient will be 
evaluated for eligibility for the study again based on randomization criteria mentioned in section 
4.3. 
All patients entering the study will be treated with single-blind pregabalin at doses of 
150-600 mg/day for 8 weeks.  The first 4 weeks of the single-blind phase comprise the dose 
optimization phase, and the next 4 weeks the single blind maintenance phase.   
During the initial week of the single-blind pregabalin treatment phase, all patients will be treated 
with pregabalin 150 mg/day, and dose is to be increased based on response and tolerability 
until the end of Week 4.  If the patient is unable to tolerate the higher dose, the dose should be 
reduced by one dose level per investigator discretion.  This dose reduction may occur outside of 
the scheduled visit.  Patients unable to tolerate a dose of 150 mg/day pregabalin during the 
Single-Blind phase will discontinue from the study (no taper necessary).  After the end of the 4th 
week of the Single-Blind phase, no further dose escalation is permitted.  During the next 
4 weeks of the Single-Blind phase, fixed dose pregabalin treatment at the optimized dose within 
the range of 150 to 600 mg/day administered BID will be provided.  One additional dose 
reduction may occur if needed during the last 4 weeks of the single blind period.  Patients 
unable to tolerate the fixed dose of study medication will be discontinued from the study. 
Patients meeting all eligibility criteria for withdrawal phase will be randomized in a 1:1 fashion to 
continue the fixed dose of pregabalin treatment as they were taking in the Single-Blind phase or 
placebo. Patients will continue in the withdrawal portion of the study for 4 weeks. 
Patients who discontinue from the study during or at the end of the single-blind pregabalin 
treatment phase will complete a taper. Patients who had been receiving pregabalin 450 or 
600 mg/day will receive pregabalin 300 mg/day for 4 days and 150 for 3 days. Patients receiving 
pregabalin 150 or 300 mg/day will receive 150 mg/day for 4 days and 50 mg for 3 days. Patients 
who have not taken study medication for the past 24 hours or more are not required to receive 
the taper medication. 
At the end of the single-blind pregabalin treatment phase, patients will be randomized to receive 
either pregabalin at the optimized dose (150-600 mg/day pregabalin), as determined during the 
treatment phase, or matching placebo.  No further dose adjustments will be allowed.  
Patients randomized to pregabalin will continue at the optimized pregabalin dose  
Patients randomized to placebo who were receiving pregabalin 450-600 mg/day will be 
tapered to placebo to mask any changes in adverse events.  The taper will consist of pregabalin 
300 mg/day for 4 days and 150 mg/day for 3 days.  Subsequently these patients will receive 
placebo.  Placebo treatment will continue until end of withdrawal period.  
Patients randomized to placebo who were receiving 150-300 mg/day pregabalin will receive 
150 mg/day for 4 days and 50 mg/day for 3 days during the first week of the withdrawal phase, 
then which will continue through the end of withdrawal phase.   


15 | P a g e  
 
At any time during the study (single-blind pregabalin treatment or withdrawal), if the patient 
cannot tolerate a dose of 150 mg/day pregabalin (or matching placebo in withdrawal phase) the 
patient will discontinue from the study, with no taper necessary.  Patients experiencing 
inadequate pain relief should be assessed to determine whether the pain level is tolerable to 
complete the study or will need to be withdrawn due to lack of efficacy.  Subjects requiring 
dosing adjustment during the withdrawal phase will be discontinued.  
5.1. Allocation to Treatment 
Subjects will be assigned a single subject identification number (SSID. This number will be 
retained throughout the study.  A separate randomization number will be assigned by the 
experimental pharmacy at randomization and will be recorded on the case report form.   
Following the treatment phase, qualified patients will be randomized in a 1:1 ratio to receive 
either pregabalin at the optimized dose or placebo.   
5.2. Breaking the Blind 
The study drug and placebo will be identical in appearance in order to preserve the study 
blinding. The investigator will be aware of the subject’s treatment during the study but will not 
share this information with the subject.  Blinding should only be broken for serious, unexpected, 
and related adverse events, and only for the subject in question, or when required by local 
regulatory authorities.  Subjects whose randomization codes are broken in this way will be 
withdrawn from the study.  The investigator must record the reason for breaking the blind in the 
subject’s source documents.   
5.3. Drug Supplies 
5.3.1. Formulation and Packaging 
Study medication will be supplied as blinded capsules of pregabalin and matching placebo.  The 
pregabalin capsules are composed of pregabalin, lactose monohydrate, cornstarch, and talc 
encapsulated in opaque hard gelatin capsule shells composed of gelatin and titanium dioxide.  
The placebo capsules will contain lactose monohydrate, microcrystalline cellulose, sucrose 
octaacetate, and magnesium stearate.   


16 | P a g e  
 
STUDY DRUG 
Generic name: 
Pregabalin 
Trade name: 
Lyrica 
Dosage form: 
Capsules 
Strength: 
75 mg, 150 mg, 225 mg, 300 mg 
Manufacturer: 
Pfizer PPD, Freiburg, Germany 
Supplier: 
Pfizer Global Research Development 
Ingredients: 
Active: Pregabalin 
Inactive: Lactose monohydrate, corn starch, talc,  
gelatin, titanium dioxide, black iron oxide 
Description: 
Grey/Grey #0 capsules  
PLACEBO 
Dosage form: 
Capsules 
Manufacturer: 
Pfizer PPD, Freiburg, Germany 
Supplier: 
Pfizer Global Research Development 
Ingredients: 
Lactose monohydrate, microcrystalline cellulose, 
sucrose octaacetate, magnesium stearate, gelatin, 
titanium dioxide, black iron oxide 
Description: 
Grey/Grey #0 capsules identical in appearance to 
Pregabalin 
The active trial medication and the placebo will be of identical appearance, and packaged in 
identical bottles. 
5.3.2. Preparation and Dispensing 
Pfizer will provide the pharmacy at investigative site with sufficient amounts of study medication. 
Study medication will be supplied in non-subject-specific bottles.  Dispensing of study 
medication will be documented in the CRF and/or other study drug records including date of 
receipt and amounts dispensed to and returned by the study subjects.  The investigator is 
responsible for assuring the retrieval of all full, partially full and empty medication bottles from 
subjects. 
The pharmacy will administer/dispense the trial medication only to subjects included in this 
study following the procedures set out in the protocol. The investigator must maintain accurate 
and adequate records regarding shipments and dispensing of study medication.  
5.3.3. Administration 
Throughout the study, patients will be blinded to the treatment they are receiving.  After the 
washout period, patients who meet eligibility criteria will be randomized to receive pregabalin or 
matching placebo for the remainder of the study phase. Once a subject has been randomized, 
the subject will be blinded to the treatment assignment. 
During the single-blind pregabalin treatment and withdrawal phase patients will take 1 capsule 
twice daily.  The study medication will be administrated orally, BID, with or without food.  
Sufficient study medication will be provided to cover visit windows.   
Subjects should be instructed on use of the study medication.  When patients are dispensed 
multiple bottles of study medication, instruct the patient carefully regarding which bottle to use 


17 | P a g e  
 
and to take study medication from only one bottle at a time.  Dose adjustments may be made by 
telephone.  
Subjects should return medication bottles and any unused tablet(s) in each bottle to the site.  
Any dosing errors must be fully documented in source documentation and (if applicable) in the 
case report form.  Dosing errors that may impact subject safety will be discussed by the 
investigator and sponsor. 
Medication errors are reportable irrespective of the presence of an associated AE/SAE, 
including: 
Medication errors involving patient exposure to the product.  
Potential medication errors or uses outside of what is foreseen in the protocol that do or do not 
involve the participating subject. 
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error and, if applicable, any associated adverse event(s) is captured 
on an adverse event (AE) CRF page (refer to Adverse Event Reporting section for further 
details).   
5.3.4. Compliance 
Investigational product compliance will be assessed at each follow up clinic visit following.  Any 
deviations in compliance should be recorded and an explanation provided.  Study drug 
compliance is assessed using dosing compliance calculation: 
% Compliance = number of tablets taken/number of tablets expected to have taken ×100.  
The subject is non-compliant with dosing if the percentage compliance according to the above 
formula is less than 80% or greater than 120% study drug compliance.  
If the subject has not been compliant with the dosing/administration regimen at a given visit, the 
subject’s participation in the study should be re-evaluated. If the subject’s compliance is outside 
this range, this will be recorded as a protocol deviation. 
Compliance with daily pain and sleep diary completion will be assessed.  Subjects must 
complete at least 4 daily pain and sleep diaries over each consecutive 7-day period in the study.  
The completion of fewer than 8 daily pain and sleep diaries over the course of 14 days will be 
recorded as a protocol deviation.  If the subject has not been compliant with diary completion, 
the subject’s participation in the study should be re-evaluated.   
5.3.5. Drug Storage  
Dispensing of study medication will be documented in study drug records including date of 
receipt and amounts dispensed to and returned by study subjects.  All bottles (including empty 
bottles) must be returned to the investigator by the subject. 
The investigator must ensure that authorized personnel correctly receive deliveries of 
investigational product from the sponsor and that all receipts are recorded in writing.   


18 | P a g e  
 
Clinical drug supplies must be stored at 25C, with excursions permitted from 15C to 30C, 
under secure (locked) conditions. The investigator, or an approved representative, e.g. 
pharmacist, will ensure that all investigational products are stored in a secured area, under 
recommended storage conditions and in accordance with applicable regulatory requirements. 
5.3.6 Concomitant Medication(s) 
Medication taken within 30 days before the first dose of study medication (V1) and all 
medications taken after the first dose during the study will be documented in the subject’s 
medical record form and on the case report forms (CRF).  Drug history for medications used to 
treat neuropathy over the prior 5 years will also be collected.  All concomitant medications and 
non-pharmacological treatments must be recorded with respect to type, dosage, duration of use 
and reason for use.  In this study, subjects may remain on existing permitted pain medications 
provided that the dose and frequency of dosing does not change during the study period and 
that the subject has been on a stable dose for at least 30 days prior to Screening.  
Permitted medications for pain management include -the-counter medications such as aspirin, 
acetaminophen, and NSAIDS such as ibuprofen if used by the patient for a condition other than 
neuropathic pain.  Herbal and homeopathic remedies should not be initiated during the study; 
however, subjects who have taken a stable dose of these products for at least 30 days prior to 
the screening visit will be allowed to continue their regimen.  The sponsor should be consulted 
on a case by case basis in determining whether or not specific medications are permitted. 
Medications with activity at Alpha-2-delta binding site or sodium channels e.g. gabapentin, 
lamotrigine, carbamazapine, oxcarbazapine, mexiletine, amitryptiline, topical analgesics e.g. 
lidocaine patches, and oral/injectable corticosteroids are prohibited until the end of the study 
period and require a washout period prior to the Screening visit, and capsaisin patches for 90 
days prior to screening. Drugs with possible efficacy for neuropathic pain including opioids or 
other mu agonists including tramadol  and tapentadol, SNRI’s (eg, duloxetine) are disallowed. 
Patients should also be excluded that use marijuana either illicitly or prescribed.  
5.3.7. Allowed Medications 
The following medications are permitted as described below.  Medications listed must be taken 
for the indications specified, must be stable for the periods indicated prior to the first visit, and 
may not exceed the doses specified for subjects to be eligible for study participation.  Subjects 
who do not meet these criteria are excluded from participation in the study.  
Class of Medication 
Examples 
(not a comprehensive list) 
Minimum 
Period 
on 
Medication Prior to V1 


19 | P a g e  
 
Analgesics 
 
Acetaminophen 
Maximum 
dose 
of 
acetaminophen 
or 
any 
acetaminophen-containing 
products should not exceed 
3 grams/day 
 
NSAIDS, COX-2 inhibitors 
Patients using NSAIDS at the 
start of  the trial for conditions 
other than neuropathic pain 
may continue but should not 
change the pattern of use 
during the trial. NSAIDs may 
be 
initiated 
for 
acute 
conditions 
during 
the 
trial 
unrelated to neuropathic pain 
if clearly clinically necessary 
for the care of the patient.  
Aspirin 
For myocardial infarction and 
stroke prophylaxis 
 
Antidepressants 
Antidperessants 
other 
than 
TCAs and SNRIs 
Stable for one month prior to 
V1; 
therapy 
may 
not 
be 
initiated during the study. A 
maximum 
of 
one 
antidepressant may be used.  
 
Benzodiazepines 
Lorazepam  
Subjects must be on a stable 
regimen within the last month  
(only 
bedtime 
dose; 
prescription for sleep only).  
Therapy may not be initiated 
during the Single-Blind or 
Double-Blind Phase.  Long 
Life 
benzodiazepines(Diazepam) 
are not allowed. 
.  


20 | P a g e  
 
 
5.3.8. Disallowed Medications 
Certain concomitant medications must be discontinued during the washout.  These include but 
are not limited to those described below. 
Class of Medication 
Examples 
(not a comprehensive list) 
Washout Period 
PRN Local/topical agents 
for relief of PNeP 
Lidoderm patch or other 
local anesthetics, steroids, 
capsaicin, 
topical 
opioid 
analgesics 
 
At least 7 days prior to V1 or 
5 half-lives. 
 
Injections for relief of pain 
Local 
anesthetics 
and 
steroids 
 
At least 1 month prior to V1, 
and 
no 
injections 
over 
course of study 
 
Oral 
or 
injectable 
medications for diabetes 
Metformin,,Rosiglitazone, 
Exenatide (Byetta), 
Liraglutide  
 
N/A 
Antidepressants 
TCA's, amitriptyline, SNRI's 
>7 days 
anticonvulsants 
Gabapentin, 
carbamazepine, lamotrigine 
 > 7 days 
Antidepressants used for 
pain control 
SNRI’s 
(eg, 
duloxetine), 
TCAs (eg, amitriptyline) 
 
Oral/IV 
Corticosteroids 
(topical corticosteroids are 
allowed) 
dexamethasone, 
hydrocortisone 
, 
methylprednisolone, 
≥7 days 
 
GABAA partial agonists 
Zolpidem 
Eszopiclone  
Subjects must be on a stable 
regimen within the last month. 
Therapy may not be initiated 
during the Single-Blind or 
Double-Blind Phase.   
Antihistamines 
 
For 
allergy 
nonsedating 
antihistamines 
should 
be 


21 | P a g e  
 
5.3.9. Non Pharmacologic Treatment 
Non Pharmacologic treatments, including but not limited to, TENS unit, acupuncture, 
acupressure, therapeutic massage, are disallowed during the entire study.  
5.3.10. Rescue Therapy  
Subjects may remain on their stable allowed pain medications as specified in Section 0 
Acetaminophen doses of up to 3 g/day are allowed as rescue medication, and must be 
documented in the CRF.  
6. STUDY PROCEDURES  
6.1. Screening/Visit1 
This is the clinic visit during which a new patient is diagnosed with idiopathic small fiber 
neuropathy or a patient who has been diagnosed with idiopathic small fiber neuropathy from 
peripheral neuropathy registry has presented for follow up and is informed about the study.  
Informed consent procedures must be completed prior to initiating any study procedures during 
this visit. Visit 1 must occur between 14 days and 30 days prior to Visit 2, based on the amount 
of time required for screening procedures or washout period. The duration between Visits 1 and 
2 will typically be approximately 14-30 days.  A minimum 14 days is required to allow the 
washout phase. 
The following procedures are to be performed at Visit 1.  These procedures are not required to 
occur on the same day, but all results must be available by Visit 2.   
 
Informed consent 
 
Medical history, concomitant medications, prior treatments for neuropathy, any non-drug 
treatments, and adverse events will be reviewed.  
 
Weekly pain intensity score (1-week recall period) is completed by the patient  
 
Physical exam and neurological examination are performed, including height, weight 
heart rate and blood pressure   
 
SFN-SIQ 
 
BPI-sf 
 
EQ-5D 
 
Laboratory assessments are performed 
 
Columbia Suicidality Severity Rating Scale(C-SSRS) baseline and PHQ-8 are completed 
and reviewed  
 
Skin Biopsy if not performed previously 


22 | P a g e  
 
If the patient continues to meet entry criteria for the study following the completion of these 
procedures, the following will be completed: 
 
The patient will be instructed to complete a pain and sleep diary daily.  A sample diary is 
to be completed and IVRS procedures reviewed with the patient to ensure 
comprehension. 
 
Blood draw to collect sample for proteomics and lipidomics. 
 
The patient will be instructed how to discontinue the current disallowed pain medication 
and will be scheduled to come to the clinic for Visit 2.   
6.2. Treatment Phase 
6.2.1. Visit 2 – Clinic Visit 
 
Review concomitant treatments, adverse events, and any non-drug treatments.  
 
Review laboratory results and Visit 1 assessments for eligibility. 
 
Review daily pain and sleep diaries for compliance and eligibility.   
 
Perform the following assessments:   BPI-SF, SFN-SIQ and EQ-5D 
 
Review the study entry criteria to determine if the patient meets all inclusion and 
exclusion criteria (Section 4).  Patients not meeting eligibility criteria should not complete 
the other assessments listed for this visit and will not continue in the trial.  
For patients meeting study entry criteria, the following procedures will be performed: 
 
The patient will be reminded to continue completing daily pain and sleep IVRS diaries 
each evening.  
 
Study medication will be dispensed.  Blinding must be maintained with the patient.  If a 
supply is being dispensed to last through the next clinic visit (Visit 6/Week 4), instruct the 
patient regarding which bottle to use, and to take one capsule in the morning and once 
daily in the evening from a single bottle.  The patient will be instructed to begin dosing 
the following morning.   
 
Schedule a telephone Visit for Day 7.   
6.2.2. Visit 3 (Day 7) – Phone Visit 
If the subject is tolerating the study medication, this visit may be completed by phone.  At the 
investigator’s discretion (eg, to further assess an adverse event), this visit may instead be 
conducted in the clinic. 
The following will be completed at this visit: 
Review adverse events, the daily pain and sleep diary, concomitant medications, and non-drug 
treatments.  Remind the patient to continue completing diaries until the next scheduled visit. 


23 | P a g e  
 
Confirm that the patient is taking one study medication capsule twice daily from the correct 
bottle.  Determine and discuss the pregabalin dose level to be administered and provide 
instructions for dose administration.  This dose level should be taken at the next scheduled 
dose.  Blinding must be maintained with the patient.  
Schedule a phone visit for Visit 4 (Day 14).  
6.2.3. Visit 4 (Day 14) – Phone Visit 
If the subject is tolerating the study medication, this visit may be completed by phone. At the 
investigator’s discretion (eg, to further assess an adverse event), this visit may instead be 
conducted in the clinic. 
The following will be completed at this visit: 
Review adverse events, the daily pain and sleep diary, the dosing diary, concomitant 
medications, and non-drug treatments.  Confirm that the patient is taking one study medication 
capsule twice daily from the correct bottle.  Remind the patient to continue completing diaries 
until the next scheduled visit. 
Determine and discuss the pregabalin dose level to be administered and provide instructions for 
dose administration.  This dose level should be taken at the next scheduled dose.  Blinding 
must be maintained with the patient.  
Schedule a Phone visit for Visit 5 (Day 28).   
6.2.4. Visit 5 (Day 28) – Phone Visit 
If the subject is tolerating the study medication, this visit may be completed by phone. At the 
investigator’s discretion (eg, to further assess an adverse event), this visit may instead be 
conducted in the clinic. 
The following will be completed at this visit: 
Review adverse events, the daily pain and sleep diary, the dosing diary, concomitant 
medications, and non-drug treatments.  Confirm that the patient is taking one study medication 
capsule twice daily from the correct bottle.  Remind the patient to continue completing diaries 
until the next scheduled visit. 
Determine and discuss the pregabalin dose level to be administered and provide instructions for 
dose administration.  This dose level should be taken at the next scheduled dose.  Blinding 
must be maintained with the patient.  
Schedule a clinic visit for Visit 6 (Day 56).  Remind the patient to bring the study medication 
(used and unused packages) with them to the clinic visit.  
6.2.5. Visit 6 (Day 56) – Clinic Visit 
Review adverse events, the daily pain and sleep diary, the dosing diary, concomitant 
medications, and non-drug treatments.  Remind the patient to continue completing diaries until 
the next scheduled visit. 


24 | P a g e  
 
The C-SSRS will be completed by the patient and reviewed to determine if a risk assessment is 
required. 
Perform the following assessments:  NPSI, SFN-SIQ, BPI-SF, and EQ-5D 
Determine from the IVRS system whether the patient meets the pain improvement criterion to 
be randomized into the withdrawal Phase of the study. If the patient meets response criteria, the 
patient continues in the study and is to be randomized at this visit.  Blinding is to be maintained.  
6.2.5.1. Discontinuation 
 
Patients discontinuing from the study will complete a taper.  Dispense a bottle of taper 
medication to the patient and schedule a Follow-Up phone visit.  
    6.2.5.2. Randomization 
 
If the patient meets response criteria, the patient should not be informed that 
randomization will occur or that a treatment change may occur at this visit.  The following 
procedures are to be performed for patients  
 
Randomize the patient.  Dispense study medication and provide instructions for dose 
administration.  Instruct the patient as to study medication instructions, and to continue 
to take one capsule twice times daily as directed.  Remind the patient to bring the study 
medication (used and unused packages) with them to the next clinic visit. 
 
Remind the patient to continue completing diaries until the next scheduled visit. 
 
Schedule a clinic visit for Visit 7 (Week 14).  
6.2.6. Visits 7 (at Weeks 14) – Clinic Visits 
 
Review adverse events, the daily pain and sleep diary, the dosing diary, concomitant 
medications, and non-drug treatments.  Confirm that the patient is taking one study 
medication capsule twice daily.  Remind the patient to continue completing diaries daily.   
 
The C-SSRS will be completed by the patient and reviewed to determine if a risk 
assessment is required. 
 
Perform the following assessments:  SFN-SIQ questionnaire, BPI-SF, and EQ-5D 
 
Dispense a bottle of taper medication to the patient and provide instructions for dose 
administration.  
 
Schedule a follow-Up phone visit. 
6.3. Subject Withdrawal 
Subjects may withdraw from the study at any time at their own request, or they may be 
withdrawn at any time at the discretion of the investigator or sponsor for safety, behavioral, or 
administrative reasons.  If a subject does not return for a scheduled visit, every effort should be 
made to contact the subject.  In any circumstance, every effort should be made to document 


25 | P a g e  
 
subject outcome, if possible.  The investigator should inquire about the reason for withdrawal, 
request the subjects to return all unused investigational product(s), request the subjects to 
return for a final visit, if applicable and follow-up with the subject regarding any unresolved 
adverse events. 
If the subject withdraws from the study, and also withdraws consent for disclosure of future 
information, no further evaluations should be performed, and no additional data should be 
collected.  The investigator may retain and continue to use any data collected before such 
withdrawal of consent. 
7. ASSESSMENTS 
Every effort should be made to ensure that the protocol required tests and procedures are 
completed as described.  However it is anticipated that from time to time there may be 
circumstances, outside of the control of the investigator that may make it unfeasible to perform 
the test.  In these cases the investigator will take all steps necessary to ensure the safety and 
wellbeing of the subject.  When a protocol required test cannot performed the investigator will 
document the reason for this and any corrective and preventive actions which he/she has taken 
to ensure that normal processes are adhered to as soon as possible.  The study team will be 
informed of these incidents in a timely fashion. 
7.1. Intra-epidermal Nerve Fiber (IENF) Biopsy 
Skin biopsies will be obtained during the screening period. One 3-mm punch skin biopsy will be 
obtained from the distal-leg, approximately 10 cm proximal to the malleolus. And one biopsy 
from the proximal thigh (10 cm distal to the greater trochanter in the mid-axillary line. The biopsy 
sites will be prepped with alcohol and a subcutaneous wheel of 2% lidocaine with epinephrine 
will be subcutaneously injected using an insulin syringe for the purpose of anesthesia. Biopsies 
will be obtained at a depth of ~2 mm using disposable skin punches (Acuderm, Fort Lauderdale, 
FL). The tissue will be placed immediately into 2-3 ml of fixative for approximately 12-24 hours 
and then transferred to cryoprotectant solution. Samples will then be shipped overnight to the 
Johns Hopkins Cutaneous Nerve Laboratory. 
  
Hemostasis at the biopsy site may be accomplished by local pressure. In very rare instances, 
Gelfoam can be applied to the biopsy site in order to stop any bleeding. A sterile adhesive 
Band-Aid is placed over the biopsy site. The bandage should be replaced daily until a scab 
forms. An antibacterial cream, such as Neosporin should only be used if the subject has 
successfully used them before without any local irritation. It is normal for the biopsy site to 
develop mild erythema along the border of the incision though this typically does not extend 
more than 1-2mm. The biopsy site should never express puss. Infections are rare (about 1:500), 
and should be evaluated and treated on an individual basis. 
 
7.2. Efficacy Assessments 
7.2.1. Daily IVRS Diary 
The daily diary, comprising the daily pain NRS and the SIRS is to be completed daily by IVRS, 
every evening, from Visit 1 until study completion.   


26 | P a g e  
 
The daily diary assessments obtained via IVRS during the 7 days between Visit 1 and Visit 2 will 
be used to determine subject eligibility into the trial.  A minimum of 4 days of daily diaries 
between Visits 1 and 2 must be completed for a subject to be considered compliant.   
7.2.1.1. Primary Efficacy Parameter: Daily Pain  
The Daily Pain scores will be assessed on an 11-point numerical rating scale (NRS-Pain) 
ranging from 0 (no pain) to 10 (worst possible pain). Subjects are to describe their pain during 
the past 24 hours by choosing the appropriate number between 0 and 10. A rating of 1-3 is 
considered mild pain; 4-6, moderate pain; and 7-10, severe pain. The NRS-Pain is included in 
the subject electronic diary and self-assessment will be completed twice daily upon awakening 
and in the evening. Subjects will complete an NRS Pain assessment for 2 questions: Average 
pain and Current pain, for each day. Average pain and Current pain will be asked in the 
evening, and Current pain will also be asked in the morning upon awakening. Subjects should 
be trained to use the electronic diary during Visit 2 to confirm subjects are comfortable with the 
electronic diary and are familiar with the protocol anchors. The site should document in source 
notes that the subject was able to rate themselves with the electronic diary successfully in the 
clinic and agrees to complete all diary ratings at the 
times specified prior to being randomized. The NRS-Pain will be completed by daily diary (twice 
per day) starting at Visit 2 until the completion of the study. 
Daily IVRS diaries will be completed by the subject from the evening of Visit 1/Screening 
through Visit 10 /Termination.  
At Screening only, subjects will be asked to rate their “pain during the past week” on a similar 
11 point scale.  This will be completed on paper for screening only. 
7.2.1.2. Secondary Efficacy Assessment: Sleep Interference Rating Scale (SIRS) 
The Daily Sleep Interference Rating Scale (SIRS) consists of an 11-point NRS ranging from 0 
(“pain does not interfere with sleep”) to 10 ("pain completely interferes with sleep" [unable to 
sleep due to pain]).  Subjects describe how pain has interfered with their sleep during the past 
24 hours: 
Select the number that best describes how your neuropathic pain has interfered with your sleep 
during the past 24 hours on a scale from 0 to 10 where 0 represents ‘does not interfere with 
sleep’ and 10 represents ‘completely interferes which means you are unable to sleep due to 
pain. 
Daily IVRS diaries will be completed by the subject from the evening of Visit 1/Screening 
through Termination. 
7.3. Other Assessments 
7.3.1. Small Fiber Neuropathy – Symptom Inventory Questionnaire (SFN-SIQ) 
The SFN-SIQ has been developed specifically for evaluation of autonomic symptoms in SFN 
patients.  It includes 13 questions that address the following aspects: presence of palpitations, 


27 | P a g e  
 
flushes, constipation or diarrhea, urination problems (incontinence or hesitation), changes in 
sweating pattern, restless legs, orthostatic dizziness, dry eyes or mouth, oversensitivity and 
intolerance to sheets on legs and burning feet. Responses are graded as “never”, “sometimes”, 
“often” or “always”.   
 
7.3.2. Brief Pain Inventory-Short Form (BPI-sf) 
The Brief Pain Inventory-Short Form (BPI-sf) is a self-administered questionnaire developed to 
assess pain severity and pain interference with functional activities during a 24 hour period prior 
to evaluation. Four questions assess pain severity on an 11-point scale ranging from “no pain” 
(0) to “pain as bad as you can imagine” (10): worst pain in the past 24 hours, least pain in the 
past 24 hours, average pain in the past 24 hours and current pain (“right now”). Seven items 
assess pain interference with functional activities: general activity, mood, walking ability, normal 
work (includes both work outside the home and housework), relations with other people, sleep 
and enjoyment of life. These items are also measured on an 11-point scale, ranging from “does 
not interfere” (0) to “completely interferes” (10). The Brief Pain Inventory-Short Form will be 
completed by the subject at all scheduled face to face visits.  
7.3.3. Sleep Score from the Daily Sleep Diary (NRS-Sleep) 
Pain-related sleep interference will be assessed on an 11-point numerical rating scale 
(NRS Sleep) ranging from 0 (did not interfere with sleep) to 10 (completely interfered [unable to 
sleep due to pain]). Subjects are to describe how their pain has interfered with their sleep during 
the past 24 hours by choosing the appropriate number between 0 and 10. The NRS-Sleep is 
included in the subject electronic diary and self-assessment will be performed daily upon 
awakening from baseline to the end of the study.  
7.3.4. Patient Global Impression of Change (PGIC) 
The PGIC is a subject rated global measure that provides a clinically relevant and easy to 
interpret account of a patient’s perception of the clinical importance of their improvement or 
worsening during their involvement in a clinical study. Subjects rate their overall improvement 
on a 7-point scale where scores range from 1 (very much improved) to 7 (very much worse). 
The PGIC is recommended by the Initiative on Methods, Measurement, and Pain Assessment in 
Clinical Trials (IMMPACT) as a measure of “participant rating of global improvement and 
satisfaction with treatment.” It is one of six core outcomes measures recommended for use in 
clinical trials of chronic pain treatment efficacy and effectiveness. The PGIC will be completed 
by the subject at Visits 5 and 6.  Completion instructions for subjects will indicate that global 
improvement refers to the condition under study. 
7.3.5. EuroQol-5D (EQ-5D) 
The EQ-5D is a brief health status measure used in clinical and health economic appraisals 
(The EuroQol Group, 1990).  The EQ-5D comprises of 5 items that assess the level of difficulty 
(none, some, severe) subjects report in 5 health status domains:  mobility, self-care, usual 


28 | P a g e  
 
activities, pain/discomfort and anxiety/depression.  The EQ-5D also includes a visual analogue 
scale that rates the patient’s current perception of overall health status that is scored from 0 
(worst imaginable health state) to 100 (best imaginable health state).  It takes approximately 2-5 
minutes to complete.   
7.3.6. Proteomics, Lipidomics and Metabolomics analysis 
Proteomics and Lipidomics are large scale study of proteins and lipids in biological systems. 
These techniques are being extensively used to determine biomarkers of the disease, as well 
predictors of the response to treatment. Metabolomics is the scientific study of chemical 
processes involving metabolites. Specifically, metabolomics is the systematic study of the 
unique chemical fingerprints that specific cellular processes leave behind by studying their 
small-molecule metabolite profiles. The metabolome represents the collection of all metabolites 
in a biological cell, tissue, organ or organism, which are the end products of cellular processes. 
Thus, while proteomic analyses do not tell the whole story of what might be happening in a cell, 
metabolic profiling can give an instantaneous snapshot of the physiology of that cell. By using 
these methods, we hope to find biomarkers of idiopathic small fiber neuropathy, as well as 
predictors of response to treatment. 
7.4. Safety Assessments 
7.4.1. Laboratory Assessments 
 
Samples for laboratory testing will be analyzed by laboratory.  
 
Tests required at Visit 1 are: 
 
Hematology: hemoglobin, hematocrit, WBC count including differential (neutrophils, 
lymphocytes, monocytes, eosinophils, basophils), red blood cell (RBC) count, platelet 
count.  
 
Chemistry: amylase, aspartate aminotransferase (AST), alanine aminotransferase (ALT), 
albumin, alkaline phosphatase, blood urea nitrogen, creatinine, electrolytes (sodium, 
potassium, chloride, calcium), glucose, total protein, total bilirubin, uric acid,  
 
Fasting plasma glucose and HbA1C 
 
A standard 3-mm dermatologic punch biopsy for intraepidermal small fiber nerve  
assessment if not done previously 
 
Thyroid-stimulating hormone (TSH) with reflex T4 done if TSH abnormal,  
 
 B12/Folate. 
 
HIV Elisa (confirm with Western Blot if positive) 
 
Hep C Ab 
 
SED rate (ESR) 
 
RPR or similar test for syphillis 


29 | P a g e  
 
 
CLcr will be estimated from creatinine at baseline using the Cockcroft and Gault 
equation: 
CLcr= [[140-age (years)] x weight (kg)]   (x 0.85 for female patients) 
 [72 x Serum creatinine (mg/dl)] 
SI Units: 
CLcr=[1.23 x [140-age (years)] x weight (kg)]   (x 0.85 for female patients) 
Serum creatinine (µmoles/l) 
 
Monitoring for Hy’s Law (Drug-Induced Hepatotoxicity) 
Every effort should be made to ensure that the protocol required tests and procedures are 
completed as described.  However it is anticipated that from time to time there may be 
circumstances, outside of the control of the investigator that may make it unfeasible to perform 
the test.  In these cases the investigator will take all steps necessary to ensure the safety and 
wellbeing of the subject.  When a protocol required test cannot be performed the investigator 
will document the reason for this and any corrective and preventive actions which he/she has 
taken to ensure that normal processes are adhered to as soon as possible.  The study team will 
be informed of these incidents in a timely fashion. 
7.4.2. Physical and Neurological Examination 
Physical examinations at Screening/Visit 1 and every clinic visit afterwards will include the 
following: 
 
General appearance (including height at baseline). 
 
Skin (examination for the presence of rash). 
 
HEENT (examination of head, eyes, ears, nose, and throat). 
 
Chest (auscultation of lung fields). 
 
Cardiovascular (auscultation of heart sounds [S1 and S2] and for the presence of 
murmurs, gallops, or rubs).  
 
Gastrointestinal (abdominal rigidity and tenderness). 
 
Edema 
assessment 
(severity 
of 
any 
peripheral 
edema, 
presence 
of 
generalized/abdominal edema or facial/periorbital edema). 
Additional physical assessments may be performed as necessary to evaluate subjects.  Any 
clinically significant negative changes from the entry examination should be recorded as an 
adverse event. 


30 | P a g e  
 
7.4.3. Neurological Examination  
Neurological exam (including examination of mental status, motor function, sensory function, 
coordination) will be conducted at Screening (Visit 1) and end of study or in the event of early 
termination ET.   
As part of the neurological exam a specific neuropathic pain assessment is to be conducted to 
assess eligibility for the study.  
Patients will be assessed for the following: 
 
Mental status exam for short term memory, alertness, orientation, ability to do 
simple calculations and serial 7’s, demonstrates comprehension of the concept of 
a numerical rating scale for pain severity. 
 
Burning, stabbing or tingling sensation/pain in the feet 
 
Numbness 
 
Increased or decreased temperature sensation 
 
Self-report of  hypersensitivity to touch, heat, or cold  
 
Pin prick perception in feet and legs 
 
Increased or decreased sharp sensation (eg, pinprick testing); 
 
Position sense for big toe  
 
Vibratory sensation with 128 Hz tuning for at large toe; 
 
Reflexes: patellar, biceps, and Achilles 
 
Motor strength for toe dorsiflexion, and any evidence of muscle wasting in legs or 
arms 
 
Screening only: Complete and submit a copy of the neuropathic pain eligibility worksheets.  
The neuropathic pain eligibility worksheet should be kept in the subject’s source 
documentation. 
 
For quality assurance purposes, Pfizer, or its designated representative, may review and 
validate subject eligibility based on the Screening neurological examination and neuropathic 
pain assessment, painDETECT, skin biopsy results, and worksheets.  Subjects may be 
deemed eligible or ineligible based upon this review. 
 
painDETECT: painDETECT is a questionnaire that was developed to detect neuropathic 
components of pain.  Exploratory analyses of efficacy results will be conducted based on 
painDetect scores at Screening (Visit 1).  The painDETECT will also assist the clinician in 
confirming that the patient has a symptom profile that is consistent with small fiber 
neuropathy though no specific score is required for inclusion. 


31 | P a g e  
 
7.4.4. Vital Signs 
Vital signs (sitting heart rate and blood pressure, weight; height at Screening only) will be 
obtained at Screening visit and every clinic visit afterwards. 
7.5. Suicidality Assessment 
7.5.1. Patient Health Questionnaire-8 (PHQ) 
The PHQ-8 is a self-administered version of the PRIME-MD diagnostic instrument for common 
mental disorders.  The PHQ-9 is the depression module, which scores each of the 9 DSM-IV 
criteria as 0 (not at all) to 3 (nearly every day.  The PHQ-8, a validated subset of the PHQ-9 (the 
first 8 items of the PHQ-9) will be completed by subjects at Screening (Visit 1).  
7.5.2. Columbia Suicidal Severity Rating Scale(C-SSRS) 
This semi-structured interview was originally developed to evaluate the link between 
antidepressants and suicidal behavior and ideation in youth, adverse events from pediatric 
clinical trials.  C-SSRS is utilized in current study to provide a summary measure of suicidal 
risks. 
7.5.2.1. Risk Assessment During Screening 
The Investigator will review the results of the C-SSRS (baseline), and medical history.  The 
following criteria would indicate a potential suicide risk: 
 
The subject may have had suicidal ideation associated with actual intent and/or plan in 
the past year based on C-SSRS assessment. 
Note: in an event a suicidal ideation is identified in baseline C-SSRS, the Investigator 
should inquiry the timeframe of the event and determine whether it occurred during the 
past year. 
 
Any previous lifetime history of suicide behaviors based on C-SSRS assessment. 
 
Investigator’s judgment that a risk assessment is required. 
If any of these criteria are met the subject is considered not eligible to participate in the trial. 
Beginning with Visit 2, if there are any positive responses on C-SSRS (since last visit), a risk 
assessment should be done by a qualified mental health provider. Suicidal risk should be 
managed appropriately by the Investigator together with a qualified MHP.  In addition, the 
Investigator should consult with the Pfizer medical monitor to determine whether the subject can 
continue the trial.  
A suicidal narrative should be constructed for subjects who have undergone any post-baseline 
risk assessment, using information from the C-SSRS and should be kept as a source document. 


32 | P a g e  
 
8. ADVERSE EVENT REPORTING 
8.1. Adverse Events 
All observed or volunteered adverse events regardless of treatment group or suspected causal 
relationship to the investigational product(s) will be reported as described in the following 
sections.  
For all adverse events, the investigator must pursue and obtain information adequate both to 
determine the outcome of the adverse event and to assess whether it meets the criteria for 
classification as a serious adverse event requiring immediate notification to Pfizer or its 
designated representative.  For all adverse events, sufficient information should be obtained by 
the investigator to determine the causality of the adverse event.  The investigator is required to 
assess causality.  For adverse events with a causal relationship to the investigational product, 
follow-up by the investigator is required until the event or its squeal resolve or stabilize at a level 
acceptable to the investigator. 
8.2. Reporting Period 
For serious adverse events, the reporting period to Pfizer or its designated representative 
begins from the time that the subject provides informed consent, which is obtained prior to the 
subject’s participation in the study, ie, prior to undergoing any study-related procedure and/or 
receiving investigational product, through and including 28 calendar days after the last 
administration of the investigational product.  Any serious adverse event occurring any time 
after the reporting period must be promptly reported if a causal relationship to investigational 
product is suspected.  
 
Adverse events (serious and non-serious) should be recorded on the CRF from the time 
the subject has taken at least one dose of study treatment through last subject visit. 
8.3. Definition of an Adverse Event 
An adverse event is any untoward medical occurrence in a clinical investigation subject 
administered a product or medical device; the event need not necessarily have a causal 
relationship with the treatment or usage.  Examples of adverse events include but are not 
limited to:   
 
Abnormal test findings; 
 
Clinically significant symptoms and signs; 
 
Changes in physical examination findings; 
 
Hypersensitivity; 
 
Progression/worsening of underlying disease. 
Additionally, they may include the signs or symptoms resulting from: 
 
Drug overdose; 


33 | P a g e  
 
 
Drug withdrawal; 
 
Drug abuse; 
 
Drug misuse;  
 
Drug interactions; 
 
Drug dependency; 
 
Exposure during pregnancy; 
 
Exposure during breast feeding. 
8.4. Abnormal Test Findings 
The criteria for determining whether an abnormal objective test finding should be reported as an 
adverse event are as follows:  
 
Test result is associated with accompanying symptoms, and/or 
 
Test result requires additional diagnostic testing or medical/surgical intervention, and/or 
 
Test result leads to a change in study dosing or discontinuation from the study, 
significant additional concomitant drug treatment, or other therapy, and/or 
 
Test result is considered to be an adverse event by the investigator or sponsor. 
Merely repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an adverse event.  Any abnormal test result that is determined to be an error does not 
require reporting as an adverse event. 
8.5. Serious Adverse Events 
A serious adverse event is any untoward medical occurrence at any dose that: 
 
Results in death; 
 
Is life-threatening (immediate risk of death); 
 
Requires inpatient hospitalization or prolongation of existing hospitalization; 
 
Results in persistent or significant disability/incapacity; 
 
Results in congenital anomaly/birth defect. 
Medical and scientific judgment is exercised in determining whether an event is an important 
medical event.  An important medical event may not be immediately life-threatening and/or 
result in death or hospitalization.  However, if it is determined that the event may jeopardize the 
subject or may require intervention to prevent one of the other adverse event outcomes, the 
important medical event should be reported as serious. 


34 | P a g e  
 
Examples of such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; or 
development of drug dependency or drug abuse. 
8.5.1. Potential Cases of Drug-Induced Liver Injury  
Abnormal values in aspartate transaminase (AST) and/or alanine transaminase (ALT) 
concurrent with abnormal elevations in total bilirubin that meet the criteria outlined below in the 
absence of other causes of liver injury are considered potential cases of drug-induced liver 
injury (potential Hy’s Law cases) and should always be considered important medical events.   
The threshold of laboratory abnormalities for a potential case of drug-induced liver injury 
depends on the subject’s individual baseline values and underlying conditions.  Subjects who 
present with the following laboratory abnormalities should be evaluated further to definitively 
determine the etiology of the abnormal laboratory values: 
A. Subjects with AST or ALT baseline values within the normal range who subsequently 
present with AST or ALT 3 times the upper limit of normal concurrent with a total bilirubin 
2 times the upper limit of normal with no evidence of hemolysis and an alkaline 
phosphatase 2 times the upper limit of normal or not available. 
B. Subjects with pre-existing AST or ALT baseline values above the normal range who 
subsequently present with AST or ALT 2 times the baseline values and 3 times the upper 
limit of normal, or 8 times the upper limit of normal (whichever is smaller) concurrent with a 
total bilirubin of 2 times the upper limit of normal and increased by one upper limit of 
normal over baseline or >3 times the upper limit of normal (whichever is smaller) with no 
evidence of hemolysis and an alkaline phosphatase 2 times the upper limit of normal or not 
available. 
The subject should return to the investigational site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the abnormal results.  This evaluation should 
include laboratory tests, detailed history and physical assessment and for oncology studies, the 
possibility of hepatic neoplasia (primary or secondary) should be considered).  In addition to 
repeating AST and ALT, laboratory tests should include albumin, creatine kinase, total bilirubin, 
direct and indirect bilirubin, gamma-glutamyl transferase (GGT), international normalized ratio 
(INR) and alkaline phosphatase.  A detailed history, including relevant information, such as 
review of ethanol, recreational drug and supplement consumption, family history, sexual history, 
travel history, history of contact with a jaundiced subject, surgery, blood transfusion, history of 
liver or allergic disease, and work exposure, should be collected.  Further testing for acute 
hepatitis A, B, or C infection and liver imaging (eg, biliary tract) may be warranted.  All cases 
confirmed on repeat testing as meeting criteria A or B, with no other cause for LFT 
abnormalities identified at the time should be considered potential Hy’s Law cases irrespective 
of availability of all the results of the investigations performed to determine etiology of the 
abnormal LFTs.  Such potential Hy’s Law cases should be reported as serious adverse events. 
8.6. Hospitalization 
Adverse events reported from studies associated with hospitalization or prolongations of 
hospitalization are considered serious.  Any initial admission (even if less than 24 hours) to a 
healthcare facility meets these criteria.  Admission also includes transfer within the hospital to 


35 | P a g e  
 
an acute/intensive care unit (eg, from the psychiatric wing to a medical floor, medical floor to a 
coronary care unit, neurological floor to a tuberculosis unit). 
Hospitalization does not include the following: 
 
Rehabilitation facilities; 
 
Hospice facilities; 
 
Respite care (eg, caregiver relief); 
 
Skilled nursing facilities; 
 
Nursing homes; 
 
Routine emergency room admissions; 
 
Same day surgeries (as outpatient/same day/ambulatory procedures). 
Hospitalization or prolongation of hospitalization in the absence of a precipitating, clinical 
adverse event is not in itself a serious adverse event.  Examples include:  
 
Admission for treatment of a preexisting condition not associated with the development 
of a new adverse event or with a worsening of the preexisting condition (eg, for work-up 
of persistent pre-treatment lab abnormality); 
 
Social admission (eg, subject has no place to sleep); 
 
Administrative admission (eg, for yearly physical exam); 
 
Protocol-specified admission during a study (eg, for a procedure required by the study 
protocol); 
 
Optional admission not associated with a precipitating clinical adverse event (eg, for 
elective cosmetic surgery); 
 
Hospitalization for observation without a medical AE; 
 
Pre-planned treatments or surgical procedures should be noted in the baseline 
documentation for the entire protocol and/or for the individual subject. 
Diagnostic and therapeutic non-invasive and invasive procedures, such as surgery, should not 
be reported as adverse events.  However, the medical condition for which the procedure was 
performed should be reported if it meets the definition of an adverse event.  For example, an 
acute appendicitis that begins during the adverse event reporting period should be reported as 
the adverse event, and the resulting appendectomy should be recorded as treatment of the 
adverse event. 


36 | P a g e  
 
8.7. Severity Assessment 
If required on the adverse event case report forms, the investigator will use the adjectives MILD, 
MODERATE, or SEVERE to describe the maximum intensity of the adverse event.  For 
purposes of consistency, these intensity grades are defined as follows: 
MILD 
Does not interfere with subject's usual function. 
MODERATE 
Interferes to some extent with subject's usual function. 
SEVERE 
Interferes significantly with subject's usual function. 
Note the distinction between the severity and the seriousness of an adverse event.  A severe 
event is not necessarily a serious event.  For example, a headache may be severe (interferes 
significantly with subject's usual function) but would not be classified as serious unless it met 
one of the criteria for serious adverse events, listed above. 
8.8. Causality Assessment 
The investigator’s assessment of causality must be provided for all adverse events (serious and 
non-serious); the investigator must record the causal relationship in the CRF, as appropriate, 
and report such an assessment in accordance with the serious adverse reporting requirements 
if applicable.  An investigator’s causality assessment is the determination of whether there 
exists a reasonable possibility that the investigational product caused or contributed to an 
adverse event.  If the investigator does not know whether or not investigational product caused 
the event, then the event will be handled as “related to investigational product” for reporting 
purposes, as defined by the Sponsor (see Section on Reporting Requirements).  If the 
investigator's causality assessment is "unknown but not related to investigational product", this 
should be clearly documented on study records.   
In addition, if the investigator determines a serious adverse event is associated with study 
procedures, the investigator must record this causal relationship in the source documents and 
CRF, as appropriate, and report such an assessment in accordance with the serious adverse 
event reporting requirements, if applicable. 
8.9. Withdrawal Due to Adverse Events  
Withdrawal due to adverse event should be distinguished from withdrawal due to insufficient 
response, according to the definition of adverse event noted earlier, and recorded on the 
appropriate adverse event CRF page.   
When a subject withdraws due to a serious adverse event, the serious adverse event must be 
reported in accordance with the reporting requirements defined below. 
8.10. Eliciting Adverse Event Information 
The investigator is to report all directly observed adverse events and all adverse events 
spontaneously reported by the study subject.  In addition, each study subject will be questioned 
about adverse events. 


37 | P a g e  
 
8.11. Reporting Requirements 
Each adverse event is to be assessed to determine if it meets the criteria for serious adverse 
events.  If a serious adverse event occurs, expedited reporting will follow local and international 
regulations, as appropriate. 
8.11.1. Serious Adverse Event Reporting Requirements 
If a serious adverse event occurs, Pfizer is to be notified within 24 hours of awareness of the 
event by the investigator.  In particular, if the serious adverse event is fatal or life-threatening, 
notification to Pfizer must be made immediately, irrespective of the extent of available adverse 
event information.  This timeframe also applies to additional new information (follow-up) on 
previously forwarded serious adverse event reports as well as to the initial and follow-up 
reporting of exposure during pregnancy and exposure during breast feeding cases.   
In the rare event that the investigator does not become aware of the occurrence of a serious 
adverse event immediately (eg, if an outpatient study subject initially seeks treatment 
elsewhere), the investigator is to report the event within 24 hours after learning of it and 
document the time of his/her first awareness of the adverse event. 
For all serious adverse events, the investigator is obligated to pursue and provide information to 
Pfizer in accordance with the timeframes for reporting specified above.  In addition, an 
investigator may be requested by Pfizer to obtain specific additional follow-up information in an 
expedited fashion.  This information collected for serious adverse events is more detailed than 
that captured on the adverse event case report form.  In general, this will include a description 
of the adverse event in sufficient detail to allow for a complete medical assessment of the case 
and independent determination of possible causality.  Information on other possible causes of 
the event, such as concomitant medications and illnesses must be provided.  In the case of a 
subject death, a summary of available autopsy findings must be submitted as soon as possible 
to Pfizer or its designated representative.  
8.11.2. Non-Serious Adverse Event Reporting Requirements 
All adverse events will be reported on the adverse event page(s) of the CRF.  It should be noted 
that the form for collection of serious adverse event information is not the same as the adverse 
event CRF.  Where the same data are collected, the forms must be completed in a consistent 
manner.  For example, the same adverse event term should be used on both forms.  Adverse 
events should be reported using concise medical terminology on the CRFs as well as on the 
form for collection of serious adverse event information. 
8.11.3. Sponsor Reporting Requirements to Regulatory Authorities 
Adverse events reporting, including suspected serious unexpected adverse reactions, will be 
carried out in accordance with applicable local regulations. 
9. DATA ANALYSIS/STATISTICAL METHODS 
9.1. Sample Size Determination 
The study is designed to provide 90% power to detect a difference of at least 1.1 (a clinically 
meaningful difference) in the pain severity score from baseline between pregabalin-treated 


38 | P a g e  
 
subjects and placebo at an alpha level of 0.05, a tolerance for type II error set at beta 0.10, and 
a common SD of 2. This requires 20 patients in each group for a total of 40 patients. 
9.1.1.  Analysis of Primary Endpoint  
• 
To evaluate efficacy, we will compare the endpoint mean pain score for the Lyrica group 
compared to the placebo group using an analysis of covariance (ANCOVA) model with 
treatment and center as main effects and the baseline PI score as a covariate. 
• 
A BOCF and a modified or hybrid approach (mBOCF) will be used to account for missing 
data at last treatment Week. As a sensitivity we will look at the LOCF, MMRM and the 
missing imputation (suggested the National Academy of Sciences report).  
 
9.1.2. Analysis of Secondary Endpoints 
Secondary analyses included examination of the PGIC and sleep interference rate will be 
compared between treatment groups using a Cochran-Mantel-Haenszel test.  
 
9.2. Safety Analysis 
Safety data will be presented separately for both single-blind and double-blind phases of the 
study.  Safety data will be tabulated and listed according to Pfizer’s standard reporting 
algorithms. 
10. QUALITY CONTROL AND QUALITY ASSURANCE 
The study site may be subject to review by the Institutional Review Board (IRB). It is important 
that the investigator(s) and their relevant personnel are available during the monitoring visits 
and possible audits or inspections and that sufficient time is devoted to the process. 
11. DATA HANDLING AND RECORD KEEPING 
11.1. Case Report Forms/Electronic Data Record 
As used in this protocol, the term CRF should be understood to refer to either a paper form or 
an electronic data record or both, depending on the data collection method used in this study. 
A CRF is required and should be completed for each included subject. The investigator has 
ultimate responsibility for the collection and reporting of all clinical, safety and laboratory data 
entered on the CRFs and any other data collection forms (source documents) and ensuring that 
they are accurate, authentic / original, attributable, complete, consistent, legible, timely 
(contemporaneous), enduring and available when required.  The CRFs must be signed by the 
investigator or by an authorized staff member to attest that the data contained on the CRFs is 
true.  Any corrections to entries made in the CRFs, source documents must be dated, initialed 
and explained (if necessary) and should not obscure the original entry.  
In most cases, the source documents are the hospital's or the physician's subject chart.  In 
these cases data collected on the CRFs must match the data in those charts.  


39 | P a g e  
 
11.2. Record Retention 
To enable evaluations and/or audits from regulatory authorities, the investigator agrees to keep 
records, including the identity of all participating subjects (sufficient information to link records, 
eg, CRFs and hospital records), all original signed informed consent documents, copies of all 
CRFs, safety reporting forms, source documents, and detailed records of treatment disposition, 
and adequate documentation of relevant correspondence (eg, letters, telephone calls reports).  
The records should be retained by the investigator according to International Conference on 
Harmonization (ICH), local regulations, or as specified in the Clinical Study Agreement (CSA), 
whichever is longer. 
12. ETHICS 
12.1. Institutional Review Board (IRB) 
It is the responsibility of the investigator to have prospective approval of the study protocol, 
protocol amendments, informed consent documents, and other relevant documents, eg, 
recruitment advertisements, if applicable, from the IRB.  All correspondence with the IRB should 
be retained in the Investigator File.   
The only circumstance in which an amendment may be initiated prior to IRB approval is where 
the change is necessary to eliminate apparent immediate hazards to the subjects.  In that event, 
the investigator must notify the IRB in writing immediately after the implementation. 
12.2. Ethical Conduct of the Study 
The study will be conducted in accordance with legal and regulatory requirements, as well as 
the general principles set forth in the International Ethical Guidelines for Biomedical Research 
Involving Human Subjects (Council for International Organizations of Medical Sciences 2002), 
Guidelines for GCP (ICH 1996), and the Declaration of Helsinki (World Medical Association 
2008).  
In addition, the study will be conducted in accordance with the protocol, the ICH guideline on 
GCP, and applicable local regulatory requirements and laws. 
12.3. Subject Information and Consent 
All parties will ensure protection of subject personal data and will not include subject names on 
any sponsor forms, reports, publications, or in any other disclosures, except where required by 
laws.  
Subject names, address, birth date and other identifiable data will be replaced by a numerical 
code consisting of a numbering system in order to de-identify the trial subject 
The informed consent document must be in compliance with ICH GCP, local regulatory 
requirements, and legal requirements. 
The informed consent document used in this study, and any changes made during the course of 
the study, must be prospectively approved by the IRB before use. 


40 | P a g e  
 
The investigator must ensure that each study subject, or his/her legal representative, is fully 
informed about the nature and objectives of the study and possible risks associated with 
participation.   
The investigator, or a person designated by the investigator, will obtain written informed consent 
from each subject or the subject's legal representative before any study-specific activity is 
performed.  The investigator will retain the original of each subject's signed consent document. 
13. DEFINITION OF END OF TRIAL 
End of Trial is defined as the time at which it is deemed that sufficient subjects have been 
recruited and completed the study as stated in the protocol. 
14. SPONSOR DISCONTINUATION CRITERIA 
Premature termination of this study may occur because of a regulatory authority decision, 
change in opinion of the IRB, drug safety problems, or at the discretion of Pfizer.   
If a study is prematurely terminated or discontinued, the investigator must contact all 
participating subjects and the hospital pharmacy (if applicable) within 2 weeks. All study 
materials must be collected and all CRFs completed to the greatest extent possible. 
15. PUBLICATION OF STUDY RESULTS 
Results will be publicly disclose through posting the results of this study on 
www.clinicaltrials.gov (ClinicalTrials.gov).   
For all publications relating to the Study, investigator will comply with recognized ethical 
standards concerning publications and authorship, including Section II - “Ethical Considerations 
in the Conduct and Reporting of Research” of the Uniform Requirements for Manuscripts 
Submitted to Biomedical Journals, http://www.icmje.org/index.html#authorship, established by 
the International Committee of Medical Journal Editors. 
 
16. REFERENCES 
1. 
Stewart, J.D., P.A. Low, and R.D. Fealey, Distal small fiber neuropathy: results of tests 
of sweating and autonomic cardiovascular reflexes. Muscle Nerve, 1992. 15(6): p. 661-5. 
2. 
Lacomis, D., Small-fiber neuropathy. Muscle Nerve, 2002. 26(2): p. 173-88. 
3. 
Krarup, C., An update on electrophysiological studies in neuropathy. Curr Opin Neurol, 
2003. 16(5): p. 603-12. 
4. 
Holland, N.R., et al., Small-fiber sensory neuropathies: clinical course and 
neuropathology of idiopathic cases. Ann Neurol, 1998. 44(1): p. 47-59. 
5. 
McCarthy, B.G., et al., Cutaneous innervation in sensory neuropathies: evaluation by 
skin biopsy. Neurology, 1995. 45(10): p. 1848-55. 
6. 
Boruchow, S.A. and C.H. Gibbons, Utility of skin biopsy in management of small fiber 
neuropathy. Muscle Nerve, 2013. 48(6): p. 877-82. 
7. 
Lauria, G., et al., European Federation of Neurological Societies/Peripheral Nerve 
Society Guideline on the use of skin biopsy in the diagnosis of small fiber neuropathy. 


41 | P a g e  
 
Report of a joint task force of the European Federation of Neurological Societies and the 
Peripheral Nerve Society. Eur J Neurol, 2010. 17(7): p. 903-12, e44-9. 
8. 
Periquet, M.I., et al., Painful sensory neuropathy: prospective evaluation using skin 
biopsy. Neurology, 1999. 53(8): p. 1641-7. 
9. 
Peters, M.J., et al., Incidence and prevalence of small-fiber neuropathy: a survey in the 
Netherlands. Neurology, 2013. 81(15): p. 1356-60. 
10. 
Bakkers, M., et al., Small fibers, large impact: quality of life in small-fiber neuropathy. 
Muscle Nerve, 2014. 49(3): p. 329-36. 
11. 
Schaefer, C., et al., Health status, function, productivity, and costs among individuals 
with idiopathic painful peripheral neuropathy with small fiber involvement in the United 
States: results from a retrospective chart review and cross-sectional survey. J Med 
Econ, 2014. 17(6): p. 394-407. 
12. 
Hoeijmakers, J.G., et al., Small-fibre neuropathies--advances in diagnosis, 
pathophysiology and management. Nat Rev Neurol, 2012. 8(7): p. 369-79. 
13. 
Hoitsma, E., et al., Small fiber neuropathy: a common and important clinical disorder. J 
Neurol Sci, 2004. 227(1): p. 119-30. 
14. 
Katz, N., Enriched enrollment randomized withdrawal trial designs of analgesics: focus 
on methodology. Clin J Pain, 2009. 25(9): p. 797-807. 
15. 
Straube, S., et al., Enriched enrollment: definition and effects of enrichment and dose in 
trials of pregabalin and gabapentin in neuropathic pain. A systematic review. Br J Clin 
Pharmacol, 2008. 66(2): p. 266-75. 
16. 
Gilron, I., et al., Pregabalin for peripheral neuropathic pain: a multicenter, enriched 
enrollment randomized withdrawal placebo-controlled trial. Clin J Pain, 2011. 27(3): p. 
185-93. 
17. 
Simpson, D.M., et al., Pregabalin for painful HIV neuropathy: a randomized, double-
blind, placebo-controlled trial. Neurology, 2010. 74(5): p. 413-20. 
18. 
Semel, D., et al., Evaluation of the safety and efficacy of pregabalin in older patients with 
neuropathic pain: results from a pooled analysis of 11 clinical studies. BMC Fam Pract, 
2010. 11: p. 85. 
19. 
Tarride, J.E., et al., Cost-effectiveness of pregabalin for the management of neuropathic 
pain associated with diabetic peripheral neuropathy and postherpetic neuralgia: a 
Canadian perspective. Clin Ther, 2006. 28(11): p. 1922-34. 
20. 
Vinik, A., et al., Relationship between pain relief and improvements in patient 
function/quality of life in patients with painful diabetic peripheral neuropathy or 
postherpetic neuralgia treated with pregabalin. Clin Ther, 2013. 35(5): p. 612-23. 
21. 
Ho, T.W., et al., Efficient assessment of neuropathic pain drugs in patients with small 
fiber sensory neuropathies. Pain, 2009. 141(1-2): p. 19-24. 
 
 
 
 
 
 
 


42 | P a g e  
 
APPENDIX 1.  SCHEDULE OF ACTIVITIES 
The Schedule of Activities table provides an overview of the protocol visits and procedures.  
Refer to Study Procedures and Assessments for detailed information on each procedure and 
assessment required for compliance with the protocol.    
Study Phase:
Baseline 
(V1 to V2)
Single-Blind Treatment Phase 
(8 weeks) 
Randomized Withdrawal 
Phase (4 weeks) 
 
Clinic Visit No.:
V1a,e 
V2 a,c 
V3 
V4 
V5 
V6 
V7 
Visit: Screening
Enrollment
Wk 1 
Wk2 
Wk 4 
Wk 8 
Wk 12 
Study Day: -30 to -14
0 
7 
14 
28 
56 
84 
Visit Type:
Clinic 
Clinic 
Phone 
Phone 
Phone 
Clinic 
Clinic 
Visit Window:
N/A 
7 - 21 days 2 days
2 days
2 days
3 days 
3 days 
Observation/Procedure 
 
 
 
 
 
 
 
Informed consentb 
X 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
X 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
Physical exam/Neurological exam 
X 
 
 
 
 
 
X 
Vital Signse 
X 
X 
 
 
 
 
X 
Clinical labs 
X 
 
 
 
 
 
 
Retained blood sample for proteomics, 
etc. 
X 
 
 
 
 
 
 
IENF biopsy 
X 
 
 
 
 
 
 
PainDETECT 
X 
 
 
 
 
 
 
PHQ-8 
X 
 
 
 
 
 
 
Suicidality Assessment (C-SSRS) 
X 
X 
 
 
 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
Concomitant/Rescue medicationsf 
X 
X 
X 
X 
X 
X 
X 
Study medication dispensing 
 
X 
 
 
 
X 
X
NPSI 
 
X 
 
 
 
X 
X 


43 | P a g e  
 
Study Phase:
Baseline 
(V1 to V2)
Single-Blind Treatment Phase 
(8 weeks) 
Randomized Withdrawal 
Phase (4 weeks) 
 
SFN-SIQ 
 
X 
 
 
 
X 
X 
Numeric Rating Scale for Pain 
(NRS-Pain - 1 week recall) 
X 
 
 
 
 
 
 
IVRS Daily Diary, (Pain NRS and 
SIRS) 
X 
X 
X 
X 
X 
X 
X 
Brief Pain Inventory - short form (BPI-
sf) 
X 
X 
 
 
 
X 
X 
EuroQOL 5-Dimensions (EQ-5D) 
 
X 
 
 
 
X 
X 
Patient Global Impression of Change 
(PGIC) 
 
 
 
 
 
X 
X 
a  Visit 1 may occur between 30 days and 14 days prior to Visit 2, based on the amount of time required for 
screening procedures such as punch biopsy or washout period for previous pain medications.  The screening visit 
may also be split into two visits. A 14-day minimum baseline between Visit 1 and Visit 2 is required to establish 
baseline pain level.  The maximum 30-day screening period does not include prior completion of the informed 
consent. 
b  Informed consent must be completed prior to performing any other study procedures, including any medication 
changes made to participate in the study.  Any such medication changes must be considered for medical 
appropriateness to protect patient well-being.   
c  V2 is the Single-blind Baseline visit (enrollment).   
d  V6 is the final visit of the single-blind phase and also the randomization visit for subjects who are eligible to 
continue in the withdrawal phase.   
e  Includes weight, blood pressure, and pulse at all clinic visits, and height at Visit 1 only.  
f   Rescue medications may NOT be taken  within the 2 hours prior to daily diary completion 


44 | P a g e  
 
APPENDIX 2.  Dose Assessment and Adjustment 
Visit Days 
Response/Assessment 
                  Action 
 
Bottle 
V2 
0-7 
-- 
Start 150 mg/day pregabalin/placebo 
(75 mg BID):  
 
Bottle A 
V3 
7-14 
Subject tolerates 
150 mg/day well 
Increase dose to 300 mg/day 
pregabalin/placebo (150 mg BID) 
 
Bottle B 
In investigator’s judgement, 
dose should not be 
increased based tolerability 
(ie, subject has pregabalin 
associated adverse events 
that clinically preclude dose 
increase 
Remain at 150 mg/day pregabalin/placebo 
Continue with Bottle A
V4 
 
14-28 
 
Subject tolerates 
300 mg/day well 
 
Subject tolerates 
150 mg/day  
If at 300 mg/day pregabalin/placebo, increase 
dose to 450 mg/day.  
 
If still at 150 mg/day pregabalin/placebo, 
increase dose to 300 mg/day.  
 
If at Bottle B, proceed 
to Bottle C  
 
If at Bottle A, proceed 
to Bottle B 
 
In investigator’s judgement, 
dose should not be 
increased based tolerability 
(ie, subject has pregabalin 
associated adverse events 
that clinically precludes 
dose increase 
 
Remain at current dose pregabalin/placebo.  
Maintain current bottle 
and dosing 
Not acceptable tolerability 
while receiving 300 mg/day
 
Reduce to 150 mg/day pregabalin/placebo. 
Return to Bottle A 
V5 
 
28 
 
Acceptable tolerability 
Remain at current dose level; no further 
changes.  
 
Maintain current 
bottle and dosing 
 
 
 
Not acceptable while 
receiving current dose 
 
Reduce dose 1 level 
 
V6 
 
Acceptable tolerability 
 
Remain at current dose level; no further 
changes 
Maintain current bottle 
and dosing 
 
 
Not  acceptable while 
receiving current dose  
 
Reduce dose 1 level 
 
 
 
 


45 | P a g e  
 
APPENDIX 3. Study Medication Taper Schedule  
Pregabalin 
Dose 
Taper 
Day 1 
(mg/day) 
Taper Day 2
(mg/day) 
Taper Day 3
(mg/day) 
Taper Day 4
(mg/day) 
Taper 
Day 5 
(mg/day) 
Taper 
Day 6 
(mg/day) 
Taper 
Day 7 
(mg/day) 
150 mg 
150 
150 
150
150
50
50 
50
300 mg 
150 
150 
150
150
50
50 
50
450 mg 
300 
300 
300
300
150
150 
150
600 mg 
300 
300 
300
300
150
150 
150