Topiramate for Cryptogenic Sensory Peripheral Neuropathy in Metabolic Syndrome (CSPN)

Inclusion Criteria

1. Age 18-80

2. Diagnosis of confirmed cryptogenic symptomatic distal symmetric peripheral
polyneuropathy based on the Toronto consensus criteria for probable neuropathy (the
presence of unequivocal signs and symptoms of neuropathy)

3. Evidence of symptomatic neuropathy based on a screening visit NQOL-DN score of >9

4. Metabolic syndrome based on modified ATPIII criteria, with a BMI ≥ 25 kg/m2. Specific
criteria require 3 of the following 6 to be present at the screening visit.

- Waist circumference >102 cm for men, >88 cm for women

- Serum triglycerides of > 150 mg/dl

- HDL < 40 mg/dl for men, < 50 mg/dl for women

- Those with either a normal HDL or TRG who are taking a lipid lowering medication
for this purpose.

- Blood pressure 130/85 mm Hg or use of anti-hypertension drug

- Prediabetes based on American Diabetes Association (ADA) criteria at screening
based on any one or more of the following: fasting plasma glucose - 100 mg/dL to
125 mg/dL (5.6 mmol/L to 6.9 mmol/L), 2-hour glucose tolerance test - 140 mg/dL
to 199 mg/dL (7.8 mmol/L to 11.0 mmol/L), or hemoglobin A1c between 5.7% and
6.4%.

5. No current or prior history of therapy with topiramate.

6. If female of child-bearing potential (i.e., not surgically sterile or post-menopausal
defined as age > 51 years without menses for ≥ 2 years), negative serum pregnancy test
at screening and negative urine pregnancy test at baseline visit.

7. Women of child-bearing potential or men with sexual partners of childbearing potential
be willing to use an acceptable method of birth control for the duration of the study
and for 12 weeks following completion of study drug therapy. Acceptable methods of
birth control include abstinence, oral contraceptives, the contraceptive patch,
intra-uterine device, the contraceptive ring, and or barrier contraception such as
condoms with spermicide.

Exclusion Criteria

1. CSS-PI clinical determination of an alternative cause for peripheral neuropathy
(including but not limited to rheumatological disorders, Hepatitis B or C, Breast
Cancer treated with neurotoxic chemotherapy within the past 15 years). All potential
subjects will have screening neuropathy labs including assessment for diabetes
(Hemoglobin A1c, oral glucose tolerance test), vitamin B12 level, and immunofixation.

2. Diagnosis of diabetes by history, or screening laboratory results including: HgA1c ≥
6.5%, fasting plasma glucose ≥ 126 mg/dL (7.0 mmol/L), or 2-hour oral glucose
tolerance ≥ 200 mg/dL (11.1 mmol/L). Borderline screening labs can be repeated within
two weeks with PPI approval.

3. History of recurrent nephrolithiasis, a single episode of nephrolithiasis within one
year prior to screening, or use of ongoing preventative treatment.

4. Family history of a hereditary neuropathy in a first-degree relative.

5. Severe neuropathy: Utah Early Neuropathy Score > 24 at screening

6. Active foot ulceration or a history of a nontraumatic foot amputation.

7. ECG with QTc more than 450 ms in men, or 470 ms in women.

8. Current or planned therapeutic anticoagulation including coumadin or oral factor X or
thrombin inhibitor therapy (anti-platelet agents are permissible).

9. Chronic corticosteroid use excluding topical or inhaled treatment.

10. Use of a carbonic anhydrase inhibitor (such as acetazolamide) due to risk of
nephrolithiasis.

11. Planned bariatric surgery

12. Use of other weight loss medications.

13. Use of scheduled opiates, or as needed opiate medications more than three times
weekly.

14. Use of topical capsaicin products within 16 weeks of screening or at any time on
study.

15. Medication change for neuropathy symptoms during the 8 weeks prior to screening; or
anticipated change for the duration of study participation.

16. Current use of an intrathecal pain pump or spinal cord stimulator.

17. Screening laboratory creatinine ≥ 2.0 mg/dl.

18. Severe edema, dermatologic or lower extremity condition that would increase risk of
skin biopsy.

19. Major depression, bipolar affective disorder, or other mental health disorders that
are sufficiently severe to increase adverse event risk or impact neuropathy assessment
in the opinion of the responsible site principal investigator.

20. Current suicidal ideation within one year prior to the baseline visit as evidenced by
answering "yes" to Questions 4 or 5 on the suicidal ideation portion of the
Columbia-Suicide Severity Rating Scale (C-SSRS).

21. Ataxia sufficiently severe to represent an unacceptable fall risk in the opinion of
the site principal investigator.

22. A serious medical condition expected to dramatically shorten life span or prevent
participation.

23. Any clinically significant condition or illness, which, in the opinion of the CSS-PI,
would pose a risk to the subject or might confound the study including metabolic
acidosis, bone marrow suppression, blood dyscrasias, bleeding disorder, or closed
angle glaucoma.

24. History of alcohol or drug abuse within the past two years, or existing neuropathy
related to past drug or alcohol abuse.

25. History of malignancy within five years prior to study enrollment, except for
adequately treated basal cell or squamous cell skin cancer or in situ cervical cancer.

26. A history of epilepsy.

27. An inability to understand or cooperate with the procedures of the study

28. Pregnant, or intending to become pregnant, or breastfeeding.