Topiramate for Cryptogenic Sensory Peripheral Neuropathy in Metabolic Syndrome (CSPN)
Condition: Cryptogenic Sensory Peripheral Neuropathy in Metabolic Syndrome
MeSH terms: Peripheral Nervous System Diseases; Metabolic Syndrome; Syndrome
Intervention: topiramate; Placebo
Intervention description: Oral topiramate at a target dose of 50mg twice daily.; overencapsulated placebo of identical color, shape and packaging to topiramate
Intervention MeSH terms: Topiramate
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 132.0
Sex: All
Minimum age: 18 Years
Maximum age: 80 Years
Healthy volunteers: No

Summary:

      The TopCSPN trial is a double blinded randomized placebo controlled study of oral topiramate
      as a potential disease modifying therapy for cryptogenic sensory peripheral neuropathy
      (CSPN). Patients with CSPN who also have metabolic syndrome (defined by the ATPIII criteria)
      who do not have an alternative cause for neuropathy will be potentially eligible. The co
      primary outcome measures are change in the Norfolk Quality of Life - Diabetic Neuropathy
      (NQOL-DN) Scale and intraepidermal nerve fiber density (IEFND) at the distal thigh. The
      treatment phase will last 24 months.
    

Eligibility criteria:

        Inclusion Criteria

          1. Age 18-80

          2. Diagnosis of confirmed symptomatic distal symmetric peripheral polyneuropathy based on
             the Toronto consensus criteria for probable neuropathy (the presence of unequivocal
             signs and symptoms of neuropathy)45.

          3. Evidence of symptomatic neuropathy based on a screening visit NQOL-DN score of >9.

          4. Metabolic syndrome based on modified ATPIII criteria. 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

               -  Hyperglycemia based on American Diabetes Association (ADA) criteria at screening
                  based on any one or more of the following: fasting plasma glucose > 100 mg/dL
                  (5.6 mmol/L), 2-hour glucose tolerance test > 140 mg/dL (7.8 mmol/L), or
                  hemoglobin A1c > 5.7% .

          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
             immunofixation47.

          2. Type I diabetes or current use of insulin or use of insulin in the past 3 months.

          3. HgA1c > 7.5%. Borderline screening labs can be repeated within two weeks with PPI
             approval.

          4. History of recurrent nephrolithiasis, a single episode of nephrolithiasis within one
             year prior to screening, or use of ongoing preventative treatment.

          5. Family history of a hereditary neuropathy in a first-degree relative.

          6. Severe neuropathy: Utah Early Neuropathy Score > 24 at screening

          7. Active foot ulceration or a history of a nontraumatic foot amputation.

          8. ECG with QTc more than 450 ms in men, or 470 ms in women.

          9. Risk of excessive bleeding at the skin biopsy site based on the clinical assessment of
             the CSS-PI.

         10. Chronic corticosteroid use excluding topical or inhaled treatment.

         11. Use of a carbonic anhydrase inhibitor (such as acetazolamide) due to risk of
             nephrolithiasis.

         12. Planned bariatric surgery.

         13. Use of other weight loss medications.

         14. Use of scheduled opiates, or as needed opiate medications more than three times
             weekly.

         15. Use of topical capsaicin products within 16 weeks of screening or at any time on
             study.

         16. Medication change for neuropathy symptoms during the 8 weeks prior to screening; or
             anticipated change for the duration of study participation.

         17. Current use of an intrathecal pain pump or spinal cord stimulator.

         18. Screening laboratory creatinine ≥ 2.0 mg/dl.

         19. Severe edema, dermatologic or lower extremity condition that would increase risk of
             skin biopsy.

         20. 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.

         21. 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).

         22. Ataxia sufficiently severe to represent an unacceptable fall risk in the opinion of
             the site principal investigator.

         23. A serious medical condition expected to dramatically shorten life span or prevent
             participation.

         24. 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.

         25. History of alcohol or drug abuse within the past two years, or existing neuropathy
             related to past drug or alcohol abuse.

         26. 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.

         27. A history of epilepsy.

         28. An inability to understand or cooperate with the procedures of the study.

         29. Pregnant, or intending to become pregnant, or breastfeeding.