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

• ClinicalTrials.gov Identifier: NCT02878798
• Recruitment Status: Completed
• First Posted: August 25, 2016
• Last Update Posted: March 9, 2023
• Sponsor: Virginia Commonwealth University
• Collaborators: National Institute of Neurological Disorders and Stroke (NINDS); NeuroNEXT Network
• Information provided by (Responsible Party): Virginia Commonwealth University

Study Description

Brief 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.

Condition or disease	Intervention/treatment	Phase
Cryptogenic Sensory Peripheral Neuropathy in Metabolic Syndrome	Drug: topiramate; Other: Placebo	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 132 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: Topiramate as a Disease Modifying Therapy for Cryptogenic Sensory Peripheral Neuropathy in Metabolic Syndrome (CSPN)
• Actual Study Start Date: February 12, 2018
• Actual Primary Completion Date: September 28, 2021
• Actual Study Completion Date: September 28, 2021

Arms and Interventions

Arm	Intervention/treatment
Placebo Comparator: Placebo; An overencapsulated placebo of identical color, shape and packaging to topiramate will be used.	Other: Placebo; overencapsulated placebo of identical color, shape and packaging to topiramate
Experimental: Topiramate; Oral topiramate	Drug: topiramate; Oral topiramate at a target dose of 50mg twice daily.; Other Name: Topamax

Outcome Measures

Primary Outcome Measures :

1. Intraepidermal nerve fiber density (IENFD) [ Time Frame: Baseline, 32, 64, 96 weeks, Early Termination ]
   Difference in IENFD change between treatment groups over 96 weeks.
2. Norfolk Quality of Life - Diabetic Neuropathy [ Time Frame: Screening, 16, 32, 48, 64, 80, 96 weeks ]
   Difference in NQOL between treatment groups over 96 weeks.

Secondary Outcome Measures :

1. Brief pain inventory - diabetic neuropathy (BPI-DN) [ Time Frame: Baseline, 16, 32, 48, 64, 80, 96 weeks, Early Termination ]
   Pain interference score
2. Brief pain inventory - diabetic neuropathy (BPI-DN) [ Time Frame: Baseline, 16, 32, 48, 64, 80, 96 weeks, Early Termination ]
   Average pain severity
3. Utah Early Neuropathy Scale [ Time Frame: Screening, 16, 32, 48, 64, 80, 96 weeks, Early Termination ]
   Association of UENS
4. Sural sensory amplitude (SSA) [ Time Frame: Baseline, 32, 64, 96 weeks, Early Termination ]
   SSA change
5. Peroneal motor conduction velocity (PMCV) [ Time Frame: Baseline, 32, 64, 96 weeks, Early Termination ]
   PMCV change
6. Body mass index (BMI) [ Time Frame: Screening, Baseline, 16, 32, 48, 64, 80, 96 weeks, Early Termination ]
   BMI change
7. Hemoglobin A1C [ Time Frame: Screening, 32, 64, 96 weeks, Early Termination ]
   A1C change
8. Serum Triglycerides (TRG) [ Time Frame: Screening, 32, 64, 96 weeks, Early Termination ]
   TRG change
9. LDL Cholesterol [ Time Frame: Screening, 32, 64, 96 weeks, Early Termination ]
   LDL change
10. HDL Cholesterol [ Time Frame: Screening, 32, 64, 96 weeks, Early Termination ]
    HDL change

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 80 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

United States, Alabama

University of Alabama Birmingham

Birmingham, Alabama, United States, 35233

United States, Arizona

Barrow Neurological Institute

Phoenix, Arizona, United States, 85013

United States, California

University of California Irvine

Orange, California, United States, 92868

United States, Florida

University of Miami

Miami, Florida, United States, 33136

United States, Illinois

Northwestern University

Chicago, Illinois, United States, 60611

United States, Iowa

University of Iowa

Iowa City, Iowa, United States, 52242

United States, Kansas

University of Kansas Medical Center

Kansas City, Kansas, United States, 66160

United States, Massachusetts

Massachusetts General Hospital

Boston, Massachusetts, United States, 02114

United States, Michigan

University of Michigan Neurology Clinical Trials Organization

Ann Arbor, Michigan, United States, 48105-2945

United States, Missouri

Washington University School of Medicine

Saint Louis, Missouri, United States, 63110

United States, New York

Columbia University Medical Center

New York, New York, United States, 10032

University of Rochester Medical Center

Rochester, New York, United States, 14642

United States, North Carolina

Wake Forest University Baptist Medical Center

Winston-Salem, North Carolina, United States, 27157

United States, Ohio

Ohio State University

Columbus, Ohio, United States, 43221

United States, Pennsylvania

University of Pennsylvania

Philadelphia, Pennsylvania, United States, 19104

United States, Tennessee

Vanderbilt University Medical Center

Nashville, Tennessee, United States, 37232

United States, Texas

UT Southwestern Medical Center

Dallas, Texas, United States, 75390

United States, Utah

University of Utah

Salt Lake City, Utah, United States, 84132

United States, Virginia

Eastern Virginia Medical Center

Norfolk, Virginia, United States, 23510

Virginia Commonwealth University

Richmond, Virginia, United States, 23298

Sponsors and Collaborators

Virginia Commonwealth University

National Institute of Neurological Disorders and Stroke (NINDS)

NeuroNEXT Network

Investigators

• Principal Investigator: Gordon Smith, MD; Virginia Commonwealth University

  Study Documents (Full-Text)

Documents provided by Virginia Commonwealth University:

Study Protocol and Statistical Analysis Plan  [PDF] August 8, 2018

Informed Consent Form  [PDF] August 19, 2021

More Information

• Responsible Party: Virginia Commonwealth University
• ClinicalTrials.gov Identifier: NCT02878798
• Other Study ID Numbers: URNN001 / HM20014083; 1U01NS095388 ( U.S. NIH Grant/Contract )
• First Posted: August 25, 2016
• Last Update Posted: March 9, 2023
• Last Verified: February 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

Additional relevant MeSH terms:

Peripheral Nervous System Diseases; Metabolic Syndrome; Syndrome; Disease; Pathologic Processes; Neuromuscular Diseases; Nervous System Diseases; Insulin Resistance; Hyperinsulinism; Glucose Metabolism Disorders; Metabolic Diseases; Topiramate; Anticonvulsants; Hypoglycemic Agents; Physiological Effects of Drugs