Cryptogenic Sensory Peripheral Neuropathy in Metabolic Syndrome
Conditions
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.
Interventions
DRUGtopiramate
Oral topiramate at a target dose of 50mg twice daily.
OTHERPlacebo
overencapsulated placebo of identical color, shape and packaging to topiramate
Sponsors
National Institute of Neurological Disorders and Stroke (NINDS)
NeuroNEXT Network
Virginia Commonwealth University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Intraepidermal Nerve Fiber Density (IENFD) | 96 weeks | Difference in IENFD change between treatment groups over 96 weeks (fibers/mm) (i.e. the slope of change). A skin biopsy is obtained. The sample is stained for nerve fibers. The rate of change in IENFD in fibers/mm is calculated over the 96 week duration of the study and expressed in change in fibers/mm/year (defined as 52 weeks) over the study period (i.e. the slope of change expressed and change in IENFD in fibers/mm over a 52 week period). |
| Norfolk Quality of Life - Diabetic Neuropathy | 96 weeks (expressed as a slope in change of total score/52 weeks) | Difference in NQOL between treatment groups over 96 weeks. The Norfolk QOL-DN is a validated 47-item, patient-reported outcome measure, sensitive to the different features of diabetic neuropathy (DN) including small fiber, large fiber, and autonomic function. A lower score is better. The range of the score is from -4 to 136. The slope of the change in total Norfolk QOL-DD is calculated as the change in total score/52 weeks (one year) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Utah Early Neuropathy Scale | 96 weeks (expressed as a slope of change in total UENS over 52 weeks). | The UENS is a validated examination score of neuropathy severity based on a physical examination (Singleton et al 2008). Total score is 42 (minimum 0 and maximum 42). The higher the score, the worse the outcome is. The change in UENS over the 96 week period is expressed as a slope of change in total UENS over one year defined as 52 weeks. |
| Sural Sensory Amplitude (SSA) | 96 weeks (slope of change in mV/52weeks) | Change in SSA measured in microvolts. SSA is measured by electrically stimulating a nerve through the skin and recording the response. A larger value is better. The normal values vary based on age, with a minimum of 0 (absent). Across all ages, the lower limit of normal is 6 microvolts, although the normal cutoff declines with aging. The change in SSA over the 96 week study period is expressed as a slope of change in uV/52 weeks (the 52 week log (mV) change of non-zero values). |
| Peroneal Motor Conduction Velocity (PMCV) | 96 weeks (expressed as a slope of change in meter/sec over 52 weeks) | PMCV change. PMCV is measured by electrically stimulating the nerve through the skin at two different locations and measuring how fast the response travels between the two in meters/second. A higher value is better. The slope of the change in PMCV is expressed as change in meters/second/52 weeks (one year). |
| Body Mass Index (BMI) | 96 weeks (slope of change in kg/m2/52 weeks) | BMI change in kg/m2. BMI is a measure of weight relative to height. The slope of the change in BMI over the study was expressed as change in kg/m2/52 weeks. |
| Brief Pain Inventory - Diabetic Neuropathy (BPI-DN) Pain Interference | 96 weeks (expressed as a change in change in pain interference/52weeks) | Pain interference score. Each item is scored from 0-10 with a total possible number of points of 70, higher worse. The range of the score is 0-70. The change in score is expressed as a slope of change in pain interference score/52 weeks (one year) |
| Serum Triglycerides (TRG) | 96 weeks (slope of change mg/dl over 52 weeks) | TRG change. TRG are a type of lipid or fat circulating in the blood. A higher value is associated with increased cardiovascular risk. The slope of the change in TRG was calculated as change in mg/dl over 52 weeks (one year). |
| LDL Cholesterol | 96 weeks (expressed as a slope of change in mg/dl/52 weeks) | LDL change. LDL is bad cholesterol, measured in mg/dL. A higher value is associated with elevated cardiovascular risk. A slope of change is calculated change in LDL in mg/dL/52 weeks (one year) |
| HDL Cholesterol | 96 weeks (expressed as slope of change in mg/dL/52 weeks) | HDL change. HDL is good cholesterol, measured in mg/dL. A lower value is associated with higher cardiovascular risk. The slope of change is calculated as change in mg/dL/52 weeks (one year) |
| Hemoglobin A1C | The annual slope of the change in A1C over 96 weeks expressed in change in percent/52 weeks | Slope of the Hemoglobin A1C change. A1C is measured in percent. It provides an estimate of how high blood sugar has been over the past three months. A higher value indicates poor diabetic control. |
| Brief Pain Inventory - Diabetic Neuropathy (BPI-DN) Average Pain Intensity | 96 weeks (expressed as a slope of change over 52 weeks) | Average pain severity. Each item is scored 0-10 with a total of 40 possible points, higher is worse. The range of the score is 0-40. The slope of the change in this score is expressed as change/one year (defined as 52 weeks) |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo An overencapsulated placebo of identical color, shape and packaging to topiramate will be used.
Placebo: overencapsulated placebo of identical color, shape and packaging to topiramate | 66 |
| Topiramate Oral topiramate
topiramate: Oral topiramate at a target dose of 50mg twice daily. | 66 |
| Total | 132 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 2 | 2 |
| Overall Study | Protocol Violation | 0 | 1 |
| Overall Study | Withdrawal by Subject | 5 | 4 |
Baseline characteristics
| Characteristic | Placebo | Total | Topiramate |
|---|---|---|---|
| Age, Continuous | 62.7 years STANDARD_DEVIATION 10.7 | 62.3 years STANDARD_DEVIATION 10.3 | 61.9 years STANDARD_DEVIATION 9.9 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 3 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 62 Participants | 128 Participants | 66 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 6 Participants | 9 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 60 Participants | 122 Participants | 62 Participants |
| Region of Enrollment United States | 66 participants | 132 participants | 66 participants |
| Sex: Female, Male Female | 22 Participants | 50 Participants | 28 Participants |
| Sex: Female, Male Male | 44 Participants | 82 Participants | 38 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 66 | 0 / 66 |
| other Total, other adverse events | 56 / 66 | 61 / 66 |
| serious Total, serious adverse events | 9 / 66 | 4 / 66 |
Outcome results
Primary
Intraepidermal Nerve Fiber Density (IENFD)
Difference in IENFD change between treatment groups over 96 weeks (fibers/mm) (i.e. the slope of change). A skin biopsy is obtained. The sample is stained for nerve fibers. The rate of change in IENFD in fibers/mm is calculated over the 96 week duration of the study and expressed in change in fibers/mm/year (defined as 52 weeks) over the study period (i.e. the slope of change expressed and change in IENFD in fibers/mm over a 52 week period).
Time frame: 96 weeks
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo | Intraepidermal Nerve Fiber Density (IENFD) | -0.6064 fibers/mm/year (52 weeks) |
| Topiramate | Intraepidermal Nerve Fiber Density (IENFD) | -0.396 fibers/mm/year (52 weeks) |
Primary
Norfolk Quality of Life - Diabetic Neuropathy
Difference in NQOL between treatment groups over 96 weeks. The Norfolk QOL-DN is a validated 47-item, patient-reported outcome measure, sensitive to the different features of diabetic neuropathy (DN) including small fiber, large fiber, and autonomic function. A lower score is better. The range of the score is from -4 to 136. The slope of the change in total Norfolk QOL-DD is calculated as the change in total score/52 weeks (one year)
Time frame: 96 weeks (expressed as a slope in change of total score/52 weeks)
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo | Norfolk Quality of Life - Diabetic Neuropathy | 3.5815 Change inTotal NQOL-DN score over 52 wks |
| Topiramate | Norfolk Quality of Life - Diabetic Neuropathy | 2.0596 Change inTotal NQOL-DN score over 52 wks |
Secondary
Body Mass Index (BMI)
BMI change in kg/m2. BMI is a measure of weight relative to height. The slope of the change in BMI over the study was expressed as change in kg/m2/52 weeks.
Time frame: 96 weeks (slope of change in kg/m2/52 weeks)
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo | Body Mass Index (BMI) | -0.1537 Slope of change in BMI kg/m2 over 52wks |
| Topiramate | Body Mass Index (BMI) | -0.2865 Slope of change in BMI kg/m2 over 52wks |
p-value: 0.758695% CI: [-0.982, 0.7164]Mixed Models Analysis
Secondary
Brief Pain Inventory - Diabetic Neuropathy (BPI-DN) Average Pain Intensity
Average pain severity. Each item is scored 0-10 with a total of 40 possible points, higher is worse. The range of the score is 0-40. The slope of the change in this score is expressed as change/one year (defined as 52 weeks)
Time frame: 96 weeks (expressed as a slope of change over 52 weeks)
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo | Brief Pain Inventory - Diabetic Neuropathy (BPI-DN) Average Pain Intensity | -0.1046 Slope of change in BPI-DN pain over 52 w |
| Topiramate | Brief Pain Inventory - Diabetic Neuropathy (BPI-DN) Average Pain Intensity | -0.2726 Slope of change in BPI-DN pain over 52 w |
p-value: 0.26195% CI: [-0.4612, 0.1253]Mixed Models Analysis
Secondary
Brief Pain Inventory - Diabetic Neuropathy (BPI-DN) Pain Interference
Pain interference score. Each item is scored from 0-10 with a total possible number of points of 70, higher worse. The range of the score is 0-70. The change in score is expressed as a slope of change in pain interference score/52 weeks (one year)
Time frame: 96 weeks (expressed as a change in change in pain interference/52weeks)
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo | Brief Pain Inventory - Diabetic Neuropathy (BPI-DN) Pain Interference | 0.1999 Slope of change in BPI-DN PI over 52 wks |
| Topiramate | Brief Pain Inventory - Diabetic Neuropathy (BPI-DN) Pain Interference | 0.1767 Slope of change in BPI-DN PI over 52 wks |
95% CI: [-0.6337, 0.5872]Mixed Models Analysis
Secondary
HDL Cholesterol
HDL change. HDL is good cholesterol, measured in mg/dL. A lower value is associated with higher cardiovascular risk. The slope of change is calculated as change in mg/dL/52 weeks (one year)
Time frame: 96 weeks (expressed as slope of change in mg/dL/52 weeks)
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo | HDL Cholesterol | 0.8156 change in mg/dl/52 weeks at 96 weeks |
| Topiramate | HDL Cholesterol | -0.2391 change in mg/dl/52 weeks at 96 weeks |
p-value: 0.409295% CI: [-3.5705, 1.4611]Mixed Models Analysis
Secondary
Hemoglobin A1C
Slope of the Hemoglobin A1C change. A1C is measured in percent. It provides an estimate of how high blood sugar has been over the past three months. A higher value indicates poor diabetic control.
Time frame: The annual slope of the change in A1C over 96 weeks expressed in change in percent/52 weeks
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo | Hemoglobin A1C | 0.03 change in %/52 weeks over 96 weeks |
| Topiramate | Hemoglobin A1C | 0.0279 change in %/52 weeks over 96 weeks |
p-value: 0.960495% CI: [-0.084, 0.0799]Mixed Models Analysis
Secondary
LDL Cholesterol
LDL change. LDL is bad cholesterol, measured in mg/dL. A higher value is associated with elevated cardiovascular risk. A slope of change is calculated change in LDL in mg/dL/52 weeks (one year)
Time frame: 96 weeks (expressed as a slope of change in mg/dl/52 weeks)
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo | LDL Cholesterol | -6.6584 change in mg/dl/52 weeks at 96 weeks |
| Topiramate | LDL Cholesterol | -4.2736 change in mg/dl/52 weeks at 96 weeks |
p-value: 0.581395% CI: [-6.1336, 10.9032]Mixed Models Analysis
Secondary
Peroneal Motor Conduction Velocity (PMCV)
PMCV change. PMCV is measured by electrically stimulating the nerve through the skin at two different locations and measuring how fast the response travels between the two in meters/second. A higher value is better. The slope of the change in PMCV is expressed as change in meters/second/52 weeks (one year).
Time frame: 96 weeks (expressed as a slope of change in meter/sec over 52 weeks)
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo | Peroneal Motor Conduction Velocity (PMCV) | -0.04363 Slope of change in M/S over 52 wks |
| Topiramate | Peroneal Motor Conduction Velocity (PMCV) | -0.783 Slope of change in M/S over 52 wks |
p-value: 0.023395% CI: [-1.3775, -0.1013]Mixed Models Analysis
Secondary
Serum Triglycerides (TRG)
TRG change. TRG are a type of lipid or fat circulating in the blood. A higher value is associated with increased cardiovascular risk. The slope of the change in TRG was calculated as change in mg/dl over 52 weeks (one year).
Time frame: 96 weeks (slope of change mg/dl over 52 weeks)
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo | Serum Triglycerides (TRG) | 0.022 change in mg/dl/52 weeks over 96 weeks |
| Topiramate | Serum Triglycerides (TRG) | -0.0176 change in mg/dl/52 weeks over 96 weeks |
p-value: 0.236595% CI: [-0.1053, 0.0261]Mixed Models Analysis
Secondary
Sural Sensory Amplitude (SSA)
Change in SSA measured in microvolts. SSA is measured by electrically stimulating a nerve through the skin and recording the response. A larger value is better. The normal values vary based on age, with a minimum of 0 (absent). Across all ages, the lower limit of normal is 6 microvolts, although the normal cutoff declines with aging. The change in SSA over the 96 week study period is expressed as a slope of change in uV/52 weeks (the 52 week log (mV) change of non-zero values).
Time frame: 96 weeks (slope of change in mV/52weeks)
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo | Sural Sensory Amplitude (SSA) | 0.0334 slope of change in SSA uV over 52 wks |
| Topiramate | Sural Sensory Amplitude (SSA) | 0.044 slope of change in SSA uV over 52 wks |
p-value: 0.817495% CI: [-0.0793, 0.1005]Hurdle model
Secondary
Utah Early Neuropathy Scale
The UENS is a validated examination score of neuropathy severity based on a physical examination (Singleton et al 2008). Total score is 42 (minimum 0 and maximum 42). The higher the score, the worse the outcome is. The change in UENS over the 96 week period is expressed as a slope of change in total UENS over one year defined as 52 weeks.
Time frame: 96 weeks (expressed as a slope of change in total UENS over 52 weeks).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo | Utah Early Neuropathy Scale | 0.4281 Slope of change in Total UENS over 52wks |
| Topiramate | Utah Early Neuropathy Scale | 0.3671 Slope of change in Total UENS over 52wks |
p-value: 0.900795% CI: [-1.0213, 0.8992]Mixed Models Analysis