Muscarinic Receptor Antagonists as a Therapy for Diabetic Neuropathy
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 51
- 试验地点
- 1
- 主要终点
- Intraepidermal Nerve Fiber Density
研究概览
简要总结
Investigators propose a placebo controlled, double blinded study to examine efficacy of topical Gelnique 3%TM (3% oxybutynin) daily for 20 weeks) in improving IENF density in type 2 diabetic subjects with established peripheral neuropathy. This site most clearly demonstrated efficacy of topiramate in reversing IENF loss within 18 weeks in our prior study. Subjects will also undergo quantitative sensory testing (QST) and assays of laser Doppler skin blood flow (SkBF), neuropathy total symptom score (NTSS-6), and quality of life (Norfolk QOL-DN), along with standard measures of physiology and fasting blood chemistry. Subjects with IENF loss of between 20-75% of normative values and thus amenable to therapy-induced recovery, will be randomized into placebo (N=30) or active drug (N=30) arms and instructed in how to apply 84 mg Gelnique 3%TM or hydrogel placebo to cover a 2 in2 region of skin adjacent to the initial biopsy site, as per the manufacturers instructions (http://www.gelnique.com/gel3/). Treatment will continue daily for 20 weeks, with monthly phone calls to monitor compliance. After 20 weeks, subjects will return for a second series of measurements and 3 mm skin biopsy from the treated region of skin.
详细描述
Patient selection and characterization A total of 60 adults of both sexes and varying ethnicities, 30-80 years of age, will be recruited from Dr. Vinik's clinic. All participants will be diagnosed with established type 2 diabetes (>2 years) and diabetic peripheral neuropathy. Potential subjects will undergo a complete physical exam and a neurological exam to assess motor function and sensory perception28.
Randomizing and blinding an investigational drug will be done by assigning each patient/subject a study number in the order they are recruited. The patients are randomized using a randomizing web site at (www.randomizer.org). The randomized patient numbers are recorded. This code is then placed in an envelope and sealed. This envelope will remain sealed until the study is concluded. A blinding/randomization patient form will be completed for each patient and sealed in the individual envelopes. The outside of the envelopes will contain patient numbers for identification purposes. This will allow the research coordinator to break the individual blind in emergency situations without compromising the rest of the blinding data. All instances where the blind is broken will be documented appropriately.
Subject Recruitment Subjects of both sexes and all ethnicities will be recruited locally using the database of subjects available at The Strelitz Diabetes Research Center (SDRC) at Eastern Virginia Medical School (EVMS) as well as locally distributed flyers and notices, if needed. Approximately 60 randomized subjects are needed in this study to make a useful determination for current and future studies. Subjects who are dropped or withdraw from the study will be replaced.
Sample size estimation and data analysis:
Investigators have primarily powered the study based on variance data obtained in studies demonstrating efficacy of Topiramate on IENF density in diabetic subjects11. The sample size of 20 in each group (placebo vs. active drug) reflects the ability to detect a 20% deviation following treatment and was also sufficient to to identify therapy-induced improvements in SkBF and NTTS-6 score using a similar study design28. We intend to use ANOVA and MANOVA where data is normally distributed in raw form or in some cases after simple log-transformations. Based on these considerations, the 20 subjects in each group provide power greater than 0.80 for observing statistical significance at the p < 0.05 level. Relationships among measures of neurovascular function and changes in IENF will be determined with Spearman's rank correlation. If data are not normally distributed, the Wilcoxon signed-rank (within group) or Mann Whitney (between group) tests may be employed. The level of significance will be set at p<0.05.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Triple (Participant, Care Provider, Investigator)
盲法说明
Randomizing and blinding an investigational drug will be done by assigning each patient/subject a study number in the order they are recruited. The patients are randomized using a randomizing web site at (www.randomizer.org). The randomized patient numbers are recorded. This code is then placed in an envelope and sealed. This envelope will remain sealed until the study is concluded. A blinding/randomization patient form will be completed for each patient and sealed in the individual envelopes. The outside of the envelopes will contain patient numbers for identification purposes. This will allow the research coordinator to break the individual blind in emergency situations without compromising the rest of the blinding data. All instances where the blind is broken will be documented appropriately.
入排标准
- 年龄范围
- 30 Years 至 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Presence of type 2 diabetes
- •Participants between the ages of 30 and 80
排除标准
- •Presence of type 1 diabetes
- •Presence of renal insufficiency or pulmonary disease
- •Presence of clinically significant neuropathy that is clearly of non-diabetic origin
- •Amputations of lower extremities or presence of foot ulcers
- •Major macrovascular events such as myocardial infarction or stroke within the past 3 months
- •Uncontrolled or untreated hypothyroidism
- •Abnormalities of liver function defined as any liver enzymes (AST, ALT, SGPT, SGOT) greater than 3 times the upper limit of normal
- •Other serious medical conditions which, in the opinion of the investigator, would compromise the subject's participation in the study
- •Stable use (> 3 months) of antioxidant supplements or drugs known to affect oxidative stress and PDN
- •Allergy to oxybutynin or other ingredients in Gelnique 3%
- •Pregnancy or breastfeeding
- •History of alcohol abuse in the last year 14) Urinary retention or an enlarged prostate 15) Uncontrolled glaucoma 16) Gastric retention or gastroparesis (hard to digest food) 17) Currently taking other medicines to treat overactive bladder (Anticholinergics)
研究组 & 干预措施
3% oxybutynin
Subjects with IENF loss of between 20-75% of normative values11 and thus amenable to therapy-induced recovery, will be randomized into the active drug arm (N=30) and instructed in how to apply 84 mg Gelnique 3%TM or hydrogel placebo to cover a 2 in2 region of skin adjacent to the initial biopsy site,
干预措施: 3% oxybutynin (Drug)
Placebo
Subjects with IENF loss of between 20-75% of normative values11 and thus amenable to therapy-induced recovery, will be randomized into the placebo group arm (N=30) and instructed in how to apply 84 mg Gelnique 3%TM or hydrogel placebo to cover a 2 in2 region of skin adjacent to the initial biopsy site,
干预措施: Placebo (Drug)
结局指标
主要结局
Intraepidermal Nerve Fiber Density
时间窗: One Year
Three mm skin biopsies will be taken at the two sites (lateral aspect of the proximal lower limb), on the non-dominant limb. Patients are pre-treated with 2% lidocaine with epinephrine and the biopsy is done with a sharp punch biopsy. All biopsy procedures are performed by a physician or physician's assistant under sterile conditions. Once removed the tissues are immediately transferred to storage buffer and frozen prior to sectioning and immunohistochemistry staining with PGP 9.5. Intraepidermal nerve fiber density and dendrite length. Sweat gland innervation in skin biopsies from diabetic subjects will also be determined. Sensitivity has been increased by using a 20 x 20 grid sampling system and our preliminary data shows correlation between IENF and sweat gland innervation in human skin biopsies.
Sudomotor Function
时间窗: One Year
Sudoscan will be used to measure the impact of reduced autonomic innervation of the sweat gland system using reverse iontophoresis. Sudoscan will employ sudorimetry to assess the sweat gland nerve fibers.
Ocular Nerve Fiber Density
时间窗: One Year
The investigators will use the Heidelberg Retina Tomograph (HRT) confocal corneal microscope. The corneal module will be used to study a very detailed view of cornea structure and pathology. Digital images of the patient's cornea will be taken with a microscope and laser scanning camera. A topical anesthetic (in the form of eye drops) will be used temporarily numb the cornea.
次要结局
- Nerve Conduction Studies(One Year)
- Quantitative Sensory Test - Cold Thermal Sensation(One Year)
- Autonomic Function Tests - Root Mean Square of the Successive Differences(One Year)
- Quantitative Sensory Tests - Cold Pain Threshold(One Year)
- Quantitative Sensory Tests - Heat Pain Threshold(One Year)
- Quantitative Sensory Tests - Warm Thermal Sensation(One Year)
- Autonomic Function Tests - Standard Deviation of N-N interval(One Year)
研究者
Aaron I. Vinik, MD, PhD
Director of Research & Neuroendocrine Unit
Eastern Virginia Medical School