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Muscarinic Receptor Antagonists as a Therapy for Diabetic Neuropathy

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ClinicalTrials.gov Identifier: NCT03050827
Recruitment Status : Completed
First Posted : February 13, 2017
Last Update Posted : February 22, 2019
Sponsor:
Collaborator:
National Institutes of Health (NIH)
Information provided by (Responsible Party):
Aaron I. Vinik, MD, PhD, Eastern Virginia Medical School

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Diabetic; Neuropathic, Polyneuropathy (Manifestation) Drug: 3% oxybutynin Drug: Placebo Phase 3

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 51 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: The 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. Subjects with IENF loss of between 20-75% of normative values11 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 study visit and will undergo a series of measurements and 3 mm skin biopsy from the treated region of skin.
Masking: Triple (Participant, Care Provider, Investigator)
Masking Description: 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.
Primary Purpose: Treatment
Official Title: Muscarinic Receptor Antagonists as a Therapy for Diabetic Neuropathy
Actual Study Start Date : May 1, 2014
Actual Primary Completion Date : August 17, 2017
Actual Study Completion Date : December 31, 2017

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Arm Intervention/treatment
Active Comparator: 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,
Drug: 3% oxybutynin
Topical Gelnique 3%TM (3% oxybutynin) applied daily for 20 weeks in type 2 diabetic subjects with established peripheral neuropathy. Subjects will be randomized into placebo or active drug arms and instructed in how to apply 84 mg Gelnique 3%TM or hydrogel placebo to cover a 2 by 2 region of skin adjacent to the initial biopsy site. Treatment will continue daily for 20 weeks, with monthly phone calls to monitor compliance.
Other Name: Gelnique 3%TM

Placebo Comparator: 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,
Drug: Placebo
Non-active placebo for 3% oxybutynin




Primary Outcome Measures :
  1. Intraepidermal Nerve Fiber Density [ Time Frame: 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.

  2. Sudomotor Function [ Time Frame: 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.

  3. Ocular Nerve Fiber Density [ Time Frame: 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.


Secondary Outcome Measures :
  1. Nerve Conduction Studies [ Time Frame: One Year ]
    The XLtek Neuromax (XLtek, Inc., Ontario) and standard electrophysiological leads, stimulators, and techniques will be used for the nerve conduction tests. It is performed on the upper extremities (hands) and lower extremities (legs).

  2. Quantitative Sensory Tests - Cold Pain Threshold [ Time Frame: One Year ]
    The investigators will measure small fiber somatosensory function including cold pain thresholds at the dominant great toe, forearm, lateral aspect of proximal lower limb and finger in all subjects. Generally for each of these non-noxious sensations we will use the method of limits, 4 ascending trials with an inter-stimulus interval randomly varying from 4 to 20 seconds using the Medoc TSA 2001 / VSA 3000 (Medoc Advanced Medical, Minneapolis, MN).

  3. Quantitative Sensory Tests - Heat Pain Threshold [ Time Frame: One Year ]
    The investigators will measure small fiber somatosensory function including heat pain thresholds at the dominant great toe, forearm, lateral aspect of proximal lower limb and finger in all subjects. Generally for each of these non-noxious sensations we will use the method of limits, 4 ascending trials with an inter-stimulus interval randomly varying from 4 to 20 seconds using the Medoc TSA 2001 / VSA 3000 (Medoc Advanced Medical, Minneapolis, MN).

  4. Quantitative Sensory Test - Cold Thermal Sensation [ Time Frame: One Year ]
    The investigators will measure small fiber somatosensory function including cold thermal sensation at the dominant great toe, forearm, lateral aspect of proximal lower limb and finger in all subjects. Generally for each of these non-noxious sensations we will use the method of limits, 4 ascending trials with an inter-stimulus interval randomly varying from 4 to 20 seconds using the Medoc TSA 2001 / VSA 3000 (Medoc Advanced Medical, Minneapolis, MN).

  5. Quantitative Sensory Tests - Warm Thermal Sensation [ Time Frame: One Year ]
    The investigators will measure small fiber somatosensory function including warm thermal sensation at the dominant great toe, forearm, lateral aspect of proximal lower limb and finger in all subjects. Generally for each of these non-noxious sensations we will use the method of limits, 4 ascending trials with an inter-stimulus interval randomly varying from 4 to 20 seconds using the Medoc TSA 2001 / VSA 3000 (Medoc Advanced Medical, Minneapolis, MN).

  6. Autonomic Function Tests - Standard Deviation of N-N interval [ Time Frame: One Year ]
    The investigators will use the ANSAR device, which is the most sensitive measure of cardiac variation with respiration, to the standard deviation of N-N interval. This measurement will be used to separate sympathetic and parasympathetic function and relate these results to glabrous and hairy skin innervations.

  7. Autonomic Function Tests - Root Mean Square of the Successive Differences [ Time Frame: One Year ]
    The investigators will use the ANSAR device, which is the most sensitive measure of cardiac variation with respiration, to the Root Mean Square of the Successive Differences This measurement will be used to separate sympathetic and parasympathetic function and relate these results to glabrous and hairy skin innervations.



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Ages Eligible for Study:   30 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Presence of type 2 diabetes
  • Participants between the ages of 30 and 80

Exclusion Criteria:

  1. Presence of type 1 diabetes
  2. Presence of renal insufficiency or pulmonary disease
  3. Presence of clinically significant neuropathy that is clearly of non-diabetic origin
  4. Amputations of lower extremities or presence of foot ulcers
  5. Major macrovascular events such as myocardial infarction or stroke within the past 3 months
  6. Uncontrolled or untreated hypothyroidism
  7. Abnormalities of liver function defined as any liver enzymes (AST, ALT, SGPT, SGOT) greater than 3 times the upper limit of normal
  8. Other serious medical conditions which, in the opinion of the investigator, would compromise the subject's participation in the study
  9. Stable use (> 3 months) of antioxidant supplements or drugs known to affect oxidative stress and PDN
  10. Allergy to oxybutynin or other ingredients in Gelnique 3%
  11. Pregnancy or breastfeeding

13) 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)


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03050827


Locations
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United States, Virginia
Eastern Virgnia Medical School, Strelitz Diabetes Center
Norfolk, Virginia, United States, 23510f
Sponsors and Collaborators
Eastern Virginia Medical School
National Institutes of Health (NIH)
Investigators
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Principal Investigator: Aaron I Vinik, MD, PhD Eastern Virginia Medical School
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Responsible Party: Aaron I. Vinik, MD, PhD, Director of Research & Neuroendocrine Unit, Eastern Virginia Medical School
ClinicalTrials.gov Identifier: NCT03050827    
Other Study ID Numbers: 14-04-FB-0054
First Posted: February 13, 2017    Key Record Dates
Last Update Posted: February 22, 2019
Last Verified: February 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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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:
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Diabetic Neuropathies
Polyneuropathies
Peripheral Nervous System Diseases
Neuromuscular Diseases
Nervous System Diseases
Diabetes Complications
Diabetes Mellitus
Endocrine System Diseases
Oxybutynin
Parasympatholytics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Muscarinic Antagonists
Cholinergic Antagonists
Cholinergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Urological Agents