Evaluation of Corneal Confocal Microscopy for the Identification and Prediction of Neuropathy in Type 1 Diabetes

November 4, 2019 updated by: Samuel Lunenfeld Research Institute, Mount Sinai Hospital

Multinational Collaborative Evaluation of Corneal Confocal Microscopy as a Surrogate Endpoint for the Identification and Prediction of Diabetic Neuropathy in Type 1 Diabetes

Through the multinational pooled dataset approach, this trial will aim to derive and validate specific in vivo Corneal Confocal Microscopy (CCM) parameter thresholds for the identification of diabetic polyneuropathy, and - more importantly - the identification of individuals at future risk. Results of the study will permit application in clinical practice and intervention trials for diabetic polyneuropathy (DPN) risk stratification.

The primary goal of the study is to re-examine individuals with type 1 and type 2 diabetes with and without neuropathy, who had CCM performed in the past as a part of their neurological examination, to assess concurrent and predictive validity of different CCM parameters in individuals . These subjects will be invited to the study to be re-examined by CCM along with other neurological tests (physical exam, nerve conduction studies, quantitative sensory testing, blood test and in some centres also skin biopsy) during the single study visit. Additionally CCM data will be analyzed both manually and by recently developed automated analytical software to evaluate accuracy of the automated method. Evaluation of automated image analysis will influence likelihood of successful knowledge translation of this surrogate biomarker for DPN into clinical practice - in which the procedure could be harmonized with annual retinal examinations - and into intervention trials.

Secondary aim of the study is to determine the factors associated with CCM parameters and their longitudinal change and collect bio-samples for future research in this field.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

The diffuse injury to peripheral nerves (diabetic neuropathy) is exceptionally common in type 1 diabetes, but there is a lack of an objective surrogate marker to identify early subclinical stages when treatments might be most effective, prior to late-stage progression to troublesome and costly foot infection, ulceration, and limb amputation. In contrast to the ability to objectively measure disease-specific surrogate markers for retinopathy and nephropathy, this lack of a diabetic neuropathy surrogate marker has seriously impeded the development of specific interventions in clinical research trials. Representing 5 independent research groups that have together created a consortium of investigators dedicated to the development of a surrogate marker for early diabetic neuropathy, we have focused on using the eye as a window to non-invasively image by a method of in-vivo corneal confocal microscopy (CCM) the small nerve fibres that innervate the cornea. We have demonstrated that changes in these nerve fibre endings occur early in the development of neuropathy, reflect well the changes seen in other peripheral nerves by invasive skin biopsy evaluation, and that their measurement is feasible and reproducible. As a multinational consortium, we have the benefit in this proposal of pooling multiple cohorts to apply the most valid study methods in biomarker development. First, we aim to determine in the analysis of an existing pooled dataset of 516 type 1 and 524 type 2 diabetes subjects the exact levels of CCM measurement that can identify the presence of diabetic neuropathy. Secondly, we propose over three years to re-examine at least 70% of this cohort, which will provide 5- to 7-year follow-up data to determine which type and level of CCM measurement can predict the future onset of neuropathy, as well as its progression in those who had neuropathy at baseline. Finally, we will evaluate the role of time- and cost-saving automated image analysis software. By virtue of large sample size from data pooling, we are uniquely afforded the methodological power to confirm our objectives by way of separate derivation and validation analysis sets. Through a unique and unprecedented multinational pooled dataset approach for diabetic neuropathy, this work will derive and validate specific CCM parameter thresholds for the identification of neuropathy, and - more importantly - the identification of individuals at future risk. These results will permit application in clinical practice and intervention trials for neuropathy risk stratification. Evaluation of automated image analysis will influence likelihood of successful knowledge translation of this surrogate biomarker into clinical practice - in which the procedure could be harmonized with annual retinal examinations - and into intervention trials.

Study Type

Observational

Enrollment (Actual)

624

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Australia
      • Brisbane, Australia, 4059
        • Queensland University of Technology
  • Canada
    • Alberta
      • Calgary, Alberta, Canada, T3B6A8
        • University of Calgary
    • Ontario
      • Toronto, Ontario, Canada, M5G 2C4
        • Mount Sinai Hospital and University Health Network
  • United Kingdom
      • Manchester, United Kingdom, M139PT
        • University of Manchester
  • United States
    • Michigan
      • Ann Arbor, Michigan, United States, 48105
        • University of Michigan

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Sampling Method

Non-Probability Sample

Study Population

This longitudinal observational cohort study of diagnosis involves follow-up in two study groups:

A. Five- to seven-year follow-up re-examination of 5 well-characterized type 1 diabetes (T1D) cohorts (N=516) comprising a neuropathic subset and a non-neuropathic subset.

B. Three- to six-year follow-up re-examination of 4 well-characterized type 2 diabetes (T2D) cohorts (N=524) each comprising a neuropathic subset and a non-neuropathic subset.

T1D Subjects. The five study sites are composed of cohort studies for T1D initiated between 2008 and 2011. Together, the five sites have studied 516 subjects at baseline with T1D, 363 without DPN and 151 with DPN at baseline.

T2D Subjects. Four of the sites have studied subjects with T2D. Together, the four sites have studied 524 subjects at baseline with T2D, 241 without DPN and 283 with DPN at baseline.

Of the 1040 total subjects examined in baseline procedures, we anticipate follow-up of 70% for a total re-examined cohort 729.

Description

Inclusion Criteria:

  • Individuals of any gender or race aged 18 or above
  • Type 1 diabetes mellitus or type 2 diabetes mellitus as defined by the American Diabetes Association guidelines (2014) of any duration
  • Availability of the initial CCM examination performed two to eight years ago
  • Ability to understand and cooperate with study procedures

Exclusion Criteria:

  • Confirmed to have neuropathy owing to non-diabetic causes (such as familial, alcoholic, nutritional, uremic)
  • Current eye infection, corneal damage, or severe movement disorders which could preclude a safe CCM exam
  • Allergy to proparacaine (the ocular topical anaesthetic used for the CCM exam)

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Cohorts and Interventions

Group / Cohort
Intervention / Treatment
Corneal Confocal Microscopy subjects
Other: Exposure: Corneal nerve fibre morphology by the CCM Procedure

CCM is a non-invasive method for direct visualization of corneal nerve fibers. Previous research work has confirmed that corneal nerves status correlates with both small and large fibre damage as assessed by quantitative sensory testing and nerve conduction.

In the current trial subjects will undergo a bilateral examination of the Bowman's layer of the cornea using the Rostock Cornea Module of the Heidelberg Tomograph III (Heidelberg Engineering, Smithfield RI, USA) to determine their corneal nerve fiber length, corneal nerve fiber density, corneal nerve branch density, and the tortuosity coefficient. Topical anaesthetic and a viscous gel medium will be applied to the eye, which will create a visual gel bridge between the cornea and the sterile single-use cap on the microscope objective lens. After the interface between the corneal epithelium and Bowman's layer is identified, batches of images will be taken and the most technically sound images will be identified and analyzed.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Evaluate the Concurrent Validity of CCM Parameters from Cross-Sectional Analysis of Well-Characterized T1D and T2D Subjects.
Time Frame: Any data obtained from pre-study measurements
Any data obtained from pre-study measurements
Evaluate the Predictive Validity of CCM Parameters based on the 5-7 year Incidence of Neuropathy in Well-Characterized T1D and T2D Subjects Without Neuropathy at Baseline
Time Frame: Study visit
Study visit
Evaluate the Predictive Validity of CCM Parameters for 5-7 year Progression of Neuropathy
Time Frame: Study visit
Study visit
Comparison of Manual versus Automated Image analysis
Time Frame: Pre-study and study visit data
Pre-study and study visit data

Secondary Outcome Measures

Outcome Measure
Time Frame
Determination of the Factors associated with CCM Parameters and their Longitudinal Change
Time Frame: Study visit
Study visit

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Samuel Lunenfeld Research Institute, Mount Sinai Hospital

Collaborators

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
University of Michigan
University of Calgary
University of Manchester
Queensland University of Technology

Investigators

  • Principal Investigator: Bruce A Perkins, MD, Mount Sinai Hospital

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

September 1, 2014

Primary Completion (Actual)

August 1, 2018

Study Completion (Actual)

August 1, 2018

Study Registration Dates

First Submitted

April 17, 2015

First Submitted That Met QC Criteria

April 17, 2015

First Posted (Estimate)

April 22, 2015

Study Record Updates

Last Update Posted (Actual)

November 6, 2019

Last Update Submitted That Met QC Criteria

November 4, 2019

Last Verified

November 1, 2019

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • DP3DK104386 (U.S. NIH Grant/Contract)
  • 1DP3DK104386-01 (U.S. NIH Grant/Contract)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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