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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Diabetic Polyneuropathy, Diabetes Mellitus, Diabetes Mellitus, Type 1, Diabetes Mellitus, Type 2, Diabetes Complications

Intervention / Treatment
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* Other: Exposure: Corneal nerve fibre morphology by the CCM Procedure


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Corneal Confocal Microscopy subjects<br> | Other: Exposure: Corneal nerve fibre morphology by the CCM Procedure<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluate the Concurrent Validity of CCM Parameters from Cross-Sectional Analysis of Well-Characterized T1D and T2D Subjects. |  | 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 |  | Study visit | 
| Evaluate the Predictive Validity of CCM Parameters for 5-7 year Progression of Neuropathy |  | Study visit | 
| Comparison of Manual versus Automated Image analysis |  | Pre-study and study visit data | 

Secondary Outcome Measures

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

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Corneal Confocal Microscopy, Diabetes Mellitus, Type 1 Diabetes Mellitus, Type 2 Diabetes Mellitus, Diabetic Neuropathy, Diabetes Complications