Clinical trial NCT02423434: Evaluation of Corneal Confocal Microscopy for the Identification and Prediction of Neuropathy in Type 1 Diabetes
Official title: Multinational Collaborative Evaluation of Corneal Confocal Microscopy as a Surrogate Endpoint for the Identification and Prediction of Diabetic Neuropathy in Type 1 Diabetes
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Diabetic Polyneuropathy
Diabetes Mellitus
Diabetes Mellitus, Type 1
Diabetes Mellitus, Type 2
Diabetes Complications
Keywords: Corneal Confocal Microscopy
Diabetes Mellitus
Type 1 Diabetes Mellitus
Type 2 Diabetes Mellitus
Diabetic Neuropathy
Diabetes Complications
Lead sponsor: Samuel Lunenfeld Research Institute, Mount Sinai Hospital
Sponsor class: OTHER
Collaborators: name: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
name: University of Calgary
name: Queensland University of Technology
name: University of Michigan
name: University of Manchester
First posted: 2015-04-22
Enrollment: 624
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
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.

Brief summary: 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: 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.

Eligibility criteria: 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)

Primary outcomes:
measure: Evaluate the Concurrent Validity of CCM Parameters from Cross-Sectional Analysis of Well-Characterized T1D and T2D Subjects.
timeFrame: Any data obtained from pre-study measurements
measure: 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
timeFrame: Study visit
measure: Evaluate the Predictive Validity of CCM Parameters for 5-7 year Progression of Neuropathy
timeFrame: Study visit
measure: Comparison of Manual versus Automated Image analysis
timeFrame: Pre-study and study visit data
Secondary outcomes:
measure: Determination of the Factors associated with CCM Parameters and their Longitudinal Change
timeFrame: Study visit
Other outcomes:
Locations:
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Brisbane
country: Australia
facility: Queensland University of Technology
city: Calgary
country: Canada
facility: University of Calgary
state: Alberta
city: Toronto
country: Canada
facility: Mount Sinai Hospital and University Health Network
state: Ontario
city: Manchester
country: United Kingdom
facility: University of Manchester
Study officials:
affiliation: MOUNT SINAI HOSPITAL
name: Bruce A Perkins, MD
role: PRINCIPAL_INVESTIGATOR
References:
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