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

NCT02423434 | Completed DMC

• 2 other identifiers: DP3DK1043861DP3DK104386-01
• Study Type: observational
• Target: 624
• Locations: 4 countries
• Sites: 5

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.

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

Outcome Measures

Primary Outcomes (4)

• 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 Outcomes (1)

• Determination of the Factors associated with CCM Parameters and their Longitudinal Change

  Study visit

Study Arms (1)

Corneal Confocal Microscopy subjects

Other: Exposure: Corneal nerve fibre morphology by the CCM Procedure

Interventions

Exposure: Corneal nerve fibre morphology by the CCM Procedure OTHER

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.

Corneal Confocal Microscopy subjects

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• 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.

You may qualify if:

• 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

You may not qualify if:

• 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)

Sponsors & Collaborators

• Samuel Lunenfeld Research Institute, Mount Sinai Hospital: lead
• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK): collaborator
• University of Calgary: collaborator
• Queensland University of Technology: collaborator
• University of Michigan: collaborator
• University of Manchester: collaborator

Study Sites (5)

University of Michigan

Ann Arbor, Michigan, 48105, United States

Location

Queensland University of Technology

Brisbane, 4059, Australia

Location

University of Calgary

Calgary, Alberta, T3B6A8, Canada

Location

Mount Sinai Hospital and University Health Network

Toronto, Ontario, M5G 2C4, Canada

Location

University of Manchester

Manchester, M139PT, United Kingdom

Location

Related Publications (33)

• Tavakoli M, Ferdousi M, Petropoulos IN, Morris J, Pritchard N, Zhivov A, Ziegler D, Pacaud D, Romanchuk K, Perkins BA, Lovblom LE, Bril V, Singleton JR, Smith G, Boulton AJ, Efron N, Malik RA. Normative values for corneal nerve morphology assessed using corneal confocal microscopy: a multinational normative data set. Diabetes Care. 2015 May;38(5):838-43. doi: 10.2337/dc14-2311. Epub 2015 Jan 29.

  PMID: 25633665 BACKGROUND

• Pritchard N, Edwards K, Russell AW, Perkins BA, Malik RA, Efron N. Corneal confocal microscopy predicts 4-year incident peripheral neuropathy in type 1 diabetes. Diabetes Care. 2015 Apr;38(4):671-5. doi: 10.2337/dc14-2114. Epub 2015 Jan 8.

  PMID: 25573881 BACKGROUND

• Tavakoli M, Begum P, McLaughlin J, Malik RA. Corneal confocal microscopy for the diagnosis of diabetic autonomic neuropathy. Muscle Nerve. 2015 Sep;52(3):363-70. doi: 10.1002/mus.24553. Epub 2015 Jun 18.

  PMID: 25556884 BACKGROUND

• Dehghani C, Pritchard N, Edwards K, Vagenas D, Russell AW, Malik RA, Efron N. Natural history of corneal nerve morphology in mild neuropathy associated with type 1 diabetes: development of a potential measure of diabetic peripheral neuropathy. Invest Ophthalmol Vis Sci. 2014 Nov 18;55(12):7982-90. doi: 10.1167/iovs.14-15605.

  PMID: 25406279 BACKGROUND

• Maddaloni E, Sabatino F, Del Toro R, Crugliano S, Grande S, Lauria Pantano A, Maurizi AR, Palermo A, Bonini S, Pozzilli P, Manfrini S. In vivo corneal confocal microscopy as a novel non-invasive tool to investigate cardiac autonomic neuropathy in Type 1 diabetes. Diabet Med. 2015 Feb;32(2):262-6. doi: 10.1111/dme.12583. Epub 2014 Sep 24.

  PMID: 25251450 BACKGROUND

• Stem MS, Hussain M, Lentz SI, Raval N, Gardner TW, Pop-Busui R, Shtein RM. Differential reduction in corneal nerve fiber length in patients with type 1 or type 2 diabetes mellitus. J Diabetes Complications. 2014 Sep-Oct;28(5):658-61. doi: 10.1016/j.jdiacomp.2014.06.007. Epub 2014 Jun 17.

  PMID: 25044236 BACKGROUND

• Asghar O, Petropoulos IN, Alam U, Jones W, Jeziorska M, Marshall A, Ponirakis G, Fadavi H, Boulton AJ, Tavakoli M, Malik RA. Corneal confocal microscopy detects neuropathy in subjects with impaired glucose tolerance. Diabetes Care. 2014 Sep;37(9):2643-6. doi: 10.2337/dc14-0279. Epub 2014 Jun 26.

  PMID: 24969581 BACKGROUND

• Edwards K, Pritchard N, Vagenas D, Russell A, Malik RA, Efron N. Standardizing corneal nerve fibre length for nerve tortuosity increases its association with measures of diabetic neuropathy. Diabet Med. 2014 Oct;31(10):1205-9. doi: 10.1111/dme.12466. Epub 2014 May 24.

  PMID: 24750318 BACKGROUND

• Ziegler D, Papanas N, Zhivov A, Allgeier S, Winter K, Ziegler I, Bruggemann J, Strom A, Peschel S, Kohler B, Stachs O, Guthoff RF, Roden M; German Diabetes Study (GDS) Group. Early detection of nerve fiber loss by corneal confocal microscopy and skin biopsy in recently diagnosed type 2 diabetes. Diabetes. 2014 Jul;63(7):2454-63. doi: 10.2337/db13-1819. Epub 2014 Feb 26.

  PMID: 24574045 BACKGROUND

• Petropoulos IN, Alam U, Fadavi H, Marshall A, Asghar O, Dabbah MA, Chen X, Graham J, Ponirakis G, Boulton AJ, Tavakoli M, Malik RA. Rapid automated diagnosis of diabetic peripheral neuropathy with in vivo corneal confocal microscopy. Invest Ophthalmol Vis Sci. 2014 Apr 3;55(4):2071-8. doi: 10.1167/iovs.13-13787.

  PMID: 24569580 BACKGROUND

• Tavakoli M, Petropoulos IN, Malik RA. Corneal confocal microscopy to assess diabetic neuropathy: an eye on the foot. J Diabetes Sci Technol. 2013 Sep 1;7(5):1179-89. doi: 10.1177/193229681300700509.

  PMID: 24124944 BACKGROUND

• Petropoulos IN, Alam U, Fadavi H, Asghar O, Green P, Ponirakis G, Marshall A, Boulton AJ, Tavakoli M, Malik RA. Corneal nerve loss detected with corneal confocal microscopy is symmetrical and related to the severity of diabetic polyneuropathy. Diabetes Care. 2013 Nov;36(11):3646-51. doi: 10.2337/dc13-0193. Epub 2013 Jul 22.

  PMID: 23877983 BACKGROUND

• Papanas N, Ziegler D. Corneal confocal microscopy: a new technique for early detection of diabetic neuropathy. Curr Diab Rep. 2013 Aug;13(4):488-99. doi: 10.1007/s11892-013-0390-z.

  PMID: 23666893 BACKGROUND

• Sivaskandarajah GA, Halpern EM, Lovblom LE, Weisman A, Orlov S, Bril V, Perkins BA. Structure-function relationship between corneal nerves and conventional small-fiber tests in type 1 diabetes. Diabetes Care. 2013 Sep;36(9):2748-55. doi: 10.2337/dc12-2075. Epub 2013 Apr 11.

  PMID: 23579181 BACKGROUND

• Halpern EM, Lovblom LE, Orlov S, Ahmed A, Bril V, Perkins BA. The impact of common variation in the definition of diabetic sensorimotor polyneuropathy on the validity of corneal in vivo confocal microscopy in patients with type 1 diabetes: a brief report. J Diabetes Complications. 2013 May-Jun;27(3):240-2. doi: 10.1016/j.jdiacomp.2012.10.011. Epub 2012 Dec 21.

  PMID: 23266297 BACKGROUND

• Shtein RM, Callaghan BC. Corneal confocal microscopy as a measure of diabetic neuropathy. Diabetes. 2013 Jan;62(1):25-6. doi: 10.2337/db12-1114. No abstract available.

  PMID: 23258907 BACKGROUND

• Efron N. Assessing diabetic neuropathy using corneal confocal microscopy. Invest Ophthalmol Vis Sci. 2012 Dec 7;53(13):8075. doi: 10.1167/iovs.12-11308. No abstract available.

  PMID: 23221463 BACKGROUND

• Tavakoli M, Petropoulos IN, Malik RA. Assessing corneal nerve structure and function in diabetic neuropathy. Clin Exp Optom. 2012 May;95(3):338-47. doi: 10.1111/j.1444-0938.2012.00743.x.

  PMID: 22594548 BACKGROUND

• Wu T, Ahmed A, Bril V, Orszag A, Ng E, Nwe P, Perkins BA. Variables associated with corneal confocal microscopy parameters in healthy volunteers: implications for diabetic neuropathy screening. Diabet Med. 2012 Sep;29(9):e297-303. doi: 10.1111/j.1464-5491.2012.03678.x.

  PMID: 22519850 BACKGROUND

• Ahmed A, Bril V, Orszag A, Paulson J, Yeung E, Ngo M, Orlov S, Perkins BA. Detection of diabetic sensorimotor polyneuropathy by corneal confocal microscopy in type 1 diabetes: a concurrent validity study. Diabetes Care. 2012 Apr;35(4):821-8. doi: 10.2337/dc11-1396. Epub 2012 Feb 8.

  PMID: 22323412 BACKGROUND

• Dabbah MA, Graham J, Petropoulos IN, Tavakoli M, Malik RA. Automatic analysis of diabetic peripheral neuropathy using multi-scale quantitative morphology of nerve fibres in corneal confocal microscopy imaging. Med Image Anal. 2011 Oct;15(5):738-47. doi: 10.1016/j.media.2011.05.016. Epub 2011 Jun 13.

  PMID: 21719344 BACKGROUND

• Tavakoli M, Kallinikos P, Iqbal A, Herbert A, Fadavi H, Efron N, Boulton AJ, A Malik R. Corneal confocal microscopy detects improvement in corneal nerve morphology with an improvement in risk factors for diabetic neuropathy. Diabet Med. 2011 Oct;28(10):1261-7. doi: 10.1111/j.1464-5491.2011.03372.x.

  PMID: 21699561 BACKGROUND

• Malik RA, Veves A, Tesfaye S, Smith G, Cameron N, Zochodne D, Lauria G; Toronto Consensus Panel on Diabetic Neuropathy. Small fibre neuropathy: role in the diagnosis of diabetic sensorimotor polyneuropathy. Diabetes Metab Res Rev. 2011 Oct;27(7):678-84. doi: 10.1002/dmrr.1222.

  PMID: 21695760 BACKGROUND

• Hertz P, Bril V, Orszag A, Ahmed A, Ng E, Nwe P, Ngo M, Perkins BA. Reproducibility of in vivo corneal confocal microscopy as a novel screening test for early diabetic sensorimotor polyneuropathy. Diabet Med. 2011 Oct;28(10):1253-60. doi: 10.1111/j.1464-5491.2011.03299.x.

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• Pritchard N, Edwards K, Shahidi AM, Sampson GP, Russell AW, Malik RA, Efron N. Corneal markers of diabetic neuropathy. Ocul Surf. 2011 Jan;9(1):17-28. doi: 10.1016/s1542-0124(11)70006-4.

  PMID: 21338566 BACKGROUND

• Efron N, Edwards K, Roper N, Pritchard N, Sampson GP, Shahidi AM, Vagenas D, Russell A, Graham J, Dabbah MA, Malik RA. Repeatability of measuring corneal subbasal nerve fiber length in individuals with type 2 diabetes. Eye Contact Lens. 2010 Sep;36(5):245-8. doi: 10.1097/ICL.0b013e3181eea915.

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• Messmer EM, Schmid-Tannwald C, Zapp D, Kampik A. In vivo confocal microscopy of corneal small fiber damage in diabetes mellitus. Graefes Arch Clin Exp Ophthalmol. 2010 Sep;248(9):1307-12. doi: 10.1007/s00417-010-1396-8. Epub 2010 May 21.

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• Tavakoli M, Quattrini C, Abbott C, Kallinikos P, Marshall A, Finnigan J, Morgan P, Efron N, Boulton AJ, Malik RA. Corneal confocal microscopy: a novel noninvasive test to diagnose and stratify the severity of human diabetic neuropathy. Diabetes Care. 2010 Aug;33(8):1792-7. doi: 10.2337/dc10-0253. Epub 2010 Apr 30.

  PMID: 20435796 BACKGROUND

• Midena E, Brugin E, Ghirlando A, Sommavilla M, Avogaro A. Corneal diabetic neuropathy: a confocal microscopy study. J Refract Surg. 2006 Nov;22(9 Suppl):S1047-52. doi: 10.3928/1081-597X-20061102-08.

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• Mocan MC, Durukan I, Irkec M, Orhan M. Morphologic alterations of both the stromal and subbasal nerves in the corneas of patients with diabetes. Cornea. 2006 Aug;25(7):769-73. doi: 10.1097/01.ico.0000224640.58848.54.

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• Hossain P, Sachdev A, Malik RA. Early detection of diabetic peripheral neuropathy with corneal confocal microscopy. Lancet. 2005 Oct 15-21;366(9494):1340-3. doi: 10.1016/S0140-6736(05)67546-0. No abstract available.

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• Kallinikos P, Berhanu M, O'Donnell C, Boulton AJ, Efron N, Malik RA. Corneal nerve tortuosity in diabetic patients with neuropathy. Invest Ophthalmol Vis Sci. 2004 Feb;45(2):418-22. doi: 10.1167/iovs.03-0637.

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• Malik RA, Kallinikos P, Abbott CA, van Schie CH, Morgan P, Efron N, Boulton AJ. Corneal confocal microscopy: a non-invasive surrogate of nerve fibre damage and repair in diabetic patients. Diabetologia. 2003 May;46(5):683-8. doi: 10.1007/s00125-003-1086-8. Epub 2003 May 9.

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MeSH Terms

Conditions

Diabetic Neuropathies; Diabetes Mellitus; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetes Complications

Condition Hierarchy (Ancestors)

Peripheral Nervous System Diseases; Neuromuscular Diseases; Nervous System Diseases; Endocrine System Diseases; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Autoimmune Diseases; Immune System Diseases

Study Officials

• Bruce A Perkins, MD

  MOUNT SINAI HOSPITAL

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 17, 2015
• First Posted: April 22, 2015
• Study Start: September 1, 2014
• Primary Completion: August 1, 2018
• Study Completion: August 1, 2018
• Last Updated: November 6, 2019

Record last verified: 2019-11

Locations

AU (1); US (1); GB (1); CA (2)