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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT02423434




Registration number
NCT02423434
Ethics application status
Date submitted
17/04/2015
Date registered
22/04/2015
Date last updated
6/11/2019

Titles & IDs
Public title
Evaluation of Corneal Confocal Microscopy for the Identification and Prediction of Neuropathy in Type 1 Diabetes
Scientific title
Multinational Collaborative Evaluation of Corneal Confocal Microscopy as a Surrogate Endpoint for the Identification and Prediction of Diabetic Neuropathy in Type 1 Diabetes
Secondary ID [1] 0 0
1DP3DK104386-01
Secondary ID [2] 0 0
DP3DK104386
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Diabetic Polyneuropathy 0 0
Diabetes Mellitus 0 0
Diabetes Mellitus, Type 1 0 0
Diabetes Mellitus, Type 2 0 0
Diabetes Complications 0 0
Condition category
Condition code
Metabolic and Endocrine 0 0 0 0
Diabetes
Neurological 0 0 0 0
Other neurological disorders

Intervention/exposure
Study type
Observational
Patient registry
Target follow-up duration
Target follow-up type
Description of intervention(s) / exposure
Other interventions - Exposure: Corneal nerve fibre morphology by the CCM Procedure

Corneal Confocal Microscopy subjects -


Other interventions: 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.
Intervention code [1] 0 0
Other interventions
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Evaluate the Concurrent Validity of CCM Parameters from Cross-Sectional Analysis of Well-Characterized T1D and T2D Subjects.
Timepoint [1] 0 0
Any data obtained from pre-study measurements
Primary outcome [2] 0 0
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
Timepoint [2] 0 0
Study visit
Primary outcome [3] 0 0
Evaluate the Predictive Validity of CCM Parameters for 5-7 year Progression of Neuropathy
Timepoint [3] 0 0
Study visit
Primary outcome [4] 0 0
Comparison of Manual versus Automated Image analysis
Timepoint [4] 0 0
Pre-study and study visit data
Secondary outcome [1] 0 0
Determination of the Factors associated with CCM Parameters and their Longitudinal Change
Timepoint [1] 0 0
Study visit

Eligibility
Key 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
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key 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 design
Purpose
Duration
Selection
Timing
Prospective
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
1/09/2014
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
1/08/2018
Sample size
Target
Accrual to date
Final
624
Recruitment in Australia
Recruitment state(s)
Recruitment hospital [1] 0 0
Queensland University of Technology - Brisbane
Recruitment postcode(s) [1] 0 0
4059 - Brisbane
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
Michigan
Country [2] 0 0
Canada
State/province [2] 0 0
Alberta
Country [3] 0 0
Canada
State/province [3] 0 0
Ontario
Country [4] 0 0
United Kingdom
State/province [4] 0 0
Manchester

Funding & Sponsors
Primary sponsor type
Other
Name
Samuel Lunenfeld Research Institute, Mount Sinai Hospital
Address
Country
Other collaborator category [1] 0 0
Government body
Name [1] 0 0
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Address [1] 0 0
Country [1] 0 0
Other collaborator category [2] 0 0
Other
Name [2] 0 0
University of Calgary
Address [2] 0 0
Country [2] 0 0
Other collaborator category [3] 0 0
Other
Name [3] 0 0
Queensland University of Technology
Address [3] 0 0
Country [3] 0 0
Other collaborator category [4] 0 0
Other
Name [4] 0 0
University of Michigan
Address [4] 0 0
Country [4] 0 0
Other collaborator category [5] 0 0
Other
Name [5] 0 0
University of Manchester
Address [5] 0 0
Country [5] 0 0

Ethics approval
Ethics application status

Summary
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.
Trial website
https://clinicaltrials.gov/study/NCT02423434
Trial related presentations / publications
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Public notes

Contacts
Principal investigator
Name 0 0
Bruce A Perkins, MD
Address 0 0
MOUNT SINAI HOSPITAL
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries



Summary Results

For IPD and results data, please see https://clinicaltrials.gov/study/NCT02423434