Methods of Early Detection and Grading Of Diabetic Peripheral Neuropathy (MEDON) (MEDON)

Perception Threshold Tracking(PTT): A Novel Method for Early Detection and Grading of Diabetic Peripheral Neuropathy

MEDON aims to examine new methods for early detection and grading of diabetic peripheral neuropathy focusing on both small- and large nerve fibers. Furthermore, MEDON aims to describe differences between people with classic diabetic peripheral neuropathy and those with painful diabetic neuropathy.

Study Overview

• Status: Completed
• Conditions: Neuropathy, Diabetic; Neuropathy, Painful
• Intervention / Treatment: Diagnostic test: Perception Threshold Tracking (PTT); Diagnostic test: Axon-flair mediated respons; Diagnostic test: Heart rate variability; Diagnostic test: Quantitative Sensory Testing (QST); Diagnostic test: Peripheral blood pressure and transcutaneous oxygen tension; Diagnostic test: Magnetic Resonance Imaging (MRI); Diagnostic test: Questionnaires; Diagnostic test: Corneal Confocal Microscopy /CCM)

• Study Type: Observational
• Enrollment (Actual): 80

Contacts and Locations

Study Locations

• Denmark
  • North Denmark
    • Aalborg, North Denmark, Denmark, 9000
      • Aalborg University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

The study population include four well-defined groups of subjects:

1. Patients with Type 1 diabetes and painful diabetic peripheral neuropathy (DPN).
2. Patients with Type 1 diabetes and non-painful diabetic peripheral neuropathy (DPN)
3. Patients with Type 1 diabetes and without diabetic peripheral neuropathy (VPT<15) (DPN).
4. Healthy control subjects matched for age, BMI, and gender. Diabetes duration, HbA1c, insulin use, ethnicity, and co-morbidities will be matched between group 1, 2 and 3 to best ability.

Description

Inclusion Criteria:

1. Men and women minimum 18 years of age and maximum 75 years of age
2. Signed informed consent form
3. Diagnosed with diabetes type I (for group 1-3)
4. Diagnosed with DPN defined as a threshold above 25-volt biothesiometry or absent feeling on the big toe using 10g-monofilament. (for group 1-2)
5. Answered questionnaire: PainDETECT
6. Nothing abnormal on initial tests (group 4)
7. Accepted initial screening blood samples
8. MRI-compatible participant

Exclusion Criteria:

• 1. Current or previous alcohol- or drug abuse 2. Abnormal screening blood samples 3. Not being able to understand Danish written and/or verbally 4. Not being able to corporate to examination (e.g. not being able to speak, suffering from senile dementia etc.) 5. Previous chemotherapy or intake of experimental medicine 6. Active HSV- or VZV-infection or known HIV 7. Known severe skin disease 8. Known neural damage or disease in the neural system (e.g. MS, Guillain-Barre etc.) 9. Critical limb ischemia defined as in current clinical consensus 10. Allergy or intolerance to histamine or inability to make do without for one day 11. Pregnancy 12. Active cancer-disease

Study Plan

How is the study designed?

Number of groups / cohorts

4

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Type 1 diabetes and painful neuropathy; No interventions. A series of observationel/expirimental methods for detecting and grading neuropathy will be applied.	Diagnostic test: Perception Threshold Tracking (PTT); low-current electrical stimulation of both large- and small nerve fibers.; Diagnostic test: Axon-flair mediated respons; Laser-doppler examination of small blood vessels in the peripheral skin.; Other Names: Laser-doppler; Diagnostic test: Heart rate variability; 4 measurements of heart rate.; Other Names: Vagus TM; Diagnostic test: Quantitative Sensory Testing (QST); Seven tests measuring 13 parameters including heat- and cold-detection and pain thresholds, mechanical pain treshold, mechanical detection threshold, pressure pain treshold and vibration threshold.; Other Names: German Research Network on Neuropathic Pain (DFNS) standard protocol; Diagnostic test: Peripheral blood pressure and transcutaneous oxygen tension; Ankle/brachial index, toe/brachial index, TcpO2.; Other Names: Perimed 6000; Diagnostic test: Magnetic Resonance Imaging (MRI); MRI-scans of peripheral nerves and the central nervous system. Blood oxygen level dependent (BOLD) MRI.; Diagnostic test: Questionnaires; Questionnaires for detecting painful neuropathy; Other Names: PainDETECT, Douleur Neuropathique 4; Diagnostic test: Corneal Confocal Microscopy /CCM); Confocal microscopy of the cornea measuring NBD, NFD, NFL
Type 1 diabetes and non-painful neuropathy; No interventions. A series of observationel/expirimental methods for detecting and grading neuropathy will be applied.	Diagnostic test: Perception Threshold Tracking (PTT); low-current electrical stimulation of both large- and small nerve fibers.; Diagnostic test: Axon-flair mediated respons; Laser-doppler examination of small blood vessels in the peripheral skin.; Other Names: Laser-doppler; Diagnostic test: Heart rate variability; 4 measurements of heart rate.; Other Names: Vagus TM; Diagnostic test: Quantitative Sensory Testing (QST); Seven tests measuring 13 parameters including heat- and cold-detection and pain thresholds, mechanical pain treshold, mechanical detection threshold, pressure pain treshold and vibration threshold.; Other Names: German Research Network on Neuropathic Pain (DFNS) standard protocol; Diagnostic test: Peripheral blood pressure and transcutaneous oxygen tension; Ankle/brachial index, toe/brachial index, TcpO2.; Other Names: Perimed 6000; Diagnostic test: Magnetic Resonance Imaging (MRI); MRI-scans of peripheral nerves and the central nervous system. Blood oxygen level dependent (BOLD) MRI.; Diagnostic test: Questionnaires; Questionnaires for detecting painful neuropathy; Other Names: PainDETECT, Douleur Neuropathique 4; Diagnostic test: Corneal Confocal Microscopy /CCM); Confocal microscopy of the cornea measuring NBD, NFD, NFL
Type 1 diabetes and no neuropathy; No interventions. A series of observationel/expirimental methods for detecting and grading neuropathy will be applied.	Diagnostic test: Perception Threshold Tracking (PTT); low-current electrical stimulation of both large- and small nerve fibers.; Diagnostic test: Axon-flair mediated respons; Laser-doppler examination of small blood vessels in the peripheral skin.; Other Names: Laser-doppler; Diagnostic test: Heart rate variability; 4 measurements of heart rate.; Other Names: Vagus TM; Diagnostic test: Quantitative Sensory Testing (QST); Seven tests measuring 13 parameters including heat- and cold-detection and pain thresholds, mechanical pain treshold, mechanical detection threshold, pressure pain treshold and vibration threshold.; Other Names: German Research Network on Neuropathic Pain (DFNS) standard protocol; Diagnostic test: Peripheral blood pressure and transcutaneous oxygen tension; Ankle/brachial index, toe/brachial index, TcpO2.; Other Names: Perimed 6000; Diagnostic test: Magnetic Resonance Imaging (MRI); MRI-scans of peripheral nerves and the central nervous system. Blood oxygen level dependent (BOLD) MRI.; Diagnostic test: Questionnaires; Questionnaires for detecting painful neuropathy; Other Names: PainDETECT, Douleur Neuropathique 4; Diagnostic test: Corneal Confocal Microscopy /CCM); Confocal microscopy of the cornea measuring NBD, NFD, NFL
Matched controls without diabetes; No interventions. A series of observationel/expirimental methods for detecting and grading neuropathy will be applied.	Diagnostic test: Perception Threshold Tracking (PTT); low-current electrical stimulation of both large- and small nerve fibers.; Diagnostic test: Axon-flair mediated respons; Laser-doppler examination of small blood vessels in the peripheral skin.; Other Names: Laser-doppler; Diagnostic test: Heart rate variability; 4 measurements of heart rate.; Other Names: Vagus TM; Diagnostic test: Quantitative Sensory Testing (QST); Seven tests measuring 13 parameters including heat- and cold-detection and pain thresholds, mechanical pain treshold, mechanical detection threshold, pressure pain treshold and vibration threshold.; Other Names: German Research Network on Neuropathic Pain (DFNS) standard protocol; Diagnostic test: Peripheral blood pressure and transcutaneous oxygen tension; Ankle/brachial index, toe/brachial index, TcpO2.; Other Names: Perimed 6000; Diagnostic test: Magnetic Resonance Imaging (MRI); MRI-scans of peripheral nerves and the central nervous system. Blood oxygen level dependent (BOLD) MRI.; Diagnostic test: Questionnaires; Questionnaires for detecting painful neuropathy; Other Names: PainDETECT, Douleur Neuropathique 4; Diagnostic test: Corneal Confocal Microscopy /CCM); Confocal microscopy of the cornea measuring NBD, NFD, NFL

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Diagnostic value of CCM, PTT, AF and MRI	Using Quantitative Sensory Testing (small fibers) and conventional nerve conduction studies (large fibers) as golden standards, we will determine the prognostic value of: Perception Threshold Tracking Corneal Confocal Microscopy Axon-flair mediated response MRI-scans in detecting neuropathy. Sensitivity and specificity will be reported. OBS! Tests will be tested in the initial groups and AFTER a group re-arrangement based on results from QST and NCS.	End of study (when all patients have completed all sessions. Latest 31. december 2021)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Validation of PainDETECT in diabetes	Correlation between PainDETECT and DN4 will be reported.	End of study / end of inclusion (when all patients have completed the screening session. Latest 31. november 2021)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Exploratory measures	An multi-variant analysis to determine the predictive ability of combinations of primary outcome measures.	End of study (latest december 31 2021).

Collaborators and Investigators

• Sponsor: Aalborg University Hospital
• Collaborators: Aalborg University
• Investigators: Principal Investigator: Niels Ejskjær, Professor, Steno Diabtes Center North Denmark, Aalborg University Hospital

Publications and helpful links

General Publications

• Roikjer J, Croosu SS, Frokjaer JB, Hansen TM, Arendt-Nielsen L, Ejskjaer N, Morch CD. Perception threshold tracking: validating a novel method for assessing function of large and small sensory nerve fibers in diabetic peripheral neuropathy with and without pain. Pain. 2022 Sep 19. doi: 10.1097/j.pain.0000000000002780. Online ahead of print.

Study record dates

Study Major Dates

• Study Start (ACTUAL): August 12, 2019
• Primary Completion (ACTUAL): August 31, 2021
• Study Completion (ACTUAL): August 31, 2021

Study Registration Dates

• First Submitted: August 28, 2019
• First Submitted That Met QC Criteria: September 2, 2019
• First Posted (ACTUAL): September 6, 2019

Study Record Updates

• Last Update Posted (ACTUAL): November 2, 2021
• Last Update Submitted That Met QC Criteria: November 1, 2021
• Last Verified: November 1, 2021

More Information

Terms related to this study

• Keywords: diabetes; early detection; neuropathy; small nerve fibers
• Additional Relevant MeSH Terms: Nervous System Diseases; Endocrine System Diseases; Diabetes Complications; Diabetes Mellitus; Neuromuscular Diseases; Peripheral Nervous System Diseases; Diabetic Neuropathies
• Other Study ID Numbers: N-20190003

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Data will be shared with collaborating department: Department of Radiology with the purpose of analyzing the data and comparing it to their MRI scans.

Data will be shared with Aalborg University with the purpose of analyzing data.

• IPD Sharing Time Frame: During and after the study. Data will be available no longer than needed for analyzing.
• IPD Sharing Access Criteria: anonymized data
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No