Comparison of Histamine and Local Heating for Evoking the Axon-reflex Flare Response in Diabetes (HistaHeat)

Diabetic peripheral neuropathy is the most common complication to diabetes mellitus affecting as much as 50% of the population with diabetes. Symmetrical sensory neuropathy is by far the most common pattern, which often progress slowly over many years, although some individuals experience faster and more severe courses. Despite the frequent occurrence, the causes of diabetic peripheral neuropathy are largely unknown, which is reflected in the fact that no disease-modifying treatments are available for preventing, treating or even halting the progression of the disease. The consequences can be dire, as neuropathy frequently leads to foot ulcers, amputations or intolerable neuropathic pain in the lower extremities. Sensory loss may go completely undetected in diabetes, as there often are literally no symptoms. For many individuals, the development of diabetic peripheral neuropathy can therefore proceed completely unnoticed, making regular screening the most important tool for diagnosing the condition. Unfortunately, unlike nephropathy or retinopathy, diabetic peripheral neuropathy is not easily screened for, as the condition lacks reliable markers for early- or progressing disease. Therefore, screening for diabetic peripheral neuropathy currently revolves around diagnosing loss of protective sensation, judged by the inability to feel vibration or light touch. However, in their most recent guidelines, the American Diabetes Association has included screening for small fibre neuropathy using either the cold- and heat perception thresholds or pinprick as a clinical standard. Although this acknowledgement of the importance of assessing not only large- but also small nerve fibres is a huge step towards early detection of diabetic peripheral neuropathy, the overriding issue of insensitive, unreproducible, and inaccurate bedside tests for small nerve fibres remains. While cold- and heat perception and pinprick sensation are indeed mediated by small nerve fibres, the sensitivity of these methods, outside of extreme standardization only achievable in dedicated neuropathy research-centres, remain poor and not usable on an individual level. This lack of sensitivity has also become apparent in several large clinical trials, where the methods have continuously failed as robust clinical endpoints. Due to this, the hunt for a sensitive and reproducible method for adequate assessment of the small nerve fibres have begun. Amongst several interesting methods, two have gained particular interest (corneal confocal microscopy and skin biopsies with quantification of intra-epidermal nerve fiber density), due to their diverse strengths, although clinical application is currently limited to a few specialized sites. Furthermore, both methods suffer several inherent issues including that fact that they only provide information about the structure of the nerves and not the function. One method to assess the function of small cutaneous C-fibers is the assessment of the axon reflex flare response using laser doppler imaging (LDI) or Full-field laser perfusion imaging (FLPI), which has classically been studied using local heating. Unfortunately, this method is limited in clinical usage due to time-consumption. The investigators recently published an alternative method using a simple skin-prick application of histamine to evoke the response, which reduced the examination-time markedly. Before claiming the method to be a better alternative, the investigators do however need to prove that the method is as good as the original.

In addition to the direct comparison of the histamine-induced and the heating-induced axon-reflex flare response the study will also assess spatial acuity in the same cohort as a secondary aim. Spatial acuity is considered as a measure of the sensory systems ability to code spatial information regarding an external stimulus. To investigate the spatial acuity, the 2-point discrimination task (2PDT) is often used. Spatial acuity has been shown to be impaired in several chronic pain condition. Additionally, it has been shown that the 2PDT may be a useful tool to understand the sensory changes in diabetes[8].

Study Overview

• Status: Enrolling by invitation
• Conditions: Diabetes; Diabetes Mellitus, Type 1; Diabetic Neuropathy Peripheral; Small Fiber Neuropathy
• Intervention / Treatment: Diagnostic test: Histamin-induced axon-reflex flare response; Diagnostic test: Local heating-induced axon-reflex flare response; Diagnostic test: 2-point discrimination tasks; Diagnostic test: NC-Stat DPNCheck; Diagnostic test: QST; Diagnostic test: Biothesiometry

• Study Type: Observational
• Enrollment (Estimated): 50

Contacts and Locations

• Study Contact: Name: Johan Røikjer, PhD; Phone Number: +45 97663651; Email: j.roeikjaer@rn.dk
• Study Contact Backup: Name: Niels Ejskjaer, PhD; Phone Number: +45 97663656; Email: n.ejskjaer@rn.dk

Study Locations

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: N/A

• Sampling Method: Probability Sample

Study Population

People with T1DM

Description

Inclusion Criteria:

• Age 18-75 years and diagnosed with type 1 diabetes

Exclusion Criteria:

• Known critical limb ischemia (ankle-brachial index < 50 mmHg or toe-brachial index < 30 mmHg)
• Symptoms of claudicatio intermittens
• Inability to do without antihistamine for 24h prior to examination
• Known neurological disease (e.g., multiple sclerosis)
• Severe skin diseases on either foot (e.g., fulminant pemphigoid)
• Previous or current alcohol or drug abuse
• Previous or current chemotherapy or current disseminated cancer
• Known cause of neuropathy other than diabetes
• Previous amputation on either foot
• Active diabetic foot ulcer on either foot
• Pregnancy
• Inability to participate or other condition thought to impact the results (evaluated by investigator)
• Asymmetrical neuropathy (i.e., previous accident with radiating pain)

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort

Intervention / Treatment

T1DM; People with type 1 diabetes

Diagnostic test: Histamin-induced axon-reflex flare response; Histamin-induced axon-reflex flare response; Diagnostic test: Local heating-induced axon-reflex flare response; Local heating-induced axon-reflex flare response; Diagnostic test: 2-point discrimination tasks; 2-point discrimination tasks; Diagnostic test: NC-Stat DPNCheck; NC-Stat DPNCheck; Diagnostic test: QST; QST; Other Names: Quantitative Sensory Testing, thermal; Diagnostic test: Biothesiometry; Biothesiometry; Other Names: VPT

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Comparison of axon-reflex flare responses with QST	Comparison of axon reflex flare responses with an established method (area size vs cold and heat detection threshold)	Through study completion, an average of 1-2 years
Comparison of histamine and local heating (area size)	The evoked area (assessed by full-field laser speckle perfusion imaging) by histamine and local heating will be compared as a proxy for small fiber neuropathy in diabetes	Through study completion, an average of 1-2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
2PDT in diabetes with and without DPN	Assess spatial acuity through 2PDT in people with diabetes with and without DPN.	Through study completion, an average of 1-2 years
Comparison of axon-reflex flare responses with NC-Stat DPNCheck	Comparison of axon reflex flare responses with an established method (sural nerve conduction velocity/amplitude)	Through study completion, an average of 1-2 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
DPN severity and pain	Correlations between DPN severity (including pain) and methods	Through study completion, an average of 1-2 years
Exploratory	This endpoint will report correlations between the different methods used in the study. These correlations are exploratory and not predetermined	Through study completion, an average of 1-2 years

Collaborators and Investigators

• Sponsor: Aalborg University Hospital
• Collaborators: Aalborg University

Study record dates

Study Major Dates

• Study Start (Actual): June 17, 2023
• Primary Completion (Estimated): June 17, 2024
• Study Completion (Estimated): December 31, 2024

Study Registration Dates

• First Submitted: June 7, 2023
• First Submitted That Met QC Criteria: June 26, 2023
• First Posted (Actual): June 27, 2023

Study Record Updates

• Last Update Posted (Actual): June 29, 2023
• Last Update Submitted That Met QC Criteria: June 28, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Keywords: Diabetes; Neuropahty
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Nervous System Diseases; Immune System Diseases; Autoimmune Diseases; Endocrine System Diseases; Diabetes Complications; Neuromuscular Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 1; Peripheral Nervous System Diseases; Diabetic Neuropathies; Small Fiber Neuropathy; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Histamine Agents; Histamine Agonists; Histamine
• Other Study ID Numbers: N-20230007

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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