The MIND Study - Microangiopathy IN Diabetes

This clinical feasibility study aims to evaluate the potential of contactless and non-invasive technologies for measurement of skin microcirculatory properties and their regulatory function in healthy individuals and patients with diabetes type 1. The clinical investigation incorporates two investigational devices:

• Neko Health TCI P4: a contactless optical device based on SFDI technology, to be used for quantification of the skin microcirculation via molecular composition, such as haemoglobin / blood volume and oxygen concentrations.
• Perimed Multiflow: a contactless optical device based on laser speckle technology, to be used for quantification of the skin micro-circulation via speed resolved perfusion based on movement of the red blood cells.

These technologies are promising tools for diagnostic support of pathology in the microcirculation, such as diabetic microangiopathy. Since they are imaging technologies, collecting data over a two-dimensional surface of the skin; they may be more robust than single-point measurements as well as allowing for quantification of differences and distribution over different skin sections.

The two investigational devices are good complements, as the TCI P4 can quantify composition (concentration of molecules) and the MultiFlow can quantify flow properties (perfusion), this way one gets a good foundation to study the key properties of the micro-circulation: blood volume, oxygenation and hemodynamics.

The state of the art concerning diabetic complications and PAD (Peripheral Arterial Disease) in clinical practice is currently not proactive, but rather aimed towards reactive treatment, management, and monitoring during the later phase of tissue damage and microvascular impairment. The aim with the investigation is to find indication of disease / pathology at an early stage, by evaluation of parameters / physiological changes before manifestation of clinical complications. The state-of-the-art guidelines on diagnosis, prognosis, and management of PAD in patients with foot ulcers and diabetes are well described in the 2023 WGDF Guidelines on the Prevention and Management of Diabetes-related Foot Disease. These guidelines are based on pressure-based measurements, ABI (Ankle Brachial Index), TBI (Toe Brachial Index) and tcpO2. The pathophysiological features of PAD and diabetes foot ulcers is primarily due to altered blood perfusion and tissue oxygenation whereas the investigational device is assessing the micro-circulation (smaller vessels). However, since the micro-circulation is connected downstream to the larger vessels (macro-circulation) its perfusion will be affected by both macro- and micro-circulatory factors. Therefore, the investigational device may enable finding early indications of pathology regardless of if the issue starts in the macro- or micro-circulation. Furthermore, micro-circulatory changes correlated to PAD and diabetes in skin tissue has been proven in published research, for skin in feet [1], as well as skin in the forearm [2], [3].

The hypotheses will be analysed by correlation analysis (simple regression coefficients) between physiological response and the measured parameters, along with other analytical methods suitable for understanding these correlations. Interpretation of the observed physiological response will be based on theoretical background as well as results from the comparator devices. Data of patients with diabetes type 1 and different severities of clinical microangiopathy will be compared to healthy controls, in order to see if responses are altered by diabetes microangiopathy and if they can be isolated from normal variation in the control group.

Furthermore, the hypothesis is also that different body sites are affected differently and at different stages of pathology, due to the local properties and environment of the different sites. The relation in properties between the sites may also be altered by diabetes microangiopathy. For example, peripheral body sites are usually seen to be affected first by pathology. The following body sites will be investigated:

• Volar side of forearm
• Palm of hand
• Dorsal and plantar side of feet

The main outcomes are listed below, however all generated datatypes of each examination will be analysed for any correlations between them and the status of the patient, to ensure that important correlations and learnings are not missed, even if the specific correlation was not expected.

Phase 1: Severe Diabetic Complications (50 patients)

Inclusion criteria

• Severe type 1 diabetes (microangiopathy / diabetic feet), severe angiopathy defined as proliferative retinopathy, macroalbuminuria, and kidney failure with at least CKD-class 3B and severe neuropathy with or without foot ulcers.
• Age range: primarily 18-45 years, if not sufficient number of subjects can be found, then 18-60 years span is considered

Phase 2: Scale of severity. In phase 2, patients are included with a broad range of severity levels. Patients with diabetes type 1 will be included.

Inclusion criteria

• Age range: 18-45 years (younger patients are targeted for focus on microvascular complications, rather than age-related cardiovascular disease)
• Patient with no microangiopathy, except for simplex or background retinopathy, which is in an early and reversible state (group a), 100 patients.
• Patient with mild microangiopathy, mild-moderate non-proliferative retinopathy and/or microalbuminuria and/or early signs of neuropathy (group b), 100 patients.
• Patient with moderate microangiopathy. moderate non-proliferative retinopathy or proliferative retinopathy, macroalbuminuria or kidney failure (defined as estimated glomerular filtration rate <60 mL/min/1.73 m2 body surface) up to CKD-class 3A, and manifest neuropathy, (group c), 50 patients.

Healthy controls:

• Healthy control matched to the type 1 diabetes patients in age and gender, with no known risk of increased cardiovascular disease.

Exclusion criteria

• Patients unable to understand patient information due to cognitive impairment
• Patients unable to understand patient information due to language barriers
• Ongoing acute infection or inflammatory condition
• Pregnant or breastfeeding women
• Patients with damaged and/or scarred tissue in the areas of interest for the investigational or comparator devices