INTACT Trial - an Observational Study to Assess Neuropathy in Diabetic Children

It is a prospective, cross-sectional, observational, controlled, single centre clinical study. Diabetic patients fulfilling the inclusion criteria and healthy controls will have uroflowmetry examination, cardiovascular autonomic dysfunction tests (heart rate response to deep breathing, to Valsalva maneuver, blood pressure and heart rate response to standing up, and to sustained handgrip), and peripheral nerve conduction test. The primary endpoint is the diagnostic accuracy (sensitivity, specificity, negative and positive predictive values) of the tests. The secondary endpoints are: differences in metabolic status (weight, height, body surface, BMI, laboratory parameters, body composition), fluid turnover, and clinical symptoms of diabetic patients comparing to healthy children.

The autonomic nervous system function is examined by the reproducible and standardized cardiovascular reflex tests described by Ewing et al.. During the examination, electrocardiogram and blood pressure values are recorded continuously. Heart rate response to deep inspiration is executed to investigate the parasympathetic nervous system. Peripheral neuropathy is evaluated by nerve conduction test.

The trial will start with a pilot period, when the first 50 diabetic and 50 healthy children will be assessed. This will be followed by a short evaluation period, during which the principal investigators and the study team could make adjustments in the study protocol to ensure feasibility.

Eligibility Criteria:
Inclusion Criteria:

* 5-18 years (boys, girls) with type 1, type 2 and monogenic DM

Exclusion Criteria:

1. Acute febrile condition (≥38 °C core temperature) in the past seven days
2. Acute or chronical urinary tract or kidney disease: renal insufficiency (GFR ≤ 60 mL/min per 1.73 m2, urinary tract infection
3. Urological disease: bladder cancer, urolithiasis, urethral stricture, posterior urethral valve, meatal stenosis, previous genitourinary surgery, conditions causing urinary outflow problems (phimosis, hypospadias, vesicoureteral reflux)
4. Cystic fibrosis-related diabetes (CFRD)
5. Neurological disorders (multiple sclerosis, transient ischaemic attack, transverse myelitis, myelocele, meningomyelocele, previous spinal cord operation, or operation which might injure the sacral nerve plexus)
6. Medicines taken which can cause neuropathy:

   1. Cytostatic agents: cyclophosphamide, platinum-based antineoplastic agents, vinca alkaloids, epothilones, taxanes, proteasome inhibitors, immunomodulatory drugs
   2. Immunosuppressive agents: TNF-alfa inhibitors (adalimumab, infliximab, etanercept), interferon
   3. Cardiovascular medicines: statins, digoxin, amiodaron
   4. Antimicrobial agents: nitrofurantoin, linezolid, voriconazole, itraconazole, antituberculotics, metronidazole, fluoroquinolone
   5. Anti-ulcerative agent: cimetidin
   6. Neuropsychological agents: levodopa, fenitoin
7. Psychiatric disorders that prevents participation / collaboration in the study
8. Constipation (defined according to the Rome IV criteria)
9. Voided volume \<20 mL
10. Patients who are pregnant, or gave birth in the last 12 months
11. Lack of consent of the patient or legal representative; the patient or legal representative withdraws his or her voluntary consent during the study