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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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INvesTigation the Abnormality of Detrusor ConTractility by Uroflowmetry in Diabetic Children (INTACT Trial) - a Prospective, Cross-sectional, Observational, Controlled Study

Conditions
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Diabetes Mellitus

Intervention / Treatment
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* Diagnostic Test: uroflowmetry
* Diagnostic Test: Cardiovascular autonomic dysfunction test proposed by Ewing et al.
* Diagnostic Test: peripheral nerve conduction test


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 5-18 years (boys, girls) with type 1, type 2 and monogenic DM Exclusion Criteria: Acute febrile condition (≥38 °C core temperature) in the past seven days Acute or chronical urinary tract or kidney disease: renal insufficiency (GFR ≤ 60 mL/min per 1.73 m2, urinary tract infection Urological disease: bladder cancer, urolithiasis, urethral stricture, posterior urethral valve, meatal stenosis, previous genitourinary surgery, conditions causing urinary outflow problems (phimosis, hypospadias, vesicoureteral reflux) Cystic fibrosis-related diabetes (CFRD) Neurological disorders (multiple sclerosis, transient ischaemic attack, transverse myelitis, myelocele, meningomyelocele, previous spinal cord operation, or operation which might injure the sacral nerve plexus) Medicines taken which can cause neuropathy: Cytostatic agents: cyclophosphamide, platinum-based antineoplastic agents, vinca alkaloids, epothilones, taxanes, proteasome inhibitors, immunomodulatory drugs Immunosuppressive agents: TNF-alfa inhibitors (adalimumab, infliximab, etanercept), interferon Cardiovascular medicines: statins, digoxin, amiodaron Antimicrobial agents: nitrofurantoin, linezolid, voriconazole, itraconazole, antituberculotics, metronidazole, fluoroquinolone Anti-ulcerative agent: cimetidin Neuropsychological agents: levodopa, fenitoin Psychiatric disorders that prevents participation / collaboration in the study Constipation (defined according to the Rome IV criteria) Voided volume <20 mL Patients who are pregnant, or gave birth in the last 12 months Lack of consent of the patient or legal representative; the patient or legal representative withdraws his or her voluntary consent during the study

Ages Eligible for Study
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Minimum Age: 5 Years
Maximum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| diabetic children<br>Children aged 5-18 years (boys, girls) with type 1, type 2 and monogenic diabetes mellitus who are treated at the Endocrinology Department and Outpatient Clinic of Heim Pál National Pediatric Institute (HOGYI, Budapest, Hungary) will be enrolled. Definition of diabetes is based on the American Diabetes Association (ADA) criteria. All patients who meet the inclusion criteria will be informed of the possibility of taking part in the INTACT Trial. | Diagnostic Test: uroflowmetry<br>* Uroflowmetry will be performed using a uroflow-cystometer (UroDoc Frytech) which determines Qmax, Qave and TQmax. Voided volume (in mL), voiding time (in sec), average and maximum urinary flow rate (Qave and Qmax in mL/sec), and time to maximum urinary flow (TQmax in sec) will be measured; urine flow acceleration (Qacc in mL/sec2) will be calculated. Qmax and Qave are defined according to the International Children's Continence Society. Voided volume will be measured by the uroflow-cystometer device; boys void in a standing, girls in a sitting position. Postvoid bladder diameter (mm) will be measured by ultrasonography and converted to bladder residual volume (mL). The device will be calibrated according to the prescribed instructions for use by a skilled technician. The examinations will take approximately 10 minutes.<br>* Other names: non-invasive urodynamic test;Diagnostic Test: Cardiovascular autonomic dysfunction test proposed by Ewing et al.<br>* CAD will be assessed by five reproducible and standardized cardiovascular reflex tests described by Ewing et al. Three of the five tests assess parasympathetic function: heart rate response to deep breathing, to standing, and the Valsalva maneuver. Two tests evaluate sympathetic function which are blood pressure responses from lying to standing and at sustained handgrip. Each of these five tests is assigned a score of 0 for normal, 0.5 for borderline, and 1 for abnormal results. The sum of these 5 scores - which is the Ewing score - is used to assess severity of CAD. Patients having Ewing score ≥ 2 form the CAD + group, and patients who have less than 2 form the CAD - group.<br>Diagnostic Test: peripheral nerve conduction test<br>* Peripheral neuropathy will be evaluated by nerve conduction test. The device measures motor conduction in the lower extremities. It operates at two dedicated frequencies in order to perform a thick myelin sheath cordless fibre (5Hz) and thin myelinated nerve fibre (2000Hz) examination. The device will be calibrated according to the prescribed instructions for use by a skilled technician.<br>|
| healthy children<br>Healthy children aged 5-18 years (boys, girls) without any acute or chronical disease will be will enrolled and the same tests will be performed on them as in diabetic children. Children with voided volume <20 mL, postvoid residual volume >15%, and signs of an overstretched bladder [voided volume more than: 30 x age (years) + 30 mL] will be excluded. | Diagnostic Test: uroflowmetry<br>* Uroflowmetry will be performed using a uroflow-cystometer (UroDoc Frytech) which determines Qmax, Qave and TQmax. Voided volume (in mL), voiding time (in sec), average and maximum urinary flow rate (Qave and Qmax in mL/sec), and time to maximum urinary flow (TQmax in sec) will be measured; urine flow acceleration (Qacc in mL/sec2) will be calculated. Qmax and Qave are defined according to the International Children's Continence Society. Voided volume will be measured by the uroflow-cystometer device; boys void in a standing, girls in a sitting position. Postvoid bladder diameter (mm) will be measured by ultrasonography and converted to bladder residual volume (mL). The device will be calibrated according to the prescribed instructions for use by a skilled technician. The examinations will take approximately 10 minutes.<br>* Other names: non-invasive urodynamic test;Diagnostic Test: Cardiovascular autonomic dysfunction test proposed by Ewing et al.<br>* CAD will be assessed by five reproducible and standardized cardiovascular reflex tests described by Ewing et al. Three of the five tests assess parasympathetic function: heart rate response to deep breathing, to standing, and the Valsalva maneuver. Two tests evaluate sympathetic function which are blood pressure responses from lying to standing and at sustained handgrip. Each of these five tests is assigned a score of 0 for normal, 0.5 for borderline, and 1 for abnormal results. The sum of these 5 scores - which is the Ewing score - is used to assess severity of CAD. Patients having Ewing score ≥ 2 form the CAD + group, and patients who have less than 2 form the CAD - group.<br>Diagnostic Test: peripheral nerve conduction test<br>* Peripheral neuropathy will be evaluated by nerve conduction test. The device measures motor conduction in the lower extremities. It operates at two dedicated frequencies in order to perform a thick myelin sheath cordless fibre (5Hz) and thin myelinated nerve fibre (2000Hz) examination. The device will be calibrated according to the prescribed instructions for use by a skilled technician.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| diagnostic accuracy of uroflowmetry test 1.1 | sensitivity, specificity, positive predictive value, negative predictive value | baseline | 
| diagnostic accuracy of uroflowmetry test 1.2 | sensitivity, specificity, positive predictive value, negative predictive value | change from baseline at 12 months | 
| diagnostic accuracy of uroflowmetry test 1.3 | sensitivity, specificity, positive predictive value, negative predictive value | change from baseline at 24 months | 
| diagnostic accuracy of uroflowmetry test 1.4 | sensitivity, specificity, positive predictive value, negative predictive value | change from baseline at 36 months | 
| diagnostic accuracy of uroflowmetry test 1.5 | sensitivity, specificity, positive predictive value, negative predictive value | change from baseline at 48 months | 
| diagnostic accuracy of uroflowmetry test 1.6 | sensitivity, specificity, positive predictive value, negative predictive value | change from baseline at 60 months | 
| diagnostic accuracy of cardiovascular autonomic dysfunction test 2.1 | sensitivity, specificity, positive predictive value, negative predictive value | baseline | 
| diagnostic accuracy of cardiovascular autonomic dysfunction test 2.2 | sensitivity, specificity, positive predictive value, negative predictive value | change from baseline at 12 months | 
| diagnostic accuracy of cardiovascular autonomic dysfunction test 2.3 | sensitivity, specificity, positive predictive value, negative predictive value | change from baseline at 24 months | 
| diagnostic accuracy of cardiovascular autonomic dysfunction test 2.4 | sensitivity, specificity, positive predictive value, negative predictive value | change from baseline at 36 months | 
| diagnostic accuracy of cardiovascular autonomic dysfunction test 2.5 | sensitivity, specificity, positive predictive value, negative predictive value | change from baseline at 48 months | 
| diagnostic accuracy of cardiovascular autonomic dysfunction test 2.6 | sensitivity, specificity, positive predictive value, negative predictive value | change from baseline at 60 months | 
| diagnostic accuracy of peripheral nerve conduction test 3.1 | sensitivity, specificity, positive predictive value, negative predictive value | baseline | 
| diagnostic accuracy of peripheral nerve conduction test 3.2 | sensitivity, specificity, positive predictive value, negative predictive value | change from baseline at 12 months | 
| diagnostic accuracy of peripheral nerve conduction test 3.3 | sensitivity, specificity, positive predictive value, negative predictive value | change from baseline at 24 months | 
| diagnostic accuracy of peripheral nerve conduction test 3.4 | sensitivity, specificity, positive predictive value, negative predictive value | change from baseline at 36 months | 
| diagnostic accuracy of peripheral nerve conduction test 3.5 | sensitivity, specificity, positive predictive value, negative predictive value | change from baseline at 48 months | 
| diagnostic accuracy of peripheral nerve conduction test 3.6 | sensitivity, specificity, positive predictive value, negative predictive value | change from baseline at 60 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| metabolic status 1.1 | weight (kg) | baseline | 
| metabolic status 1.2 | weight (kg) | change from baseline at 12 months | 
| metabolic status 1.3 | weight (kg) | change from baseline at 24 months | 
| metabolic status 1.4 | weight (kg) | change from baseline at 36 months | 
| metabolic status 1.5 | weight (kg) | change from baseline at 48 months | 
| metabolic status 1.6 | weight (kg) | change from baseline at 60 months | 
| metabolic status 2.1 | height (cm) | baseline | 
| metabolic status 2.2 | height (cm) | change from baseline at 12 months | 
| metabolic status 2.3 | height (cm) | change from baseline at 24 months | 
| metabolic status 2.4 | height (cm) | change from baseline at 36 months | 
| metabolic status 2.5 | height (cm) | change from baseline at 48 months | 
| metabolic status 2.6 | height (cm) | change from baseline at 60 months | 
| metabolic status 3.1 | body surface (m2 calculated by the Mosteller formula) | baseline | 
| metabolic status 3.2 | body surface (m2 calculated by the Mosteller formula) | change from baseline at 12 months | 
| metabolic status 3.3 | body surface (m2 calculated by the Mosteller formula) | change from baseline at 24 months | 
| metabolic status 3.4 | body surface (m2 calculated by the Mosteller formula) | change from baseline at 36 months | 
| metabolic status 3.5 | body surface (m2 calculated by the Mosteller formula) | change from baseline at 48 months | 
| metabolic status 3.6 | body surface (m2 calculated by the Mosteller formula) | change from baseline at 60 months | 
| metabolic status 4.1 | BMI (kg/m2) | baseline | 
| metabolic status 4.2 | BMI (kg/m2) | change from baseline at 12 months | 
| metabolic status 4.3 | BMI (kg/m2) | change from baseline at 24 months | 
| metabolic status 4.4 | BMI (kg/m2) | change from baseline at 36 months | 
| metabolic status 4.5 | BMI (kg/m2) | change from baseline at 48 months | 
| metabolic status 4.6 | BMI (kg/m2) | change from baseline at 60 months | 
| metabolic status 5.1 | body composition evaluated by the Inbody device | baseline | 
| metabolic status 5.2 | body composition evaluated by the Inbody device | change from baseline at 12 months | 
| metabolic status 5.3 | body composition evaluated by the Inbody device | change from baseline at 24 months | 
| metabolic status 5.4 | body composition evaluated by the Inbody device | change from baseline at 36 months | 
| metabolic status 5.5 | body composition evaluated by the Inbody device | change from baseline at 48 months | 
| metabolic status 5.6 | body composition evaluated by the Inbody device | change from baseline at 60 months | 
| metabolic status 6.1 | laboratory parameters (CRP, ESR, full blood count, Hemoglobin, hematocrit, thrombocyte, glucose, C-peptide, HbA1c, triglyceride, cholesterol, uric acid, creatinine, carbamide, AST, ALT, GGT, LDH, ALP, Na, K, P, Ca, albumin, serum total protein, lipase, amylase, urine rapid test) | baseline | 
| metabolic status 6.2 | laboratory parameters (CRP, ESR, full blood count, Hemoglobin, hematocrit, thrombocyte, glucose, C-peptide, HbA1c, triglyceride, cholesterol, uric acid, creatinine, carbamide, AST, ALT, GGT, LDH, ALP, Na, K, P, Ca, albumin, serum total protein, lipase, amylase, urine rapid test) | change from baseline at 12 months | 
| metabolic status 6.3 | laboratory parameters (CRP, ESR, full blood count, Hemoglobin, hematocrit, thrombocyte, glucose, C-peptide, HbA1c, triglyceride, cholesterol, uric acid, creatinine, carbamide, AST, ALT, GGT, LDH, ALP, Na, K, P, Ca, albumin, serum total protein, lipase, amylase, urine rapid test) | change from baseline at 24 months | 
| metabolic status 6.4 | laboratory parameters (CRP, ESR, full blood count, Hemoglobin, hematocrit, thrombocyte, glucose, C-peptide, HbA1c, triglyceride, cholesterol, uric acid, creatinine, carbamide, AST, ALT, GGT, LDH, ALP, Na, K, P, Ca, albumin, serum total protein, lipase, amylase, urine rapid test) | change from baseline at 36 months | 
| metabolic status 6.5 | laboratory parameters (CRP, ESR, full blood count, Hemoglobin, hematocrit, thrombocyte, glucose, C-peptide, HbA1c, triglyceride, cholesterol, uric acid, creatinine, carbamide, AST, ALT, GGT, LDH, ALP, Na, K, P, Ca, albumin, serum total protein, lipase, amylase, urine rapid test) | change from baseline at 48 months | 
| metabolic status 6.6 | laboratory parameters (CRP, ESR, full blood count, Hemoglobin, hematocrit, thrombocyte, glucose, C-peptide, HbA1c, triglyceride, cholesterol, uric acid, creatinine, carbamide, AST, ALT, GGT, LDH, ALP, Na, K, P, Ca, albumin, serum total protein, lipase, amylase, urine rapid test) | change from baseline at 60 months | 
| metabolic status 7.1 | fluid turnover in 24 hours (mL) | baseline | 
| metabolic status 7.2 | fluid turnover in 24 hours (mL) | change from baseline at 12 months | 
| metabolic status 7.3 | fluid turnover in 24 hours (mL) | change from baseline at 24 months | 
| metabolic status 7.4 | fluid turnover in 24 hours (mL) | change from baseline at 36 months | 
| metabolic status 7.5 | fluid turnover in 24 hours (mL) | change from baseline at 48 months | 
| metabolic status 7.6 | fluid turnover in 24 hours (mL) | change from baseline at 60 months | 
| clinical symptoms of diabetic patients will be measured and compared to healthy children. 8.1 | clinical symptoms (Urgent urination, Daily urine incontinence, Urination during night time, Nocturia, Frequency of bowel movement, Consistency of the stool) | baseline | 
| clinical symptoms of diabetic patients will be measured and compared to healthy children. 8.2 | clinical symptoms (Urgent urination, Daily urine incontinence, Urination during night time, Nocturia, Frequency of bowel movement, Consistency of the stool) | change from baseline at 12 months | 
| clinical symptoms of diabetic patients will be measured and compared to healthy children. 8.3 | clinical symptoms (Urgent urination, Daily urine incontinence, Urination during night time, Nocturia, Frequency of bowel movement, Consistency of the stool) | change from baseline at 24 months | 
| clinical symptoms of diabetic patients will be measured and compared to healthy children. 8.4 | clinical symptoms (Urgent urination, Daily urine incontinence, Urination during night time, Nocturia, Frequency of bowel movement, Consistency of the stool) | change from baseline at 36 months | 
| clinical symptoms of diabetic patients will be measured and compared to healthy children. 8.5 | clinical symptoms (Urgent urination, Daily urine incontinence, Urination during night time, Nocturia, Frequency of bowel movement, Consistency of the stool) | change from baseline at 48 months | 
| clinical symptoms of diabetic patients will be measured and compared to healthy children. 8.6 | clinical symptoms (Urgent urination, Daily urine incontinence, Urination during night time, Nocturia, Frequency of bowel movement, Consistency of the stool) | change from baseline at 60 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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diabetes, uroflowmetry, neuropathy, paediatric, children