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

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

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Diabetes Mellitus
• Intervention / Treatment: Diagnostic test: uroflowmetry; Diagnostic test: Cardiovascular autonomic dysfunction test proposed by Ewing et al.; Diagnostic test: peripheral nerve conduction test

Detailed Description

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.

• Study Type: Observational
• Enrollment (Anticipated): 350

Contacts and Locations

• Study Contact: Name: Szabó; Phone Number: 1155 0614599100; Email: szabo.laszlo.md@gmail.com
• Study Contact Backup: Name: Martonosi; Email: agirmartonosi@gmail.com

Study Locations

• Hungary
  • Budapest, Hungary, 1089
    • Heim Pal National Pediatric Institute
    • Contact: Martonosi; Email: agirmartonosi@gmail.com
    • Principal Investigator: László Szabó

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 5 years to 18 years (ADULT, CHILD)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

Diabetic patients who are treated at the Endocrinology Department and Outpatient Clinic of Heim Pál National Pediatric Institute (HOGYI, Budapest, Hungary) will be enrolled.

Description

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

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
diabetic children; 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; 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.; Other Names: non-invasive urodynamic test; Diagnostic test: Cardiovascular autonomic dysfunction test proposed by Ewing et al.; 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.; Diagnostic test: peripheral nerve conduction test; 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.
healthy children; 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; 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.; Other Names: non-invasive urodynamic test; Diagnostic test: Cardiovascular autonomic dysfunction test proposed by Ewing et al.; 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.; Diagnostic test: peripheral nerve conduction test; 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.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Heim Pal Children's Hospital

Publications and helpful links

General Publications

• Petropoulos IN, Ponirakis G, Khan A, Almuhannadi H, Gad H, Malik RA. Diagnosing Diabetic Neuropathy: Something Old, Something New. Diabetes Metab J. 2018 Aug;42(4):255-269. doi: 10.4093/dmj.2018.0056.
• Yuan Z, Tang Z, He C, Tang W. Diabetic cystopathy: A review. J Diabetes. 2015 Jul;7(4):442-7. doi: 10.1111/1753-0407.12272. Epub 2015 Mar 24. Erratum In: J Diabetes. 2016 Jan;8(1):170.
• Arrellano-Valdez F, Urrutia-Osorio M, Arroyo C, Soto-Vega E. A comprehensive review of urologic complications in patients with diabetes. Springerplus. 2014 Sep 23;3:549. doi: 10.1186/2193-1801-3-549. eCollection 2014.
• Fayyad AM, Hill SR, Jones G. Prevalence and risk factors for bothersome lower urinary tract symptoms in women with diabetes mellitus from hospital-based diabetes clinic. Int Urogynecol J Pelvic Floor Dysfunct. 2009 Nov;20(11):1339-44. doi: 10.1007/s00192-009-0949-z. Epub 2009 Jul 15.
• Kaplan SA, Te AE, Blaivas JG. Urodynamic findings in patients with diabetic cystopathy. J Urol. 1995 Feb;153(2):342-4. doi: 10.1097/00005392-199502000-00013.
• Agashe S, Petak S. Cardiac Autonomic Neuropathy in Diabetes Mellitus. Methodist Debakey Cardiovasc J. 2018 Oct-Dec;14(4):251-256. doi: 10.14797/mdcj-14-4-251.
• Ewing DJ, Clarke BF. Autonomic neuropathy: its diagnosis and prognosis. Clin Endocrinol Metab. 1986 Nov;15(4):855-88. doi: 10.1016/s0300-595x(86)80078-0.
• Barkai L, Szabo L. Urinary bladder dysfunction in diabetic children with and without subclinical cardiovascular autonomic neuropathy. Eur J Pediatr. 1993 Mar;152(3):190-2. doi: 10.1007/BF01956141.
• Szabo L, Barkai L, Lombay B. Urinary flow disturbance as an early sign of autonomic neuropathy in diabetic children and adolescents. Neurourol Urodyn. 2007;26(2):218-21. doi: 10.1002/nau.20349.
• Zajaczkowska R, Kocot-Kepska M, Leppert W, Wrzosek A, Mika J, Wordliczek J. Mechanisms of Chemotherapy-Induced Peripheral Neuropathy. Int J Mol Sci. 2019 Mar 22;20(6):1451. doi: 10.3390/ijms20061451.
• Jones MR, Urits I, Wolf J, Corrigan D, Colburn L, Peterson E, Williamson A, Viswanath O. Drug-Induced Peripheral Neuropathy: A Narrative Review. Curr Clin Pharmacol. 2020;15(1):38-48. doi: 10.2174/1574884714666190121154813.
• Ewing DJ, Martyn CN, Young RJ, Clarke BF. The value of cardiovascular autonomic function tests: 10 years experience in diabetes. Diabetes Care. 1985 Sep-Oct;8(5):491-8. doi: 10.2337/diacare.8.5.491.
• Spallone V, Bellavere F, Scionti L, Maule S, Quadri R, Bax G, Melga P, Viviani GL, Esposito K, Morganti R, Cortelli P; Diabetic Neuropathy Study Group of the Italian Society of Diabetology. Recommendations for the use of cardiovascular tests in diagnosing diabetic autonomic neuropathy. Nutr Metab Cardiovasc Dis. 2011 Jan;21(1):69-78. doi: 10.1016/j.numecd.2010.07.005.
• Lin K, Wei L, Huang Z, Zeng Q. Combination of Ewing test, heart rate variability, and heart rate turbulence analysis for early diagnosis of diabetic cardiac autonomic neuropathy. Medicine (Baltimore). 2017 Nov;96(45):e8296. doi: 10.1097/MD.0000000000008296.
• Liu G, Li M, Vasanji A, Daneshgari F. Temporal diabetes and diuresis-induced alteration of nerves and vasculature of the urinary bladder in the rat. BJU Int. 2011 Jun;107(12):1988-93. doi: 10.1111/j.1464-410X.2010.09840.x. Epub 2010 Nov 18.
• Beshay E, Carrier S. Oxidative stress plays a role in diabetes-induced bladder dysfunction in a rat model. Urology. 2004 Nov;64(5):1062-7. doi: 10.1016/j.urology.2004.06.021.
• Martonosi AR, Pazmany P, Kiss S, Zsakai A, Szabo L. INvesTigating the Abnormality of detrusor ConTractility by uroflowmetry in diabetic children (INTACT Trial): protocol of a prospective, observational study. BMJ Open. 2022 Nov 14;12(11):e062198. doi: 10.1136/bmjopen-2022-062198.

Study record dates

Study Major Dates

• Study Start (ANTICIPATED): September 1, 2022
• Primary Completion (ANTICIPATED): September 1, 2023
• Study Completion (ANTICIPATED): September 1, 2027

Study Registration Dates

• First Submitted: January 18, 2022
• First Submitted That Met QC Criteria: February 9, 2022
• First Posted (ACTUAL): February 21, 2022

Study Record Updates

• Last Update Posted (ACTUAL): August 5, 2022
• Last Update Submitted That Met QC Criteria: August 3, 2022
• Last Verified: August 1, 2022

More Information

Terms related to this study

• Keywords: diabetes; children; neuropathy; paediatric; uroflowmetry
• Other Study ID Numbers: KUT-37/2021

Plan for Individual participant data (IPD)

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

Drug and device information, study documents

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