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

Official title

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

Overview

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

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.

Interventions

• 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 de
• 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
• 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.

Primary outcome measures

• diagnostic accuracy of uroflowmetry test 1.1 [Time frame: baseline]
• diagnostic accuracy of uroflowmetry test 1.2 [Time frame: change from baseline at 12 months]
• diagnostic accuracy of uroflowmetry test 1.3 [Time frame: change from baseline at 24 months]
• diagnostic accuracy of uroflowmetry test 1.4 [Time frame: change from baseline at 36 months]
• diagnostic accuracy of uroflowmetry test 1.5 [Time frame: change from baseline at 48 months]
• diagnostic accuracy of uroflowmetry test 1.6 [Time frame: change from baseline at 60 months]
• diagnostic accuracy of cardiovascular autonomic dysfunction test 2.1 [Time frame: baseline]
• diagnostic accuracy of cardiovascular autonomic dysfunction test 2.2 [Time frame: change from baseline at 12 months]
• diagnostic accuracy of cardiovascular autonomic dysfunction test 2.3 [Time frame: change from baseline at 24 months]
• diagnostic accuracy of cardiovascular autonomic dysfunction test 2.4 [Time frame: change from baseline at 36 months]

Secondary outcome measures (12)

• metabolic status 1.1 [Time frame: baseline]
• metabolic status 1.2 [Time frame: change from baseline at 12 months]
• metabolic status 1.3 [Time frame: change from baseline at 24 months]
• metabolic status 1.4 [Time frame: change from baseline at 36 months]
• metabolic status 1.5 [Time frame: change from baseline at 48 months]
• metabolic status 1.6 [Time frame: change from baseline at 60 months]
• metabolic status 2.1 [Time frame: baseline]
• metabolic status 2.2 [Time frame: change from baseline at 12 months]
• metabolic status 2.3 [Time frame: change from baseline at 24 months]
• metabolic status 2.4 [Time frame: change from baseline at 36 months]
• metabolic status 2.5 [Time frame: change from baseline at 48 months]
• metabolic status 2.6 [Time frame: change from baseline at 60 months]

Eligibility criteria

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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: Yes

Study design

Observational model

Case-control

Study locations

Hungary · 1 center

• Heim Pal National Pediatric Institute — Budapest

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. PMID 30136449
• 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. PMID 25619174
• 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. PMID 25332855
• 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. PMID 19603127
• 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. PMID 7815578
• 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. PMID 30788010
• 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. PMID 3536203
• 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. PMID 8444242

Identifiers

NCT: NCT05247840 · KUT-37/2021

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗