CeVUS With Intravesical Administration of OPTISON TM (Trademark) in Children

Study Overview
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Brief Summary
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In this clinical trial the investigators aim to evaluate the diagnostic feasibility and safety of ceVUS with the intravesical use of OPTISON for vesicoureteral reflux detection and urethral imaging in children.

Detailed Description
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Contrast enhanced Voiding Urosonography (ceVUS) is a radiation free, highly sensitive imaging modality for vesicoureteral reflux (VUR) and urethral imaging in children. It employs ultrasound technology in combination with ultrasound contrast agent, which is administered intravesically via a bladder catheter. Currently, second generation ultrasound contrast agents are commercially available, comprising of gas-filled microbubbles. CeVUS in children is being widely practiced, primarily in Europe, despite the fact that none of the commercially available ultrasound contrast agents are yet approved for clinical applications in pediatric population. In the United States, there is limited clinical experience with ceVUS in children. Among the currently commercially available ultrasound contrast agents, OPTISON has already been used in research and off-label in clinical settings involving adults and children. One in-vitro study has been conducted aiming to optimize the ultrasound technical parameters and the dose of OPTISON for intravesical administration in children. In this clinical trial the investigators aim to evaluate the diagnostic feasibility and safety of ceVUS with the intravesical use of OPTISON for vesicoureteral reflux detection and urethral imaging in children.

Official Title
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Contrast Enhanced Voiding Urosonography (ceVUS) With the Intravesical Administration of the Ultrasound Contrast Agent OPTISON TM (Trademark) for Vesicoureteral Reflux Detection and Urethral Imaging in Children.

Conditions
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Vesico-Ureteral Reflux

Intervention / Treatment
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* Drug: OPTISON


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Children 2-18 years (first age cohort). Children 0-18 years (second age cohort). Referred to the Children's Hospital of Philadelphia (CHOP) for the performance of the clinically indicated Voiding Cystourethrography (VCUG) examination. Parental/guardian permission (informed consent) and if appropriate, child's assent for additional performance of contrast enhanced Voiding Urosonography (ceVUS) examination. Exclusion criteria: Hypersensitivity to perflutren, blood, blood products or albumin. Children requiring sedation for VCUG or ceVUS examinations. Parents/guardians or subjects who, in the opinion of the principal investigator, may be non-compliant with study schedules or procedures.

Ages Eligible for Study
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Maximum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Diagnostic
Intervention Model: Single Group Assignment
Interventional Model Description: Comparative performance of contrast enhanced Voiding Urosonography (ceVUS) and Voiding Cystourethrography (VCUG) in the same participant and in the same session.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Comparative performance of ceVUS & VCUG<br>Contrast enhanced Voiding Urosonography (ceVUS) will be performed with the intravesical administration of 0.1%-0.5% OPTISON / normal saline solution. The exact OPTISON dose (ml) that will be adjusted according to the age-related bladder filling capacity with a dose (ml) range from 0.3 mL in newborns to 3 mL in 18 year-old children. Voiding Cystourethrography (VCUG) exam will be subsequently performed using the same bladder catheter with intravesical administration of the x-ray contrast agent. | Drug: OPTISON<br>* Contrast enhanced Voiding Urosonography (ceVUS) with intravesical administration of OPTISON for vesicoureteral reflux detection and urethral imaging in children. Voiding Cystourethrography (VCUG) examination will be subsequently performed as part of the standard care.<br>* Other names: Perflutren Protein-Type A Microspheres;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Pelvic-ureter-units (PUUs) Detected With Vesicoureteral Reflux by Contrast Enhanced Voiding Urosonography (ceVUS) and by Voiding Cystourethrography (VCUG). | Presence or absence of vesicoureteral reflux identified by ceVUS and VCUG in each pelvic-ureter-unit (PUU) of each participant. PUU is an anatomic term that is used to describe the part of the urinary tract consisting of the renal calyces, pelvis and ureter. Grading the severity of reflux detected by ceVUS and VCUG. Grade 0: absence of reflux. If reflux is present, a 5 grade scale (grades I-V) is used to evaluate its severity. Grade I: reflux in the ureter, grade II: reflux up to the renal pelvis, grade III: reflux up to the renal pelvis with mild dilation of the ureter and pelvicalyceal system, grade IV reflux up to the renal pelvis with moderate dilation but preserved papillary impressions, grade V: reflux up to the renal pelvis with severe dilation and loss of papillary impressions. Higher grades of reflux are associated with increased risk of urinary tract infection. Imaging of the urethra during voiding (urethra visualized or not) and urethra pathology detection. | 10-15 minutes. | 
| Number of Participants With Adverse Events Following Contrast Enhanced Voiding Urosonography (ceVUS) With OPTISON and Voiding Cystourethrography (VCUG). | The overall safety and tolerability of ceVUS with OPTISON was assessed before, during and immediately after each ceVUS and VCUG examinations, and in follow-up telephone interviews. Assessments included: evaluation of body systems for signs of generalized hypersensitivity, allergic or anaphylactoid reactions monitoring of heart rate and pulse oxygen saturation telephone questionnaire-based interview of parents/guardians and children 48 hours after the examinations for delayed adverse events. The severity of any possible adverse event was classified as mild, moderate or serious and the onset of symptoms was categorized as acute, subacute or delayed according to the World Health Organization (WHO) classifications. In addition, the adverse event was classified as anticipated if it was expected given the study related procedures or unanticipated if the subject was exposed to greater risk than previously known or recognized. | Within 1 hour and up to 2 days after ceVUS and VCUG examinations completion. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Compare the Diagnostic Accuracy of Contrast Enhanced Voiding Urosonography (ceVUS) With Voiding CystoUrethroGraphy (VCUG) for Vesicoureteral Reflux Detection and Urethral Imaging in Children. | The diagnostic accuracy of ceVUS will be assessed by evaluation of the true positive, true negative, false positive and false negative cases of reflux and urethral imaging findings detected by ceVUS and VCUG examinations. | 10-15 minutes. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Ultrasound, Ultrasound Contrast Agents, Optison, contrast enhanced Voiding Urosonography (ceVUS), ceVUS, Vesicoureteral Reflux, Children, Kidney, Bladder, Urethra, Voiding Cystourethrography (VCUG), VCUG, Safety, Urinary tract