Vesico-Ureteral Reflux
Conditions
Keywords
Ultrasound, Ultrasound Contrast Agents, Optison, contrast enhanced Voiding Urosonography (ceVUS), ceVUS, Vesicoureteral Reflux, Children, Kidney, Bladder, Urethra, Voiding Cystourethrography (VCUG), VCUG, Safety, Urinary tract
Brief summary
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
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.
Interventions
DRUGOPTISON
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.
Sponsors
Kassa Darge
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
DIAGNOSTIC
Masking
NONE
Intervention model description
Comparative performance of contrast enhanced Voiding Urosonography (ceVUS) and Voiding Cystourethrography (VCUG) in the same participant and in the same session.
Eligibility
Sex/Gender
ALL
Age
No minimum to 18 Years
Healthy volunteers
No
Inclusion criteria
1. Children 2-18 years (first age cohort). 2. Children 0-18 years (second age cohort). 3. Referred to the Children's Hospital of Philadelphia (CHOP) for the performance of the clinically indicated Voiding Cystourethrography (VCUG) examination. 4. Parental/guardian permission (informed consent) and if appropriate, child's assent for additional performance of contrast enhanced Voiding Urosonography (ceVUS) examination.
Exclusion criteria
1. Hypersensitivity to perflutren, blood, blood products or albumin. 2. Children requiring sedation for VCUG or ceVUS examinations. 3. Parents/guardians or subjects who, in the opinion of the principal investigator, may be non-compliant with study schedules or procedures.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Pelvic-ureter-units (PUUs) Detected With Vesicoureteral Reflux by Contrast Enhanced Voiding Urosonography (ceVUS) and by Voiding Cystourethrography (VCUG). | 10-15 minutes. | 1. 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. 2. 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. 3. Imaging of the urethra during voiding (urethra visualized or not) and urethra pathology detection. |
| Number of Participants With Adverse Events Following Contrast Enhanced Voiding Urosonography (ceVUS) With OPTISON and Voiding Cystourethrography (VCUG). | Within 1 hour and up to 2 days after ceVUS and VCUG examinations completion. | 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: 1. evaluation of body systems for signs of generalized hypersensitivity, allergic or anaphylactoid reactions 2. monitoring of heart rate and pulse oxygen saturation 3. 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Compare the Diagnostic Accuracy of Contrast Enhanced Voiding Urosonography (ceVUS) With Voiding CystoUrethroGraphy (VCUG) for Vesicoureteral Reflux Detection and Urethral Imaging in Children. | 10-15 minutes. | 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. |
Countries
United States
Participant flow
Recruitment details
From September 2014 to April 2015, the study team recruited and enrolled 31 eligible subjects scheduled for the clinically indicated voiding cysteourethrography (VCUG) examination from the daily inpatients/outpatients program of the Radiology Department at the Children's Hospital of Philadelphia.
Pre-assignment details
One subject was enrolled into the study (informed consent signed), however, sedation was required as standard of care to perform the clinically indicated VCUG examination. Sedation constitutes an exclusion criterion. Therefore, this subject although enrolled into the study, did not actually complete it.
Participants by arm
| Arm | Count |
|---|---|
| ceVUS With the Use of OPTISON & VCUG in the Same Session OPTISON will be resuspended just before the performance of ceVUS examination, and 01%-0.5% OPTISON solution will be used for intravesical administration. The exact OPTISON dose (ml) will be adjusted according to the age-related bladder filling capacity with a maximum dose (ml) range from 0.3 mL in newborns to 3 mL in 18 year-old children. VCUG exam will be performed as part of the standard care using the same bladder catheter with intravesical administration of the x-ray contrast agent. | 30 |
| Total | 30 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Protocol Violation | 1 |
Baseline characteristics
| Characteristic | ceVUS With the Use of OPTISON & VCUG in the Same Session |
|---|---|
| Age, Categorical <=18 years | 30 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 27 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants |
| Race (NIH/OMB) More than one race | 6 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 17 Participants |
| Region of Enrollment United States | 30 Participants |
| Sex: Female, Male Female | 21 Participants |
| Sex: Female, Male Male | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 30 |
| other Total, other adverse events | 1 / 30 |
| serious Total, serious adverse events | 0 / 30 |
Outcome results
Primary
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: 1. evaluation of body systems for signs of generalized hypersensitivity, allergic or anaphylactoid reactions 2. monitoring of heart rate and pulse oxygen saturation 3. 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.
Time frame: Within 1 hour and up to 2 days after ceVUS and VCUG examinations completion.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Severity of Reflux With ceVUS | Number of Participants With Adverse Events Following Contrast Enhanced Voiding Urosonography (ceVUS) With OPTISON and Voiding Cystourethrography (VCUG). | Number of Participants without Adverse Events | 29 participants |
| Severity of Reflux With ceVUS | Number of Participants With Adverse Events Following Contrast Enhanced Voiding Urosonography (ceVUS) With OPTISON and Voiding Cystourethrography (VCUG). | Number of Participants with Adverse Events | 1 participants |
Primary
Number of Pelvic-ureter-units (PUUs) Detected With Vesicoureteral Reflux by Contrast Enhanced Voiding Urosonography (ceVUS) and by Voiding Cystourethrography (VCUG).
1. 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. 2. 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. 3. Imaging of the urethra during voiding (urethra visualized or not) and urethra pathology detection.
Time frame: 10-15 minutes.
Population: In total, 59 kidneys with 62 pelvic-ureteric units (PUUs) in 30 children were analyzed.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Severity of Reflux With ceVUS | Number of Pelvic-ureter-units (PUUs) Detected With Vesicoureteral Reflux by Contrast Enhanced Voiding Urosonography (ceVUS) and by Voiding Cystourethrography (VCUG). | Grade 0 reflux | 50 pelvic-ureteric units (PUUs) |
| Severity of Reflux With ceVUS | Number of Pelvic-ureter-units (PUUs) Detected With Vesicoureteral Reflux by Contrast Enhanced Voiding Urosonography (ceVUS) and by Voiding Cystourethrography (VCUG). | Grade I reflux | 2 pelvic-ureteric units (PUUs) |
| Severity of Reflux With ceVUS | Number of Pelvic-ureter-units (PUUs) Detected With Vesicoureteral Reflux by Contrast Enhanced Voiding Urosonography (ceVUS) and by Voiding Cystourethrography (VCUG). | Grade II reflux | 8 pelvic-ureteric units (PUUs) |
| Severity of Reflux With ceVUS | Number of Pelvic-ureter-units (PUUs) Detected With Vesicoureteral Reflux by Contrast Enhanced Voiding Urosonography (ceVUS) and by Voiding Cystourethrography (VCUG). | Grade III reflux | 2 pelvic-ureteric units (PUUs) |
| Severity of Reflux With ceVUS | Number of Pelvic-ureter-units (PUUs) Detected With Vesicoureteral Reflux by Contrast Enhanced Voiding Urosonography (ceVUS) and by Voiding Cystourethrography (VCUG). | Grade IV reflux | 0 pelvic-ureteric units (PUUs) |
| Severity of Reflux With ceVUS | Number of Pelvic-ureter-units (PUUs) Detected With Vesicoureteral Reflux by Contrast Enhanced Voiding Urosonography (ceVUS) and by Voiding Cystourethrography (VCUG). | Grade V reflux | 0 pelvic-ureteric units (PUUs) |
| Severity of Reflux With VCUG | Number of Pelvic-ureter-units (PUUs) Detected With Vesicoureteral Reflux by Contrast Enhanced Voiding Urosonography (ceVUS) and by Voiding Cystourethrography (VCUG). | Grade IV reflux | 0 pelvic-ureteric units (PUUs) |
| Severity of Reflux With VCUG | Number of Pelvic-ureter-units (PUUs) Detected With Vesicoureteral Reflux by Contrast Enhanced Voiding Urosonography (ceVUS) and by Voiding Cystourethrography (VCUG). | Grade 0 reflux | 50 pelvic-ureteric units (PUUs) |
| Severity of Reflux With VCUG | Number of Pelvic-ureter-units (PUUs) Detected With Vesicoureteral Reflux by Contrast Enhanced Voiding Urosonography (ceVUS) and by Voiding Cystourethrography (VCUG). | Grade III reflux | 4 pelvic-ureteric units (PUUs) |
| Severity of Reflux With VCUG | Number of Pelvic-ureter-units (PUUs) Detected With Vesicoureteral Reflux by Contrast Enhanced Voiding Urosonography (ceVUS) and by Voiding Cystourethrography (VCUG). | Grade I reflux | 2 pelvic-ureteric units (PUUs) |
| Severity of Reflux With VCUG | Number of Pelvic-ureter-units (PUUs) Detected With Vesicoureteral Reflux by Contrast Enhanced Voiding Urosonography (ceVUS) and by Voiding Cystourethrography (VCUG). | Grade V reflux | 0 pelvic-ureteric units (PUUs) |
| Severity of Reflux With VCUG | Number of Pelvic-ureter-units (PUUs) Detected With Vesicoureteral Reflux by Contrast Enhanced Voiding Urosonography (ceVUS) and by Voiding Cystourethrography (VCUG). | Grade II reflux | 6 pelvic-ureteric units (PUUs) |
Secondary
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.
Time frame: 10-15 minutes.
Population: Voiding Cysteourethrography (VCUG) is used as the reference standard the results for ceVUS.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Severity of Reflux With ceVUS | Compare the Diagnostic Accuracy of Contrast Enhanced Voiding Urosonography (ceVUS) With Voiding CystoUrethroGraphy (VCUG) for Vesicoureteral Reflux Detection and Urethral Imaging in Children. | sensitivity | 91.7 percentage |
| Severity of Reflux With ceVUS | Compare the Diagnostic Accuracy of Contrast Enhanced Voiding Urosonography (ceVUS) With Voiding CystoUrethroGraphy (VCUG) for Vesicoureteral Reflux Detection and Urethral Imaging in Children. | specificity | 98.0 percentage |
| Severity of Reflux With ceVUS | Compare the Diagnostic Accuracy of Contrast Enhanced Voiding Urosonography (ceVUS) With Voiding CystoUrethroGraphy (VCUG) for Vesicoureteral Reflux Detection and Urethral Imaging in Children. | positive predictive value | 91.7 percentage |
| Severity of Reflux With ceVUS | Compare the Diagnostic Accuracy of Contrast Enhanced Voiding Urosonography (ceVUS) With Voiding CystoUrethroGraphy (VCUG) for Vesicoureteral Reflux Detection and Urethral Imaging in Children. | negative predictive value | 98.0 percentage |