Contrast-Enhanced Ultrasound for Hydrocephalus

Overseen By Santiago Martinez-Correa, MD

Age: < 18

Sex: Any

Trial Phase: Phase 2

Sponsor: Children's Hospital of Philadelphia

Disqualifiers: Lumason hypersensitivity, Hemodynamic instability, Respiratory instability

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 2

20 Participants Needed

Trial Summary

What is the purpose of this trial?

Hydrocephalus affects up to 2 out of every 500 births and results in long-term disability in up to 78% of those affected. The standard treatment of hydrocephalus is cerebrospinal fluid (CSF) diversion via placement of an invasive ventricular shunt to relieve elevated intracranial pressure (ICP). The clinical decision for CSF diversion is based on the ventricular size and clinical symptoms which are not robust indicators of brain health in neonatal hydrocephalus. The purpose of this study is to assess the safety and feasibility of performing brain contrast-enhanced ultrasound (CEUS) in neonates and infants with diagnosed and/or suspected hydrocephalus.

Will I have to stop taking my current medications?

The trial information does not specify whether participants need to stop taking their current medications.

What data supports the effectiveness of the treatment Sulfur Hexafluoride Lipid Type A Microspheres for hydrocephalus?

Research shows that sulfur hexafluoride microbubbles are safe for use in a large number of patients during ultrasound procedures, and they have been used effectively as a contrast agent in brain imaging, which suggests potential for use in hydrocephalus treatment. ^{1 2 3 4 5}

Is sulfur hexafluoride microbubble contrast agent safe for use in humans?

Sulfur hexafluoride microbubble contrast agents have been used in a large number of ultrasound exams and are generally considered safe, with very few adverse reactions reported. In children, studies have shown that these agents are safe, with only rare cases of mild reactions like itching, and no serious side effects observed. ^{1 6 7 8 9}

How does the treatment with Sulfur Hexafluoride Lipid Type A Microspheres differ from other treatments for hydrocephalus?

This treatment uses microbubbles as a contrast agent for ultrasound, which can enhance imaging and potentially aid in drug delivery to the brain. Unlike traditional treatments for hydrocephalus, which often involve surgical interventions, this approach is non-invasive and leverages the unique properties of microbubbles to improve visualization and treatment precision. ^{2 3 10 11 12}

Eligibility Criteria

This trial is for newborns and infants diagnosed with or suspected to have hydrocephalus, which is a condition where fluid builds up in the brain. It's important that participants haven't had previous treatments that could interfere with the study.

Inclusion Criteria

My child is under 1.5 years old and may have hydrocephalus.

I am at least 26 weeks post-menstrual age.

Inpatients at the Children's Hospital of Philadelphia

Exclusion Criteria

Medical history of Lumason hypersensitivity

Hemodynamic instability as defined by rapid escalation of cardiopulmonary support in the past 12-24 hours, as defined by the clinical care team

My breathing support needs have quickly increased recently.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

CEUS Examination

Participants undergo brain contrast-enhanced ultrasound (CEUS) to assess safety and feasibility

1-2 weeks

Up to 2 visits (in-person)

Monitoring

Participants are monitored for 60 minutes post-CEUS and for adverse events up to 48 hours post-scanning

48 hours

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Sulfur Hexafluoride Lipid Type A Microspheres

Trial Overview The trial tests if a special ultrasound using Sulfur Hexafluoride Lipid microspheres can safely assess brain health in babies with hydrocephalus, potentially offering an alternative to current invasive methods.

Participant Groups

Group I: Brain contrast-enhanced ultrasound Experimental Treatment 1 Intervention

The study duration per subject will be up to 30 minutes including the time to prepare the contrast agent, perform the pre-contrast imaging and the contrast-enhanced ultrasound (CEUS), as well as the 60-minute monitoring period after the administration of the contrast agent. A second CEUS exam may be performed within 1-2 weeks from the first scan for up to two CEUS exams of 1 hour and 30-minute duration each. Study participation will be complete when the 60-minute monitoring period of the last CEUS performed is complete.

Who Is Running the Clinical Trial?

Children's Hospital of Philadelphia

Lead Sponsor

Trials

749

Recruited

11,400,000+

Findings from Research

In a large study of 463,434 contrast-enhanced ultrasound examinations, the use of sulfur hexafluoride microbubbles resulted in a very low adverse event (AE) frequency of only 0.034%, indicating a high safety profile for this contrast agent.

Among the reported AEs, only 4 were classified as serious, and the majority were non-serious, with most reactions occurring within 30 minutes of administration, confirming that sulfur hexafluoride microbubbles are safe for routine clinical use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety findings after intravenous administration of sulfur hexafluoride microbubbles to 463,434 examinations at 24 centers. Shang, Y., Xie, X., Luo, Y., et al.[2023]

Gas-filled microbubbles, specifically custom-made albumin-coated microbubbles and SonoVue, have shown promising results as MR contrast agents in brain imaging, with similar transverse relaxation rate enhancements observed in a study involving 5 Sprague-Dawley rats.

These microbubbles can potentially enable real-time MRI guidance for drug delivery and therapeutic applications in the central nervous system, highlighting their biocompatibility and effectiveness in enhancing imaging contrast.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Microbubbles as a novel contrast agent for brain MRI. Cheung, JS., Chow, AM., Guo, H., et al.[2015]

The study demonstrated that a perfluorochemical stabilized microbubble-based ultrasound contrast agent significantly enhances color-Doppler-amplitude and gray-scale imaging of cerebral blood flow (CBF) in dogs, indicating its potential effectiveness for visualizing blood flow in the brain.

The results showed a strong correlation between the ultrasound intensity changes and regional CBF, suggesting that this method could be a valuable noninvasive tool for evaluating CBF, particularly in critically ill newborns.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Analysis of regional cerebral blood flow in dogs, with an experimental microbubble-based US contrast agent. Greenberg, RS., Taylor, GA., Stapleton, JC., et al.[2015]

The study developed new microbubbles using lipids and sulfur hexafluoride (SF6) that significantly enhance the echogenicity of thrombi, improving their visibility during ultrasound imaging.

These targeted microbubbles demonstrated high stability and maintained their characteristics for up to 8 hours, providing a longer diagnostic window compared to traditional nontargeted microbubbles.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prolonging the ultrasound signal enhancement from thrombi using targeted microbubbles based on sulfur-hexafluoride-filled gas. Wang, B., Zang, WJ., Wang, M., et al.[2016]

Microbubbles (MBs) made with perfluoropropane and perfluorobutane showed better stability for ultrasound imaging and more effective drug delivery to the brain compared to those made with sulfur hexafluoride, based on in vitro and in vivo assessments.

The use of these gas-loaded MBs did not cause significant damage to brain tissue, indicating their potential safety for therapeutic applications in drug delivery systems.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of encapsulated gas on stability of lipid-based microbubbles and ultrasound-triggered drug delivery. Omata, D., Maruyama, T., Unga, J., et al.[2020]

In a study involving 167 contrast-enhanced ultrasound examinations in 137 children with oncologic diseases, only one severe anaphylactic reaction (0.6%) was reported, indicating a generally favorable safety profile for intravenous second-generation ultrasound contrast agents containing sulfur hexafluoride.

No other adverse events were observed, such as changes in vital signs or common side effects like flushing or nausea, suggesting that these agents are well-tolerated in pediatric patients, although ongoing monitoring for potential reactions is recommended.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of intravenous application of second-generation ultrasound contrast agent in children: prospective analysis. Piskunowicz, M., Kosiak, W., Batko, T., et al.[2022]

A study analyzing the FDA Adverse Event Reporting System found no significant new safety concerns or major cardiovascular events associated with perflutren ultrasound contrast agents, reinforcing their relative cardiovascular safety.

The most reported adverse events were back pain and flank pain, but these were not linked to serious cardiovascular issues, suggesting that while some discomfort may occur, the overall safety profile remains favorable.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of Perflutren Ultrasound Contrast Agents: A Disproportionality Analysis of the US FAERS Database. Hauben, M., Hung, EY., Hanretta, KC., et al.[2018]

Contrast-enhanced ultrasound (CEUS) using sulfur hexafluoride is safe for use in pediatric patients, as demonstrated in a study involving 173 children with a mean age of 11 years.

The study included a total of 287 CEUS exams, indicating a robust evaluation of the safety of this imaging technique in a diverse age range from 0.1 to 18 years.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Corrigendum. [2019]

In a study of 173 children who underwent 287 contrast-enhanced ultrasound (CEUS) exams using sulfur hexafluoride microbubbles, no immediate adverse effects were reported, suggesting that CEUS is safe for use in pediatric patients.

The study indicates that CEUS can be effectively used for various indications in children, including assessing liver conditions, without significant safety concerns, challenging the current restrictions on its use in this age group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Contrast-enhanced ultrasound using sulfur hexafluoride is safe in the pediatric setting. Torres, A., Koskinen, SK., Gjertsen, H., et al.[2018]

Lipid-coated microbubbles can enhance ultrasound imaging of brain tumors, allowing for earlier detection of gliomas in rats, with a significant reduction in time to visual detection from 6.67 days to 4.09 days when injected daily.

These microbubbles are stable for at least 6 months in vitro and have a half-life of over 20 hours in vivo, making them a promising contrast agent for intraoperative neurosonology.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lipid-coated uniform microbubbles for earlier sonographic detection of brain tumors. D'Arrigo, JS., Simon, RH., Ho, SY.[2019]

The novel ultrasound contrast agent BR 14 significantly enhances signal intensity in the brain parenchyma, with a mean increase of +61% at a lower dose (0.05 ml/kg) and +24% at a higher dose (0.2 ml/kg) in a study involving six sedated beagle dogs.

Higher doses of BR 14 can lead to a paradoxical 'shadowing effect,' where increased signal intensity near the ultrasound probe results in decreased visibility of structures further away, demonstrating the importance of dose selection in ultrasound imaging.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Harmonic imaging of the brain parenchyma using a perfluorobutane-containing ultrasound contrast agent. Seidel, G., Meyer, K., Algermissen, C., et al.[2019]

Lipid-shelled microbubbles used for focused ultrasound (FUS) to open the blood-brain barrier (BBB) remain stable for up to 3 weeks post-activation, maintaining their therapeutic efficacy despite a natural decay in concentration.

In a mouse model, BBB opening achieved with these microbubbles showed consistent volume and contrast enhancement over 21 days, indicating that the microbubbles can effectively facilitate drug delivery into the brain without significant loss of performance over time.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Temporal stability of lipid-shelled microbubbles during acoustically-mediated blood-brain barrier opening. Pouliopoulos, AN., Jimenez, DA., Frank, A., et al.[2021]

References

1. Germany pubmed.ncbi.nlm.nih.gov

Safety findings after intravenous administration of sulfur hexafluoride microbubbles to 463,434 examinations at 24 centers. [2023]

2. United States pubmed.ncbi.nlm.nih.gov

Microbubbles as a novel contrast agent for brain MRI. [2015]

3. United States pubmed.ncbi.nlm.nih.gov

Analysis of regional cerebral blood flow in dogs, with an experimental microbubble-based US contrast agent. [2015]

4. United States pubmed.ncbi.nlm.nih.gov

Prolonging the ultrasound signal enhancement from thrombi using targeted microbubbles based on sulfur-hexafluoride-filled gas. [2016]

5. Netherlands pubmed.ncbi.nlm.nih.gov

Effects of encapsulated gas on stability of lipid-based microbubbles and ultrasound-triggered drug delivery. [2020]

6. England pubmed.ncbi.nlm.nih.gov

Safety of intravenous application of second-generation ultrasound contrast agent in children: prospective analysis. [2022]

7. New Zealand pubmed.ncbi.nlm.nih.gov

Safety of Perflutren Ultrasound Contrast Agents: A Disproportionality Analysis of the US FAERS Database. [2018]

8. England pubmed.ncbi.nlm.nih.gov

Corrigendum. [2019]

9. England pubmed.ncbi.nlm.nih.gov

Contrast-enhanced ultrasound using sulfur hexafluoride is safe in the pediatric setting. [2018]

10. United States pubmed.ncbi.nlm.nih.gov

Lipid-coated uniform microbubbles for earlier sonographic detection of brain tumors. [2019]

11. England pubmed.ncbi.nlm.nih.gov

Harmonic imaging of the brain parenchyma using a perfluorobutane-containing ultrasound contrast agent. [2019]

12. Switzerland pubmed.ncbi.nlm.nih.gov

Temporal stability of lipid-shelled microbubbles during acoustically-mediated blood-brain barrier opening. [2021]