- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT00591669
Non-invasive Imaging of GI Inflammation Using Microbubble Contrast Enhanced Ultrasonography
Study Overview
Detailed Description
GI inflammation may indicate a number of complications or diseases, one of which is inflammatory bowel disease (IBD), now the second most prevalent inflammatory disorder in the world. Symptoms of the disease include severe abdominal pain, bloody diarrhea, persistent fever, weight loss, and significant malnutrition. There is also an increased risk of colon cancer. If left untreated, the disease is debilitating. Prompt intervention may reduce the amount of immunosuppressive therapy that is required to control the disease, but by the time the patient becomes symptomatic, the inflammatory response is difficult to suppress and much of the damage has already been done. It is therefore important to closely monitor patients with IBD. The location, extent, and severity of the inflammation are of primary consideration for correct diagnosis and treatment. However, no inexpensive and non-invasive procedure exists in protocol for the assessment of these factors of IBD. A non-invasive diagnostic that can detect the onset of inflammation and measure the extent of inflammatory involvement would be a valuable tool for the evaluation of patients with IBD.
Endoscopy, barium contrast X-ray studies, computed tomography (CT), magnetic resonance imaging (MRI), and transabdominal ultrasound (US) are currently the most common procedures used by gastroenterologists. The preferred manner of investigating GI inflammation includes endoscopy with biopsy, as only endoscopy can confirm the presence of inflammation. However, this procedure is highly invasive and limited to areas accessible to the endoscope. There are also limited but real risks associated with endoscopy. In addition, the cost of such a procedure may be prohibitive, or a qualified professional inaccessible, for some patients. Barium contrast X-ray studies remain the best way to visualize stricture and fistulae in the small intestine, but do not provide insight into the degree and extent of active inflammation. Repeated X-rays in chronic and younger patients also contribute to risk of irradiation. CT and MRI are the gold-standard for imaging extra-intestinal inflammatory disease, but fail in their ability to identify active inflammation. There have recently been many studies attempting to improve these means of assessing GI inflammation.
Transabdominal US presents a non-invasive means of imaging internal organs that imposes no significant health risks or undue discomfort upon the patient. The use of abdominal US for the evaluation of IBD was implemented as early as 1979, where wall thickening of the terminal ileum and cecum, with accompanying inflammatory changes in the mesentery, yielded recognizable patterns in both longitudinal and transverse images.11 These initial ultrasonographic images lacked sufficient resolution to provide a sensitive measure of disease activity, but technological advances in high frequency US have greatly improved resolution over the past twenty years. Still, the location and chronicity of certain conditions may decrease the efficacy of this imaging technique, making endoscopy the preferred method of investigation of GI problems. At present, there are several research groups actively investigating the application of US for the management of IBD. The combined results of these studies, in addition to the relatively wide availability, low cost, and easy use of US equipment, support the rationale for developing US into a useful tool for the evaluation of IBD.
Contrast-enhanced ultrasonography (CEU) is the main strategy for improving US quality. One contrast agent that has been studied in the imaging of inflammation, but which has not yet been human-tested for improvement of US quality in inflammation due to IBD, is microbubbles (MB). MB contrast agents are FDA-approved, and are becoming a common clinical tool for the enhancement of US imaging of cardiovascular hemodynamics around the world. Unlike tissue signal, which is produced by US reflection, the strong signal generated by MB is produced by radial oscillation of the MB in the acoustic field. Current MB used for perfusion imaging have lipid or albumin shells and contain high-molecular weight gases (perfluorocarbons, sulfur hexafluoride), which contribute to their high intravascular stability by preventing outward diffusion of gas. MB are generally 2-4µm in size - smaller than average capillary dimension - and passes unimpeded through the microcirculation. They are also hemodynamically inert, and behave similar to red blood cells in vivo. In animal models the acoustic properties of activated Definity® (Perflutren Lipid Microsphere) injectable suspension, were established at or below a mechanical index of 0.7 (1.8 MHz frequency). In clinical trials, the majority of the patients were imaged at or below a mechanical index of .08.
There are two ways that microbubbles might contribute to a strong signal in areas of inflammation in the small intestine or colon. The first is directly through neoangiogenesis and the increase in blood flow to the site. Defined as the growth of new blood vessels, neoangiogenesis is important to the pathogenesis of both Crohn's disease and ulcerative colitis. An expanded microvascular bed in the mucosa and submucosa of IBD patients with active inflammation has been confirmed, and is consistent with the high levels of integrins characteristic for proliferating endothelium (e.g. IL-8, bFGF, and VEGF) found in the microvessels of tissue affected by IBD. The hope is that the increased blood flow in actively inflamed IBD will be correlated with a stronger US signal from the increased concentration of MB flowing through the site.
The second way microbubble CEU may be effective at identifying active inflammation is an indirect effect of new microvasculature. Neoangiogenesis is thought to contribute to pathogenesis by fostering the recruitment and activation of an increased number of leukocyte into the inflamed mucosa. It has been observed that both albumin and lipid shell MB used for echocardiographic studies are phagocytosed intact by activated leukocytes, some of which are adherent to the inflamed endothelium of small intestine or colon. These phagocytosed MB retain a percentage of their acoustic properties, enabling US to image inflammation non-invasively in an in vivo setting. Incorporation of specific lipid moieties into the microbubble shell increases retention and phagocytosis by activated leukocytes.
An investigation of the efficacy of microbubble contrast agents in imaging GI inflammation is the first step towards such targeted imaging and tissue-targeted therapy.
Study Type
Enrollment (Actual)
Phase
- Not Applicable
Contacts and Locations
Study Locations
-
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Virginia
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Charlottesville, Virginia, United States, 22908
- University of Virginia
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
- Patients with inflammatory bowel disease (IBD), scheduled for diagnostic colonoscopy or
- Patients scheduled for diagnostic colonoscopy for other indications other than IBD (e.g. screening, family history of colon cancer).
Exclusion Criteria:
- Ineligibility for colonoscopy
- For control patients: a personal history of IBD or clinical history suspicious for IBD or other disease associated with intestinal inflammation. To be determined by investigators at the time of screening.
- Abnormal QT, Tic, or PR intervals during screening ECG
- Life-threatening ventricular arrhythmias during screening ECG
- Abnormally low oxygen saturation (<80%)
- History of the following:
- An intracardial or intrapulmonary shunt
- Unstable coronary artery disease
- Cerebrovascular disease (e.g. stroke or aneurysm)
- Diagnosed and or current signs or symptoms of severe, progressive or uncontrolled congenital heart failure
- Diagnosed and/or current signs or symptoms of severe, progressive or uncontrolled emphysema/COPD
- Diagnosed and/or current signs or symptoms of severe, progressive or uncontrolled pulmonary hypertension (known PA pressures >50mmHg)
- Uncontrolled high blood pressure (>140/90)
- Abnormal kidney function (creatinine > 2.0 mg/dl or GFR > 90)
- Abnormal liver function (Aspartate transaminase (AST), alanine transaminase (ALT), and alkaline phosphatase levels greater than 2 times the upper limit of normal.)
- Known hypersensitivity to octafluoropropane
- Pregnancy or nursing, confirmed by urine pregnancy test.
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Diagnostic
- Allocation: Non-Randomized
- Interventional Model: Parallel Assignment
- Masking: Single
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: 1
IBD patients
|
We will be placing one vial (1.3) of Definity® in 50 mL of preservative-free saline.
Our infusions will be initiated at slightly lower than recommended starting rate (3mL/min) and will be adjusted as necessary to produce optimal enhancement.
The rate will not exceed 10 ml/min and we will not give more than 1.3 mL of Definity® in 50mL saline in any 24-hour period.
|
Other: 2
Control subjects
|
We will be placing one vial (1.3) of Definity® in 50 mL of preservative-free saline.
Our infusions will be initiated at slightly lower than recommended starting rate (3mL/min) and will be adjusted as necessary to produce optimal enhancement.
The rate will not exceed 10 ml/min and we will not give more than 1.3 mL of Definity® in 50mL saline in any 24-hour period.
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Time Frame |
---|---|
The primary study endpoint is to assess the degree of correlation of the video intensity score from microbubble imaging with an endoscopic scoring system for IBD, the Crohn's Disease Endoscopic Inflammatory Index (CDEIS).
Time Frame: Following data collection
|
Following data collection
|
Secondary Outcome Measures
Outcome Measure |
Time Frame |
---|---|
Secondary endpoint includes comparing the level of video intensity between 30 subjects with inflammatory bowel disease with 10 control patients who are undergoing endoscopic evaluation for non-inflammatory conditions of the large bowel.
Time Frame: Following data collection
|
Following data collection
|
Collaborators and Investigators
Sponsor
Study record dates
Study Major Dates
Study Start
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Estimate)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
Other Study ID Numbers
- 11971
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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