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Ultrasound Elastography to Predict Development of SOS

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT03858530
Recruitment Status : Active, not recruiting
First Posted : February 28, 2019
Last Update Posted : June 11, 2020
Information provided by (Responsible Party):
Children's Mercy Hospital Kansas City

Tracking Information
First Submitted Date  ICMJE December 10, 2018
First Posted Date  ICMJE February 28, 2019
Last Update Posted Date June 11, 2020
Actual Study Start Date  ICMJE May 1, 2018
Estimated Primary Completion Date December 31, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 27, 2019)
SWE Accuracy for Diagnosing SOS [ Time Frame: 100 days post transplant ]
Determining accuracy of shear wave ultrasound elastography (SWE) for diagnosis of sinusoidal obstruction syndrome (SOS) compared to diagnosis and severity grading using the European Bone Marrow Consoritium (EBMT) clinical criteria.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: February 27, 2019)
Evaluate SWE Accuracy for Severity Grading [ Time Frame: 100 days post transplant ]
Evaluate the accuracy of SWE for grading severity of SOS severity compared to severity grading according EBMT clinical criteria.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
Descriptive Information
Brief Title  ICMJE Ultrasound Elastography to Predict Development of SOS
Official Title  ICMJE Using Ultrasound Elastography to Predict Development of Sinusoidal Obstruction Syndrome
Brief Summary The long-term goal of our research is to accurately identify SOS patients who would benefit from defibrotide treatment using US SWE. The overall objective of this study is to validate SWE as an early diagnostic marker for SOS. Our central hypothesis is that SWE changes will precede clinical and conventional US diagnostic criteria for SOS. Our hypothesis has been formulated on the basis of our own preliminary data. The investigators completed the first prospective cohort trial demonstrating that US SWE provides SOS diagnosis (80% sensitivity and 67% specificity) nine days earlier than current clinical criteria. SWE is widely available, has no known side effects, and is easy to learn and interpret. Our study enrolled 25 high-risk BMT patients over 18 months (five with SOS and two with severe SOS). More data is needed to determine the optimal window for testing to balance between improved test characteristics and early detection of disease. The investigators propose conducting a prospective cohort study with 80 additional patients, 12 of which will likely develop SOS (including four with severe SOS) to optimize SWE timing. This study will increase the confidence in the findings from our preliminary study and allow us to test SWE against newly published clinical criteria. The rationale for the proposed research is that, if SWE can diagnose SOS earlier than clinical criteria, then SWE can guide early initiation of SOS treatment.
Detailed Description

Hepatic sinusoidal obstructive syndrome (SOS) is a complication of blood and marrow transplant (BMT) that is associated with high morbidity and mortality. 57,000 patients in the United States and Europe undergo BMT annually, and SOS affects up to 15% of these patients. SOS pathogenesis is thought to be caused by damage to the hepatic venous endothelium due to the preparative regimen used before BMT. This damage results in obstruction of blood flow through the liver. Pathology shows collagen deposition in the sinusoids and fibrosis of venous lumens. The severity of the disease is correlated to the number and severity of the histological changes. Mild and moderate SOS can resolve with supportive treatment. Severe SOS (30% of SOS) is commonly associated with multi-organ failure and has a mortality rate of 80% despite available prophylaxis and treatment (Table 1).

SOS is most commonly defined by two clinical criteria: the modified Seattle criteria and the Baltimore criteria (Table 2). The modified Seattle criteria state that at least two of the following criteria must be present within 20 days of BMT: bilirubin > 2mg/dL; hepatomegaly and/or ascites; and/or weight gain > 5% above baseline weight. Pediatric SOS incidence in BMT is 20% and is higher compared to adults. Death or multi-organ dysfunction affects 30-60% children who develop SOS. The most common definition of severe SOS is retrospective, namely death from SOS-related causes or persistent multi-organ dysfunction at 100 days post BMT. However, the European Society for Blood and Marrow Transplantation has proposed a new prospective SOS grading scheme that will likely become standard of care since it is pediatric patient specific and it is can be performed prospectively and thus can guide treatment.

Recently, a promising drug for SOS treatment has been discovered, defibrotide, which is a DNA derivative from porcine intestine that protects and repairs endothelial cells. Prior trials showed that defibrotide decreased the incidence of multi-organ failure and death from SOS. The main caveat is that treatment must be initiated very close to the time of clinical diagnosis using the Baltimore criteria to be effective. A study showed that 31/33 (94%) patients had complete remission of their SOS when treated with defibrotide <3 days after diagnosis, whereas only 3/12 (25%) patients had complete remission when treated >3 days of diagnosis. However, universal prophylaxis is infeasible due to high drug costs ($155,000 for patient) (2016). There is a critical need for an early and effective SOS diagnostic test that can identify patients who would benefit from defibrotide treatment.

Several adult and pediatric prospective studies have evaluated the efficacy of grayscale and Doppler ultrasound (US) in diagnosing SOS and have concluded that the clinical criteria are superior to US criteria for SOS diagnosis. The main reason for this conclusion is that conventional US is able to diagnose SOS only after the clinical diagnosis. This research has resulted in multiple recent guidelines recommending US only for confirming clinical diagnoses or following disease progression and not for primary diagnosis. Ultrasound shear wave elastography (SWE) has been shown to effectively diagnose passive hepatic congestion. Fontan physiology is the best studied example. SWE values markedly increased after the Fontan operation. This surgery connects the hepatic venous circulation to the pulmonary arteries exposing the liver to increased resistance from the pulmonary circulation thereby increasing hepatic venous congestion. Additionally, the effect sizes in the Fontan studies are large compared with the effect sizes in hepatic fibrosis studies. The common thread of hepatic venous congestion between Fontan physiology and SOS physiology led us to hypothesize that SWE could be useful in SOS diagnosis. Additionally, preliminary SWE studies in adults showed that it might be useful in the setting of SOS.

Data Collection Procedures Candidates for the study will be identified by a BMT physician taking care of the patient and will be identified as a potential candidate for the study. Subjects will be approached for consent by a member of the research team prior to start of conditioning regimen. Consented subjects will have demographic, laboratory and clinical data collected from the chart at each ultrasound time point.

Ultrasound Examinations and Timeline After enrollment and within two weeks prior to starting their conditioning regimen, a limited abdominal US with Doppler measurements of the hepatic arteries, hepatic and portal veins, as well as SWE will be performed.

Subjects will be undergo US examinations based on disease course as outlined below:

  1. All Patients: Patients will undergo limited abdominal US with Doppler and SWE once a week upon admission for conditioning until the patient day +30 BMT or discharge, whichever comes first.
  2. Inpatient SOS: patients will undergo limited abdominal US with doppler and SWE once a week upon admission for conditioning until resolution of SOS.
  3. Late Onset SOS: patients will undergo limited abdominal US with Doppler and SWE once a week upon admission for conditioning until resolution of SOS.

Clinically indicated US and SWE exams for suspicion for SOS will be included in our analysis. All imaging will be performed using General Electric Logiq E9 US machines by dedicated pediatric sonographers and interpreted by board-certified pediatric radiologists. Twelve shear wave velocity measurements will be taken 2-3 cm below the liver capsule at the mid-clavicular line in the right hepatic lobe and another 12 will be taken in the left hepatic lobe near midline avoiding areas of vasculature. By necessity, the sonographer and interpreting radiologist will not be blinded to the clinical status of the patient. US and clinical data will be collected weekly and managed using REDCap electronic data capture tools hosted at Children's Mercy Hospital.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Diagnostic
Condition  ICMJE
  • Bone Marrow Transplant Complications
  • Sinusoidal Obstruction Syndrome
  • Veno-occlusive Disease
  • Stem Cell Transplant Complications
Intervention  ICMJE Diagnostic Test: Ultrasound Examination
Grayscale ultrasound, Doppler ultrasound, ultrasound elastography with or without ultrasound intravenous contrast will be performed.
Study Arms  ICMJE Experimental: All Patients Enrolled
All patients will undergo limited abdominal US with Doppler and SWE once a week upon admission for conditioning until the patient day +30 BMT or discharge, whichever comes first. Additional ultrasounds will also be performed if SOS is suspected.
Intervention: Diagnostic Test: Ultrasound Examination
Publications *

*   Includes publications given by the data provider as well as publications identified by Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Estimated Enrollment  ICMJE
 (submitted: February 27, 2019)
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE June 30, 2021
Estimated Primary Completion Date December 31, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Children and adults, ages 1 month through 21 years who are undergoing allogenic or autologous myeloablative stem cell transplant.

Exclusion Criteria:

  • Any other medical or social condition that in the opinion of the investigator would make them unsuitable to participate.
  • Inability to properly image patient by ultrasound (e.g. uncooperative)
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 1 Month to 21 Years   (Child, Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
Administrative Information
NCT Number  ICMJE NCT03858530
Other Study ID Numbers  ICMJE 17110684
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: Yes
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Children's Mercy Hospital Kansas City
Study Sponsor  ICMJE Children's Mercy Hospital Kansas City
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Shewin Chan, MD, PhD Children's Mercy Hospital Kansas City
PRS Account Children's Mercy Hospital Kansas City
Verification Date June 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP