Bone Marrow Transplant ComplicationsNCT03858530
Ultrasound Elastography to Predict Development of SOS
A study testing Ultrasound Examination in people with Bone Marrow Transplant Complications and Sinusoidal Obstruction Syndrome, run by Children's Mercy Hospital Kansas City at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 1 month to 21 years
- Conditions the study is for
- Bone Marrow Transplant Complications, Sinusoidal Obstruction Syndrome, Veno-occlusive Disease
- What is being tested?
- Ultrasound Examination
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 21 participants
- Where
- 1 siteUnited States
- Study dates
- 1 May 2018to 16 Jan 2024
- Phase
- Interventional
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 1 month to 21 years
- All sexes
- No healthy volunteers
- Child, Adult
Who may be able to join
- Children and adults, ages 1 month through 21 years who are undergoing allogenic or autologous myeloablative stem cell transplant.
Who cannot join
- 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)
Trial locations and contacts
1 site in 1 country.
United States1 site
Children's Mercy Hospital
Kansas City, Missouri, 64108
About this study
Official title: Using Ultrasound Elastography to Predict Development of Sinusoidal Obstruction Syndrome
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.
Read the 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:
- 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.
- Inpatient SOS: patients will undergo limited abdominal US with doppler and SWE once a week upon admission for conditioning until resolution of SOS.
- 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.
- Conditions
- Bone Marrow Transplant Complications, Sinusoidal Obstruction Syndrome, Veno-occlusive Disease, Stem Cell Transplant Complications
- Being tested
- Ultrasound Examination
- Keywords
- Ultrasound elastography
- Medical subject headings
- Hepatic Veno-Occlusive Disease
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Ultrasound ExaminationDiagnostic test
Grayscale ultrasound, Doppler ultrasound, ultrasound elastography with or without ultrasound intravenous contrast will be performed.
| Study group | Role | What they receive |
|---|---|---|
| All Patients Enrolled | Experimental | 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. Receives: Diagnostic Test: Ultrasound Examination |
What is being measured
The primary outcome is the main question the study is designed to answer.
Number of Days Between SWE Exams for VOD/SOS
We performed SWE exams once a week for all of our patients. We looked at when patients met clinical criteria for VOD/SOS and then we looked at the SWE exams that were performed before the clinical diagnosis. If the exam immediately preceding the date of clinical diagnosis crossed the threshold for SWE diagnosis, then a frequency of 7 days was sufficient. If it did not, then testing should be more frequent. If multiple preceding exams were positive by SWE, then the optimal testing frequency could be longer than 7 days.
Measured: Once a week through study completion assessed for up to 14 weeks
Secondary outcomes (3)
Determine if SWE Can Provide Earlier SOS Diagnosis Compared to Clinical Criteria.
Number of days where SWE became positive before the clinical criteria became positive.
Measured: Daily through study completion assessed for up to 100 days
Difference in Maximum SWE Value in Patients With Severe and Very Severe VOD Compared to Those With Mild and Moderate VOD.
Measured: Weekly through study completion assessed for up to 14 weeks
CEUS Variables Versus Grayscale and Doppler Variables
Quantify relative ability to CEUS parameters versus grayscale and Doppler ultrasound.
We will compare sensitivity and specificity of time to peak and mean transit time to grayscale and Doppler ultrasound variables for VOD diagnosis.
Measured: Study period
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted28 Feb 2019
- Study start1 May 2018
- Primary completion26 Jan 2022
- Study completion16 Jan 2024
Why it stopped: Slow patient accrual and so Multicenter study was started that had similar aims.
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (23)Papers the sponsor has linked to this study.
- Other trials for Bone Marrow Transplant ComplicationsStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Diagnosis
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 21 participants (actual)
Sponsor and investigators
- Lead sponsor
- Children's Mercy Hospital Kansas City
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Sherwin Chan MD PhD, Children's Mercy Hospital Kansas City
- Investigators
- Shewin Chan, MD, PhD, Principal investigator, Children's Mercy Hospital Kansas City
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03858530
- Sponsor's protocol ID
- 17110684
- Status last verified
- Aug 2024
- First submitted
- 10 Dec 2018
- Last updated
- 4 Sep 2024
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- Yes
- Individual data sharing
- No
Publications
Shulman HM, Fisher LB, Schoch HG, Henne KW, McDonald GB. Veno-occlusive disease of the liver after marrow transplantation: histological correlates of clinical signs and symptoms. Hepatology. 1994 May;19(5):1171-81.
PubMed 8175139Mohty M, Malard F, Abecassis M, Aerts E, Alaskar AS, Aljurf M, Arat M, Bader P, Baron F, Bazarbachi A, Blaise D, Ciceri F, Corbacioglu S, Dalle JH, Dignan F, Fukuda T, Huynh A, Masszi T, Michallet M, Nagler A, NiChonghaile M, Okamoto S, Pagliuca A, Peters C, Petersen FB, Richardson PG, Ruutu T, Savani BN, Wallhult E, Yakoub-Agha I, Duarte RF, Carreras E. Revised diagnosis and severity criteria for sinusoidal obstruction syndrome/veno-occlusive disease in adult patients: a new classification from the European Society for Blood and Marrow Transplantation. Bone Marrow Transplant. 2016 Jul;51(7):906-12. doi: 10.1038/bmt.2016.130. Epub 2016 May 16.
PubMed 27183098McDonald GB, Hinds MS, Fisher LD, Schoch HG, Wolford JL, Banaji M, Hardin BJ, Shulman HM, Clift RA. Veno-occlusive disease of the liver and multiorgan failure after bone marrow transplantation: a cohort study of 355 patients. Ann Intern Med. 1993 Feb 15;118(4):255-67. doi: 10.7326/0003-4819-118-4-199302150-00003.
PubMed 8420443Jones RJ, Lee KS, Beschorner WE, Vogel VG, Grochow LB, Braine HG, Vogelsang GB, Sensenbrenner LL, Santos GW, Saral R. Venoocclusive disease of the liver following bone marrow transplantation. Transplantation. 1987 Dec;44(6):778-83. doi: 10.1097/00007890-198712000-00011.
PubMed 3321587Corbacioglu S, Cesaro S, Faraci M, Valteau-Couanet D, Gruhn B, Rovelli A, Boelens JJ, Hewitt A, Schrum J, Schulz AS, Muller I, Stein J, Wynn R, Greil J, Sykora KW, Matthes-Martin S, Fuhrer M, O'Meara A, Toporski J, Sedlacek P, Schlegel PG, Ehlert K, Fasth A, Winiarski J, Arvidson J, Mauz-Korholz C, Ozsahin H, Schrauder A, Bader P, Massaro J, D'Agostino R, Hoyle M, Iacobelli M, Debatin KM, Peters C, Dini G. Defibrotide for prophylaxis of hepatic veno-occlusive disease in paediatric haemopoietic stem-cell transplantation: an open-label, phase 3, randomised controlled trial. Lancet. 2012 Apr 7;379(9823):1301-9. doi: 10.1016/S0140-6736(11)61938-7. Epub 2012 Feb 23.
PubMed 22364685Barker CC, Butzner JD, Anderson RA, Brant R, Sauve RS. Incidence, survival and risk factors for the development of veno-occlusive disease in pediatric hematopoietic stem cell transplant recipients. Bone Marrow Transplant. 2003 Jul;32(1):79-87. doi: 10.1038/sj.bmt.1704069.
PubMed 12815482Cesaro S, Pillon M, Talenti E, Toffolutti T, Calore E, Tridello G, Strugo L, Destro R, Gazzola MV, Varotto S, Errigo G, Carli M, Zanesco L, Messina C. A prospective survey on incidence, risk factors and therapy of hepatic veno-occlusive disease in children after hematopoietic stem cell transplantation. Haematologica. 2005 Oct;90(10):1396-404.
PubMed 16219577Coppell JA, Richardson PG, Soiffer R, Martin PL, Kernan NA, Chen A, Guinan E, Vogelsang G, Krishnan A, Giralt S, Revta C, Carreau NA, Iacobelli M, Carreras E, Ruutu T, Barbui T, Antin JH, Niederwieser D. Hepatic veno-occlusive disease following stem cell transplantation: incidence, clinical course, and outcome. Biol Blood Marrow Transplant. 2010 Feb;16(2):157-68. doi: 10.1016/j.bbmt.2009.08.024. Epub 2009 Sep 18.
PubMed 19766729Richardson PG, Soiffer RJ, Antin JH, Uno H, Jin Z, Kurtzberg J, Martin PL, Steinbach G, Murray KF, Vogelsang GB, Chen AR, Krishnan A, Kernan NA, Avigan DE, Spitzer TR, Shulman HM, Di Salvo DN, Revta C, Warren D, Momtaz P, Bradwin G, Wei LJ, Iacobelli M, McDonald GB, Guinan EC. Defibrotide for the treatment of severe hepatic veno-occlusive disease and multiorgan failure after stem cell transplantation: a multicenter, randomized, dose-finding trial. Biol Blood Marrow Transplant. 2010 Jul;16(7):1005-17. doi: 10.1016/j.bbmt.2010.02.009. Epub 2010 Feb 16.
PubMed 20167278Corbacioglu S, Carreras E, Ansari M, Balduzzi A, Cesaro S, Dalle JH, Dignan F, Gibson B, Guengoer T, Gruhn B, Lankester A, Locatelli F, Pagliuca A, Peters C, Richardson PG, Schulz AS, Sedlacek P, Stein J, Sykora KW, Toporski J, Trigoso E, Vetteranta K, Wachowiak J, Wallhult E, Wynn R, Yaniv I, Yesilipek A, Mohty M, Bader P. Diagnosis and severity criteria for sinusoidal obstruction syndrome/veno-occlusive disease in pediatric patients: a new classification from the European society for blood and marrow transplantation. Bone Marrow Transplant. 2018 Feb;53(2):138-145. doi: 10.1038/bmt.2017.161. Epub 2017 Jul 31.
PubMed 28759025Corbacioglu S, Greil J, Peters C, Wulffraat N, Laws HJ, Dilloo D, Straham B, Gross-Wieltsch U, Sykora KW, Ridolfi-Luthy A, Basu O, Gruhn B, Gungor T, Mihatsch W, Schulz AS. Defibrotide in the treatment of children with veno-occlusive disease (VOD): a retrospective multicentre study demonstrates therapeutic efficacy upon early intervention. Bone Marrow Transplant. 2004 Jan;33(2):189-95. doi: 10.1038/sj.bmt.1704329.
PubMed 14661036McCarville MB, Hoffer FA, Howard SC, Goloubeva O, Kauffman WM. Hepatic veno-occlusive disease in children undergoing bone-marrow transplantation: usefulness of sonographic findings. Pediatr Radiol. 2001 Feb;31(2):102-5. doi: 10.1007/s002470000373.
PubMed 11214676Hommeyer SC, Teefey SA, Jacobson AF, Higano CS, Bianco JA, Colacurcio CJ, McDonald GB. Venocclusive disease of the liver: prospective study of US evaluation. Radiology. 1992 Sep;184(3):683-6. doi: 10.1148/radiology.184.3.1509050.
PubMed 1509050Teefey SA, Brink JA, Borson RA, Middleton WD. Diagnosis of venoocclusive disease of the liver after bone marrow transplantation: value of duplex sonography. AJR Am J Roentgenol. 1995 Jun;164(6):1397-401. doi: 10.2214/ajr.164.6.7754881.
PubMed 7754881Bajwa RPS, Mahadeo KM, Taragin BH, Dvorak CC, McArthur J, Jeyapalan A, Duncan CN, Tamburro R, Gehred A, Lehmann L, Richardson P, Auletta JJ, Woolfrey AE. Consensus Report by Pediatric Acute Lung Injury and Sepsis Investigators and Pediatric Blood and Marrow Transplantation Consortium Joint Working Committees: Supportive Care Guidelines for Management of Veno-Occlusive Disease in Children and Adolescents, Part 1: Focus on Investigations, Prophylaxis, and Specific Treatment. Biol Blood Marrow Transplant. 2017 Nov;23(11):1817-1825. doi: 10.1016/j.bbmt.2017.07.021. Epub 2017 Jul 25.
PubMed 28754544
Study at a glance
From the registry record, last updated by the sponsor on 4 Sep 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Using Ultrasound Elastography to Predict Development of Sinusoidal Obstruction Syndrome
- ClinicalTrials.gov ID
- NCT03858530
- Acronym / sponsor ID
- 17110684
- Conditions
- Bone Marrow Transplant Complications, Sinusoidal Obstruction Syndrome, Veno-occlusive Disease, Stem Cell Transplant Complications
- Keywords
- Ultrasound elastography
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: Slow patient accrual and so Multicenter study was started that had similar aims.
- Enrolment
- 21 participants (actual)
- Lead sponsor
- Children's Mercy Hospital Kansas CityUniversity, hospital or other
- Study start
- 1 May 2018 (actual)
- Primary completion
- 26 Jan 2022 (actual)
- Study completion
- 16 Jan 2024 (actual)
- First posted
- 28 Feb 2019 (actual)
- Results
- Posted 4 Sep 2024
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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:
- 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.
- Inpatient SOS: patients will undergo limited abdominal US with doppler and SWE once a week upon admission for conditioning until resolution of SOS.
- 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 design
- Primary purpose
- Diagnosis
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| All Patients Enrolled | Experimental | Diagnostic Test: Ultrasound ExaminationAll 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. |
Who may qualify
- Ages
- 1 month to 21 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult
Key inclusion criteria (1 listed)
- Children and adults, ages 1 month through 21 years who are undergoing allogenic or autologous myeloablative stem cell transplant.
Key exclusion criteria (2 listed)
- 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)
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Ultrasound ExaminationGrayscale ultrasound, Doppler ultrasound, ultrasound elastography with or without ultrasound intravenous contrast will be performed. | Diagnostic test | All Patients Enrolled |
Primary outcome
Number of Days Between SWE Exams for VOD/SOS
Time frame: Once a week through study completion assessed for up to 14 weeks
We performed SWE exams once a week for all of our patients. We looked at when patients met clinical criteria for VOD/SOS and then we looked at the SWE exams that were performed before the clinical diagnosis. If the exam immediately preceding the date of clinical diagnosis crossed the threshold for SWE diagnosis, then a frequency of 7 days was sufficient. If it did not, then testing should be more frequent. If multiple preceding exams were positive by SWE, then the optimal testing frequency could be longer than 7 days.
3 secondary outcomes
Determine if SWE Can Provide Earlier SOS Diagnosis Compared to Clinical Criteria.
Time frame: Daily through study completion assessed for up to 100 days
Difference in Maximum SWE Value in Patients With Severe and Very Severe VOD Compared to Those With Mild and Moderate VOD.
Time frame: Weekly through study completion assessed for up to 14 weeks
CEUS Variables Versus Grayscale and Doppler Variables
Time frame: Study period
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 4 Sep 2024.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 8175139Shulman HM, Fisher LB, Schoch HG, Henne KW, McDonald GB. Veno-occlusive disease of the liver after marrow transplantation: histological correlates of clinical signs and symptoms. Hepatology. 1994 May;19(5):1171-81.
- Background: PubMed 27183098Mohty M, Malard F, Abecassis M, Aerts E, Alaskar AS, Aljurf M, Arat M, Bader P, Baron F, Bazarbachi A, Blaise D, Ciceri F, Corbacioglu S, Dalle JH, Dignan F, Fukuda T, Huynh A, Masszi T, Michallet M, Nagler A, NiChonghaile M, Okamoto S, Pagliuca A, Peters C, Petersen FB, Richardson PG, Ruutu T, Savani BN, Wallhult E, Yakoub-Agha I, Duarte RF, Carreras E. Revised diagnosis and severity criteria for sinusoidal obstruction syndrome/veno-occlusive disease in adult patients: a new classification from the European Society for Blood and Marrow Transplantation. Bone Marrow Transplant. 2016 Jul;51(7):906-12. doi: 10.1038/bmt.2016.130. Epub 2016 May 16.
- Background: PubMed 8420443McDonald GB, Hinds MS, Fisher LD, Schoch HG, Wolford JL, Banaji M, Hardin BJ, Shulman HM, Clift RA. Veno-occlusive disease of the liver and multiorgan failure after bone marrow transplantation: a cohort study of 355 patients. Ann Intern Med. 1993 Feb 15;118(4):255-67. doi: 10.7326/0003-4819-118-4-199302150-00003.
- Background: PubMed 3321587Jones RJ, Lee KS, Beschorner WE, Vogel VG, Grochow LB, Braine HG, Vogelsang GB, Sensenbrenner LL, Santos GW, Saral R. Venoocclusive disease of the liver following bone marrow transplantation. Transplantation. 1987 Dec;44(6):778-83. doi: 10.1097/00007890-198712000-00011.
- Background: PubMed 22364685Corbacioglu S, Cesaro S, Faraci M, Valteau-Couanet D, Gruhn B, Rovelli A, Boelens JJ, Hewitt A, Schrum J, Schulz AS, Muller I, Stein J, Wynn R, Greil J, Sykora KW, Matthes-Martin S, Fuhrer M, O'Meara A, Toporski J, Sedlacek P, Schlegel PG, Ehlert K, Fasth A, Winiarski J, Arvidson J, Mauz-Korholz C, Ozsahin H, Schrauder A, Bader P, Massaro J, D'Agostino R, Hoyle M, Iacobelli M, Debatin KM, Peters C, Dini G. Defibrotide for prophylaxis of hepatic veno-occlusive disease in paediatric haemopoietic stem-cell transplantation: an open-label, phase 3, randomised controlled trial. Lancet. 2012 Apr 7;379(9823):1301-9. doi: 10.1016/S0140-6736(11)61938-7. Epub 2012 Feb 23.
- Background: PubMed 12815482Barker CC, Butzner JD, Anderson RA, Brant R, Sauve RS. Incidence, survival and risk factors for the development of veno-occlusive disease in pediatric hematopoietic stem cell transplant recipients. Bone Marrow Transplant. 2003 Jul;32(1):79-87. doi: 10.1038/sj.bmt.1704069.
- Background: PubMed 16219577Cesaro S, Pillon M, Talenti E, Toffolutti T, Calore E, Tridello G, Strugo L, Destro R, Gazzola MV, Varotto S, Errigo G, Carli M, Zanesco L, Messina C. A prospective survey on incidence, risk factors and therapy of hepatic veno-occlusive disease in children after hematopoietic stem cell transplantation. Haematologica. 2005 Oct;90(10):1396-404.
- Background: PubMed 19766729Coppell JA, Richardson PG, Soiffer R, Martin PL, Kernan NA, Chen A, Guinan E, Vogelsang G, Krishnan A, Giralt S, Revta C, Carreau NA, Iacobelli M, Carreras E, Ruutu T, Barbui T, Antin JH, Niederwieser D. Hepatic veno-occlusive disease following stem cell transplantation: incidence, clinical course, and outcome. Biol Blood Marrow Transplant. 2010 Feb;16(2):157-68. doi: 10.1016/j.bbmt.2009.08.024. Epub 2009 Sep 18.
- Background: PubMed 20167278Richardson PG, Soiffer RJ, Antin JH, Uno H, Jin Z, Kurtzberg J, Martin PL, Steinbach G, Murray KF, Vogelsang GB, Chen AR, Krishnan A, Kernan NA, Avigan DE, Spitzer TR, Shulman HM, Di Salvo DN, Revta C, Warren D, Momtaz P, Bradwin G, Wei LJ, Iacobelli M, McDonald GB, Guinan EC. Defibrotide for the treatment of severe hepatic veno-occlusive disease and multiorgan failure after stem cell transplantation: a multicenter, randomized, dose-finding trial. Biol Blood Marrow Transplant. 2010 Jul;16(7):1005-17. doi: 10.1016/j.bbmt.2010.02.009. Epub 2010 Feb 16.
- Background: PubMed 28759025Corbacioglu S, Carreras E, Ansari M, Balduzzi A, Cesaro S, Dalle JH, Dignan F, Gibson B, Guengoer T, Gruhn B, Lankester A, Locatelli F, Pagliuca A, Peters C, Richardson PG, Schulz AS, Sedlacek P, Stein J, Sykora KW, Toporski J, Trigoso E, Vetteranta K, Wachowiak J, Wallhult E, Wynn R, Yaniv I, Yesilipek A, Mohty M, Bader P. Diagnosis and severity criteria for sinusoidal obstruction syndrome/veno-occlusive disease in pediatric patients: a new classification from the European society for blood and marrow transplantation. Bone Marrow Transplant. 2018 Feb;53(2):138-145. doi: 10.1038/bmt.2017.161. Epub 2017 Jul 31.
- Background: PubMed 14661036Corbacioglu S, Greil J, Peters C, Wulffraat N, Laws HJ, Dilloo D, Straham B, Gross-Wieltsch U, Sykora KW, Ridolfi-Luthy A, Basu O, Gruhn B, Gungor T, Mihatsch W, Schulz AS. Defibrotide in the treatment of children with veno-occlusive disease (VOD): a retrospective multicentre study demonstrates therapeutic efficacy upon early intervention. Bone Marrow Transplant. 2004 Jan;33(2):189-95. doi: 10.1038/sj.bmt.1704329.
- Background: PubMed 11214676McCarville MB, Hoffer FA, Howard SC, Goloubeva O, Kauffman WM. Hepatic veno-occlusive disease in children undergoing bone-marrow transplantation: usefulness of sonographic findings. Pediatr Radiol. 2001 Feb;31(2):102-5. doi: 10.1007/s002470000373.
- D'Souza A ZX. Current Uses and Outcomes of Hematopoietic Cell Transplantation (HCT): CIBMTR Summary Slides, 2016.Link provided by the sponsor.
- Cozadd B (2018) Jazz Pharmaceuticals. 36th Annual JP Morgan Annual Healthcare Conference, San Francisco, California.Link provided by the sponsor.
- (2016) In Brief: Defibrotide (Defitelio) for Hepatic Veno-Occlusive Disease. The Medical LetterLink provided by the sponsor.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Shewin Chan, MD, PhD principal investigator
Children's Mercy Hospital Kansas City
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Ultrasound Examination in people with Bone Marrow Transplant Complications and Sinusoidal Obstruction Syndrome, run by Children's Mercy Hospital Kansas City at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 1 inclusion and 2 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 4 Sep 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
Yes. Results are posted in the registry (first posted 4 Sep 2024). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Number of Days Between SWE Exams for VOD/SOS (time frame: Once a week through study completion assessed for up to 14 weeks). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03858530, which also lists 23 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 4 Sep 2024.