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Bone Marrow Transplant ComplicationsNCT03865589

Using Ultrasound Elastography to Predict Development of Hepatic Sinusoidal Obstruction Syndrome

A study testing Ultrasound Elastography in people with Bone Marrow Transplant Complications and Sinusoidal Obstruction Syndrome, run by Children's Mercy Hospital Kansas City at 7 sites in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

To perform an receiver operating characteristic (ROC) analysis, define a threshold and quantify the sensitivity and specificity of US SWE for risk stratification of patients into three categories as defined by the European Bone Marrow Transplant (EBMT) adult and pediatric criteria: no sinusoidal obstruction syndrome… Read more about this study

Who is it for?
Ages 1 month to 99 years
What is being tested?
Ultrasound Elastography
Could I receive a placebo?
No, everyone receives an active treatment
How many people
250 participants
Where
7 sitesUnited States
Study dates
1 Apr 2019to 31 Dec 2025
Phase
Interventional
Are there results?
None posted in the registry

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 99 years
  • All sexes
  • No healthy volunteers
  • Child, Adult, Older adult

Who may be able to join

  • Any patient undergoing a myeloablative conditioning regimen for HCT between 3/1/2019 and 12/31/2025 defined as one of the following:
  • TBI >= 1200 cGy (fractionated)
  • Cyclophosphamide + TBI (> 500 cGy (single) or > 800cGy (fractionated))
  • Cyclophosphamide + Etoposide + TBI (> 500 cGy (single) or > 800 cGy (fractionated))
  • Cyclophosphamide + Thiotepa + TBI (> 500 cGy (single) or > 800 cGy (fractionated))
  • Busulfan (Total dose > 7.2 mg/kg IV or >9.0mg/kg orally) + Cyclophosphamide
Show all 15Show fewer
  • Busulfan (Total dose >7.2 mg/kg IV or >9.0 mg/kg orally) + Melphalan
  • Busulfan (Total dose >7.2 mg/kg IV or >9.0 mg/kg orally) + Thiotepa
  • NOTE: Busulfan cumulative plasma AUC of >75 mg/L per hour or >18270 microMolar per minute could be used in the preceding criteria in lieu of the mg/kg doses.
  • OR
  • 2. Any patient who has a myeloablative conditioning regimen (as defined by the local HCT team) that includes sirolimus and tacrolimus for GVHD prophylaxis.
  • OR
  • 3. Any patient who is high risk for SOS irrespective of conditioning regimen: Neuroblastoma, HLH, Osteopetrosis, Thalassemia, treatment with inotuzumab or gemtuzumab within 3 months prior to HCT admission, 2nd HCT if it is myeloablative and within 6 months of prior, iron overload, steatohepatitis, active inflammatory or infection hepatitis or any other condition which puts the patient at a higher risk of developing SOS.
  • Subjects aged 1 month through 99 years will be eligible for the study. Patients who receive defibrotide and/or ursodiol for VOD/SOS prophylaxis will also be eligible for the study. At most 175 children (ages 1 month to 18 years) and 175 adults (>18 years old) can be enrolled into the study.
  • Inclusion dates: Patients seen between 1/1/2019 and 12/31/2025

Who cannot join

  • Any patient who has contraindication to ultrasound shear wave elastography (e.g. unable to hold still) Adults unable to consent Pregnant women Prisoners Wards of the state

Trial locations and contacts

7 sites in 1 country.

7 sites in 1 country

United States7 sites

  • Dana-Farber Cancer Institute

    Boston, Massachusetts, 02215

  • University Hospitals Cleveland Medical Center

    Cleveland, Ohio, 44106

  • Nationwide Children's Hospital

    Columbus, Ohio, 43205

  • Duke University

    Durham, North Carolina, 27705

  • Children's Mercy

    Kansas City, Missouri, 64108

  • St. Jude Children's Research Hospital

    Memphis, Tennessee, 38105

  • University of California, San Francisco

    San Francisco, California, 94143

Other trials in United States

About this study

To perform an receiver operating characteristic (ROC) analysis, define a threshold and quantify the sensitivity and specificity of US SWE for risk stratification of patients into three categories as defined by the European Bone Marrow Transplant (EBMT) adult and pediatric criteria: no sinusoidal obstruction syndrome (SOS), mild to moderate SOS, and severe to very severe SOS. Secondarily, the investigators would also like to quantify the temporal relationship between US SWE changes and SOS diagnosis according to various clinical criteria (Modified Seattle, Baltimore, EBMT consortium).

Read the detailed description

Hepatic sinusoidal obstructive syndrome (SOS), also known as veno-occlusive disease, is a complication of hematopoietic stem cell transplant (HCT) that is associated with high morbidity and mortality. 57,000 patients in the United States and Europe undergo HCT 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 HCT. 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 not 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.

SOS is most commonly defined by two clinical criteria: the modified Seattle criteria and the Baltimore criteria. The modified Seattle criteria state that at least two of the following criteria must be present within 20 days of HCT: bilirubin > 2mg/dL; hepatomegaly and/or ascites; and/or weight gain > 5% above baseline weight (6). Pediatric SOS incidence in HCT 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 HCT. However, the European Society for Blood and Marrow Transplantation has proposed new prospective SOS diagnosis and grading schemes that could become standard of care since it can be performed prospectively and thus can guide treatment.

Defibrotide 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 (14). 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 difficult due to high drug costs ($155,000 for 21-day course). 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.

The investigators of this study recently conducted a single site prospective cohort study involving 25 patients undergoing myeloablative HCT patients from December 2015 through June 2017. The investigators found increased velocities in all patients who developed SOS. US SWE velocity values showed no difference between pre-conditioning median US SWE velocity in the SOS group (1.24 + 0.09 m/s) and non-SOS group (1.41 + 0.18 m/s) (p=0.06). By day +5, patients with SOS had US SWE velocities that significantly increased by 0.25 + 0.21 m/s from baseline compared to 0.02 + 0.18 m/s in patients without SOS from baseline (p=0.02). By day +14, patients with SOS had US SWE velocities that significantly increased by 0.91 + 1.14 m/s from baseline compared to 0.03 + 0.23 m/s in patients without SOS from baseline (0.01). These values are both clinically and statistically significant, demonstrating that patients with SOS have significantly increased liver stiffness as measured by US SWE compared to patients without SOS. Additionally, SWE changes happened on average 9 to 11 days before clinical diagnostic criteria became positive. The sensitivity and specificity of this test were 60-80% and 67-93% in our small cohort of 25 patients depending on the threshold used and the test timing.

Data Collection Procedures: Candidates for the study will be identified by a HCT 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.

Consented subjects will have an US SWE within two weeks prior to starting their conditioning regimen and at the following time points based on disease course:

  1. All Patients: patients will undergo ultrasound elastography within two-weeks prior to admission for conditioning AND twice per week through Day +30 or discharge, whichever comes first. Patients whom are still an inpatient after Day +30, and are not clinically suspicious for SOS/VOD, will undergo ultrasound elastography every 30 days (Day +60 and Day +90) until discharge.
  2. Late Onset SOS/VOD as INPATIENT (AFTER DAY +30): patients will undergo ultrasound elastography twice a week during course of SOS/VOD treatment. If patient is still admitted at end of treatment, patient will undergo ultrasound elastography once every 30 days through day +100 or discharge, whichever comes first.
  3. Late Onset SOS/VOD as OUTPATIENT (DAY +30 - DAY + 100): patients will undergo ultrasound elastography once a week during course of SOS/VOD treatment
Being tested
Ultrasound Elastography
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 ElastographyDiagnostic test

    Ultrasound shear wave elastography

Study groups in NCT03865589
Study groupRoleWhat they receive
Patients Undergoing HCTExperimentalAll patients enrolled will undergo US SWE at specific time points as outlined in the protocol based on disease course.
Receives: Diagnostic Test: Ultrasound Elastography

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Define Sensitivity and Specificity Threshold for US SWE Risk

    To define a threshold and quantify the sensitivity and specificity of US SWE for risk stratification of patients into three categories as defined by the EBMTC adult and pediatric criteria: no SOS, mild to moderate SOS, and severe to very severe SOS

    Measured: 100 days post transplant

Secondary outcomes (3)

  1. Quantify Temporal Relationship between SWE and SOS and Modified Seattle Criteria

    Quantify the temporal relationship between US SWE changes and SOS diagnosis according to Modified Seattle Criteria

    Measured: 100 days post transplant

  2. Quantify Temporal Relationship between SWE and SOS and Baltimore Criteria

    Quantify the temporal relationship between US SWE changes and SOS diagnosis according to various clinical criteria Baltimore Criteria

    Measured: 100 days post transplant

  3. Quantify Temporal Relationship between SWE and SOS and EBMT Consortium

    Quantify the temporal relationship between US SWE changes and SOS diagnosis according to EBMT consortium.

    Measured: 100 days post transplant

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted7 Mar 2019
  2. Study start1 Apr 2019
  3. Primary completion31 Dec 2025
  4. Study completion31 Dec 2025

Resources

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
Model description
All patients undergoing myeloblative conditioning regimen as part of hematopoietic cell transplant will be consecutively studied
Masking
None (open label)
Enrolment
250 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03865589
Sponsor's protocol ID
STUDY0000548
Status last verified
Jul 2026
First submitted
1 Mar 2019
Last updated
14 Jul 2026
Results posted
No
Data monitoring committee
No
FDA-regulated drug
No
FDA-regulated device
Yes
Individual data sharing
No

Publications

  • B. Cozadd, paper presented at the 36th Annual J.P. Morgan Annual Healthcare Conference, San Francisco, California, January 8, 2018 2018

  • Z. X. D'Souza A. (Available at: http://www.cibmtr.org, 2016), vol. 2017

  • P. Negrin RS; Bonis, M. Nelson J Chao, Ed. (www.uptodate.com, 2017), vol. 2017

  • 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 8175139

  • Mohty 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 27183098

  • McDonald 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 8420443

  • Jones 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 3321587

  • Corbacioglu 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 22364685

  • Barker 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 12815482

  • Cesaro 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 16219577

  • Coppell 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 19766729

  • Richardson 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 20167278

  • Corbacioglu 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 28759025

  • Corbacioglu 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 14661036

  • The Medical Letter. (https://secure.medicalletter.org/w1503c, 2016), vol. 2017.

Questions about this trial

What is this clinical trial studying?

A study testing Ultrasound Elastography in people with Bone Marrow Transplant Complications and Sinusoidal Obstruction Syndrome, run by Children's Mercy Hospital Kansas City at 7 sites 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 15 inclusion and 1 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: finished, as of the sponsor's last update on 14 Jul 2026. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 7 sites 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?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

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?

Define Sensitivity and Specificity Threshold for US SWE Risk (time frame: 100 days post transplant). 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 NCT03865589, 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 14 Jul 2026.

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