Sinusoidal Obstruction SyndromePhase 4NCT03963999
Validating Ultrasound Biomarkers for Hepatic Sinusoidal Obstruction Syndrome in Pediatric Hematopoietic Cell Transplant Patients
A Phase 4 study testing Ultrasound Elastography and Contrast Enhanced Ultrasound (CEUS) in people with Sinusoidal Obstruction Syndrome and Veno Occlusive Disease, Hepatic, run by Children's Mercy Hospital Kansas City at 1 site in United States.
Trial summary
Hepatic veno-occlusive disease/sinusoidal obstructive syndrome (VOD/SOS) is a potentially fatal complication of hematopoietic cell transplant (HCT). Historically VOD/SOS has been clinically diagnosed using the modified Seattle criteria or the Baltimore criteria. Read more about this study
- Who is it for?
- Ages 1 month to 25 years
- Conditions the study is for
- Sinusoidal Obstruction Syndrome, Veno Occlusive Disease, Hepatic, Bone Marrow Transplant Complications
- What is being tested?
- Ultrasound Elastography and Contrast Enhanced Ultrasound (CEUS)
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 0 participants
- Where
- 1 siteUnited States
- Study dates
- 1 Apr 2020to 1 Apr 2025
- Phase
- Phase 4
- 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 25 years
- All sexes
- No healthy volunteers
- Child, Adult
Who may be able to join
- HCT patient under 25 years of age with
- myeloablative conditioning,
- prior liver damage or
- other high risk factor:
- Neuroblastoma,
- HLH,
Show all 13Show fewer
- Osteopetrosis,
- Thalassemia,
- Treatment with inotuzumab or gemtuzumab within 3 months prior to HCT admission,
- Hepatic iron overload,
- Steatohepatitis,
- Active inflammatory or infection hepatitis or
- Any other condition which puts the patient at a higher risk of developing VOD).
Who cannot join
- Any patient who has contraindication to any of the ultrasound procedures (e.g. unable to hold still).
Trial locations and contacts
1 site in 1 country.
United States1 site
Children's Mercy Hospital
Kansas City, Missouri, 64108
About this study
Hepatic veno-occlusive disease/sinusoidal obstructive syndrome (VOD/SOS) is a potentially fatal complication of hematopoietic cell transplant (HCT). Historically VOD/SOS has been clinically diagnosed using the modified Seattle criteria or the Baltimore criteria. The modified Seattle Criteria define VOD/SOS diagnosis is made when two of the following three criteria are present in a patient within 21 days of transplantation: hyperbilirubinemia (total serum bilirubin > 2 mg/dL), hepatomegaly or right upper quadrant liver pain, and weight gain (> 2% of baseline) or ascites. Other conditions like graft versus host disease, sepsis syndrome (fever and hypotension), cardiac failure, or tumor infiltration) have to be excluded. This definition was from a well-designed retrospective cohort study on 255 adult and pediatric HCT patients in which the VOD/SOS incidence was 21%. McDonald et al followed up this work with a prospective cohort study of 355 patients noting an incidence of VOD/SOS of 54%. These seminal studies have had a major impact on the field by defining clinical diagnostic criteria. An alternative diagnostic criteria (Baltimore criteria) was proposed by Jones et al as a part of a well-designed retrospective review of 235 HCT patients finding a VOD/SOS incidence of 22%. Jones defined VOD/SOS as the presence of hyperbilirubinemia (total serum bilirubin > 2 mg/dL) along with at least 2 of 3 other findings: hepatomegaly, ascites, and weight gain (> 5% of baseline).
Read the detailed description
Hepatic veno-occlusive disease/sinusoidal obstructive syndrome (VOD/SOS) is a potentially fatal complication of hematopoietic cell transplant (HCT). Historically VOD/SOS has been clinically diagnosed using the modified Seattle criteria or the Baltimore criteria. The modified Seattle Criteria define VOD/SOS diagnosis is made when two of the following three criteria are present in a patient within 21 days of transplantation: hyperbilirubinemia (total serum bilirubin > 2 mg/dL), hepatomegaly or right upper quadrant liver pain, and weight gain (> 2% of baseline) or ascites. Other conditions like graft versus host disease, sepsis syndrome (fever and hypotension), cardiac failure, or tumor infiltration) have to be excluded. This definition was from a well-designed retrospective cohort study on 255 adult and pediatric HCT patients in which the VOD/SOS incidence was 21%. McDonald et al followed up this work with a prospective cohort study of 355 patients noting an incidence of VOD/SOS of 54%. These seminal studies have had a major impact on the field by defining clinical diagnostic criteria. An alternative diagnostic criteria (Baltimore criteria) was proposed by Jones et al (1987) as a part of a well-designed retrospective review of 235 HCT patients finding a VOD/SOS incidence of 22%. Jones defined VOD/SOS as the presence of hyperbilirubinemia (total serum bilirubin > 2 mg/dL) along with at least 2 of 3 other findings: hepatomegaly, ascites, and weight gain (> 5% of baseline).
A large well-executed meta-analysis on 24,920 adults and pediatric patients confirms the fact that applying the more stringent Baltimore criteria results in a lower incidence rate for VOD/SOS of 9.6% as compared to 17.3% with the modified Seattle criteria. A major weakness of this large meta-analysis is that it did not perform a separate pediatric incidence. A small retrospective cohort study of 142 pediatric patients (Barker et al, BMT 2003) reported an incidence of 18% using the modified Seattle criteria corroborating the findings from the meta-analysis.
VOD/SOS is important to study because the survival rates in severe disease with multi-organ failure are very low. Day 100 (post HCT) survival rate for severe VOD/SOS in the meta-analysis was only 16%; most patients died of multi-organ failure. Fortunately, defibrotide seems to be effective in increasing survival rates. Richardson et al (2016) demonstrated in a well-designed and executed phase 3 clinical trial that defibrotide increased day 100 survival in severe VOD/SOS (defined by the Baltimore criteria) with multi-organ failure from 25% to 38%. Weaknesses of this study were that it only included 44 pediatric patients and a historical cohort was used as the control population. A well-designed small, multi-institution, retrospective cohort study in 45 pediatric patients diagnosed with VOD/SOS showed that the complete response rate was 83% in the cohort who started defibrotide treatment within two days of diagnosis and the complete response rate decreased to 10% in patients who started treatment three or more days after clinical diagnosis. A large, well conducted and executed trial of defibrotide involving 101 centers in the USA was also able to confirm this survival benefit. In the 570 pediatric (< 16 years old) patients in this study, the estimated day 100 survival rate was 67.9%. In 512 pediatric and adult patients with VOD/SOS with multi-organ failure, the estimated survival rate was 49.5%. This large study also showed that earlier initiation of defibrotide was associated with increased survival, especially if treatment could be initiated within day 2 after diagnosis. This study lacked a control arm for comparison but historical data showing a survival rate of 16% can again serve as a control here.
In 2017 the European society for Blood and Marrow Transplantation (EBMT) consortium proposed VOD/SOS diagnostic and severity grading criteria specifically for children, which are not distinguished as separate in the Baltimore or Seattle criteria (Corbacioglu et al, 2017). These criteria highlight how VOD/SOS in children differs from adults. Unlike the Baltimore or modified Seattle criteria, EBMT criteria have no time limitation for the diagnosis. The EBMT criteria reinforces the fact that hyperbilirubinemia in children is a late finding. The EBMT proposed grading of severity into four categories: mild, moderate, severe and very severe VOD/SOS. Defibrotide has been investigated and has shown benefit primarily as treatment for VOD/SOS with multi-organ failure, which corresponds to severe and very severe disease by the EBMT severity grading. The weakness of these criteria is that they are not yet tested, but this is something we also aim to do with the proposed research. One of the greatest clinical challenges is determining which patients will progress to severe disease, so that specific therapy can be initiated early. Currently, no clinical, laboratory or imaging biomarkers can reliably differentiate VOD/SOS from other HCT complications. Additionally, there is no biomarker that can reliably differentiate VOD/SOS patients who will go on to develop severe or very severe disease versus VOD/SOS patients who never progress to those severe disease states. Therefore, this research is timely because the investigator's preliminary data reviewed below show that promising imaging biomarkers may be available that can diagnose VOD/SOS earlier than current clinical criteria. These biomarkers could help refine the clinical criteria to allow earlier diagnosis of VOD/SOS, thereby allowing earlier initiation of specific therapy which can help decrease the high mortality from severe VOD/SOS. Additionally, if these biomarkers could identify the VOD/SOS patients at risk of progression to severe or very severe VOD/SOS, this therapy could even be more targeted.
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 grayscale US, Doppler US, US SWE and CEUS within 30 days prior to starting their conditioning regimen.
US Schedule (All exams can be performed +/- 2 days compared to the prescribed date):
Baseline exam: one time within 30 days before start of conditioning (~Day -9).
Inpatient exams: Day -3, day +3, day +7, day + 10, day +17, day +24, day +31, day +60 and day +90 after HCT.
If the patient is discharged earlier than day +100 from the HCT admission, then all exams after the discharge day will be canceled.
Concern for VOD/SOS:
If the HCT team is suspecting VOD/SOS a patient admitted for HCT, then US will be performed twice a week during the time of concern for VOD/SOS.
- Conditions
- Sinusoidal Obstruction Syndrome, Veno Occlusive Disease, Hepatic, Bone Marrow Transplant Complications, Stem Cell Transplant Complications
- Being tested
- Ultrasound Elastography, Contrast Enhanced Ultrasound (CEUS)
- 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
Contrast Enhanced Ultrasound (CEUS)Drug
Also called Lumason (sulfur hexafluoride lipid-type A microspheres)
Contrast-enhanced ultrasound (CEUS) uses an intravenous injection of microbubble contrast agent.
| Study group | Role | What they receive |
|---|---|---|
| Patients Undergoing HCT | Experimental | All patients enrolled will undergo grayscale US, Doppler US, US SWE and CEUS at specific time points as outlined in the protocol based on disease course. Receives: Diagnostic Test: Ultrasound Elastography; Drug: Contrast Enhanced Ultrasound (CEUS) |
What is being measured
The primary outcome is the main question the study is designed to answer.
Define Sensitivity and Specificity of US (grayscale, Doppler and SWE) for Diagnosis and Severity Grading for SOS/VOD
Determine the sensitivity and specificity of US for diagnosis and severity grading of VOD/SOS in a cohort of 250 pediatric HCT patients.
Measured: 100 days post transplant
Define Sensitivity and Specificity of CEUS for Diagnosis and Severity Grading for SOS/VOD
Determine the sensitivity and specificity of contrast enhanced ultrasound (CEUS) variables for diagnosis and severity grading of VOD/SOS as compared to the pediatric EBMT criteria.
Measured: 100 days post transplant
Define Optimal Timing for US for Early Diagnosis and Risk Stratification of VOD/SOS
Determine the optimal timing for ultrasound measurements to help predict early diagnosis and risk stratification of VOD/SOS.
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.
- First posted28 May 2019
- Study start1 Apr 2020 (estimated)
- Primary completion30 Apr 2024 (estimated)
- Study completion1 Apr 2025 (estimated)
Why it stopped: We did not receive grant funding. We will reapply in June of 2020
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (19)Papers the sponsor has linked to this study.
- Other trials for Sinusoidal Obstruction SyndromeStudies 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 4
- Primary purpose
- Diagnosis
- Allocation
- Not applicable
- Intervention model
- Single group
- Model description
- All patients undergoing myeloblative conditioning regimen as part of hematopoietic cell transplant or prior liver damage or other high risk factor will be consecutively studied
- Masking
- None (open label)
- Enrolment
- 0 participants (actual)
Sponsor and investigators
- Lead sponsor
- Children's Mercy Hospital Kansas City
- Sponsor type
- University, hospital or other
- Collaborators
- Nationwide Children's Hospital, St. Jude Children's Research Hospital, Children's Hospital Colorado
- Responsible party
- Sponsor
- Investigators
- Sherwin S Chan, MD, PhD, Principal investigator, Children's Mercy Hospital Kansas City
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03963999
- Sponsor's protocol ID
- STUDY00000792
- Status last verified
- Jan 2020
- First submitted
- 23 May 2019
- Last updated
- 13 Jan 2020
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Barr RG, Ferraioli G, Palmeri ML, Goodman ZD, Garcia-Tsao G, Rubin J, Garra B, Myers RP, Wilson SR, Rubens D, Levine D. Elastography Assessment of Liver Fibrosis: Society of Radiologists in Ultrasound Consensus Conference Statement. Radiology. 2015 Sep;276(3):845-61. doi: 10.1148/radiol.2015150619. Epub 2015 Jun 16.
PubMed 26079489Barker 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 12815482Colecchia A, Ravaioli F, Sessa M, Alemanni VL, Dajti E, Marasco G, Vestito A, Zagari RM, Barbato F, Arpinati M, Cavo M, Festi D, Bonifazi F. Liver Stiffness Measurement Allows Early Diagnosis of Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome in Adult Patients Who Undergo Hematopoietic Stem Cell Transplantation: Results from a Monocentric Prospective Study. Biol Blood Marrow Transplant. 2019 May;25(5):995-1003. doi: 10.1016/j.bbmt.2019.01.019. Epub 2019 Jan 18.
PubMed 30660772Coppell 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 19766729Corbacioglu 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 14661036Fontanilla T, Hernando CG, Claros JC, Bautista G, Minaya J, Del Carmen Vega M, Piazza A, Mendez S, Rodriguez C, Aranguena RP. Acoustic radiation force impulse elastography and contrast-enhanced sonography of sinusoidal obstructive syndrome (Veno-occlusive Disease): preliminary results. J Ultrasound Med. 2011 Nov;30(11):1593-8. doi: 10.7863/jum.2011.30.11.1593.
PubMed 22039033Jones 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 3321587Kernan NA, Grupp S, Smith AR, Arai S, Triplett B, Antin JH, Lehmann L, Shore T, Ho VT, Bunin N, Iacobelli M, Liang W, Hume R, Tappe W, Soiffer R, Richardson P. Final results from a defibrotide treatment-IND study for patients with hepatic veno-occlusive disease/sinusoidal obstruction syndrome. Br J Haematol. 2018 Jun;181(6):816-827. doi: 10.1111/bjh.15267. Epub 2018 May 16.
PubMed 29767845Kernan NA, Richardson PG, Smith AR, Triplett BM, Antin JH, Lehmann L, Messinger Y, Liang W, Hume R, Tappe W, Soiffer RJ, Grupp SA. Defibrotide for the treatment of hepatic veno-occlusive disease/sinusoidal obstruction syndrome following nontransplant-associated chemotherapy: Final results from a post hoc analysis of data from an expanded-access program. Pediatr Blood Cancer. 2018 Oct;65(10):e27269. doi: 10.1002/pbc.27269. Epub 2018 Jun 6.
PubMed 29873895Lassau N, Leclere J, Auperin A, Bourhis JH, Hartmann O, Valteau-Couanet D, Benhamou E, Bosq J, Ibrahim A, Girinski T, Pico JL, Roche A. Hepatic veno-occlusive disease after myeloablative treatment and bone marrow transplantation: value of gray-scale and Doppler US in 100 patients. Radiology. 1997 Aug;204(2):545-52. doi: 10.1148/radiology.204.2.9240551.
PubMed 9240551McDonald 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 8420443McDonald GB, Sharma P, Matthews DE, Shulman HM, Thomas ED. Venocclusive disease of the liver after bone marrow transplantation: diagnosis, incidence, and predisposing factors. Hepatology. 1984 Jan-Feb;4(1):116-22. doi: 10.1002/hep.1840040121.
PubMed 6363247Nishida M, Kahata K, Hayase E, Shigematsu A, Sato M, Kudo Y, Omotehara S, Iwai T, Sugita J, Shibuya H, Shimizu C, Teshima T. Novel Ultrasonographic Scoring System of Sinusoidal Obstruction Syndrome after Hematopoietic Stem Cell Transplantation. Biol Blood Marrow Transplant. 2018 Sep;24(9):1896-1900. doi: 10.1016/j.bbmt.2018.05.025. Epub 2018 May 24.
PubMed 29803752Reddivalla N, Robinson AL, Reid KJ, Radhi MA, Dalal J, Opfer EK, Chan SS. Using liver elastography to diagnose sinusoidal obstruction syndrome in pediatric patients undergoing hematopoetic stem cell transplant. Bone Marrow Transplant. 2020 Mar;55(3):523-530. doi: 10.1038/s41409-017-0064-6. Epub 2018 Jan 15.
PubMed 29335626
Study at a glance
From the registry record, last updated by the sponsor on 13 Jan 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Validating Ultrasound Biomarkers for Hepatic Sinusoidal Obstruction Syndrome in Pediatric Hematopoietic Cell Transplant Patients
- ClinicalTrials.gov ID
- NCT03963999
- Acronym / sponsor ID
- STUDY00000792
- Conditions
- Sinusoidal Obstruction Syndrome, Veno Occlusive Disease, Hepatic, Bone Marrow Transplant Complications, Stem Cell Transplant Complications
- Keywords
- Ultrasound Elastography
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- WithdrawnReason stopped: We did not receive grant funding. We will reapply in June of 2020
- Enrolment
- 0 participants (actual)
- Lead sponsor
- Children's Mercy Hospital Kansas CityUniversity, hospital or other
- Collaborators
- Nationwide Children's Hospital, St. Jude Children's Research Hospital, Children's Hospital Colorado
- Study start
- 1 Apr 2020 (estimated)
- Primary completion
- 30 Apr 2024 (estimated)
- Study completion
- 1 Apr 2025 (estimated)
- First posted
- 28 May 2019 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Hepatic veno-occlusive disease/sinusoidal obstructive syndrome (VOD/SOS) is a potentially fatal complication of hematopoietic cell transplant (HCT). Historically VOD/SOS has been clinically diagnosed using the modified Seattle criteria or the Baltimore criteria. The modified Seattle Criteria define VOD/SOS diagnosis is made when two of the following three criteria are present in a patient within 21 days of transplantation: hyperbilirubinemia (total serum bilirubin > 2 mg/dL), hepatomegaly or right upper quadrant liver pain, and weight gain (> 2% of baseline) or ascites. Other conditions like graft versus host disease, sepsis syndrome (fever and hypotension), cardiac failure, or tumor infiltration) have to be excluded. This definition was from a well-designed retrospective cohort study on 255 adult and pediatric HCT patients in which the VOD/SOS incidence was 21%. McDonald et al followed up this work with a prospective cohort study of 355 patients noting an incidence of VOD/SOS of 54%. These seminal studies have had a major impact on the field by defining clinical diagnostic criteria. An alternative diagnostic criteria (Baltimore criteria) was proposed by Jones et al as a part of a well-designed retrospective review of 235 HCT patients finding a VOD/SOS incidence of 22%. Jones defined VOD/SOS as the presence of hyperbilirubinemia (total serum bilirubin > 2 mg/dL) along with at least 2 of 3 other findings: hepatomegaly, ascites, and weight gain (> 5% of baseline).
Detailed description
Hepatic veno-occlusive disease/sinusoidal obstructive syndrome (VOD/SOS) is a potentially fatal complication of hematopoietic cell transplant (HCT). Historically VOD/SOS has been clinically diagnosed using the modified Seattle criteria or the Baltimore criteria. The modified Seattle Criteria define VOD/SOS diagnosis is made when two of the following three criteria are present in a patient within 21 days of transplantation: hyperbilirubinemia (total serum bilirubin > 2 mg/dL), hepatomegaly or right upper quadrant liver pain, and weight gain (> 2% of baseline) or ascites. Other conditions like graft versus host disease, sepsis syndrome (fever and hypotension), cardiac failure, or tumor infiltration) have to be excluded. This definition was from a well-designed retrospective cohort study on 255 adult and pediatric HCT patients in which the VOD/SOS incidence was 21%. McDonald et al followed up this work with a prospective cohort study of 355 patients noting an incidence of VOD/SOS of 54%. These seminal studies have had a major impact on the field by defining clinical diagnostic criteria. An alternative diagnostic criteria (Baltimore criteria) was proposed by Jones et al (1987) as a part of a well-designed retrospective review of 235 HCT patients finding a VOD/SOS incidence of 22%. Jones defined VOD/SOS as the presence of hyperbilirubinemia (total serum bilirubin > 2 mg/dL) along with at least 2 of 3 other findings: hepatomegaly, ascites, and weight gain (> 5% of baseline).
A large well-executed meta-analysis on 24,920 adults and pediatric patients confirms the fact that applying the more stringent Baltimore criteria results in a lower incidence rate for VOD/SOS of 9.6% as compared to 17.3% with the modified Seattle criteria. A major weakness of this large meta-analysis is that it did not perform a separate pediatric incidence. A small retrospective cohort study of 142 pediatric patients (Barker et al, BMT 2003) reported an incidence of 18% using the modified Seattle criteria corroborating the findings from the meta-analysis.
VOD/SOS is important to study because the survival rates in severe disease with multi-organ failure are very low. Day 100 (post HCT) survival rate for severe VOD/SOS in the meta-analysis was only 16%; most patients died of multi-organ failure. Fortunately, defibrotide seems to be effective in increasing survival rates. Richardson et al (2016) demonstrated in a well-designed and executed phase 3 clinical trial that defibrotide increased day 100 survival in severe VOD/SOS (defined by the Baltimore criteria) with multi-organ failure from 25% to 38%. Weaknesses of this study were that it only included 44 pediatric patients and a historical cohort was used as the control population. A well-designed small, multi-institution, retrospective cohort study in 45 pediatric patients diagnosed with VOD/SOS showed that the complete response rate was 83% in the cohort who started defibrotide treatment within two days of diagnosis and the complete response rate decreased to 10% in patients who started treatment three or more days after clinical diagnosis. A large, well conducted and executed trial of defibrotide involving 101 centers in the USA was also able to confirm this survival benefit. In the 570 pediatric (< 16 years old) patients in this study, the estimated day 100 survival rate was 67.9%. In 512 pediatric and adult patients with VOD/SOS with multi-organ failure, the estimated survival rate was 49.5%. This large study also showed that earlier initiation of defibrotide was associated with increased survival, especially if treatment could be initiated within day 2 after diagnosis. This study lacked a control arm for comparison but historical data showing a survival rate of 16% can again serve as a control here.
In 2017 the European society for Blood and Marrow Transplantation (EBMT) consortium proposed VOD/SOS diagnostic and severity grading criteria specifically for children, which are not distinguished as separate in the Baltimore or Seattle criteria (Corbacioglu et al, 2017). These criteria highlight how VOD/SOS in children differs from adults. Unlike the Baltimore or modified Seattle criteria, EBMT criteria have no time limitation for the diagnosis. The EBMT criteria reinforces the fact that hyperbilirubinemia in children is a late finding. The EBMT proposed grading of severity into four categories: mild, moderate, severe and very severe VOD/SOS. Defibrotide has been investigated and has shown benefit primarily as treatment for VOD/SOS with multi-organ failure, which corresponds to severe and very severe disease by the EBMT severity grading. The weakness of these criteria is that they are not yet tested, but this is something we also aim to do with the proposed research. One of the greatest clinical challenges is determining which patients will progress to severe disease, so that specific therapy can be initiated early. Currently, no clinical, laboratory or imaging biomarkers can reliably differentiate VOD/SOS from other HCT complications. Additionally, there is no biomarker that can reliably differentiate VOD/SOS patients who will go on to develop severe or very severe disease versus VOD/SOS patients who never progress to those severe disease states. Therefore, this research is timely because the investigator's preliminary data reviewed below show that promising imaging biomarkers may be available that can diagnose VOD/SOS earlier than current clinical criteria. These biomarkers could help refine the clinical criteria to allow earlier diagnosis of VOD/SOS, thereby allowing earlier initiation of specific therapy which can help decrease the high mortality from severe VOD/SOS. Additionally, if these biomarkers could identify the VOD/SOS patients at risk of progression to severe or very severe VOD/SOS, this therapy could even be more targeted.
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 grayscale US, Doppler US, US SWE and CEUS within 30 days prior to starting their conditioning regimen.
US Schedule (All exams can be performed +/- 2 days compared to the prescribed date):
Baseline exam: one time within 30 days before start of conditioning (~Day -9).
Inpatient exams: Day -3, day +3, day +7, day + 10, day +17, day +24, day +31, day +60 and day +90 after HCT.
If the patient is discharged earlier than day +100 from the HCT admission, then all exams after the discharge day will be canceled.
Concern for VOD/SOS:
If the HCT team is suspecting VOD/SOS a patient admitted for HCT, then US will be performed twice a week during the time of concern for VOD/SOS.
Study design
- Primary purpose
- Diagnosis
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
- Model description
- All patients undergoing myeloblative conditioning regimen as part of hematopoietic cell transplant or prior liver damage or other high risk factor will be consecutively studied
| Arm | Type | Receives |
|---|---|---|
| Patients Undergoing HCT | Experimental | Diagnostic Test: Ultrasound Elastography, Drug: Contrast Enhanced Ultrasound (CEUS)All patients enrolled will undergo grayscale US, Doppler US, US SWE and CEUS at specific time points as outlined in the protocol based on disease course. |
Who may qualify
- Ages
- 1 month to 25 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult
Key inclusion criteria (13 listed)
- HCT patient under 25 years of age with
- myeloablative conditioning,
- prior liver damage or
- other high risk factor:
- Neuroblastoma,
Key exclusion criteria (1 listed)
- Any patient who has contraindication to any of the ultrasound procedures (e.g. unable to hold still).
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 ElastographyUltrasound shear wave elastography | Diagnostic test | Patients Undergoing HCT |
| Contrast Enhanced Ultrasound (CEUS)Also: Lumason (sulfur hexafluoride lipid-type A microspheres)Contrast-enhanced ultrasound (CEUS) uses an intravenous injection of microbubble contrast agent. | Drug | Patients Undergoing HCT |
Primary outcome
Define Sensitivity and Specificity of US (grayscale, Doppler and SWE) for Diagnosis and Severity Grading for SOS/VOD
Time frame: 100 days post transplant
Determine the sensitivity and specificity of US for diagnosis and severity grading of VOD/SOS in a cohort of 250 pediatric HCT patients.
Define Sensitivity and Specificity of CEUS for Diagnosis and Severity Grading for SOS/VOD
Time frame: 100 days post transplant
Determine the sensitivity and specificity of contrast enhanced ultrasound (CEUS) variables for diagnosis and severity grading of VOD/SOS as compared to the pediatric EBMT criteria.
Define Optimal Timing for US for Early Diagnosis and Risk Stratification of VOD/SOS
Time frame: 100 days post transplant
Determine the optimal timing for ultrasound measurements to help predict early diagnosis and risk stratification of VOD/SOS.
Results and safety
The study was withdrawn before enrolling participants, so there are no results.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 13 Jan 2020.
- Background: PubMed 26079489Barr RG, Ferraioli G, Palmeri ML, Goodman ZD, Garcia-Tsao G, Rubin J, Garra B, Myers RP, Wilson SR, Rubens D, Levine D. Elastography Assessment of Liver Fibrosis: Society of Radiologists in Ultrasound Consensus Conference Statement. Radiology. 2015 Sep;276(3):845-61. doi: 10.1148/radiol.2015150619. Epub 2015 Jun 16.
- 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 30660772Colecchia A, Ravaioli F, Sessa M, Alemanni VL, Dajti E, Marasco G, Vestito A, Zagari RM, Barbato F, Arpinati M, Cavo M, Festi D, Bonifazi F. Liver Stiffness Measurement Allows Early Diagnosis of Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome in Adult Patients Who Undergo Hematopoietic Stem Cell Transplantation: Results from a Monocentric Prospective Study. Biol Blood Marrow Transplant. 2019 May;25(5):995-1003. doi: 10.1016/j.bbmt.2019.01.019. Epub 2019 Jan 18.
- 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 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 22039033Fontanilla T, Hernando CG, Claros JC, Bautista G, Minaya J, Del Carmen Vega M, Piazza A, Mendez S, Rodriguez C, Aranguena RP. Acoustic radiation force impulse elastography and contrast-enhanced sonography of sinusoidal obstructive syndrome (Veno-occlusive Disease): preliminary results. J Ultrasound Med. 2011 Nov;30(11):1593-8. doi: 10.7863/jum.2011.30.11.1593.
- 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 29767845Kernan NA, Grupp S, Smith AR, Arai S, Triplett B, Antin JH, Lehmann L, Shore T, Ho VT, Bunin N, Iacobelli M, Liang W, Hume R, Tappe W, Soiffer R, Richardson P. Final results from a defibrotide treatment-IND study for patients with hepatic veno-occlusive disease/sinusoidal obstruction syndrome. Br J Haematol. 2018 Jun;181(6):816-827. doi: 10.1111/bjh.15267. Epub 2018 May 16.
- Background: PubMed 29873895Kernan NA, Richardson PG, Smith AR, Triplett BM, Antin JH, Lehmann L, Messinger Y, Liang W, Hume R, Tappe W, Soiffer RJ, Grupp SA. Defibrotide for the treatment of hepatic veno-occlusive disease/sinusoidal obstruction syndrome following nontransplant-associated chemotherapy: Final results from a post hoc analysis of data from an expanded-access program. Pediatr Blood Cancer. 2018 Oct;65(10):e27269. doi: 10.1002/pbc.27269. Epub 2018 Jun 6.
- Background: PubMed 9240551Lassau N, Leclere J, Auperin A, Bourhis JH, Hartmann O, Valteau-Couanet D, Benhamou E, Bosq J, Ibrahim A, Girinski T, Pico JL, Roche A. Hepatic veno-occlusive disease after myeloablative treatment and bone marrow transplantation: value of gray-scale and Doppler US in 100 patients. Radiology. 1997 Aug;204(2):545-52. doi: 10.1148/radiology.204.2.9240551.
- 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.
- 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.
Sherwin S 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 Phase 4 study testing Ultrasound Elastography and Contrast Enhanced Ultrasound (CEUS) in people with Sinusoidal Obstruction Syndrome and Veno Occlusive Disease, Hepatic, 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 13 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: withdrawn, as of the sponsor's last update on 13 Jan 2020. 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.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study was withdrawn before enrolling participants, so there are no results.
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 of US (grayscale, Doppler and SWE) for Diagnosis and Severity Grading for SOS/VOD (time frame: 100 days post transplant). The study lists 3 primary outcomes in all. 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 NCT03963999, which also lists 19 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 13 Jan 2020.