Validating Ultrasound Biomarkers for Hepatic Sinusoidal Obstruction Syndrome in Pediatric Hematopoietic Cell Transplant Patients

NCT03963999 | Withdrawn Phase 4 FDA Drug

• 1 other identifier: STUDY00000792
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 1

Brief 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. 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).

Conditions

Sinusoidal Obstruction Syndrome; Veno Occlusive Disease, Hepatic; Bone Marrow Transplant Complications; Stem Cell Transplant Complications

Keywords

Ultrasound Elastography

Outcome Measures

Primary Outcomes (3)

• 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.

  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.

  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.

  100 days post transplant

Study Arms (1)

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.

Diagnostic Test: Ultrasound Elastography; Drug: Contrast Enhanced Ultrasound (CEUS)

Interventions

Ultrasound Elastography DIAGNOSTIC_TEST

Ultrasound shear wave elastography

Patients Undergoing HCT

Contrast Enhanced Ultrasound (CEUS) DRUG

Contrast-enhanced ultrasound (CEUS) uses an intravenous injection of microbubble contrast agent.

Also known as: Lumason (sulfur hexafluoride lipid-type A microspheres)

Patients Undergoing HCT

Eligibility Criteria

• Age: 1 Month - 25 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• HCT patient under 25 years of age with
• myeloablative conditioning,
• prior liver damage or
• other high risk factor:
• Neuroblastoma,
• HLH,
• 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).

You may not qualify if:

• Any patient who has contraindication to any of the ultrasound procedures (e.g. unable to hold still).

Sponsors & Collaborators

• Children's Mercy Hospital Kansas City: lead
• Nationwide Children's Hospital: collaborator
• St. Jude Children's Research Hospital: collaborator
• Children's Hospital Colorado: collaborator

Study Sites (1)

Children's Mercy Hospital

Kansas City, Missouri, 64108, United States

Location

Related Publications (19)

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  PMID: 26079489 BACKGROUND

• 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.

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• 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.

  PMID: 19766729 BACKGROUND

• 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.

  PMID: 28759025 BACKGROUND

• 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.

  PMID: 14661036 BACKGROUND

• Fontanilla 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.

  PMID: 22039033 BACKGROUND

• 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.

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• Kernan 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.

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• Kernan 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.

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MeSH Terms

Conditions

Hepatic Veno-Occlusive Disease

Condition Hierarchy (Ancestors)

Liver Diseases; Digestive System Diseases; Vascular Diseases; Cardiovascular Diseases

Study Officials

• Sherwin S Chan, MD, PhD

  Children's Mercy Hospital Kansas City

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: NA
• Masking: NONE
• Purpose: DIAGNOSTIC
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: 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

Study Record Dates

• First Submitted: May 23, 2019
• First Posted: May 28, 2019
• Study Start: April 1, 2020
• Primary Completion: April 30, 2024
• Study Completion: April 1, 2025
• Last Updated: January 13, 2020

Record last verified: 2020-01

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)