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(Pediatric) Defibrotide for patients with hepatic veno-occlusive disease (VOD): A treatment IND study (Under CFR 312.34)
|Bone Marrow Transplant (BMT)
|Hepatic Veno-Occlusive Disease (VOD)
- To provide Defibrotide under 21 CFR 312.34 (Treatment use of an investigational new drug).
Patients who meet both of the following criteria will be enrolled in the treatment and historical control groups:
- Clinical diagnosis of VOD, defined by jaundice (bilirubin ≥ 2 mg/dL) and at least 2 of the following clinical findings, by Day +21 post stem cell transplant:
- weight gain ≥ 5% above baseline weight (defined as weight on the first day of conditioning-- if this value is not available, the weight on the date of admission to the SCT unit may be used),
- hepatomegaly; patients with pre-existing hepatomegaly must have documentation by physical exam or imaging that liver size is increased over baseline (at the time of admission for SCT).
- Severe VOD, defined as VOD with multi-organ failure (MOF), i.e., presence of one or both of the following, by Day +28 post stem cell transplant:
- renal dysfunction: a) serum creatinine ≥ 3x value on the date of admission to the SCT unit for conditioning or ≥ 3x lowest value during conditioning prior to SCT (whichever is lowest) or b) creatinine clearance or GFR ≤ 40% of admission value, or c) dialysis dependence;
- pulmonary dysfunction: documentation of oxygen saturation ≤ 90% on room air (two consecutive measurements at least one hour apart) or requirement for oxygen supplementation /ventilator dependence. Dysfunction must be attributable to fluid overload or mechanical impingement from abdominal distention or hepatic enlargement and not to an infectious cause (e.g., documented pneumonia).
- Please note: If it is not possible to obtain a second oxygen saturation measurement on room air without jeopardizing the patient safety, a single measurement of ≤ 90% will suffice.
- Patients to be enrolled in the treatment group must also provide voluntary written informed consent to the protocol to be eligible for the study. For minor patients, parent/legal guardian will provide consent and, when possible, patient assent will also be obtained. For compromised patients, their designated proxy must provide informed consent. For patients in the historical control group, informed consent from each patient is not required by the Sponsor as part of this study; however, investigators must comply with the requirements of their own IRB in determining if patient informed consent is required.
Patients who fulfill any of the following criteria will not be enrolled in the treatment group:
- Documentation of pre-existing (at the time of SCT) cirrhosis of the liver.
- An alternative diagnosis for ascites, weight gain and jaundice, such as fulminant viral hepatitis, at the time that severe VOD criteria are met.
- Documented diagnosis of GVHD, grade B-D according to the IBMTR Severity Index (see Appendix B), involving the liver or gut, or documented diagnosis of GVHD, grade C or higher according to the IBMTR Severity Index, involving skin. Please note: 1. Patients with grade B GVHD involving only skin are eligible. 2. Grade is established without consensus grading (i.e., downgrading) for the purpose of this study. For patients with concurrent, confounding causes of liver dysfunction clinically evident or evident on ultrasound or other radiographic imaging or by medical assessment per institutional practice (such as evidence of biliary ductal dilatation, focal tissue defects or documented infectious hepatitis), biopsy (liver or other organ) and/or WHVPG measurements should be obtained as necessary to rule out the conditions in 18.104.22.168, 22.214.171.124 and 126.96.36.199. Please note: written informed consent for biopsy must be obtained separately per institutional guidelines.
- Prior solid organ transplant.
- Dependence on dialysis on admission, prior to and/or at the time of SCT, or oxygen dependence during conditioning prior to SCT. (Note: transient oxygen dependence that resolves is not excluded.)
- Use of any medication which increases the risk of hemorrhage. Use of heparin or other anticoagulants within 12 hours unless being used for routine central venous line management, fibrinolytic instillation for central venous line occlusion, intermittent dialysis or ultrafiltration of CVVH.
- Clinically significant uncontrolled acute bleeding, defined as hemorrhage requiring > 15 cc/kg of packed red blood cells (e.g., a pediatric patient weighing 20 kg and requiring > 300cc of packed red blood cells/24 hours, or an adult patient weighing 70 kg and requiring > 3 units of packed red blood cells/24 hours) to replace blood loss, OR bleeding from a site which in the Investigator opinion constitutes a potential life-threatening source (e.g. pulmonary hemorrhage or CNS bleeding), irrespective of amount of blood loss, at any point from the date of SCT through the date of severe VOD diagnosis. Please note: Transfusion of these amounts in the absence of clinically significant uncontrolled acute bleeding (i.e., for purposes of dialysis or because of hemodilution) is not a contraindication to enrollment.
- Hemodynamic instability as defined by a requirement for multiple pressors, or inability to maintain mean arterial pressure within 1 standard deviation of age-adjusted levels (see Appendix E) with single pressor support. Please note: 1. Patients on a single pressor must have stable mean arterial pressure for at least 8 hours. 2. Patients requiring renal dose dopamine alone (2-5 mcg/kg/min) are eligible without measurement of mean arterial pressure.
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