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URL http://www.rockymountainbmt.com/clinical_trials/Defibrotide-For-the-Treatment-of-Severe-Hepatic-Veno-occlusive-Disease-in-Hematopoietic-Stem-Cell-Transplant-Patients-A-Historically-Controlled-Multi-Center-Phase-3-Study-to-Determine-Safety-and-Efficacy-53.html

Defibrotide For the Treatment of Severe Hepatic Veno-occlusive Disease in Hematopoietic Stem Cell Transplant Patients: A Historically-Controlled, Multi-Center Phase 3 Study to Determine Safety and Efficacy

Principal Investigator: Scott I. Bearman, MD

Protocol Number: RMBMT 161

Major Objectives

1. To demonstrate the efficacy of Defibrotide (DF) in patients with severe VOD in terms of D+100 survival rate as the primary parameter and complete response (bilirubin less than 2 mg/dL and resolution of MOF) rate and long-term (6 month) survival as secondary parameters;



2. To assess the safety of the selected dose and schedule;



3. To collect and bank samples prior to and during therapy for special studies of potential serum and endothelial markers for VOD;



4. To collect historical information about the treatment centers, including severe VOD treatment across hospitals and over time and number and type of transplants per year.

Patient Selection

Inclusion Criteria:

1. 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:
   • ascites,
   • 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).



2. 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:
     1. 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
     2. creatinine clearance or GFR ≤ 40% of admission value, or
     3. 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’s safety, a single measurement of ≤ 90% will suffice.
     
     
3. 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.

Exclusion Criteria:

1. Documentation of pre-existing (at the time of SCT) cirrhosis of the liver.



2. An alternative diagnosis for ascites, weight gain and jaundice, such as fulminant viral hepatitis, at the time that severe VOD criteria are met.



3. Documented diagnosis of GVHD, grade B-D according to the IBMTR Severity Index, 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 6.3.1.1, 6.3.1.2 and 6.3.1.3.
   
   Please note: written informed consent for biopsy must be obtained separately per institutional guidelines.



4. Prior solid organ transplant.



5. Dependence on dialysis on admission, prior to and/or at the time of SCT, or oxygen dependence during conditioning prior to SCT. (Note: transient O2 dependence that resolves is not excluded.)



6. 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.



7. 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’s 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.



8. 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 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.

1. Documentation of pre-existing (at the time of SCT) cirrhosis of the liver.



2. an alternative diagnosis for ascites, weight gain and jaundice, such as fulminant viral hepatitis, at the time that severe VOD criteria are met.



3. Documented diagnosis of GVHD, grade B-D according to the IBMTR Severity Index, 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) reports and/or WHVPG measurements should be obtained as available to rule out the conditions in 6.3.2.1, 6.3.2.2 and 6.3.2.3.



4. Prior solid organ transplant.



5. Dependence on dialysis on admission, prior to and/or at the time of SCT, or oxygen dependence on admission and during conditioning prior to SCT. (Note: Transient O2 dependence that resolves is not excluded.)



6. 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’s 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.



7. 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 with single pressor support, at the time that VOD diagnostic and severity criteria are met.
   
   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.



8. Received treatment with Defibrotide for their VOD.