Defibrotide for Patients with Hepatic Veno-Occlusive Disease (VOD): A Treatment IND Study (Under CFR 312.34)
We plan to enroll approximately 3 patients a year on this study and the study will remain open until the company receives marketing approval for the drug. The company plans to enroll approximately 600 patients over a period of 3 to 5 years. These patients will be followed until Day+100.
The Treatment IND Protocol 2006-05 provides expanded access to Defibrotide in the Untied States and is being amended to include the details of the cost recovery program. In addition, the protocol is being amended to incorporate changes in eligibility criteria, changes in preparation of Defibrotide infusions, and omission of references to Protocol 2005-01 (now closed to accrual). A complete list of all protocol changes together with the rationale for each change is provided in this document.
Under Protocol Amendment 2, Defibrotide ampoules will no longer be provided free of charge. Due to the costs associated with the Treatment IND Protocol, including costs to manufacture Defibrotide, Gentium will begin charging for drug pursuant to FDA regulations, 21 CFR 312.7, (a similar program has been implemented in countries in outside the United States).
Under Protocol Amendment 3, Defibrotide will be supplied in ampoules or vials. Patients may only receive either Defibrotide in ampoules or Defibrotide in vials. If a patient is started on treatment with Defibrotide ampoules, a patient may not receive Defibrotide in vials, or vice versa, if a patient starts therapy on Defibrotide vials, the patient may not receive Defibrotide ampoules.
Patients who meet both of the following criteria will be enrolled in the
treatment and historical control groups:
6.2.1 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:
22.214.171.124 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),
126.96.36.199 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).
6.2.2 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:
188.8.131.52 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;
184.108.40.206 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[Single Quote]s safety, a single measurement of <90% will suffice.
6.2.3 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.