Defibrotide for Patients with Hepatic Veno-Occlusive Disease (VOD): A Treatment IND Study

Summary

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 1000 patients until Defibrotide receives marketing approval in the uS. These patients will be followed until Day+100.

The 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.


under Protocol amendment 6, the study objectives have been aligned to the most current regulatory approach to the
new Drug application submission that does not foresee a comparison to 2005-01 Historical Controls, alignment with the most current approach to data analysis and deletion of sections that will be more specifically addressed in the Statistical analysis Plan, identification of patients matching 2005-01 entry criteria and comparison to 2005-01
Historical Controls is no more considered in the Data Presentation and analysis Plan.

Participant Eligibility

Patients who meet both of the following criteria will be enrolled in the treatment and historical control groups:

A diagnosis of VOD may be made by Baltimore Criteria, Modified Seattle
Criteria, or biopsy proven:

Baltimore Criteria: Bilirubin >=2 mg/dL and at least 2 of the following clinical findings:

-- Ascites (radiographic or physical exam),
-- Weight gain > 5% above baseline weight (defined as: for patient who underwent HSCT, 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; for patient who underwent chemotherapy, weight before the start of last chemo cycle that induced the VOD), OR weight gain > 5% above baseline weight (defined as above),
-- hepatomegaly increased over baseline.

Modified Seattle Criteria at least 2 of the following clinical findings:

-- Bilirubin >=2 mg/dL
-- Ascites (radiographic or physical exam) and/or weight gain > 5% above baseline weight (defined as above),
-- hepatomegaly increased over baseline.

Patients who do not meet the Baltimore Criteria or Modified Seattle Criteria and have biopsy proven VOD are eligible.

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.