E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Prevention of Hepatic Veno-Occlusive Disease following Hematopoietic Stem Cell Transplant |
|
E.1.1.1 | Medical condition in easily understood language |
Prevention of Hepatic Veno-Occlusive Disease |
|
E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10047207 |
E.1.2 | Term | Veno-occlusive liver damage |
E.1.2 | System Organ Class | 10019805 - Hepatobiliary disorders |
|
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10047217 |
E.1.2 | Term | Venoocclusive syndrome of the liver |
E.1.2 | System Organ Class | 10019805 - Hepatobiliary disorders |
|
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10047216 |
E.1.2 | Term | Venoocclusive liver disease |
E.1.2 | System Organ Class | 10019805 - Hepatobiliary disorders |
|
E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objective of the study is to compare the efficacy of defibrotide prophylaxis in addition to BSC (DP arm) vs BSC alone (BSC arm) for the prevention of VOD as measured by VOD-free survival by Day +30 post-HSCT in patients who are at high risk or very high risk for developing VOD. |
|
E.2.2 | Secondary objectives of the trial |
The key secondary objective of the study is to compare the efficacy of defibrotide prophylaxis in addition to BSC (DP arm) vs BSC alone (BSC arm) for the prevention of VOD as measured by VOD-free survival by Day +100 post-HSCT in patients who are at high risk or very high risk for developing VOD. |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Patient must be above the age of 1 month as of Study Day 1.
2. Patient must be scheduled to undergo allogeneic (adults or pediatric
patients) or autologous HSCT (pediatric patients only) and be at high
risk or very high risk of developing VOD.
a. High-risk patients must meet both of the following criteria (i and ii):
i. Patient must be scheduled to receive myeloablative conditioning,
defined as either of the following:
a. At least 2 alkylating agents (e.g., cyclophosphamide, busulfan,
melphalan); the investigator must document in the medical chart that
the conditioning regimen is considered to be myeloablative or b. TBI
(single dose of ≥5 Gy, or ≥8 Gy fractionated dose) and at least 1
alkylating agent, and ii. Patient must meet at least 1 of the following criteria:
a. Has at least 1 hepatic-related risk factor, as defined by the European
Society for Blood and Marrow Transplantation (EBMT) position
statement, during screening as follows:
• Transaminase level >2.5 times the upper limit of normal (ULN) during
screening or within 14 days prior to screening on a non-screening test if
the test was performed as part of patient's routine standard of care
• Serum total bilirubin level >1.5 times the ULN during screening or
within 14 days prior to screening on a non-screening test if the test was
performed as part of patient's routine standard of care
• Prior history of cirrhosis (with biopsy evidence)
• Prior history of hepatic fibrosis (by histology or other diagnostic
scoring system per institutional guidelines)
• Prior history of viral hepatitis within 1 year before the start of study
treatment as indicated by a positive test for any of the following:
– hepatitis A virus (HAV) immunoglobulin M (IgM) (anti-HAV IgM)
– hepatitis B virus (HBV) core immunoglobulin G (IgG) or IgM (anti-HBc
IgG or anti-HBc IgM)
– HBV surface antigen (HBsAg)
– HBV DNA by polymerase chain reaction (PCR) or nucleic acid
amplification testing (NAAT)
– hepatitis C virus (HCV) antibody (anti-HCV) and HCV RNA by PCR or
NAAT
• Any prior hepatic irradiation, including abdominal irradiation covering
the hepatic area
• Documented diagnosis and confirmed evidence of iron overload in
medical notes (repeated serum ferritin >2000 ng/mL and/or liver iron
content ≥5.0 mg/gdw as estimated by magnetic resonance imaging T2*)
within 3 months prior to screening.
or
b. Has advanced-stage neuroblastoma requiring myeloablative
conditioning.
b. Very high-risk patients must meet 1 of the following criteria:
i. Osteopetrosis and patient must be scheduled to receive myeloablative
conditioning defined as either of the following:
a. At least 2 alkylating agents (e.g., cyclophosphamide, busulfan,
melphalan); the investigator must document in the medical chart that
the conditioning regimen is considered to be myeloablative or
b. TBI (single dose of ≥5 Gy, or ≥8 Gy fractionated dose) and at least 1
alkylating agent
ii. Primary HLH, Griscelli II Chediak-Higashi syndrome, HermanskyPudiak
II, X-linked lymphoproliferative disorders, X-linked severe
combined
immunodeficiency, X-linked hypogammaglobulinemia, or
familial
HLH 1-5 and undergoing myeloablative conditioning (as defined
in
2.b.i. above)
iii.Prior
treatment with an ozogamicin-containing monoclonal antibody
using
the minimum dose and schedule, according to the patient
prescribing
information;
•
Gemtuzumab ozogamicin, at least 9 mg/m2 total dose
•
Inotuzumab ozogamicin, at least 1.5 mg/m2 over 28 days
iv.Class
III, high-risk thalassemia (i.e., patients who are ≥7 years old
and
have a confirmed diagnosis of hepatomegaly (e.g., a liver size ≥5 cm
below
the costal margin on clinical examination) at the time of screening
3.Female patients (and female partners of male patients) of childbearing
potential who are sexually active must agree to use a highly effective
method of contraception with their partners during exposure to
defibrotide and for 1 week after the last dose of defibrotide. Highly
effective methods of contraception that may be used by the patient or
partner include abstinence, combined (estrogen- and progestogencontaining)
hormonal contraception associated with inhibition of ovulation (i.e., birth control pills, patches, vaginal ring), progestogenonly
hormonal contraception associated with inhibition of ovulation (i.e.,
progestin
implant or injection), intrauterine device (IUD), intrauterine
hormone-releasing
system (IUS), surgical sterilization, and vasectomy
(>6
months before Study Day 1). Post-menopausal women (i.e., women
with
>2 years of amenorrhea) do not need to use contraception.
4.
Adult patients must be able to understand and sign a written informed
consent.
For minor patients, the parent /legal guardian or representative
must
be able to understand and sign a written informed consent. Assent,
when
appropriate, will be obtained according to institutional guidelines. |
|
E.4 | Principal exclusion criteria |
1. Patient has hemodynamic instability within 24 hours before the start
of study treatment.
2. Patient has acute bleeding that is clinically significant within 24 hours
before the start of study treatment, defined as either of the following (a
or b):
a. hemorrhage requiring >15 cc/kg of packed red blood cells (e.g.,
pediatric patient weighing 20 kg and requiring 300 cc packed red blood
cells/24 hours, or an adult weighing >70 kg and requiring 3 units of
packed red blood cells/24 hours) to replace blood loss, or
b. bleeding from a site which, in the investigator's opinion, constitutes a
potential life-threatening source (e.g., pulmonary hemorrhage or central
nervous system bleeding), irrespective of amount of blood loss
3. Patient used any medication that increases the risk of bleeding within
24 hours before the start of study treatment, including, but not limited
to, systemic heparin, low molecular weight heparin, heparin analogs,
alteplase (tPA), streptokinase, urokinase,
antithrombin III (ATIII), and oral anticoagulants including warfarin, and
other agents that increase the risk of bleeding. Patients may receive
heparin or other anticoagulants for routine central venous line
management and intermittent dialysis or ultrafiltration. Fibrinolytic
instillation for central venous line occlusion is also permitted. Note:
Heparin use will be allowed in both treatment arms (up to a maximum of
100 U/kg/day).
4. Patient is using or plans to use an investigational agent for the
prevention or treatment of VOD.
5. Patient, in the opinion of the investigator, may not be able to comply
with the safety monitoring requirements of the study.
6. Patient or parent/legal guardian or representative has a psychiatric
illness that would prevent the patient or parent/legal guardian or
representative from giving informed consent and/or assent.
7. Patient has a serious active disease or co-morbid medical condition, as
judged by the investigator, which would interfere with the conduct of
this study.
8. Patient is pregnant or lactating and does not agree to stop
breastfeeding.
9. Patient has a known history of hypersensitivity to defibrotide or any of
the excipients.
10. Patient or parent/legal guardian or representative lacks the full
mental capacity to understand and sign a written informed consent.
11. Patient is receiving or plans to receive other investigational therapy
during study. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoint is the VOD-free survival rate by Day +30 post-HSCT, as adjudicated by the independent Endpoint Adjudication Committee (EPAC). |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
E.5.2 | Secondary end point(s) |
The key secondary efficacy endpoint is VOD-free survival by Day +100 post-HSCT |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | Yes |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | Yes |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
|
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 7 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 45 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Australia |
Belgium |
Canada |
France |
Germany |
Israel |
Italy |
Japan |
Korea, Republic of |
New Zealand |
Spain |
Turkey |
United Kingdom |
United States |
|
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
E.8.9.1 | In the Member State concerned months | 4 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 5 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |