Clinical Trials Register

Summary
EudraCT Number:	2016-002004-10
Sponsor's Protocol Code Number:	15-007
National Competent Authority:	UK - MHRA
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2016-08-18
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

UK - MHRA

A.2

EudraCT number

2016-002004-10

A.3

Full title of the trial

A Phase 3, Randomized, Adaptive Study Comparing the Efficacy and Safety of Defibrotide vs Best Supportive Care in the Prevention of Hepatic Veno-Occlusive Disease in Adult and Pediatric Patients Undergoing Hematopoietic Stem Cell Transplant

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

A clinical study to investigate the efficacy and safety of Defibrotide compared with Best Supportive Care in the prevention of Hepatic Veno-Occlusive Disease in adult and pediatric patients Undergoing Hematopoietic Stem Cell Transplant.

A.4.1

Sponsor's protocol code number

15-007

A.5.4

Other Identifiers

Name:

IND

Number:

62,118

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Jazz Pharmaceuticals, Inc.
B.1.3.4	Country	United States
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Jazz Pharmaceuticals, Inc.
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Jazz Pharmaceuticals, Inc.
B.5.2	Functional name of contact point	Clinical Trial Information Desk
B.5.3	Address:
B.5.3.1	Street Address	3180 Porter Drive
B.5.3.2	Town/ city	Palo Alto
B.5.3.3	Post code	CA 94304
B.5.3.4	Country	United States
B.5.6	E-mail	HarmonyTrialInfo@jazzpharma.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Defitelio
D.2.1.1.2	Name of the Marketing Authorisation holder	Gentium Srl, Italy
D.2.1.2	Country which granted the Marketing Authorisation	European Union
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	Yes
D.2.5.1	Orphan drug designation number	EU/3/04/211
D.3 Description of the IMP
D.3.1	Product name	Defibrotide
D.3.4	Pharmaceutical form	Concentrate for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	DEFIBROTIDE
D.3.9.1	CAS number	83712-60-1
D.3.9.3	Other descriptive name	"Defibrotide sodium"
D.3.9.4	EV Substance Code	SUB01572MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	80
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

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

E.3

Principal inclusion criteria

1. Patient must be above the age of 1 month as of the start date of study treatment.
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 or b):
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 of iron overload 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 undergoing myeloablative conditioning
ii. Primary HLH, Griscelli II Chediak-Higashi syndrome, Hermansky-Pudiak II, X-linked lymphoproliferative disorders, X-linked severe combined immunodeficiency, X-linked hypogammaglobulinemia, or familial HLH 1-5 and undergoing myeloablative conditioning
iii.Prior treatment with an ozogamicin-containing monoclonal antibody using the minimum dose and schedule, according to the patient prescribing information;
examples include the following:
• Gemtuzumab ozogamicin, at least 9 mg/m2 total dose
• Inotuzumab ozogamicin, at least 1.5 mg/mg2 over 28 days
iv.Class III, high-risk thalassemia (i.e., patients who are ≥7 years old and have a liver size ≥5 cm 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 (when this is in line with the preferred and usual lifestyle of the patient [periodic abstinence, e.g., calendar, post-ovulation, symptothermal methods, and withdrawal are not acceptable methods]), combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of ovulation (i.e., birth control pills, patches, vaginal ring), progestogen-only 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

Day +30 post- HSCT

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

Day +100 post-HSCT

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

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

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

Yes

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

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

E.8.1.4

Double blind

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

Yes

E.8.1.7.1

Other trial design description

Adaptive Clinical Trial

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Yes

E.8.2.2

Placebo

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

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

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

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

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

LPLV

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

Yes

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

Yes

F.1.1.4.1