Clinical trial NCT02851407: Study Comparing Efficacy and Safety of Defibrotide vs Best Supportive Care in the Prevention of Hepatic Veno-Occlusive Disease in Adult and Pediatric Patients
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Veno-occlusive Disease
Keywords: stem cell transplant
hematopoietic stem cell transplant (HSCT)
veno-occlusive disease (VOD)
sinusoidal obstruction syndrome (SOS)
Lead sponsor: Jazz Pharmaceuticals
Sponsor class: INDUSTRY
First posted: 2016-08-01
Enrollment: 372
Sex: ALL
Minimum age (years): 1
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: This study is to compare the efficacy and safety of defibrotide prophylaxis in addition to best supportive care versus best supportive care alone in the prevention of hepatic veno- occlusive disease (VOD) in adult and pediatric patients undergoing hematopoietic stem cell transplant who are at high risk or very high risk of developing VOD.


Eligibility criteria: 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 hematopoietic stem cell transplant (HSCT) (adults or pediatric patients) or autologous HSCT (pediatric patients only) and be at high risk or very high risk of developing veno-occlusive disease (VOD).
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.
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.

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.
3. Patient used any medication that increases the risk of bleeding within 24 hours before the start of study treatment.
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.

Primary outcomes:
measure: Veno-occlusive Disease (VOD)-Free Survival by Day +30 Post-Hematopoietic Stem Cell Transplant (HSCT) Per the Independent Endpoint Adjudication Committee (EPAC)
timeFrame: Day +30 Post-HSCT
Secondary outcomes:
measure: Veno-Occlusive Disease (VOD)-Free Survival by Day +100 Post-Hematopoietic Stem Cell Transplant (HSCT) Per the Independent Endpoint Adjudication Committee (EPAC)
timeFrame: Day +100 Post-HSCT
measure: Percentage of Participants With Veno-Occlusive Disease (VOD) by Day +30 Post-Hematopoietic Stem Cell Transplant (HSCT)
timeFrame: Day +30 Post-HSCT
measure: Veno-Occlusive Disease (VOD)-Free Survival Rate by Day +180 Post-Hematopoietic Stem Cell Transplant (HSCT)
timeFrame: Day +180 Post-HSCT
measure: Non-Relapse Mortality (NRM) for Defibrotide (DP) and Best Supportive Care (BSC) by Days +100 and +180 Post-Hematopoietic Stem Cell Transplant (HSCT)
timeFrame: Days +100 and +180 Post-HSCT
measure: Percentage of Participants With Veno-Occlusive Disease (VOD)-Associated Multi-Organ Dysfunction (MOD) by Days +30 and Days +100 Post-Hematopoietic Stem Cell Transplant (HSCT) in Patients Who Developed VOD
timeFrame: Days +30 and +100 Post-HSCT
measure: Percentage of Participants Who Had Resolution of Veno-Occlusive Disease (VOD) by Day +180 Post-Hematopoietic Stem Cell Transplant (HSCT)
timeFrame: Day +180 Post-HSCT
measure: Time to Resolution of Veno-Occlusive Disease (VOD) by Day +180 Post-Hematopoietic Stem Cell Transplant (HSCT)
timeFrame: Day +180 Post-HSCT
measure: Percentage of Participants With Veno-Occlusive Disease (VOD) After Day +30 Post-Hematopoietic Stem Cell Transplant (HSCT) up to Days +100 and +180 Post-HSCT
timeFrame: Days +100 and +180 Post-HSCT
measure: Change in 5-Level EuroQol-5D (EQ-5D-5L) Dimensions From Baseline to Day +180 Post-Hematopoietic Stem Cell Transplant (HSCT) for Adult Participants Age ≥ 16 Years: Mobility
timeFrame: Day +180 Post-HSCT
measure: Change in 5-Level EuroQol-5D (EQ-5D-5L) Dimensions From Baseline to Day +180 Post-Hematopoietic Stem Cell Transplant (HSCT) for Adult Participants Age ≥ 16 Years: Self-Care
timeFrame: Day +180 Post-HSCT
measure: Change in 5-Level EuroQol-5D (EQ-5D-5L) Dimensions From Baseline to Day +180 Post-Hematopoietic Stem Cell Transplant (HSCT) for Adult Participants Age ≥ 16 Years: Activity
timeFrame: Day +180 Post-HSCT
measure: Change in 5-Level EuroQol-5D (EQ-5D-5L) Dimensions From Baseline to Day +180 Post-Hematopoietic Stem Cell Transplant (HSCT) for Adult Participants Age ≥ 16 Years: Pain
timeFrame: Day +180 Post-HSCT
measure: Change in 5-Level EuroQol-5D (EQ-5D-5L) Dimensions From Baseline to Day +180 Post-Hematopoietic Stem Cell Transplant (HSCT) for Adult Participants Age ≥ 16 Years: Anxiety
timeFrame: Day +180 Post-HSCT
measure: Change in EuroQol-5D for Youth (EQ-5D-Y) Dimensions From Baseline to Day +180 Post-Hematopoietic Stem Cell Transplant (HSCT) for Pediatric Participants Age ≥ 4 and ≤ 7 Years: Mobility
timeFrame: Day +180 Post-HSCT
measure: Change in EuroQol-5D for Youth (EQ-5D-Y) Dimensions From Baseline to Day +180 Post-Hematopoietic Stem Cell Transplant (HSCT) for Pediatric Participants Age ≥ 4 and ≤ 7 Years: Self-Care
timeFrame: Day +180 Post-HSCT
measure: Change in EuroQol-5D for Youth (EQ-5D-Y) Dimensions From Baseline to Day +180 Post-Hematopoietic Stem Cell Transplant (HSCT) for Pediatric Participants Age ≥ 4 and ≤ 7 Years: Activity
timeFrame: Day +180 Post-HSCT
measure: Change in EuroQol-5D for Youth (EQ-5D-Y) Dimensions From Baseline to Day +180 Post-Hematopoietic Stem Cell Transplant (HSCT) for Pediatric Participants Age ≥ 4 and ≤ 7 Years: Pain
timeFrame: Day +180 Post-HSCT
measure: Change in EuroQol-5D for Youth (EQ-5D-Y) Dimensions From Baseline to Day +180 Post-Hematopoietic Stem Cell Transplant (HSCT) for Pediatric Participants Age ≥ 4 and ≤ 7 Years: Anxiety
timeFrame: Day +180 Post-HSCT
measure: Change in EuroQol-5D for Youth (EQ-5D-Y) Dimensions From Baseline to Day +180 Post-Hematopoietic Stem Cell Transplant (HSCT) for Pediatric Participants Age ≥ 8 and ≤ 15 Years: Mobility
timeFrame: Day +180 Post-HSCT
measure: Change in EuroQol-5D for Youth (EQ-5D-Y) Dimensions From Baseline to Day +180 Post-Hematopoietic Stem Cell Transplant (HSCT) for Pediatric Participants Age ≥ 8 and ≤ 15 Years: Self-Care
timeFrame: Day +180 Post-HSCT
measure: Change in EuroQol-5D for Youth (EQ-5D-Y) Dimensions From Baseline to Day +180 Post-Hematopoietic Stem Cell Transplant (HSCT) for Pediatric Participants Age ≥ 8 and ≤ 15 Years: Activity
timeFrame: Day +180 Post-HSCT
measure: Change in EuroQol-5D for Youth (EQ-5D-Y) Dimensions From Baseline to Day +180 Post-Hematopoietic Stem Cell Transplant (HSCT) for Pediatric Participants Age ≥ 8 and ≤ 15 Years: Pain
timeFrame: Day +180 Post-HSCT
measure: Change in EuroQol-5D for Youth (EQ-5D-Y) Dimensions From Baseline to Day +180 Post-Hematopoietic Stem Cell Transplant (HSCT) for Pediatric Participants Age ≥ 8 and ≤ 15 Years: Anxiety
timeFrame: Day +180 Post-HSCT
measure: Maximum Plasma Concentration (Cmax) of Defibrotide Prophylaxis During the Prophylaxis Phase
timeFrame: Day +1 and +7 Post-HSCT
measure: Area Under the Defibrotide Concentration-Time Curve (AUClast) of Defibrotide Prophylaxis During the Prophylaxis Phase
timeFrame: Day +1 and +7 Post-HSCT
measure: Mean Clearance of Defibrotide Prophylaxis During the Prophylaxis Phase
timeFrame: Day +1 and +7 Post-HSCT
measure: Volume of Distribution of Defibrotide Prophylaxis During the Prophylaxis Phase
timeFrame: Day +1 and +7 Post-HSCT
measure: Maximum Plasma Concentration (Cmax) of Defibrotide Prophylaxis During the Rescue Phase
timeFrame: Day +14 Post-VOD Treatment
measure: Area Under the Defibrotide Concentration-Time Curve (AUClast) of Defibrotide Prophylaxis During the Rescue Phase
timeFrame: Day +14 Post-VOD Treatment
measure: Volume of Distribution of Defibrotide Prophylaxis During the Rescue Phase
timeFrame: Day +14 Post-VOD Treatment
measure: Percentage of Participants With Grades 2, 3, and 4 Acute Graft-Versus-Host-Disease (GvHD) by Days +30, +100, and +180 Post-Hematopoietic Stem Cell Transplant (HSCT) in the Prophylaxis Phase
timeFrame: Days +30, +100, and +180 Post-HSCT
measure: Percentage of Participants With Grades 2, 3, and 4 Acute Graft-Versus-Host-Disease (GvHD) by Days +30, +100, and +180 Post-Hematopoietic Stem Cell Transplant (HSCT) in the Rescue Phase
timeFrame: Days +30, +100, and +180 Post-HSCT
measure: Percentage of Participants With Chronic Graft-Versus-Host-Disease (GvHD) by Day +180 Post-Hematopoietic Stem Cell Transplant (HSCT)
timeFrame: Day +180 Post-HSCT
measure: Number of Participants With Graft Failure During the Prophylaxis Phase and Rescue Phase
timeFrame: Day +180 Post-HSCT
measure: Number of Participants With Neutrophil Engraftment by Day +180 Post-Hematopoietic Stem Cell Transplant (HSCT)
timeFrame: Day +180 Post-HSCT
measure: Number of Participants With Platelet Engraftment by Day +180 Post-Hematopoietic Stem Cell Transplant (HSCT)
timeFrame: Day +180 Post-HSCT
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Children's Hospital of Alabama
state: Alabama
city: Phoenix
country: United States
facility: Phoenix Children's Hospital
state: Arizona
city: Tucson
country: United States
facility: University of Arizona Cancer Center
state: Arizona
city: Los Angeles
country: United States
facility: Children's Hospital Los Angeles
state: California
city: Palo Alto
country: United States
facility: Stanford University
state: California
city: San Diego
country: United States
facility: Rady Childrens Hospital San Diego
state: California
city: San Francisco
country: United States
facility: University of California San Francisco
state: California
city: Aurora
country: United States
facility: Colorado Children's Hospital
state: Colorado
city: Wilmington
country: United States
facility: Alfred I Dupont Hospital For Children
state: Delaware
city: Miami
country: United States
facility: Nicklaus Childrens Hospital
state: Florida
city: Saint Petersburg
country: United States
facility: Johns Hopkins All Children's Hospital
state: Florida
city: Atlanta
country: United States
facility: Children's Healthcare of Atlanta
state: Georgia
city: Chicago
country: United States
facility: Ann and Robert H Lurie Childrens Hospital of Chicago
state: Illinois
city: Boston
country: United States
facility: Tufts Floating Hospital for Children
state: Massachusetts
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: Detroit
country: United States
facility: Children's Hospital of Michigan
state: Michigan
city: Kansas City
country: United States
facility: Children's Mercy Hospital
state: Missouri
city: Bronx
country: United States
facility: Children's Hospital at Montefiore
state: New York
city: New York
country: United States
facility: Columbia University Medical Center
state: New York
city: New York
country: United States
facility: Weill Cornell Medical College
state: New York
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Cleveland
country: United States
facility: University Hospital Case Medical Center
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Columbus
country: United States
facility: Nationwide Children's Hospital
state: Ohio
city: Portland
country: United States
facility: Doernbecher Children's Hospital
state: Oregon
city: Hershey
country: United States
facility: Penn State Milton S Hershey Medical Center
state: Pennsylvania
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Charleston
country: United States
facility: Medical University of South Carolina - PPDS
state: South Carolina
city: Nashville
country: United States
facility: Vanderbilt Ingram Cancer Center
state: Tennessee
city: Dallas
country: United States
facility: Children's Medical Center Dallas
state: Texas
city: Fort Worth
country: United States
facility: Cook Childrens Hospital
state: Texas
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
city: Houston
country: United States
facility: Texas Childrens Hospital
state: Texas
city: Salt Lake City
country: United States
facility: Primary Children's Hospital
state: Utah
city: Seattle
country: United States
facility: Fred Hutchinson Cancer Research Center
state: Washington
city: Milwaukee
country: United States
facility: Children's Hospital of Wisconsin
state: Wisconsin
city: Adelaide
country: Australia
facility: Royal Adelaide Hospital
state: South Australia
city: Melbourne
country: Australia
facility: Royal Children's Hospital Melbourne
state: Victoria
city: Bruxelles
country: Belgium
facility: Cliniques Universitaires Saint-Luc
city: Gent
country: Belgium
facility: UZ Gent
city: Leuven
country: Belgium
facility: UZ Leuven Gasthuisberg
city: Leuven
country: Belgium
facility: UZ Leuven
city: Liege
country: Belgium
facility: Centre Hospitalier Universitaire du Sart Tilman
city: Calgary
country: Canada
facility: Alberta Children's Hospital
state: Alberta
city: Montreal
country: Canada
facility: Sainte Justine Hospital
state: Quebec
city: Besançon
country: France
facility: Hopital Jean Minjoz
city: Marseille
country: France
facility: Institut Paoli Calmettes
city: Paris
country: France
facility: Hôpital Saint Antoine
city: Poitiers
country: France
facility: CHU de Poitiers
city: Toulouse
country: France
facility: Institut Universitaire du Cancer de Toulouse - Oncopôle
city: Frankfurt (Oder)
country: Germany
facility: Klinikum Frankfurt Oder GmbH
state: Brandenburg
city: Aachen
country: Germany
facility: Universitätsklinikum der RWTH Aachen
state: Nordrhein-Westfalen
city: Münster
country: Germany
facility: Universitätsklinikum Münster
state: Nordrhein-Westfalen
city: Dresden
country: Germany
facility: Universitätsklinikum Carl Gustav Carus an der TU Dresden
state: Sachsen
city: Leipzig
country: Germany
facility: Universitätsklinikum Leipzig
state: Sachsen
city: Hamburg
country: Germany
facility: Universitätsklinikum Hamburg Eppendorf
city: Regensburg
country: Germany
facility: Klinikum der Universitat Regensburg
city: Haifa
country: Israel
facility: Rambam Health Care Campus
city: Haifa
country: Israel
facility: Rambam Health Corporation
city: Jerusalem
country: Israel
facility: Hadassah Ein Kerem Hospital
city: Petaẖ Tiqwa
country: Israel
facility: Schneider Children Medical Center of Israel
city: Ramat Gan
country: Israel
facility: Chaim Sheba Medical Center
city: Tel Aviv
country: Israel
facility: Tel Aviv Sourasky Medical Center
city: Ancona
country: Italy
facility: 11. Azienda Ospedaliero Universitaria Ospedali Riuniti di Ancona-Umberto I G M Lancisi G Salesi
city: Catania
country: Italy
facility: Azienda Ospedaliero - Universitaria
city: Firenze
country: Italy
facility: Azienda Ospedaliera Universitaria Careggi
city: Pesaro
country: Italy
facility: AORMN Marche Nord
city: Roma
country: Italy
facility: Ospedale Pediatrico Bambino Gesù
city: Roma
country: Italy
facility: Fondazione Policlinico Universitario A Gemelli
city: Anjo
country: Japan
facility: Anjo Kosei Hospital
city: Fukuoka
country: Japan
facility: Hamanomachi Hospital
city: Fukushima
country: Japan
facility: Fukushima Medical University Hospital
city: Hyōgo
country: Japan
facility: Kobe University Hospital
city: Kanagawa
country: Japan
facility: Kanagawa Children's Medical Center
city: Kumamoto
country: Japan
facility: National Hospital Organization Kumamoto Medical Center
city: Nagoya
country: Japan
facility: Japanese Red Cross Nagoya Daiichi Hospital
city: Nishinomiya
country: Japan
facility: Hyogo College of Medicine
city: Osaka
country: Japan
facility: Osaka International Cancer Institute
city: Osaka
country: Japan
facility: Osaka City University Hospital
city: Sapporo
country: Japan
facility: Hokkaido University Hospital
city: Tokyo
country: Japan
facility: Toranomon Hospital
city: Tokyo
country: Japan
facility: Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital
city: Tokyo
country: Japan
facility: Medical Hospital Tokyo Medical and Dental University
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Seoul
country: Korea, Republic of
facility: Severance Hospital at Yonsei University Health System
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
city: Seoul
country: Korea, Republic of
facility: The Catholic University of Korea Seoul St. Mary's Hospital
city: Auckland
country: New Zealand
facility: Auckland City Hospital
city: Badalona
country: Spain
facility: Hospital Universitario Germans Trias i Pujol
state: Barcelona
city: Barcelona
country: Spain
facility: Hospital Universitario Vall d Hebron
city: Cordoba
country: Spain
facility: Hospital Universitario Reina Sofia
city: Esplugues de Llobregat
country: Spain
facility: Hospital Sant Joan de Deu - PIN
city: Madrid
country: Spain
facility: Hospital Infantil Universitario Niño Jesus
city: Madrid
country: Spain
facility: Hospital Universitario Ramon y Cajal
city: Madrid
country: Spain
facility: Hospital Universitario La Paz
city: Malaga
country: Spain
facility: Hospital Regional Universitario de Malaga Hospital General
city: Murcia
country: Spain
facility: Hospital General Universitario Morales Meseguer
city: Salamanca
country: Spain
facility: Hospital Universitario de Salamanca
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen del Rocio
city: Antalya
country: Turkey
facility: Akdeniz University Medical Faculty Department of Pediatrics
state: Konyaalti
city: Kayseri
country: Turkey
facility: Erciyes University Medical Faculty
state: Talas
city: Ankara
country: Turkey
facility: Medicana International Ankara Hospital
city: Antalya
country: Turkey
facility: Medical Park Antalya Hospital
city: Bornova
country: Turkey
facility: Ege Universitesi Tip Fakultesi
city: Istanbul
country: Turkey
facility: Acibadem Universitesi Tip Fakultesi Atakent Hastanesi
city: Seyhan
country: Turkey
facility: Acibadem Adana Hospital
city: Birmingham
country: United Kingdom
facility: Birmingham Children's Hospital
city: Glasgow
country: United Kingdom
facility: Beatson West of Scotland Cancer Centre
city: Glasgow
country: United Kingdom
facility: Royal Hospital for Children
city: Leeds
country: United Kingdom
facility: St. James University Hospital
city: London
country: United Kingdom
facility: Kings College Hospital
city: London
country: United Kingdom
facility: Great Ormond Street Hospital
Study officials:
affiliation: Jazz Pharmaceuticals
name: Jazz Pharmaceuticals
role: STUDY_DIRECTOR
References: