NEJM - Appendix

Supplementary Appendix
This appendix has been provided by the authors to give readers additional information about their work.
Supplement to: Heeney MM, Hoppe CC, Abboud MR, et al. A multinational trial of prasugrel for sickle cell vaso-
occlusive events. N Engl J Med. DOI: 10.1056/NEJMoa1512021

SUPPLEMENT
TABLE OF CONTENTS
Page Content
1 DOVE Investigators
3 DOVE Contributors
5 Supplemental Tables
10 Figure Legends
11 Supplemental Figure
Heeney MM, Hoppe, CC et al. A Multinational Trial of Prasugrel for Sickle Cell Vaso-occlusive Events
1

In addition to the authors, the following investigators participated as DOVE Investigators
An Van Damme, MD, and Sophie Dupont, MD Cliniques Universitaires Saint-Luc, Brussels, Belgium,
Pierre Philippet, MD, Centre Hospitalier Chretien - Cliniques de l'Espérance, Montegnée, Belgium,
Clarisse Lopes de Castro Lobo, MD, HEMORIO - Instituto Estadual de Hematologia Arthur de Siqueira
Cavalcanti, Rio de Janeiro 20211-030, Brazil, Nancy Robitaille, MD, PhD, Division of Hematology-
Oncology, Department of Pediatrics, CHU Sainte-Justine, Montréal, QC, Canada , Azza AG Tantawy,
MD, Children's Hospital, Ain Shams University, Cairo, Egypt, Ahmed K Mansour and Youssef Al-
Tonbary, MD, Mansoura University Children Hospital, Dakahlia, Egypt, Mohamed Badr, MD, Zagazig
University Hospital, Alsharkia, Egypt, Somaya Elgawhary, MD, Fayoum University Hospital, Fayoum
University Campus, Fayoum, Egypt, Lamis Ragab, MD, Abu El Rich Hospital, Cairo University Hospital,
Cairo, Egypt, Hoda Hassab, MD, Faculty of Medicine, Clinical Research Center, Alexandria University,
Egypt.Hesham AF Mohamed El-Sayed, MD, Suez Canal University Hospital, Ismailia, Egypt
E. Tsiri Agbenyega, BSc,MBChB, PhD, Kwame Nkrumah University of Science and Technology,
Kumasi Ghana Catherine I Segbefia, MBChB, Department of Child Health, School of Medicine and
Dentistry, Korle Bu Teaching Hospital, Accra, Ghana. Raffaella Colombatti, MD, Azienda Ospedaliera
di Padova, Clinica di Oncoematologia Pediatrica Via Giustiniani, Padova, Italy. Gian L Forni, MD,Ente
Ospedaliero Ospedali Galliera, S.S.D. Microcitemia, Genova, Italy, Nicoletta Masera, MD, Azienda
Ospedaliera San Gerardo, Pediatria Fondazlone MBBM, Monza, Italy, Giovanni Palazzi, MD, A.O.U.
Policlinico di Modena, Dipartimento di Ematologia e Oncologia Pediatrica, Modena, Italy, Simone
Cesaro, MD, Azienda Ospedaliera Universitaria Integrata di Verona, U.O.C. Oncoematologia
Pediatrica, Verona, Italy, Bernhards R Ogutu, MBChB, MMed (Paediatrics), PhD, Kondele Children’s
Hospital, Walter Reed Project/Centre for Clinical Research- Kenya Medical Research Institute, Kisumu,
Kenya, Janet N Oyieko, MMed (Peds), MD, Kenya Medical Research Institute-Walter Reed Project
(KEMRI-WRP), Kisumu, Kenya, Videlis Nduba, MBChB, MPH, PhD, Kenya Medical Research Institute
(KEMRI)/CGHR Research and Public Health Collaboration, Kisumu, Kenya, Jessie N Githanga,
MBChB, MMed(path)(UON), University of Nairobi and Gertrude’s Children’s Hospital, Nairobi, Kenya,
Miguel R. Abboud, MD, Department of Pediatrics and Adolescent Medicine, American University of
Beirut Medical Center, Beirut, Lebanon, Adlette Inati, MD, Rafik Hariri University Hospital, Beirut,
Lebanon, Salam S Alkindi, MD, Sultan Qaboos University Hospital, Alkhod, Muscat, Oman, Soad K. Al
Jaouni, MD, FRCPC, King Abdulaziz University Hospital, Kingdom of Saudi Arabia, Selma Unal, MD,
Mersin University Research and Practice Hospital,Cocuk Sagligi ve Hastaliklari Anabilim Dali Cocuk
Hematolojisi Bilimdali İhsaniye Mahallesi, Mersin, Turkey, Ilgen Sasmaz, MD, Cukurova Universitesi
Tip Fakultesi Cocuk Sagligi ve Hastaliklari Anabilim Dali, Adana, Turkey, Ali B Antmen, MD, Acibadem
Adana Hospital, Department of Pediatric Hematology-Oncology, Seyhan Adana, Turkey, Azzam
2

Alzoebie, MD, Sheikh Khalfia Medical City, Abu Dhabi, United Arab Emirates, Psalm Dunlya Baba
Inusa, M.B.B.S., FMCP, DCP, MRCP, Evelina Children’s Hospital, St Thomas’ Hospital, London,
United Kingdom, David Rees, BA, MB, BS, MRCP, FRCP, MRCPath, Department of Haematological
Medicine, King’s College Hospital, King’s College Hospital NHS Foundation Trust, Denmark Hill,
London, United Kingdom, Andrew Will, M.R.C.P., M.R.C.Path, M.D., FRCPCH, FRCPath, FRCP, Royal
Manchester Children's Hospital, Manchester, United Kingdom, Carlton Dampier, MD, Emory University,
AFLAC Cancer and Blood Disorders Center, Atlanta, Georgia, USA, Matthew M. Heeney, MD, Dana-
Farber/Boston Children’s Cancer and Blood Disorders Center, Boston, Massachusetts, USA, Robert G.
Irwin, MD, Mary Bridge Children’s Hospital & Health Center, Tacoma, Washington, USA,Debra Cohen,
MD, Children’s Hospital of Pittsburgh of UPMC, Department of Hematology/Oncology/BMT,
Pittsburgh, Pennsylvania, USA, Charles T. Quinn, MD, MS, Cincinnati Children's Hospital Medical
Center, Cincinnati, Ohio, USA, Lakshmanan Krishnamurti, MD, Cincinnati Children's Hospital Medical
Center, Cincinnati, Ohio, USA, Sohail Rana, MD, Howard University Hospital, Dept. of Pediatrics,
Washington, District of Columbia, USA, Sharada A. Sarnaik, MD, Children’s Hospital of Michigan,
Detroit, Michigan, USA, Kim Smith-Whitley, MD, The Children’s Hospital of Philadelphia,
Philadelphia, Pennsylvania, USA, Carolyn Hoppe, MD, Children's Hospital Oakland Research Institute,
Oakland, California, USA, Alexis A. Thompson, MD, MPH, Ann & Robert H. Lurie Children's Hospital
of Chicago,Division of Hem/Onc/Stem-Cell Transplantation, Chicago, Illinois, USA, Donna M.
Boruchov, MD, Connecticut Children’s Medical Center, Hartford, Connecticut, Jeremie Heath Estepp,
MD, St. Jude Children’s Research Hospital, Memphis, Tennessee, USA, Rupa Redding-Lallinger, MD,
University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA, Crawford Strunk, MD,
ProMedica Health System, Inc., Toledo, Ohio, USA, Connie Piccone, MD, Rainbow Babies & Children’s
Hospital, Pediatric Hematology / Oncology, Cleveland, Ohio, USA, Michael Jeng, MD, Stanford
University School of Medicine, Palo Alto, California, USA, John Whittle, MD, Memorial Health
University Medical Center, Savannah, Georgia, USA, Jennifer Eng, MD, St. Christopher's Hospital for
Children, Department of Hematology, Philadelphia, Pennsylvania, Deepa Manwani, MD, Montefiore
Medical Center, Bronx, New York, USA, Gerald Woods, MD, Children's Mercy Hospital & Clinics,
Kansas City, Missouri, USA, Julie Kanter, MD, Medical University of South Carolina, Charleston, South
Carolina, USA
3

DOVE Contributors
The DOVE Investigators would like to thank the following who provided significant effort to the
successful completion of the study:
Belgium: Dr. Benedicte Brichard, Dr. Cécile Boulanger, Dr. Christel Van Geet, Brazil: Dr. Patricia G
Moura, Canada: Dr. Yves Pastore, Ms Christine De Castelbajac Egypt: Dr. Shaimaa Sahmoud, Dr. Samar
El-Fiky, Dr. Tamer Hasan Hassan, Dr. Ahmed Mansour, Dr. Nayera H El-Sherif, Dr. Amira Abd El
Moneam Adly, Dr. Mona Hamdy, Dr. Fadwa Abdelazim, Dr. Amal Mohamed El-Beshlawy, Dr. Ahmad
Darwish, Dr. Eman El-Sabbagh, Dr. Nashwa Balbaa, Dr. Yasmine El Chazli, Dr. Maha Zeid, Dr. Marwa
Reda, Dr. Marwa Zakaria Mohamed, Ghana: Dr. Della Adzosii, Dr. Ugonna Offor, Dr. Lily Gloria Tagoe,
Ms. Priscilla Ekpale, Ms. Obedia Seaneke, Ms. Lyudmilla Korang, Ms. Diana Dwuma-Badu, Ms.
Georgina Freeman, Mr. William Ababio, Dr. Kokou H Amegan-Aho, Dr. Yvonne Dei-Adomakoh, Dr.
Samuel Adjei, Dr. Maria T Rettig, Dr. Harry O Boateng, Dr. Daniel Ansong, Dr. Augustina Badu-
Prepah, Mr. Patrick Buabeng, Mr. Amos Kotey, Mr. Ali Idriss, Ms Lydia Badu, Ms. Lydia Appoh, Italy:
Dr. Alessandro Cattoni, Dr. Paola C Corti, Dr. Manuela Calabria, Dr. Paola Carrara, Dr. Sabrina
Quintino, Dr. Martina Lamagna, Dr. Valeria Maria Pinto, Dr. Manuela Balocco, Dr. Marta Pierobon, Dr.
Gianni Bisogno, Dr. Laura Sainati, Dr. Maria E Guerzoni, Dr. Carmen Cano, Dr. Monica Cellini, Dr.
Martina Saruggia, Dr. Elisa Bonetti, Kenya: Dr. Doreen Karimi, Dr. Nyambura Kariuki, Dr. Godfrey
Allan Otieno, Ms. Anne Wangwe, Ms. Victorine Owira, Dr. Nekoye N Otsyula, Dr. Grace Kiringa, Dr.
Walter Otieno, Dr. Lucas Otieno Tina, Dr. Milton Omondi Adongo, Emmanuel Owino, Irene Onyango,
Anne Wangwe, Lebanon: Dr. Rouba Abdennour, Dr. Mario Kahale, Dr. Rasha Ahmad, Oman: Dr. Anil
Pathare, Dr. Abdulhakim Al-Rawas, Dr Taghrid Hamad, Saudi Arabia: Dr. Magda Mohamed Hagras,
Turkey: Dr. Yurdanur Kilinc, Dr. Göksel Leblebisatan, United Kingdom: Dr. Sanjay Tewari, Sharon
Thind, Jill Wilson, Dr. Anicee Danaee, Dr. Irene Roberts, Miss Sharon Ndoro, Timothy Futter, Eniola
Nsirim and Subarna Chakravorty, United States: Dr. Jennifer Andrews, Dr. Jeffrey Schwartz, Dr. Janice
Sullivan, Ms. Valerie Cachat, Ms. Mary Campbell, Karen Ireland, Dr. A. Kim Ritchey, Dr. Peter H Shaw,
Dr. Robert I Liem, Ms. Diane Calamaras, Dr. Astrid Kyle Mack, Ms. Courtney Little, Ms. Elizabeth
Robinson, Mary Johnson, Ms. Patricia McLendon, Ms. Chandni Parikh, Dr. Staci J Weldon, Dr. Sumita
Roy, Ms. Leann Schilling, Ms Shelly Mays, Ms. Jane Chen, Dr. William J Thomas, Dr. Ronald R Louie,
Ms. Jessica Ebert, Dr. David G Speicher, Dr. Shayla M Bergmann, Dr. Meera B Chitlur, Dr. Martin
Johnston, Dr. Andrew L Pendleton, Mrs. Nicole Dockery, Mrs. Ashley V Harrison, Dr. Ulrike M Reiss,
Dr. Michael E Roth, Dr. Jeremy M Rosenblum, Dr. Jonathan B Gill, Dr. Kerry A Morrone, Mr. Travis
Brown, Dr. Nataly Apollonsky, Dr. Deepti A Raybagkar, Mrs. Wallace Adrienne, Mrs. Tamar Epstein,
Ann Mehrhof, Ms. Michelle Ung, Ms. Angela Martino, Ms. Kristin Owen, Ms. Kimberly Stepek, Ms.
Samantha Couchenour, Ms. Janet Bell, Ms. Vicki Gilchrist, Ms. Melissa Byrne, Dr. Keith Quirolo
4

SUPPLEMENTAL TABLES
Table S1. DOVE Inclusion and Exclusion Criteria
Inclusion criteria Exclusion criteria
HbSS or HbSβ0
genotype Abnormal or conditional TCD within the last year
*At least 2 VOC in the year prior to screening History of chronic RBC transfusion for prevention of
stroke
TCD within the last year for patients ≤16 years of age Current chronic treatment with RBC for any reason
Children aged 2 to <18 years Hepatic or renal dysfunction
Body weight ≥12 kg Contraindication for antiplatelet therapy
Informed consent by a legal representative in competent
mental condition. Assent from the child, if required by
local regulations
History of transient ischemic attack or ischemic or
hemorrhagic stroke
Sexually active patients must agree to a reliable form of
birth control until 1 month following the last dose of
study drug
History of severe head trauma
Females of child-bearing potential must test negative for
pregnancy
Any clinical findings associated with an increased risk for
bleeding
Receiving chronic treatment with non-steroidal anti-
inflammatory drugs
Anticipated use of anticoagulants or other antiplatelet
drugs during the study
*VOC was a composite of painful crisis or acute chest syndrome (ACS). A painful crisis was defined as an onset of
moderate to severe pain that lasts at least 2 hours for which there is no explanation other than vaso-occlusion and
which requires therapy with oral or parenteral opioids, ketorolac, or other analgesics prescribed by a health care
provider in a medical setting such as a hospital, clinic, emergency room visit, or telephone management.
ACS is defined as an acute illness characterized by fever and/or respiratory symptoms, accompanied by a new
pulmonary infiltrate on a chest X-ray. Abbreviations: DOVE, Determining Effects of Platelet Inhibition on Vaso-
Occlusive Events; HbSS, homozygous sickle cell anemia; HbSβ0
, hemoglobin Sβ0
thalassemia; RBC, red blood cell;
TCD, transcranial Doppler; VOC, vaso-occlusive crisis.
5

Table S2. VOC Landmark Analysis*
Time period Rate ratio (95% CI) P Value
Entire period 0.83 (0.66, 1.05) 0.12
Prior to 6 months 0.84 (0.66, 1.09)
After 6 months 0.81 (0.60, 1.09)
comparison prior vs after 6 months 0.74
Prior to 9 months 0.88 (0.69, 1.12)
After 9 months 0.63 (0.42, 0.94)
comparison prior vs after 9 months 0.09
Prior to 12 months 0.86 (0.68, 1.08)
After 12 months 0.49 (0.24, 1.04)
Comparison prior vs after 12 months 0.13
*6 months =180 days and 289 patients at risk, 9 months = 270 days and 270 patients at risk, and 12
months = 365 days and 88 patients at risk.
6

Table S3. Hemorrhagic Adverse Events*
Placebo Prasugrel
n/N (%)
No. of
Events
n/N (%) No. of Events
Hemorrhagic events
33/170 (19.4) 44 34/170 (20.0) 67
Age ≥2 to <6
2/33 (6.1) 2 7/34 (20.6) 12
Age ≥6 to <12
18/66 (27.3) 22 13/66 (19.7) 27
Age ≥12 to 18
13/71 (18.3) 20 14/70 (20.0) 28
Hemorrhagic events requiring medical
intervention
8/170 (4.7) 9 11/170 (6.5)
13
Age ≥2 to <6
1/33 (3.0) 1 1/34 (2.9) 1
Age ≥6 to <12
4/66 (6.1) 4 3/66 (4.5) 4
Age ≥12 to 18
3/71 (4.2) 4 7/70 (10.0) 8
Type of medical intervention, n (%) N = 8†
N = 11†
Hospitalization 3 (37.5) 4 (36.4)
Surgery 0 (0.0) 0 (0.0)
Transfusion 2 (25.0) 1 (9.1)
Packing 0 (0.0) 3 (27.3)
Cautery 0 (0.0) 0 (0.0)
Other 5 (62.5) 6 (54.5)
Location of hemorrhagic events, n, (%) N = 170 N=170
GU 3 (1.8) 4 (2.4)
7

Gingiva 0 (0.0) 2 (1.2)
Intracranial 0 (0.0) 1 (0.6)
Intraocular 0 (0.0) 1 (0.6)
GI 4 (2.4) 1 (0.6)
Nose 20 (11.8) 23 (13.5)
Other 11 (6.5) 9 ( 5.3)
Provocation of hemorrhagic events, n (%) N = 170 N = 170
Spontaneous 23 (13.5) 23 (13.5)
Trauma induced 8 (4.7) 5 (2.9)
Post-procedural (non surgical) 1 (0.6) 1 (0.6)
Post-operative 0 (0.0) 0 (0.0)
Other 6 (3.5) 8 (4.7)
*Hemorrhagic events were analyzed for events that occur from the first dose up to 10 days after the last dose of drug. N=all
treated patients, n=number of patients with an event.
†
Treated patients with hemorrhagic events requiring medical intervention
Abbreviations: GI=gastrointestinal; GU=Genitourinary system
8

Table S4. Adverse Events With and Without Hydroxyurea Use*
Placebo Prasugrel P
Value
With Hydroxyurea Use N=76 N=76
Discontinued study drug for an adverse event 3 (3.9) 4 (5.3) 0.99
Adverse event 75 (98.7) 69 (90.8) 0.06
Death 0 0 NA
Serious adverse events 49 (64.5) 46 (60.5) 0.74
Without Hydroxyurea Use N=94 N=94
Discontinued study drug for an adverse event
2 (2.1) 2 (2.1) 0.99
Adverse event
87 (92.6) 90 (95.7) 0.54
Death
2‡(2.1) 1 (1.1) 0.99
Serious adverse events
47 (50.0) 42 (44.7) 0.56
*Adverse events were analyzed for events that occur from the first dose up to 10 days after the last dose of drug. NA=not
applicable.
‡One death in the placebo group was reported after database lock.
9

SUPPLEMENTAL FIGURE LEGEND
FIGURE S1: CONSORT flow diagram. Randomization and follow-up of the DOVE trial patients. No
patients discontinued due to lost to follow-up, protocol violation, nor entry criteria not met.
The study randomized 341 patients, 171 to prasugrel and 170 to placebo. Prior to the database lock a total
of 33 subjects discontinued from study including 17 in the prasugrel group (14 prior to 9 months and 3
after 9 months) and 16 in the placebo group (10 prior to 9 months and 6 after 9 months). At the time of
database lock 42 subjects had not yet reached the 9 month visit (22 prasugrel, 20 placebo). Of these, 40
were in the youngest age group. A total of 275 subjects completed the 9 month visit (135 prasugrel and
140 placebo), of which 9 subjects discontinued the study (3 prasugrel, 6 placebo) and 2 subjects, both on
placebo, had completed 24 months. The remaining 264 subjects (132 prasugrel, 132 placebo) continuing
the double blind period of the study at the time of database lock. The gray dotted line box signifies
number of patients at database lock. *One death in the placebo group was reported after database lock.
10

Figure S1
11

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