Clinical trial NCT01064284: Survey of Inhibitors in Plasma-Product Exposed Toddlers
Official title: Inhibitor Development in Previously Untreated Patients (PUPs) or Minimally Blood Component-Treated Patients (MBCTPs) When Exposed to Plasma-derived Von Willebrand Factor-Containing Factor VIII (VWF/FVIII) Concentrates and to Recombinant Factor VIII (rFVIII) Concentrates: An Independent, International, Multicentre, Prospective, Controlled, Randomised, Open Label, Clinical Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Hemophilia A
Keywords: Hemophilia A
Factor VIII inhibitors
vWF/FVIII
rFVIII
Lead sponsor: Fondazione Angelo Bianchi Bonomi
Sponsor class: OTHER
Collaborators: name: Sintesi Research Srl
First posted: 2010-02-08
Enrollment: 303
Sex: MALE
Minimum age (years): 1
Maximum age (years): 6
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

Brief summary: The primary objective of the study is to assess the immunogenicity of VWF/FVIII and of rFVIII concentrates by determining the frequency of inhibitor development in previously untreated patients (PUPs) or minimally blood component-treated (MBCTPs) in the first 50 EDs or in the first 3 years from enrollment, whichever occurs first.

.

Detailed description: Patients meeting the enrollment criteria will be consecutively enrolled at each participating centre, randomized to be treated exclusively with a single FVIII product either plasma-derived or recombinant, and followed up until inhibitor development or until 50 exposure days (EDs) or 3 years from enrolment have elapsed, whichever comes first. Study products, belonging to the class of rFVIII concentrates and to the class of plasma-derived VWF/FVIII concentrates, will be provided for free to the patients for all the duration of the study

Eligibility criteria: Inclusion Criteria:

* Male subjects
* Any ethnicity
* Age \<6 years
* Severe haemophilia A (FVIII:C \<1%), as confirmed at enrolment by the central laboratory.

  o Those patients diagnosed locally as severe but subsequently found to have FVIII levels \>= 1% on testing at the central laboratory will be separately recorded in the screening list.
* Previously untreated (0 EDs to any FVIII concentrates or blood products) or minimally treated (\<5 EDs) with blood components, namely whole blood, fresh frozen plasma, packed red blood cells, platelets or cryoprecipitate.

  o Patients not meeting these criteria will be separately recorded in the screening list.
* Negative inhibitor measurement at both local and central laboratory at screening
* Ability to comply with study requirements
* Signed informed consent of legal tutors o Patients who will not accept to enter into the study or to be randomized will be separately recorded.

Exclusion Criteria:

* Previous history of FVIII inhibitor
* Other congenital or acquired bleeding defects
* Plasma FVIII level \>= 1%, as assayed at the central laboratory

  o Those patients originally diagnosed locally as severe but subsequently found to have FVIII levels ranging from 1% to 2% on testing at the central laboratory will be separately recorded in the screening list.
* Concomitant congenital or acquired immunodeficiency
* Concomitant treatment with systemic immunosuppressive drugs
* Concomitant treatment with any investigational drug

Primary outcomes:
measure: To Assess the Immunogenicity of Plasma Derived VWF/FVIII and rFVIII Concentrates by Determining the Frequency of Inhibitor Development in the First 50 EDs or in the First 3 Years From Enrolment, Whichever Comes First in PUPs and MBCTs
timeFrame: During the first 50 exposure days or first 3 years of enrollment, whichever occurs first
Secondary outcomes:
measure: To Evaluate the Anamnestic Response of Inhibitor Patients
timeFrame: During the first 50 exposure days or first 3 years of enrollment, whichever occurs first
measure: To Evaluate the Frequency of Transient Inhibitors
timeFrame: In the 6 months after inhibitor development
measure: To Evaluate the Modality of Occurrence of Inhibitors (Number of EDs)
timeFrame: During the first 50 exposure days or first 3 years of enrollment, whichever occurs first
measure: To Evaluate the Modality of Occurrence of Inhibitors (Titre at Onset)
timeFrame: During 6 months of observation, from the inhibitor occurrence
measure: To Evaluate Clinical Factors Potentially Associated to Inhibitor Development
timeFrame: During the first 50 exposure days or first 3 years of enrollment, whichever occurs first
measure: To Evaluate Laboratory Factors Potentially Associated to Inhibitor Development
timeFrame: During the first 50 exposure days or first 3 years of enrollment, whichever occurs first
measure: To Evaluate the Incidence of All Other Adverse Events Related and Not Related to the Products Used
timeFrame: During the first 50 exposure days or first 3 years of enrollment, whichever occurs first
Other outcomes:
Locations:
city: Duarte
country: United States
facility: City of Hope National Medical Center
state: California
city: Los Angeles
country: United States
facility: Children's Hospital Los Angeles (CHLA)
state: California
city: Aurora
country: United States
facility: Hemophilia and Thrombosis CenterUniversity of Colorado Denver - Anschutz Aurora
state: Colorado
city: Chicago
country: United States
facility: Rush Hemophilia & Trombophilia Center - Rush University Medical Center
state: Illinois
city: New Orleans
country: United States
facility: Louisiana Center for Bleeding and Clotting Disorders, Tulane University Medical Center
state: Louisiana
city: Jackson
country: United States
facility: University of Mississippi Medical Center, Division of pediatric Hematology/Oncology
state: Mississippi
city: Kansas City
country: United States
facility: Children's Mercy Hospital
state: Missouri
city: Las Vegas
country: United States
facility: Hemophilia Treatment Center of Las Vegas
state: Nevada
city: Fargo
country: United States
facility: MeritCare Roger Maris Cancer Center, Pediatric Oncology
state: North Dakota
city: Fort Worth
country: United States
facility: Cook Children's Medical Center
state: Texas
city: La Plata
country: Argentina
facility: Hospital de Ninos Sor Maria Ludovica La Plata Servicio de Hematologia
state: Buenos Aires
city: Buenos Aires
country: Argentina
facility: Fundacion de la Hemofilia
city: Linz
country: Austria
facility: Landes- Frauen- und Kinderklinik Linz Abteilung für Kinder- und Jugendheilkunde
city: Wien
country: Austria
facility: Medizinische Universität Wien, Dept. Paediatrics
city: Rio de Janeiro
country: Brazil
facility: Centro de Pesquisa Clinica HEMORIO - Instituto Estadual de Hematologia Arthur de Siqueira Cavalcanti
city: Vitória
country: Brazil
facility: Centro de Hematologia e Hemoterapia do e.s - Hemoes
city: Santiago
country: Chile
facility: Hospital de Niños Dr. Luis Calvo Mackenna Centro Hemofílico
city: Santiago
country: Chile
facility: Centro de Hemofilicos del Hospital de Niños Roberto del Rio Instituto de Investigaciones Hematologicas
city: Cairo
country: Egypt
facility: Paediatric Haematology department, Cairo University Pediatric Hospital
city: Cairo
country: Egypt
facility: Faculty of Medicine Ain Shams University Department Pediatrics
city: Chennai
country: India
facility: Centre for Blood Disorders
city: Karnataka
country: India
facility: St. John's Medical College & Hospital
city: Karnataka
country: India
facility: Kasturba Medical College, Manipal University
city: Karnataka
country: India
facility: Karnataka Hemophilia Care and Hematology Research Center
city: Kerala
country: India
facility: Kerala Institute of Medical Science (KIMS)
city: Mumbai
country: India
facility: Lokmanya TilakMunicipal Medical College &General Hospital - Sion
city: New Delhi
country: India
facility: All India Institute of Medical Sciences Department of Haematology
city: New Delhi
country: India
facility: Sir Ganga Ram Hospital
city: Pune
country: India
facility: Sahyadri Speciality Hospital
city: Pune
country: India
facility: Jehangir Clinical Development Centre, Department of Haematology, Jehangir Hospital Premises
city: Shiraz
country: Iran, Islamic Republic of
facility: Hemophilia Center - Hematoogy & Oncology Dept. Shiraz University of Medical Science Ayatollah Dastgheib Hospital
city: Tehran
country: Iran, Islamic Republic of
facility: Comprehensive Care Center for Children with Hemophilia Mofid Children Hospital
city: Milano
country: Italy
facility: Centro Emofilia e Trombosi "Angelo Bianchi Bonomi" Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano - Italy
city: Padova
country: Italy
facility: Clinica Medica II - Azienda Ospedaliera di Padova - Centro Emofilia di Padova
city: Rome
country: Italy
facility: Ematologia- UO Diagnostica Speciale e Terapia delle Malattie dell'Emostasi e della Trombosi- Università Sapienza - Policlinico Umberto I
city: Jalisco
country: Mexico
facility: Unidad Medica de Alta Especialidad (UMAE), Hospital de Pediatria. Centro Medico Nacional de Occidente Istituto Mexicano del Seguro Social
city: Monterrey (Nuevo Leòn)
country: Mexico
facility: Hospital de Especialidades UMAE Istituto Mexicano del Seguro Social (IMSS)
city: Monterrey
country: Mexico
facility: Hospital Universitario Dr. Josè Eleuterio Gonzalez de la UANL, NL. Mexico
city: México D.F.
country: Mexico
facility: Instituto Nacional de Pediatria
city: México, D.F.
country: Mexico
facility: Hospital Infantil de Mexico Federico Gomez
city: Riyadh
country: Saudi Arabia
facility: Kinf Faisal Specilist Hospital and Research Center
city: Parktown
country: South Africa
facility: Haemophilia Comprehensive Care Clinic, Area 454, Charlotte Maxeke Johannesburg Academic Hospital
city: Malaga
country: Spain
facility: Hospital Regional Universitario Carlos Haya
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen del Rocio Unidad de Hemofilia
city: Valencia
country: Spain
facility: Hospital Universitario La Fe Unidad Coagulopatias Congenitas
city: Adana
country: Turkey
facility: Cukurova Universitesi, Tip Fakultesi Pediatrik Hematoloji B.D.
city: Bornova/Izmir
country: Turkey
facility: Ege Üniversitesi Tip Fakültesi Cocuk Sağliği ve Hastalikari Anabilim Dali Pediatrik Hematoloji Bilim Dali
city: Istanbul
country: Turkey
facility: Istanbul Üniversitesi Cerrahpaşa Tip Fakültesi Pediatrik Hematoloji B.D.
Study officials:
affiliation: Fondazione Ca' Granda Ospedale Maggiore Policlinico Milano
name: Pier M. Mannucci, Professor
role: PRINCIPAL_INVESTIGATOR
affiliation: Fondazione Ca' Granda Ospedale Maggiore Policlinico Milano
name: Flora Peyvandi, Professor
role: PRINCIPAL_INVESTIGATOR
References:
citation: Addiego J, Kasper C, Abildgaard C, Hilgartner M, Lusher J, Glader B, Aledort L. Frequency of inhibitor development in haemophiliacs treated with low-purity factor VIII. Lancet. 1993 Aug 21;342(8869):462-4. doi: 10.1016/0140-6736(93)91593-b.
citation: Amano K, Arai M, Koshihara K, Suzuki T, Kagawa K, Nishida Y, Fukutake K. Autoantibody to factor VIII that has less reactivity to factor VIII/von Willebrand factor complex. Am J Hematol. 1995 Aug;49(4):310-7. doi: 10.1002/ajh.2830490409.
citation: Auerswald G, Spranger T, Brackmann HH. The role of plasma-derived factor VIII/von Willebrand factor concentrates in the treatment of hemophilia A patients. Haematologica. 2003 Jun;88(6):EREP05.
citation: Chalmers EA, Brown SA, Keeling D, Liesner R, Richards M, Stirling D, Thomas A, Vidler V, Williams MD, Young D; Paediatric Working Party of UKHCDO. Early factor VIII exposure and subsequent inhibitor development in children with severe haemophilia A. Haemophilia. 2007 Mar;13(2):149-55. doi: 10.1111/j.1365-2516.2006.01418.x.
citation: Courter SG, Bedrosian CL. Clinical evaluation of B-domain deleted recombinant factor VIII in previously untreated patients. Semin Hematol. 2001 Apr;38(2 Suppl 4):52-9. doi: 10.1016/s0037-1963(01)90109-x.
citation: Dasgupta S, Repesse Y, Bayry J, Navarrete AM, Wootla B, Delignat S, Irinopoulou T, Kamate C, Saint-Remy JM, Jacquemin M, Lenting PJ, Borel-Derlon A, Kaveri SV, Lacroix-Desmazes S. VWF protects FVIII from endocytosis by dendritic cells and subsequent presentation to immune effectors. Blood. 2007 Jan 15;109(2):610-2. doi: 10.1182/blood-2006-05-022756. Epub 2006 Sep 19.
citation: Ehrenforth S, Kreuz W, Scharrer I, Linde R, Funk M, Gungor T, Krackhardt B, Kornhuber B. Incidence of development of factor VIII and factor IX inhibitors in haemophiliacs. Lancet. 1992 Mar 7;339(8793):594-8. doi: 10.1016/0140-6736(92)90874-3.
citation: Goudemand J, Rothschild C, Demiguel V, Vinciguerrat C, Lambert T, Chambost H, Borel-Derlon A, Claeyssens S, Laurian Y, Calvez T; FVIII-LFB and Recombinant FVIII study groups. Influence of the type of factor VIII concentrate on the incidence of factor VIII inhibitors in previously untreated patients with severe hemophilia A. Blood. 2006 Jan 1;107(1):46-51. doi: 10.1182/blood-2005-04-1371. Epub 2005 Sep 15.
citation: Gouw SC, van der Bom JG, Auerswald G, Ettinghausen CE, Tedgard U, van den Berg HM. Recombinant versus plasma-derived factor VIII products and the development of inhibitors in previously untreated patients with severe hemophilia A: the CANAL cohort study. Blood. 2007 Jun 1;109(11):4693-7. doi: 10.1182/blood-2006-11-056317. Epub 2007 Jan 11.
citation: Gringeri A, Mantovani LG, Scalone L, Mannucci PM; COCIS Study Group. Cost of care and quality of life for patients with hemophilia complicated by inhibitors: the COCIS Study Group. Blood. 2003 Oct 1;102(7):2358-63. doi: 10.1182/blood-2003-03-0941. Epub 2003 Jun 19.
citation: Gringeri A, Monzini M, Tagariello G, Scaraggi FA, Mannucci PM; Emoclot15 Study Members. Occurrence of inhibitors in previously untreated or minimally treated patients with haemophilia A after exposure to a plasma-derived solvent-detergent factor VIII concentrate. Haemophilia. 2006 Mar;12(2):128-32. doi: 10.1111/j.1365-2516.2006.01201.x.
citation: Guerois C, Laurian Y, Rothschild C, Parquet-Gernez A, Duclos AM, Negrier C, Vicariot M, Fimbel B, Fressinaud E, Fiks-Sigaud M, et al. Incidence of factor VIII inhibitor development in severe hemophilia A patients treated only with one brand of highly purified plasma-derived concentrate. Thromb Haemost. 1995 Feb;73(2):215-8.
citation: Kreuz W, Gill JC, Rothschild C, Manco-Johnson MJ, Lusher JM, Kellermann E, Gorina E, Larson PJ; International Kogenate-FS Study Group. Full-length sucrose-formulated recombinant factor VIII for treatment of previously untreated or minimally treated young children with severe haemophilia A: results of an international clinical investigation. Thromb Haemost. 2005 Mar;93(3):457-67. doi: 10.1160/TH03-10-0643.
citation: Lorenzo JI, Lopez A, Altisent C, Aznar JA. Incidence of factor VIII inhibitors in severe haemophilia: the importance of patient age. Br J Haematol. 2001 Jun;113(3):600-3. doi: 10.1046/j.1365-2141.2001.02828.x.
citation: Lusher JM, Arkin S, Abildgaard CF, Schwartz RS. Recombinant factor VIII for the treatment of previously untreated patients with hemophilia A. Safety, efficacy, and development of inhibitors. Kogenate Previously Untreated Patient Study Group. N Engl J Med. 1993 Feb 18;328(7):453-9. doi: 10.1056/NEJM199302183280701.
citation: O'Brien PC, Fleming TR. A multiple testing procedure for clinical trials. Biometrics. 1979 Sep;35(3):549-56.
citation: Qadura M, Waters B, Burnett E, Chegeni R, Othman M, Lillicrap D. Investigating the mechanisms underlying FVIII antibody production in hemophilic mice following recombinant and plasma-derived FVIII infusion. Blood (ASH Annual Meeting Abstracts) 2008; 112: abstract #237.
citation: Rothschild C, Laurian Y, Satre EP, Borel Derlon A, Chambost H, Moreau P, Goudemand J, Parquet A, Peynet J, Vicariot M, Beurrier P, Claeyssens S, Durin A, Faradji A, Fressinaud E, Gaillard S, Guerin V, Guerois C, Pernod G, Pouzol P, Schved JF, Gazengel C. French previously untreated patients with severe hemophilia A after exposure to recombinant factor VIII : incidence of inhibitor and evaluation of immune tolerance. Thromb Haemost. 1998 Nov;80(5):779-83.
citation: Scharrer I, Ehrlich HJ. Reported inhibitor incidence in FVIII PUP studies: comparing apples with oranges? Haemophilia. 2004 Mar;10(2):197-8. doi: 10.1111/j.1365-2516.2004.00887.x. No abstract available.
citation: Schimpf K, Schwarz P, Kunschak M. Zero incidence of inhibitors in previously untreated patients who received intermediate purity factor VIII concentrate or factor IX complex. Thromb Haemost. 1995 Mar;73(3):553-5. No abstract available.
citation: Strauss T, Lubetsky A, Ravid B, Bashari D, Luboshitz J, Lalezari S, Misgav M, Martinowitz U, Kenet G. Recombinant factor concentrates may increase inhibitor development: a single centre cohort study. Haemophilia. 2011 Jul;17(4):625-9. doi: 10.1111/j.1365-2516.2010.02464.x. Epub 2011 Feb 7.
citation: Waters B, Qadura M, Burnett E, Chegeni R, Labelle A, Thompson P, Hough C, Lillicrap D. Anti-CD3 prevents factor VIII inhibitor development in hemophilia A mice by a regulatory CD4+CD25+-dependent mechanism and by shifting cytokine production to favor a Th1 response. Blood. 2009 Jan 1;113(1):193-203. doi: 10.1182/blood-2008-04-151597. Epub 2008 Sep 24.
citation: Wight J, Paisley S. The epidemiology of inhibitors in haemophilia A: a systematic review. Haemophilia. 2003 Jul;9(4):418-35. doi: 10.1046/j.1365-2516.2003.00780.x.
citation: Rosendaal FR, Palla R, Garagiola I, Mannucci PM, Peyvandi F; SIPPET Study Group. Genetic risk stratification to reduce inhibitor development in the early treatment of hemophilia A: a SIPPET analysis. Blood. 2017 Oct 12;130(15):1757-1759. doi: 10.1182/blood-2017-06-791756. Epub 2017 Aug 2.
citation: Peyvandi F, Mannucci PM, Garagiola I, El-Beshlawy A, Elalfy M, Ramanan V, Eshghi P, Hanagavadi S, Varadarajan R, Karimi M, Manglani MV, Ross C, Young G, Seth T, Apte S, Nayak DM, Santagostino E, Mancuso ME, Sandoval Gonzalez AC, Mahlangu JN, Bonanad Boix S, Cerqueira M, Ewing NP, Male C, Owaidah T, Soto Arellano V, Kobrinsky NL, Majumdar S, Perez Garrido R, Sachdeva A, Simpson M, Thomas M, Zanon E, Antmen B, Kavakli K, Manco-Johnson MJ, Martinez M, Marzouka E, Mazzucconi MG, Neme D, Palomo Bravo A, Paredes Aguilera R, Prezotti A, Schmitt K, Wicklund BM, Zulfikar B, Rosendaal FR. A Randomized Trial of Factor VIII and Neutralizing Antibodies in Hemophilia A. N Engl J Med. 2016 May 26;374(21):2054-64. doi: 10.1056/NEJMoa1516437.