Survey of Inhibitors in Plasma-Product Exposed Toddlers

Hemophilia A Clinical Trial

— SIPPET  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01064284
• Other study ID #: ABB - 09 - 001
• Secondary ID: 2009-011186-88
• Status: Completed
• Phase: Phase 4
• First received: February 4, 2010
• Last updated: November 16, 2015
• Start date: January 2010
• Est. completion date: May 2015

Study information

• Verified date: November 2015
• Source: Fondazione Angelo Bianchi Bonomi
• Contact: n/a
• Is FDA regulated: No
• Health authority: Austria : Federal Ministry for Labour, Health, and Social AffairsBelgium: The Federal Public Service (FPS) Health, Food Chain Safety and EnvironmentBrazil: National Health Surveillance AgencyChile: Instituto de Salud Pública de ChileColombia: INVIMA Instituto Nacional de Vigilancia de Medicamentos y AlimentosCzech Republic: State Institute for Drug ControlEgypt: Ministry of Health and PopulationFrance: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)France: French Data Protection AuthorityGermany: Federal Institute for Drugs and Medical DevicesIndia: Drugs Controller General of IndiaIran: Ministry of HealthItaly: The Italian Medicines AgencyMexico: Federal Commission for Sanitary Risks ProtectionPoland: Ministry of HealthPoland: Office for Registration of Medicinal Products, Medical Devices and Biocidal ProductsPortugal: National Pharmacy and Medicines InstituteRomania: National Medicines AgencySaudi Arabia: Saudi Food and Drug AdministrationSlovakia: State Institute for Drug ControlSouth Africa: Medicines Control CouncilSpain: Spanish Agency of MedicinesTurkey: Ministry of HealthUnited Kingdom: Medicines and Healthcare Products Regulatory AgencyUnited States: Institutional Review BoardArgentina: Administracion Nacional de Medicamentos, Alimentos y Tecnologia Medica
• Study type: Interventional

Clinical Trial 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.

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

Recruitment information / eligibility

• Status: Completed
• Enrollment: 303
• Est. completion date: May 2015
• Est. primary completion date: May 2015
• Accepts healthy volunteers: No
• Gender: Male
• Age group: N/A to 6 Years

Eligibility

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

Study Design

Allocation: Randomized, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Basic Science

Related Conditions & MeSH terms

• Hemophilia A

Intervention

Drug:
• PLASMA DERIVED Factor VIII
Maximum dosage : 50IU per kilo. 2-3 times per week or on demand during acute episode of bleeding
• Recombinant FVIII
Maximum dosage : 50IU per kilo. 2-3 times per week or on demand during acute episode of bleeding

Locations

Country	Name	City	State
Argentina	Fundacion de la Hemofilia	Buenos Aires
Argentina	Hospital de Ninos Sor Maria Ludovica La Plata Servicio de Hematologia	La Plata	Buenos Aires
Austria	Landes- Frauen- und Kinderklinik Linz Abteilung für Kinder- und Jugendheilkunde	Linz
Austria	Medizinische Universität Wien, Dept. Paediatrics	Wien
Brazil	Centro de Pesquisa Clinica HEMORIO - Instituto Estadual de Hematologia Arthur de Siqueira Cavalcanti	Rio de Janeiro
Brazil	Centro de Hematologia e Hemoterapia do e.s - Hemoes	Vitória
Chile	Centro de Hemofilicos del Hospital de Niños Roberto del Rio Instituto de Investigaciones Hematologicas	Santiago
Chile	Hospital de Niños Dr. Luis Calvo Mackenna Centro Hemofílico	Santiago
Egypt	Faculty of Medicine Ain Shams University Department Pediatrics	Cairo
Egypt	Paediatric Haematology department, Cairo University Pediatric Hospital	Cairo
India	Centre for Blood Disorders	Chennai
India	Karnataka Hemophilia Care and Hematology Research Center	Karnataka
India	Kasturba Medical College, Manipal University	Karnataka
India	St. John's Medical College & Hospital	Karnataka
India	Kerala Institute of Medical Science (KIMS)	Kerala
India	Lokmanya TilakMunicipal Medical College &General Hospital - Sion	Mumbai
India	All India Institute of Medical Sciences Department of Haematology	New Delhi
India	Sir Ganga Ram Hospital	New Delhi
India	Jehangir Clinical Development Centre, Department of Haematology, Jehangir Hospital Premises	Pune
India	Sahyadri Speciality Hospital	Pune
Iran, Islamic Republic of	Hemophilia Center - Hematoogy & Oncology Dept. Shiraz University of Medical Science Ayatollah Dastgheib Hospital	Shiraz
Iran, Islamic Republic of	Comprehensive Care Center for Children with Hemophilia Mofid Children Hospital	Tehran
Italy	Centro Emofilia e Trombosi "Angelo Bianchi Bonomi" Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano - Italy	Milano
Italy	Clinica Medica II - Azienda Ospedaliera di Padova - Centro Emofilia di Padova	Padova
Italy	Ematologia- UO Diagnostica Speciale e Terapia delle Malattie dell'Emostasi e della Trombosi- Università Sapienza - Policlinico Umberto I	Rome
Mexico	Unidad Medica de Alta Especialidad (UMAE), Hospital de Pediatria. Centro Medico Nacional de Occidente Istituto Mexicano del Seguro Social	Jalisco
Mexico	Instituto Nacional de Pediatria	México D.F.
Mexico	Hospital Infantil de Mexico Federico Gomez	México, D.F.
Mexico	Hospital Universitario Dr. Josè Eleuterio Gonzalez de la UANL, NL. Mexico	Monterrey
Mexico	Hospital de Especialidades UMAE Istituto Mexicano del Seguro Social (IMSS)	Monterrey (Nuevo Leòn)
Saudi Arabia	Kinf Faisal Specilist Hospital and Research Center	Riyadh
South Africa	Haemophilia Comprehensive Care Clinic, Area 454, Charlotte Maxeke Johannesburg Academic Hospital	Parktown
Spain	Hospital Regional Universitario Carlos Haya	Malaga
Spain	Hospital Universitario Virgen del Rocio Unidad de Hemofilia	Sevilla
Spain	Hospital Universitario La Fe Unidad Coagulopatias Congenitas	Valencia
Turkey	Cukurova Universitesi, Tip Fakultesi Pediatrik Hematoloji B.D.	Adana
Turkey	Ege Üniversitesi Tip Fakültesi Cocuk Sagligi ve Hastalikari Anabilim Dali Pediatrik Hematoloji Bilim Dali	Bornova/Izmir
Turkey	Istanbul Üniversitesi Cerrahpasa Tip Fakültesi Pediatrik Hematoloji B.D.	Istanbul
United States	Hemophilia and Thrombosis CenterUniversity of Colorado Denver - Anschutz Aurora	Aurora	Colorado
United States	Rush Hemophilia & Trombophilia Center - Rush University Medical Center	Chicago	Illinois
United States	City of Hope National Medical Center	Duarte	California
United States	MeritCare Roger Maris Cancer Center, Pediatric Oncology	Fargo	North Dakota
United States	Cook Children's Medical Center	Forth Worth	Texas
United States	University of Mississippi Medical Center, Division of pediatric Hematology/Oncology	Jackson	Mississippi
United States	Children's Mercy Hospital	Kansas City	Missouri
United States	Hemophilia Treatment Center of Las Vegas	Las Vegas	Nevada
United States	Children's Hospital Los Angeles (CHLA)	Los Angeles	California
United States	Louisiana Center for Bleeding and Clotting Disorders, Tulane University Medical Center	New Orleans	Louisiana

Sponsors (2)

Lead Sponsor	Collaborator
Fondazione Angelo Bianchi Bonomi	Sintesi Research Srl

Countries where clinical trial is conducted

United States,  Argentina,  Austria,  Brazil,  Chile,  Egypt,  India,  Iran, Islamic Republic of,  Italy,  Mexico,  Saudi Arabia,  South Africa,  Spain,  Turkey, 

References & Publications (23)

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. — View 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. — View 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. Review. — View 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. — View 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. — View Citation

Dasgupta S, Repessé Y, Bayry J, Navarrete AM, Wootla B, Delignat S, Irinopoulou T, Kamaté 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. Epub 2006 Sep 19. — View Citation

Ehrenforth S, Kreuz W, Scharrer I, Linde R, Funk M, Güngör 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. — View 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. Epub 2005 Sep 15. — View Citation

Gouw SC, van der Bom JG, Auerswald G, Ettinghausen CE, Tedgård 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. Epub 2007 Jan 11. — View 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. Epub 2003 Jun 19. — View 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. — View Citation

Guérois C, Laurian Y, Rothschild C, Parquet-Gernez A, Duclos AM, Négrier 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. — View 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. — View Citation

Lorenzo JI, López 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. — View 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. — View Citation

O'Brien PC, Fleming TR. A multiple testing procedure for clinical trials. Biometrics. 1979 Sep;35(3):549-56. — View 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.

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, Guérin V, Guérois 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. — View Citation

Scharrer I, Ehrlich HJ. Reported inhibitor incidence in FVIII PUP studies: comparing apples with oranges? Haemophilia. 2004 Mar;10(2):197-8. — View 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. — View 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. — View 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. — View Citation

Wight J, Paisley S. The epidemiology of inhibitors in haemophilia A: a systematic review. Haemophilia. 2003 Jul;9(4):418-35. Review. — View Citation

* Note: There are 23 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Frequency of FVIII inhibitor formation in patients treated with plasma-derived vWF/FVIII compared to patients treated with recombinant FVIII		During the first 50 exposure days or first 3 years of enrollment, whichever occurs first	Yes
Secondary	To evaluate the frequency of transient inhibitors		in the 6 months after inhibitor development or untill the immunosoppresive treatment	Yes
Secondary	To evaluate the modality of occurrence of inhibitors (number of EDs, titre at onset, etc)		During the first 50 exposure days or first 3 years of enrollment, whichever occurs first	No
Secondary	Evaluate clinical factors potentially associated to inhibitor development(age at first treatment, severity of bleeding,surgery,intensity of treatment,time of treatment in relation to vaccinations,concurrent disease)		During the first 50 exposure days or first 3 years of enrollment, whichever occurs first	No
Secondary	To evaluate the incidence of all other adverse events related and not related to the products used		During the first 50 exposure days or first 3 years of enrollment, whichever occurs first	Yes

External Links

•   The official web site of the SIPPET Study