Survey of Inhibitors in Plasma-Product Exposed Toddlers

NCT01064284 | Completed Phase 4 Results DMC

• 2 other identifiers: ABB - 09 - 0012009-011186-88
• Study Type: interventional
• Target: 303
• Locations: 14 countries
• Sites: 48

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. .

Conditions

Hemophilia A

Keywords

Hemophilia A; Factor VIII inhibitors; vWF/FVIII; rFVIII

Outcome Measures

Primary Outcomes (1)

• 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

  Expressed with the numebr of patients for each group who developed FVIII inhibitors. PUPs: Previously Untreated Patients MBCTPs: Minimally Blood Component-Treated Patients

  During the first 50 exposure days or first 3 years of enrollment, whichever occurs first

Secondary Outcomes (7)

• To Evaluate the Anamnestic Response of Inhibitor Patients

  During the first 50 exposure days or first 3 years of enrollment, whichever occurs first

• To Evaluate the Frequency of Transient Inhibitors

  In the 6 months after inhibitor development

• To Evaluate the Modality of Occurrence of Inhibitors (Number of EDs)

  During the first 50 exposure days or first 3 years of enrollment, whichever occurs first

• To Evaluate the Modality of Occurrence of Inhibitors (Titre at Onset)

  During 6 months of observation, from the inhibitor occurrence

• To Evaluate Clinical Factors Potentially Associated to Inhibitor Development

  During the first 50 exposure days or first 3 years of enrollment, whichever occurs first

Study Arms (2)

PLASMA DERIVED Factor VIII

ACTIVE COMPARATOR

Plasma-derived vWF/FVIII

Drug: PLASMA DERIVED Factor VIII

rFVIII

ACTIVE COMPARATOR

Recombinant FVIII

Drug: Recombinant FVIII

Interventions

PLASMA DERIVED Factor VIII DRUG

Maximum dosage : 50IU per kilo. 2-3 times per week or on demand during acute episode of bleeding

Also known as: ALPHANATE

PLASMA DERIVED Factor VIII

Recombinant FVIII DRUG

Maximum dosage : 50IU per kilo. 2-3 times per week or on demand during acute episode of bleeding

Also known as: ADVATE

rFVIII

Eligibility Criteria

• Age: 1 Minute - 6 Years
• Sex: male
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• Fondazione Angelo Bianchi Bonomi: lead
• Sintesi Research Srl: collaborator

Study Sites (48)

City of Hope National Medical Center

Duarte, California, 91010, United States

Location

Children's Hospital Los Angeles (CHLA)

Los Angeles, California, 90027, United States

Location

Hemophilia and Thrombosis CenterUniversity of Colorado Denver - Anschutz Aurora

Aurora, Colorado, 80045, United States

Location

Rush Hemophilia & Trombophilia Center - Rush University Medical Center

Chicago, Illinois, 60612, United States

Location

Louisiana Center for Bleeding and Clotting Disorders, Tulane University Medical Center

New Orleans, Louisiana, 70112, United States

Location

University of Mississippi Medical Center, Division of pediatric Hematology/Oncology

Jackson, Mississippi, 39216, United States

Location

Children's Mercy Hospital

Kansas City, Missouri, 64108, United States

Location

Hemophilia Treatment Center of Las Vegas

Las Vegas, Nevada, 89109, United States

Location

MeritCare Roger Maris Cancer Center, Pediatric Oncology

Fargo, North Dakota, 58102, United States

Location

Cook Children's Medical Center

Fort Worth, Texas, 76104, United States

Location

Hospital de Ninos Sor Maria Ludovica La Plata Servicio de Hematologia

La Plata, Buenos Aires, 1900, Argentina

Location

Fundacion de la Hemofilia

Buenos Aires, 3483, Argentina

Location

Landes- Frauen- und Kinderklinik Linz Abteilung für Kinder- und Jugendheilkunde

Linz, 4020, Austria

Location

Medizinische Universität Wien, Dept. Paediatrics

Vienna, 1090, Austria

Location

Centro de Pesquisa Clinica HEMORIO - Instituto Estadual de Hematologia Arthur de Siqueira Cavalcanti

Rio de Janeiro, 20.211-030, Brazil

Location

Centro de Hematologia e Hemoterapia do e.s - Hemoes

Vitória, 29047-100, Brazil

Location

Hospital de Niños Dr. Luis Calvo Mackenna Centro Hemofílico

Santiago, 7500539, Chile

Location

Centro de Hemofilicos del Hospital de Niños Roberto del Rio Instituto de Investigaciones Hematologicas

Santiago, 838-0418, Chile

Location

Paediatric Haematology department, Cairo University Pediatric Hospital

Cairo, 11432, Egypt

Location

Faculty of Medicine Ain Shams University Department Pediatrics

Cairo, 11566, Egypt

Location

Centre for Blood Disorders

Chennai, 600017, India

Location

St. John's Medical College & Hospital

Karnataka, 560034, India

Location

Kasturba Medical College, Manipal University

Karnataka, 576 104, India

Location

Karnataka Hemophilia Care and Hematology Research Center

Karnataka, 577004, India

Location

Kerala Institute of Medical Science (KIMS)

Kerala, 695 029, India

Location

Lokmanya TilakMunicipal Medical College &General Hospital - Sion

Mumbai, 400022, India

Location

All India Institute of Medical Sciences Department of Haematology

New Delhi, 110029, India

Location

Sir Ganga Ram Hospital

New Delhi, 110060, India

Location

Sahyadri Speciality Hospital

Pune, 411 004, India

Location

Jehangir Clinical Development Centre, Department of Haematology, Jehangir Hospital Premises

Pune, 411-001, India

Location

Hemophilia Center - Hematoogy & Oncology Dept. Shiraz University of Medical Science Ayatollah Dastgheib Hospital

Shiraz, Iran

Location

Comprehensive Care Center for Children with Hemophilia Mofid Children Hospital

Tehran, 15468-15514, Iran

Location

Centro Emofilia e Trombosi "Angelo Bianchi Bonomi" Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano - Italy

Milan, 20122, Italy

Location

Clinica Medica II - Azienda Ospedaliera di Padova - Centro Emofilia di Padova

Padua, 35128, Italy

Location

Ematologia- UO Diagnostica Speciale e Terapia delle Malattie dell'Emostasi e della Trombosi- Università Sapienza - Policlinico Umberto I

Rome, 00161, Italy

Location

Unidad Medica de Alta Especialidad (UMAE), Hospital de Pediatria. Centro Medico Nacional de Occidente Istituto Mexicano del Seguro Social

Jalisco, 44340, Mexico

Location

Instituto Nacional de Pediatria

México D.F., 04530, Mexico

Location

Hospital Infantil de Mexico Federico Gomez

México, D.F., 06720, Mexico

Location

Hospital Universitario Dr. Josè Eleuterio Gonzalez de la UANL, NL. Mexico

Monterrey, 64450, Mexico

Location

Hospital de Especialidades UMAE Istituto Mexicano del Seguro Social (IMSS)

Monterrey (Nuevo Leòn), 64330, Mexico

Location

Kinf Faisal Specilist Hospital and Research Center

Riyadh, 11211, Saudi Arabia

Location

Haemophilia Comprehensive Care Clinic, Area 454, Charlotte Maxeke Johannesburg Academic Hospital

Parktown, South Africa

Location

Hospital Regional Universitario Carlos Haya

Málaga, 29011, Spain

Location

Hospital Universitario Virgen del Rocio Unidad de Hemofilia

Seville, 41013, Spain

Location

Hospital Universitario La Fe Unidad Coagulopatias Congenitas

Valencia, 46009, Spain

Location

Cukurova Universitesi, Tip Fakultesi Pediatrik Hematoloji B.D.

Adana, 01330, Turkey (Türkiye)

Location

Ege Üniversitesi Tip Fakültesi Cocuk Sağliği ve Hastalikari Anabilim Dali Pediatrik Hematoloji Bilim Dali

Bornova/Izmir, 35100, Turkey (Türkiye)

Location

Istanbul Üniversitesi Cerrahpaşa Tip Fakültesi Pediatrik Hematoloji B.D.

Istanbul, 34300, Turkey (Türkiye)

Location

Related Publications (25)

• 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.

  PMID: 8102429 BACKGROUND

• 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.

  PMID: 7639276 BACKGROUND

• 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.

  PMID: 12826531 BACKGROUND

• 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.

  PMID: 17286767 BACKGROUND

• 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.

  PMID: 11449336 BACKGROUND

• 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.

  PMID: 16985172 BACKGROUND

• 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.

  PMID: 1347102 BACKGROUND

• 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.

  PMID: 16166584 BACKGROUND

• 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.

  PMID: 17218379 BACKGROUND

• 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.

  PMID: 12816859 BACKGROUND

• 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.

  PMID: 16476086 BACKGROUND

• 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.

  PMID: 7792732 BACKGROUND

• 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.

  PMID: 15735795 BACKGROUND

• 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.

  PMID: 11380444 BACKGROUND

• 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.

  PMID: 8421474 BACKGROUND

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

  PMID: 497341 BACKGROUND

• 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.

  BACKGROUND

• 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.

  PMID: 9843171 BACKGROUND

• 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.

  PMID: 14962213 BACKGROUND

• 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.

  PMID: 7667845 BACKGROUND

• 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.

  PMID: 21299743 BACKGROUND

• 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.

  PMID: 18815284 BACKGROUND

• 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.

  PMID: 12828678 BACKGROUND

• 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.

  PMID: 28768627 DERIVED

• 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.

  PMID: 27223147 DERIVED

Related Links

• The official web site of the SIPPET Study

MeSH Terms

Conditions

Hemophilia A

Interventions

factor VIII, von Willebrand factor drug combination; recombinant FVIII, sugar formulated; Factor VIII

Condition Hierarchy (Ancestors)

Blood Coagulation Disorders, Inherited; Blood Coagulation Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Coagulation Protein Disorders; Hemorrhagic Disorders; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Intervention Hierarchy (Ancestors)

Blood Coagulation Factors; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Protein Precursors; Biological Factors

Limitations and Caveats

Enrollment early termination,because on September2014 WFH stated:with other safe clotting-factor concentrates available,consider not to use Kogenate FS/Helixate NexGen(CSL Behring)for newly diagnosed Severe Haemophilia A patients not treated before.

Results Point of Contact

• Title: Prof. Flora Peyvandi
• Organization: Centro Emofilia e Trombosi "Angelo Bianchi Bonomi", Fondazione IRCCS Cà Granda, Ospedale Maggiore Policlinico di Milano

flora.peyvandi@unimi.it

0039 0255035414

Study Officials

• Pier M. Mannucci, Professor

  Fondazione Ca' Granda Ospedale Maggiore Policlinico Milano

  PRINCIPAL INVESTIGATOR

• Flora Peyvandi, Professor

  Fondazione Ca' Granda Ospedale Maggiore Policlinico Milano

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 4, 2010
• First Posted: February 8, 2010
• Study Start: January 1, 2010
• Primary Completion: May 1, 2015
• Study Completion: May 1, 2015
• Last Updated: August 25, 2017
• Results First Posted: April 7, 2017

Record last verified: 2017-07

Data Sharing

• IPD Sharing: Will share

Locations

IR (2); AR (2); IN (10); US (10); EG (2); ZA (1); TU (3); ES (3); AU (2); BR (2); SA (1); ME (5); IT (3); CL (2)