Safety/Efficacy Study to Assess Whether FVIII/VWF Concentrate Can Induce Immune Tolerance in Haemophilia A Patients

NCT ID: NCT02479087

Last Updated: 2015-06-23

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

UNKNOWN

Clinical Phase

PHASE4

Total Enrollment

20 participants

Study Classification

INTERVENTIONAL

Study Start Date

2015-01-31

Study Completion Date

2020-01-31

Brief Summary

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The purpose of this study is to assess the role of a FVIII/VWF complex concentrate (Emoclot) in successfully inducing immune tolerance (I.T.I.) in patients with Haemophilia A with inhibitors, including patients at high risk of failure.

Detailed Description

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The development of factor VIII inhibitors occurs in approximately 30 to 40% of patients with severe Haemophilia A. The main negative clinical and cost consequence is the ineffectiveness of replacement therapy in patients with high-titer antibodies, who have a shorter life and greater morbidity than those who do not develop inhibitors. It is known from immunology that a regular and frequent exposure to the antigen of FVIII can induce tolerance of the immune system of the patient with inhibitors. This effect, called "immune tolerance induction" (ITI) is usually achieved after a prolonged exposure of the patient to FVIII, and is a common way of managing the condition of patients with inhibitors as well as the treatment of bleeding episodes with large amounts of hemostatic agents. In vitro and retrospective clinical studies suggest that FVIII/VWF complex concentrates may have less immunogenicity with respect to those plasma-derived concentrates purified with monoclonal antibodies (MABs), and recombinant DNA factor VIII concentrates (rFVIII), in both which the von Willebrand factor (VWF) is absent. Immune tolerance induction (ITI) showed to be effective in about 70% of Haemophiliacs with inhibitors. Poor prognosis factors have been identified by different registries: age ≥ 6 years, ITI started \>1 year from inhibitor development, inhibitor peaks \>200 BU, inhibitor titer \>10 BU at the start of ITI and previously failed ITI. The results of clinical studies suggest that complex concentrates of VWF/FVIII can be effective in ITI, even in patients at high risk of failure. To explain these findings, a role for VWF (i.e. prolonged antigen exposure) has been hypothesized.

Conditions

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Hemophilia A

Study Design

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Allocation Method

NA

Intervention Model

SINGLE_GROUP

Primary Study Purpose

TREATMENT

Blinding Strategy

NONE

Study Groups

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Plasma-derived FVIII/VWF concentrate

The drug will be delivered through intravenous slow infusion/injection. The starting dosage can vary between the minimum dosage of 50 IU/Kg 3 times a week up to a maximum of 200 IU/kg per day.

This starting dosage will be decided by the Principal Investigator according to patient's condition and other variables.

The initial dosage can be then adjusted on the base of response.

Group Type EXPERIMENTAL

Plasma-derived FVIII/VWF concentrate

Intervention Type DRUG

The investigational treatment is with lyophilized plasma-derived Factor VIII. The product belongs to the factor VIII concentrates class, containing also VW Factor in an average ratio VW/VIII of \> 1: 4.5.

The product is as a powder and a solvent solution for continuous infusion of Factor VIII. The specific activity of Factor VIII is of approximately 80 IU/mg protein.

The number of units of FVIII administered is expressed in International Units (IU), which are consistent with current WHO standards for products containing Factor VIII. The activity of Factor VIII in plasma is expressed either as a percentage (compared to normal human plasma) or in International Units (compared to the international standard for FVIII in plasma).

Interventions

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Plasma-derived FVIII/VWF concentrate

The investigational treatment is with lyophilized plasma-derived Factor VIII. The product belongs to the factor VIII concentrates class, containing also VW Factor in an average ratio VW/VIII of \> 1: 4.5.

The product is as a powder and a solvent solution for continuous infusion of Factor VIII. The specific activity of Factor VIII is of approximately 80 IU/mg protein.

The number of units of FVIII administered is expressed in International Units (IU), which are consistent with current WHO standards for products containing Factor VIII. The activity of Factor VIII in plasma is expressed either as a percentage (compared to normal human plasma) or in International Units (compared to the international standard for FVIII in plasma).

Intervention Type DRUG

Other Intervention Names

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Emoclot

Eligibility Criteria

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Inclusion Criteria

1. Subjects (his/her parent/legal representative), must have given a written informed consent.
2. Male children: age \<12 years.
3. Severe or moderate Haemophilia A (FVIII \<2%).
4. High responders (clinical history of inhibitor peak \> 5BU) or low-responders (clinical history of inhibitor peak \< 5 BU) with potential bleedings, assessed by responsible physicians as not to be treated with high FVIII doses.
5. Any level of inhibitor at study enrollment.
6. Willingness and ability to participate in the study.
7. No other experimental treatments (involving or not FVIII concentrates).

Exclusion Criteria

1. Any clinically relevant abnormality, in hematological, biochemical and urinary routine examinations, or any condition or treatment which in the investigator's opinion, makes the patient not eligible for the study.
2. Intolerance to active substances or to any of the excipients of FVIII / VWF concentrates.
3. Concomitant systemic treatment with immunosuppressive drugs.
Maximum Eligible Age

12 Years

Eligible Sex

MALE

Accepts Healthy Volunteers

No

Sponsors

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Sintesi Research Srl

INDUSTRY

Sponsor Role collaborator

Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico

OTHER

Sponsor Role lead

Responsible Party

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Responsibility Role SPONSOR

Principal Investigators

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Pier Mannuccio Mannucci, MD

Role: STUDY_CHAIR

IRCCS Fondazione Ca' Granda Ospedale Maggiore Policlinico

Flora Peyvandi, MD

Role: STUDY_DIRECTOR

Università di Milano, IRCCS Fondazione Ca' Granda Ospedale Maggiore Policlinico

Elena Santagostino, MD

Role: STUDY_DIRECTOR

Centro Emofilia e Trombosi Angela Bianchi Bonomi, IRCCS Fondazione Ospedale Maggiore Policlinico

Locations

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Ain Shams Pediatric hospital, Ain Shams University

Cairo, , Egypt

Site Status NOT_YET_RECRUITING

Almoneera Pediatric Cairo University Hospital (Abu El- Reesh)

Cairo, , Egypt

Site Status NOT_YET_RECRUITING

St. John's Medical College Hospital

Bangalore, , India

Site Status RECRUITING

All India Institute of Medical Sciences

New Delhi, , India

Site Status RECRUITING

Countries

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Egypt India

Central Contacts

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Pier Mannuccio Mannucci, MD

Role: CONTACT

+39 0255038377

Elena Santagostino, MD

Role: CONTACT

+39 0255035273

Facility Contacts

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Mohssen El-Alfy, MD

Role: primary

+20 1000864343

Shereen Abdel Ghany, MD

Role: backup

+20 1200533484

Amal El-Beshlawy, MD

Role: primary

+20 1223124674

Sonia Aldof, MD

Role: backup

+20 1223431046

Cecil Ross, MD

Role: primary

+91 9448493705

Sita Lakshmi, MD

Role: backup

+91 8022065178

Tulika Seth, MD

Role: primary

+91 9868397236

Renu Saxena, MD

Role: backup

+91 1126594670

References

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Gilles JG, Saint-Remy JMR. Recombinant and plasma-derived factor VIII are immunologically distinct in in vitro assays. Thromb Haemost 1995; 73:1213.

Reference Type 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.

Reference Type BACKGROUND
PMID: 7792732 (View on PubMed)

Yee TT, Williams MD, Hill FG, Lee CA, Pasi KJ. Absence of inhibitors in previously untreated patients with severe haemophilia A after exposure to a single intermediate purity factor VIII product. Thromb Haemost. 1997 Sep;78(3):1027-9.

Reference Type BACKGROUND
PMID: 9308748 (View on PubMed)

Teitel JM. Safety of coagulation factor concentrates. Haemophilia. 1998 Jul;4(4):393-401. doi: 10.1046/j.1365-2516.1998.440393.x.

Reference Type BACKGROUND
PMID: 9873760 (View on PubMed)

Rokicka-Milewska R, Klukowska A, Dreger B, Beer H-J. Incidence of factor VIII inhibitor development in previously untreated Haemophilia A patients after exposure to a double viral inactivated factor VIII concentrate. Ann Hematol 1999; 78 (suppl 1)

Reference Type BACKGROUND

Aznar JA, Lorenzo JI, Molina R, Haya S, Querol F, Dasi MA. Zero incidence of inhibitor development in previously treated haemophilia A, HIV-negative patients upon exposure to a plasma-derived high-purity and double viral inactivated factor VIII concentrate. Haemophilia. 1998 Jan;4(1):21-4. doi: 10.1046/j.1365-2516.1998.00139.x.

Reference Type BACKGROUND
PMID: 9873861 (View on PubMed)

Smith MP, Rice KM, Savidge GF. Successful clinical use of a plasma-derived, dual virus inactivated factor VII concentrate incorporating solvent-detergent and dry heat treatment. Thromb Haemost. 1997 Feb;77(2):406-7. No abstract available.

Reference Type BACKGROUND
PMID: 9157608 (View on PubMed)

Sukhu K, Keeling DM, Giangrande PL. Variation in inhibitor reactivity in acquired haemophilia A with different concentrates. Clin Lab Haematol. 2000 Oct;22(5):287-90. doi: 10.1046/j.1365-2257.2000.00328.x.

Reference Type BACKGROUND
PMID: 11122270 (View on PubMed)

Gensana M, Altisent C. Aznar JA, Casana P, Hernandez F, Jorquera JI, Magallon M, Massot M, Puig L. Factor VIII inhibitors directed to the A2 domain and the light chain may also show less reactivity to FVIII complexed with VWF. World Federation of Haemophilia, The Hague, May 1998, (Abstract book).

Reference Type BACKGROUND

Suzuki T, Arai M, Amano K, Kagawa K, Fukutake K. Factor VIII inhibitor antibodies with C2 domain specificity are less inhibitory to factor VIII complexed with von Willebrand factor. Thromb Haemost. 1996 Nov;76(5):749-54.

Reference Type BACKGROUND
PMID: 8950785 (View on PubMed)

Gensana M, Altisent C, Aznar JA, Casana P, Hernandez F, Jorquera JI, Magallon M, Massot M, Puig L. Influence of von Willebrand factor on the reactivity of human factor VIII inhibitors with factor VIII. Haemophilia. 2001 Jul;7(4):369-74. doi: 10.1046/j.1365-2516.2001.00526.x.

Reference Type BACKGROUND
PMID: 11442641 (View on PubMed)

Berntorp E, Ekman M, Gunnarsson M, Nilsson IM. Variation in factor VIII inhibitor reactivity with different commercial factor VIII preparations. Haemophilia. 1996 Apr;2(2):95-9. doi: 10.1111/j.1365-2516.1996.tb00022.x.

Reference Type BACKGROUND
PMID: 27214015 (View on PubMed)

Kreutz W: Immune tolerance induction (ITI) in Haemophilia A-patients with inhibitors - the choice of concentrate affecting success. Haematologica 2001; 86 (S4):16-20

Reference Type BACKGROUND

Kreuz W, Steiner J, Auerswald G, Beeg T, Becker S. Successful immunetolerance therapy of FVIII-inhibitor in chldren after changing from high to intermediate purity FVIII concentrate. Ann Hematol 1996; 72 (suppl 1).

Reference Type BACKGROUND

Orsini F, Rotschild C, Beurrier P, Faradji A, Goudemand J, Polack B. Immune tolerance induction with highly purified plasma-derived factor VIII containing von Willebrand factor in hemophilia A patients with high-responding inhibitors. Haematologica. 2005 Sep;90(9):1288-90.

Reference Type BACKGROUND
PMID: 16154861 (View on PubMed)

Gringeri A, Musso R, Mazzucconi MG, Piseddu G, Schiavoni M, Pignoloni P, Mannucci PM; RITS-FITNHES Study Group. Immune tolerance induction with a high purity von Willebrand factor/VIII complex concentrate in haemophilia A patients with inhibitors at high risk of a poor response. Haemophilia. 2007 Jul;13(4):373-9. doi: 10.1111/j.1365-2516.2007.01484.x.

Reference Type BACKGROUND
PMID: 17610550 (View on PubMed)

Mauser-Bunschoten EP, Nieuwenhuis HK, Roosendaal G, van den Berg HM. Low-dose immune tolerance induction in hemophilia A patients with inhibitors. Blood. 1995 Aug 1;86(3):983-8.

Reference Type BACKGROUND
PMID: 7620189 (View on PubMed)

Hay CR, DiMichele DM; International Immune Tolerance Study. The principal results of the International Immune Tolerance Study: a randomized dose comparison. Blood. 2012 Feb 9;119(6):1335-44. doi: 10.1182/blood-2011-08-369132. Epub 2011 Nov 18.

Reference Type BACKGROUND
PMID: 22101900 (View on PubMed)

Haya S, Casaña P, Moret A, Cid RA, Cabrera N, Abad L, Aznar AJ. Immunotolerance Induction Treatments in Hemophilia. J.of Coagulation Disorders 2009; 1(1): 37-42.

Reference Type BACKGROUND

Colowick AB, Bohn RL, Avorn J, Ewenstein BM. Immune tolerance induction in hemophilia patients with inhibitors: costly can be cheaper. Blood. 2000 Sep 1;96(5):1698-702.

Reference Type BACKGROUND
PMID: 10961866 (View on PubMed)

Coppola A, Di Minno MN, Santagostino E. Optimizing management of immune tolerance induction in patients with severe haemophilia A and inhibitors: towards evidence-based approaches. Br J Haematol. 2010 Sep;150(5):515-28. doi: 10.1111/j.1365-2141.2010.08263.x. Epub 2010 Jun 22.

Reference Type BACKGROUND
PMID: 20573153 (View on PubMed)

Other Identifiers

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FCG-CNS-001

Identifier Type: -

Identifier Source: org_study_id

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