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

IMMUNE TOLERANCE INDUCTION, BY FACTOR VIII CONCENTRATE CONTAINING VON WILLEBRAND FACTOR, IN SEVERE OR MODERATE HAEMOPHILIA A PATIENTS WITH INHIBITORS

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.

Study Overview

• Status: Unknown
• Conditions: Hemophilia A
• Intervention / Treatment: Drug: Plasma-derived FVIII/VWF concentrate

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Anticipated): 20
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Pier Mannuccio Mannucci, MD; Phone Number: +39 0255038377; Email: piermannuccio.mannucci@unimi.it
• Study Contact Backup: Name: Elena Santagostino, MD; Phone Number: +39 0255035273; Email: elena.santagostino@policlinico.mi.it

Study Locations

• Egypt
  • Cairo, Egypt
    • Not yet recruiting
    • Ain Shams Pediatric hospital, Ain Shams University
    • Contact: Mohssen El-Alfy, MD; Phone Number: +20 1000864343; Email: elalfym@hotmail.com
    • Contact: Shereen Abdel Ghany, MD; Phone Number: +20 1200533484; Email: shereen22eg@yahoo.com
    • Principal Investigator: Mohssen El-Alfy, MD
    • Sub-Investigator: Shereen Abdel Ghany, MD
    • Sub-Investigator: Neveen Gamal, MD
  • Cairo, Egypt
    • Not yet recruiting
    • Almoneera Pediatric Cairo University Hospital (Abu El- Reesh)
    • Contact: Amal El-Beshlawy, MD; Phone Number: +20 1223124674; Email: amalelbeshlawy@yahoo.com
    • Contact: Sonia Aldof, MD; Phone Number: +20 1223431046; Email: sonia_adolf@yahoo.com
    • Principal Investigator: Amal El-Beshlawy, MD
    • Sub-Investigator: Sonia Aldof, MD
    • Sub-Investigator: Shaymaa Mohamed, MD
• India
  • Bangalore, India, 560034
    • Recruiting
    • St. John's Medical College Hospital
    • Contact: Cecil Ross, MD; Phone Number: +91 9448493705; Email: cecilross@bsnl.in
    • Contact: Sita Lakshmi, MD; Phone Number: +91 8022065178; Email: slvbs@yahoo.co.in
    • Sub-Investigator: Sita Lakshmi, MD
    • Sub-Investigator: Fulton D'souza, MD
  • New Delhi, India, 110029
    • Recruiting
    • All India Institute of Medical Sciences
    • Contact: Tulika Seth, MD; Phone Number: +91 9868397236; Email: tuliseth@yahoo.com
    • Contact: Renu Saxena, MD; Phone Number: +91 1126594670; Email: renusax@hotmail.com
    • Sub-Investigator: Renu Saxena, MD
    • Sub-Investigator: Vandana Sharma, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 12 years (CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

EXPERIMENTAL: 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.

Drug: 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).; Other Names: Emoclot

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Efficacy: evaluation of the success of IT induction	Success:Inhibitor disappearance/reduction to <0.6 BU/ml with FVIII activity recovery of at least ≥ 66% within 33 months of treatment ; Partial Success: inhibitor reduction to <5 BU/ml with clinical response to FVIII treatment, not followed by an inhibitor increase to values >5 BU/ml for a treatment period of 6 months on demand, or for 12 months of prophylactic treatment; No Response (Failure):Failure in relation to the above criteria defining complete response and partial response within 33 months, OR a reduction of the concentration of the inhibitor, less than 20%, compared to the peak of inhibitor in the IT, in every period of 6 months after the first 3 months of treatment. This implies that 9 months represents the minimum period of treatment and 33 months the maximum possible duration of ITI without success, OR patient withdrawal from the study for any reason.	Up to33 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety (adverse events)	Description and incidence of adverse events during the course of prophylactic treatment, with severity, correlation with the investigational product and final outcome.	Up to 33 months
Analysis of treatment compliance	Description of the patient's adherence to the optimal prolonged treatment.	Up to 33 months
Efficacy evaluation - Time to achieve ITI	Time to achieve the complete or partial response (as defined in the primary outcome measure).	Up to 33 months
Evaluation of the cost of therapy	Recording of overall amount of direct costs of therapy.	Up to 33 months
Efficacy evaluation - IT persistence	Absence of relapse, assessed at 12 months from IT achievement	Up to 33 months+ 12 months FU
Efficacy evaluation - FVIII genetic defect role in IT achievement	Role of FVIII mutations in influencing IT achievement	Up to 33 months
Efficacy evaluation - Role of an immediate IT to delayed IT in IT induction.	Time elapsing between the onset of the inhibitor and the beginning of treatment and its importance for induction of IT in achieving primary endpoints.	Up to 33 months

Collaborators and Investigators

• Sponsor: Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico
• Collaborators: Sintesi Research Srl
• Investigators: Study Chair: Pier Mannuccio Mannucci, MD, IRCCS Fondazione Ca' Granda Ospedale Maggiore Policlinico; Study Director: Flora Peyvandi, MD, Università di Milano, IRCCS Fondazione Ca' Granda Ospedale Maggiore Policlinico; Study Director: Elena Santagostino, MD, Centro Emofilia e Trombosi Angela Bianchi Bonomi, IRCCS Fondazione Ospedale Maggiore Policlinico

Publications and helpful links

General Publications

• 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.
• 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.
• Gilles JG, Saint-Remy JMR. Recombinant and plasma-derived factor VIII are immunologically distinct in in vitro assays. Thromb Haemost 1995; 73:1213.
• 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.
• 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.
• Teitel JM. Safety of coagulation factor concentrates. Haemophilia. 1998 Jul;4(4):393-401. doi: 10.1046/j.1365-2516.1998.440393.x.
• 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)
• 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.
• 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.
• 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.
• 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.
• 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.
• Kreutz W: Immune tolerance induction (ITI) in Haemophilia A-patients with inhibitors - the choice of concentrate affecting success. Haematologica 2001; 86 (S4):16-20
• 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).
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start: January 1, 2015
• Primary Completion (ANTICIPATED): January 1, 2019
• Study Completion (ANTICIPATED): January 1, 2020

Study Registration Dates

• First Submitted: June 16, 2015
• First Submitted That Met QC Criteria: June 22, 2015
• First Posted (ESTIMATE): June 23, 2015

Study Record Updates

• Last Update Posted (ESTIMATE): June 23, 2015
• Last Update Submitted That Met QC Criteria: June 22, 2015
• Last Verified: June 1, 2015

More Information

Terms related to this study

• Keywords: Hemorrhage; Factor VIII; Immune Tolerance; Hemophilia A; von Willebrand Factor
• Additional Relevant MeSH Terms: Hematologic Diseases; Blood Coagulation Disorders, Inherited; Coagulation Protein Disorders; Hemorrhagic Disorders; Genetic Diseases, Inborn; Blood Coagulation Disorders; Hemophilia A
• Other Study ID Numbers: FCG-CNS-001