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

NCT02479087 | Unknown Phase 4

• 1 other identifier: FCG-CNS-001
• Study Type: interventional
• Target: 20
• Locations: 2 countries
• Sites: 4

Brief Summary

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.

Conditions

Hemophilia A

Keywords

von Willebrand Factor; Factor VIII; Hemorrhage; Immune Tolerance; Hemophilia A

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (7)

• Safety (adverse events)

  Up to 33 months

• Analysis of treatment compliance

  Up to 33 months

• Efficacy evaluation - Time to achieve ITI

  Up to 33 months

• Evaluation of the cost of therapy

  Up to 33 months

• Efficacy evaluation - IT persistence

  Up to 33 months+ 12 months FU

Study Arms (1)

Plasma-derived FVIII/VWF concentrate

EXPERIMENTAL

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

Interventions

Plasma-derived FVIII/VWF concentrate 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).

Also known as: Emoclot

Plasma-derived FVIII/VWF concentrate

Eligibility Criteria

• Age: Up to 12 Years
• Sex: male
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• Subjects (his/her parent/legal representative), must have given a written informed consent.
• Male children: age \<12 years.
• Severe or moderate Haemophilia A (FVIII \<2%).
• 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.
• Any level of inhibitor at study enrollment.
• Willingness and ability to participate in the study.
• No other experimental treatments (involving or not FVIII concentrates).

You may not qualify if:

• 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.
• Intolerance to active substances or to any of the excipients of FVIII / VWF concentrates.
• Concomitant systemic treatment with immunosuppressive drugs.

Sponsors & Collaborators

• Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico: lead
• Sintesi Research Srl: collaborator

Study Sites (4)

Ain Shams Pediatric hospital, Ain Shams University

Cairo, Egypt

NOT YET RECRUITING

Almoneera Pediatric Cairo University Hospital (Abu El- Reesh)

Cairo, Egypt

NOT YET RECRUITING

St. John's Medical College Hospital

Bangalore, 560034, India

RECRUITING

All India Institute of Medical Sciences

New Delhi, 110029, India

RECRUITING

Related Publications (21)

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

  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

• 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.

  PMID: 9308748 BACKGROUND

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

  PMID: 9873760 BACKGROUND

• 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)

  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.

  PMID: 9873861 BACKGROUND

• 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.

  PMID: 9157608 BACKGROUND

• 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.

  PMID: 11122270 BACKGROUND

• 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).

  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.

  PMID: 8950785 BACKGROUND

• 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.

  PMID: 11442641 BACKGROUND

• 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.

  PMID: 27214015 BACKGROUND

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

  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).

  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.

  PMID: 16154861 BACKGROUND

• 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.

  PMID: 17610550 BACKGROUND

• 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.

  PMID: 7620189 BACKGROUND

• 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.

  PMID: 22101900 BACKGROUND

• 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.

  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.

  PMID: 10961866 BACKGROUND

• 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.

  PMID: 20573153 BACKGROUND

MeSH Terms

Conditions

Hemophilia A; Hemorrhage

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; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Officials

• Pier Mannuccio Mannucci, MD

  IRCCS Fondazione Ca' Granda Ospedale Maggiore Policlinico

  STUDY CHAIR

• 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

  STUDY DIRECTOR

Central Study Contacts

Pier Mannuccio Mannucci, MD

CONTACT

+39 0255038377; piermannuccio.mannucci@unimi.it

Elena Santagostino, MD

CONTACT

+39 0255035273; elena.santagostino@policlinico.mi.it

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 16, 2015
• First Posted: June 23, 2015
• Study Start: January 1, 2015
• Primary Completion: January 1, 2019
• Study Completion: January 1, 2020
• Last Updated: June 23, 2015

Record last verified: 2015-06

Locations

EG (2); IN (2)