Outcome of Acquired Haemophilia With Steroid Combined With Cyclophosphamide Versus Steroid Combined With Rituximab (CREHA Study) (CREHA)

CREHA project is a study comparing steroid combined with cyclophosphamide versus steroid combined with rituximab in patients with acquired haemophilia. The study will test the hypothesis that steroid combined with cyclophosphamide is more effective than steroid plus rituximab for FVIII inhibitor eradication in acquired haemophilia.

Study Overview

• Status: Unknown
• Conditions: Acquired Haemophilia
• Intervention / Treatment: Drug: Steroid + cyclophosphamide; Drug: Steroid + rituximab

Detailed Description

CREHA project is a multicenter, randomized, controlled efficacity and safety study comparing steroid combined with cyclophosphamide versus steroid combined with rituximab in patients with acquired haemophilia. The study will test the hypothesis that steroid combined with cyclophosphamide is more effective than steroid plus rituximab for FVIII inhibitor eradication in acquired haemophilia

• Study Type: Interventional
• Enrollment (Anticipated): 164
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Hervé LEVESQUE, MD, PhD; Phone Number: +33 (0)2 32 88 90 01; Email: herve.levesque@chu-rouen.fr

Study Locations

• France
  • Amiens, France, 80054
    • Recruiting
    • University Hospital Amiens
    • Principal Investigator: Jean SCHMIDT, MD
    • Contact: Jean SCHMIDT, MD; Phone Number: +33 (0)3 22 66 82 30; Email: schmidt.jean@chu-amiens.fr
  • Bondy, France, 93140
    • Recruiting
    • Hospital Jean Verdier
    • Contact: Olivier FAIN, MD, PhD; Phone Number: +33 (0)1 48 02 63 96; Email: olivier.fain@jvr.aphp.fr
    • Principal Investigator: Olivier FAIN, MD, PhD
    • Sub-Investigator: Yves LAURIAN, MD
  • Boulogne-Billancourt, France, 92104
    • Recruiting
    • Hospital Ambroise Pare
    • Contact: Thomas HANSLIK, MD, PhD; Phone Number: +33 (0)1 49 09 56 38; Email: thomas.hanslik@apr.aphp.fr
    • Principal Investigator: Thomas HANSLIK, MD, PhD
  • Brest, France, 29609
    • Recruiting
    • University Hospital of Brest - Hospital La cavale Blanche
    • Principal Investigator: Aurélien Delluc, MD
    • Contact: Aurélien DELLUC, MD; Phone Number: +33 (0)2 98 34 73 36; Email: aurelien.delluc@chu-brest.fr
  • Béziers, France, 34525
    • Recruiting
    • Hospital of Béziers
    • Contact: Eric OZIOL, MD; Phone Number: +33 (0)4 67 35 70 56; Email: eric.oziol@ch-beziers.fr
    • Principal Investigator: Eric OZIOL, MD
  • Caen, France, 14033
    • Recruiting
    • University Hospital Côte de Nacre
    • Contact: Boris BIENVENU, MD, PhD; Phone Number: +33 (0)2 31 06 45 84; Email: bienvenu-b@chu-caen.fr
    • Principal Investigator: Boris BIENVENU, MD, PhD
  • Clermont-Ferrand, France, 63003
    • Recruiting
    • University Hospital G. Montpied
    • Contact: Marc ANDRE, MD,PhD; Phone Number: +33 (0)4 73 75 14 35; Email: mandre@chu-clermontferrand.fr
  • Créteil, France, 94010
    • Recruiting
    • Hospital Henri Mondor
    • Contact: Marc MICHEL, MD, PhD; Phone Number: +33 (0)1 49 81 20 76; Email: marc.michel@hmn.aphp.fr
    • Principal Investigator: Marc MICHEL, MD, PhD
  • Dijon, France, 21033
    • Recruiting
    • University Hospital of Dijon - Hospital Général
    • Contact: Jean-François BESANCENOT, MD, PhD; Phone Number: +33 (0)3 80 29 37 73; Email: jean-francois.besancenot@chu-dijon.fr
    • Principal Investigator: Jean-François BESANCENOT, MD, PhD
  • Dijon, France, 21079
    • Recruiting
    • University Hospital Bocage
    • Contact: Bernard BONNOTTE, MD, PhD; Phone Number: +33 (0)3 80 29 34 32; Email: bernard.bonnotte@chu-dijon.fr
    • Principal Investigator: Bernard BONNOTTE, MD, PhD
  • Grenoble, France, 38043
    • Recruiting
    • University Hospital Michallon
    • Principal Investigator: Laurence Bouillet, MD
    • Contact: Laurence BOUILLET, MD; Phone Number: +33 (0)4 76 7655 20; Email: Lbouillet@chu-grenoble.fr
  • Le Kremlin-bicetre, France, 94270
    • Recruiting
    • Hospital Kremlin-Bicêtre
    • Contact: Olivier LAMBOTTE, MD, PhD; Phone Number: +33 (0)1 45 21 27 83; Email: olivier.lambotte@bct.aphp.fr
    • Principal Investigator: Olivier LAMBOTTE, MD, PhD
  • Lille, France, 59037
    • Recruiting
    • University Regional Hospital of Lille
    • Contact: Marc LAMBERT, MD; Phone Number: +33 (0)3 20 44 42 96; Email: marc.lambert@chru-lille.fr
    • Principal Investigator: Marc LAMBERT, MD
    • Sub-Investigator: Jenny GOUDEMAND, MD, PhD
  • Limoges, France, 87042
    • Recruiting
    • University Hospital of Limoges
    • Contact: Elizabeth VIDAL-CATHALA, MD,PhD; Phone Number: +33 (0)5 55 05 66 41; Email: elisabeth.vidal@unilim.fr
    • Principal Investigator: Elizabeth VIDAL-CATHALA, MD, PhD
  • Marseille, France, 13385
    • Recruiting
    • AP-HM, University Hospital La Conception
    • Contact: Nicolas SCHLEINITZ, MD, PhD; Phone Number: +33 (0)4 91 38 35 01; Email: nicolas.schleinitz@ap-hm.fr
    • Principal Investigator: Nicolas SCHLEINITZ, MD, PhD
  • Montpellier, France, 34295
    • Recruiting
    • University Hospital Saint-Eloi
    • Contact: Alain LE QUELLEC, MD, PhD; Phone Number: +33 (0)4 67 33 70 17; Email: a-lequellec@chu-montpellier.fr
    • Principal Investigator: Alain LE QUELLEC, MD, PhD
  • Nancy, France
    • Not yet recruiting
    • Regional Center of Haemophilia Treatment (CRTH) de Lorraine
    • Contact: Brigit FROTSCHER, MD; Phone Number: +33 (0) 03 83 15 37 84; Email: b.frotscher@chu-nancy.fr
    • Principal Investigator: Brigit FROTSCHER, MD
  • Nantes, France, 44093
    • Recruiting
    • University Hospital of Nantes, Hospital Hôtel-Dieu
    • Contact: Mohamed HAMIDOU, MD, PhD; Phone Number: +33 (0)2 40 08 31 46; Email: mohamed.hamidou@chu-nantes.fr
    • Principal Investigator: Mohamed HAMIDOU, MD, PhD
    • Principal Investigator: Marc TROSSAËRT, MD
  • Nice, France, 06202
    • Not yet recruiting
    • Hospital Archet 1
    • Principal Investigator: Pierre-Yves Jeandel, MD
    • Contact: Pierre-Yves JEANDEL, MD; Phone Number: +33 (0)4 92 03 58 23; Email: jeandel.p@chu-nice.fr
  • Paris, France, 75908
    • Recruiting
    • Europen Hospital of Georges Pompidou (HEGP)
    • Contact: Jacques POUCHOT, MD, PhD; Phone Number: +33 (0)1 56 09 33 32; Email: jacques.pouchot@egp.aphp.fr
    • Principal Investigator: Jacques POUCHOT, MD, PhD
  • Paris 10e, France, 75475
    • Not yet recruiting
    • Hospital Saint-Louis
    • Contact: Dominique FARGE-BANCEL, MD, PhD; Phone Number: +33 (0)1 42 49 97 67; Email: dominique.farge-bancel@sls.aphp.fr
    • Principal Investigator: Dominique FARGE-BANCEL, MD, PhD
  • Paris 13e, France, 75651
    • Recruiting
    • Hospital Pitie-Salpetriere
    • Contact: Zahir AMOURA, MD, PhD; Phone Number: +33 (0)1 42 17 80 01; Email: zahir.amoura@psl.aphp.fr
    • Principal Investigator: Zahir AMOURA, MD, PhD
  • Paris 14e, France, 75679
    • Not yet recruiting
    • Hospital Cochin
    • Contact: Philippe BLANCHE, MD; Phone Number: +33 (0)1 58 41 21 26; Email: philippe.blanche@cch.aphp.fr
    • Principal Investigator: Philippe BLANCHE, MD
  • Paris 18e, France, 75018
    • Recruiting
    • Hôspital Bichat
    • Contact: Thomas PAPO, MD, PhD; Phone Number: +33 (0)1 40 25 87 05; Email: thomas.papo@bch.aphp.fr
    • Principal Investigator: Thomas PAPO, MD, PhD
  • Pessac, France, 33604
    • Recruiting
    • University Hospital of Bordeaux - Hospital Haut-Lévêque
    • Contact: Jean-François VIALLARD, MD, PhD; Phone Number: +33 (0)5 57 65 64 83; Email: jean-francois.viallard@chu-bordeaux.fr
    • Principal Investigator: Jean-François VIALLARD, MD, PhD
  • Pierre-Benite, France, 69495
    • Recruiting
    • Hospital Lyon Sud
    • Contact: Isabelle DURIEU, MD, PhD; Phone Number: +33 (0)4 78 86 14 65; Email: Isabelle.durieu@chu-lyon.fr
    • Principal Investigator: Isabelle DURIEU, MD, PhD
  • Poitiers, France, 86021
    • Recruiting
    • University Hospital of Poitiers
    • Contact: Pascal ROBLOT, MD, PhD; Phone Number: +33 (0) 5 49 44 44 22; Email: p.roblot@chu-poitiers.fr
    • Principal Investigator: Pascal ROBLOT, MD, PhD
  • Rennes, France, 35000
    • Recruiting
    • Hospital Sud / Hospital Pontchaillou
    • Contact: Patrick JEGO, MD, PhD; Phone Number: +33 (0)2 99 26 71 28; Email: patrick.jego@chu-rennes.fr
    • Sub-Investigator: Benoît GUILLET, MD
  • Rouen, France, 76031
    • Recruiting
    • University Hospital of Rouen
    • Sub-Investigator: Ygal BENHAMOU, MD
    • Contact: Hervé LEVESQUE, MD, PhD; Phone Number: +33 (0) 2 32 88 90 01; Email: herve.levesque@chu-rouen.fr
    • Contact: Ygal BENHAMOU, MD; Phone Number: +33 (0)2 32 88 90 14; Email: ygal.benhamou@chu-rouen.fr
    • Principal Investigator: Hervé LEVESQUE, MD, PhD
    • Sub-Investigator: Loïc BEGARIN, MD
    • Sub-Investigator: Cyrielle ASSIE-CHAUVIER, MD
    • Sub-Investigator: Nicolas GIRSZYN, MD
    • Sub-Investigator: Alice PROUX, MD
    • Sub-Investigator: Severine JOSSE, MD
    • Sub-Investigator: Isabelle MARIE, MD, PhD
    • Sub-Investigator: Jeanne-Yvonne BORG, MD, PhD
    • Sub-Investigator: Véronique LE CAM-DUCHEZ, Md
  • Saint-Etienne, France, 42055
    • Recruiting
    • Hospital Nord
    • Contact: Pascal CATHEBRAS, MD, PhD; Phone Number: +33 (0)4 77 82 83 42; Email: pascal.cathebras@chu-st-etienne.fr
    • Principal Investigator: Pascal CATHEBRAS, MD, PhD
  • Strasbourg, France, 67098
    • Recruiting
    • University Regional Hospital Hautepierre
    • Contact: Anne BOUGARIT, MD, PhD; Phone Number: +33 (0)3 88 12 75 94; Email: anne.bourgarit-durand@chur-strasbourg.fr
    • Principal Investigator: Anne BOURGARIT, MD, PhD
    • Sub-Investigator: Bernard GOICHOT, MD, PhD
    • Sub-Investigator: Lélia GRUNEBAUM-HIMY, MD
    • Sub-Investigator: Dominique DESPREZ, MD
  • Toulouse, France, 31059
    • Recruiting
    • Hospital Purpan
    • Contact: Laurent SAILLER, MD, PhD; Phone Number: +33 (0)5 61 77 96 78; Email: sailler.l@chu-toulouse.fr
    • Principal Investigator: Laurent SAILLER, MD, PhD
    • Sub-Investigator: Marie-France THIERCELIN-LEGRAND, MD
    • Sub-Investigator: Daniel ADOUE, MD, PhD
  • Toulouse, France, 31059
    • Recruiting
    • Hospital Rangueil
    • Contact: Dominique CHAUVEAU, MD, PhD; Phone Number: +33 (0)5 61 32 32 79; Email: chauveau.d@chu-toulouse.fr
    • Principal Investigator: Dominique CHAUVEAU, MD, PhD
    • Sub-Investigator: Pierre SIE, MD, PhD
    • Sub-Investigator: Sophie VOISIN, MD
  • Tours, France, 37044
    • Recruiting
    • Hopsital Bretonneau
    • Contact: François MAILLOT, MD, PhD; Phone Number: +33 (0)2 47 47 47 27; Email: maillot@med.univ-tours.fr
    • Principal Investigator: Francois MAILLOT, MD, PhD
    • Sub-Investigator: Yves GRUEL, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• men or women
• women post-menpausal or with ongoing contraception
• 18 years old or more
• diagnosis of acquired hemophilia
• patient must be insured
• patient has provided written informed consent prior to enrolment
• patient compliant

Exclusion Criteria:

• constitutional hemophilia
• chemotherapy
• ongoing treatment with prednisone > 20mg further more 1 month
• ongoing treatment with prednisone >0.7 mg/d further more 10 days
• thrombocytopenia
• leukopenia
• chronic disease

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Bras A; Steroid 1mg/kg/d and Cyclophosphamide 2mg/kg/d	Drug: Steroid + cyclophosphamide
Experimental: Bras B; Steroid 1mg/kg/d and Rituximab 375 mg/m2 every week during four weeks	Drug: Steroid + rituximab

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Primary objective	Demonstrate the inferiority of steroid combined with rituximab as compared to the recommended immunosuppressive approach (steroid combined with cysclophosphamide for 21 to 42 days) as the first-line immunosuppressive therapy for FVIII inhibitor eradication in acquired haemophilia	During 18 months
Primary efficacy outcome	The primary efficacy outcome is the proportion of patients achieving complete remission defined as titer FVII inhibitor lower than 0.4 Bethesda unit and factor VIII level > 50%	During 18 months
Primary safety outcomes	The primary safety outcomes will be the occurrence of major bleeding and infection related immunosuppressive treatment adverse events.	During 18 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Secondary objective	Secondary objective are time to complete remission, number of relapse at M6, M12, M18, adverse events (especially related to bleeding or to immunosuppressive treatment) and mortality	6 months, 12 months and 18 months
Other key safety outcome	The other key safety outcome are clinically relevant non major bleeding, diabetes and mortality non-related with acquired haemophilia or immunosuppressive therapy	During 18 months

Collaborators and Investigators

• Sponsor: University Hospital, Rouen

Study record dates

Study Major Dates

• Study Start (Actual): May 1, 2012
• Primary Completion (Anticipated): June 1, 2020
• Study Completion (Anticipated): June 1, 2020

Study Registration Dates

• First Submitted: October 16, 2012
• First Submitted That Met QC Criteria: March 8, 2013
• First Posted (Estimate): March 11, 2013

Study Record Updates

• Last Update Posted (Actual): May 29, 2018
• Last Update Submitted That Met QC Criteria: May 25, 2018
• Last Verified: May 1, 2018

More Information

Terms related to this study

• Keywords: Rituximab; Cyclophosphamide; Acquired haemophilia; Comparative and randomized study
• Additional Relevant MeSH Terms: Hematologic Diseases; Blood Coagulation Disorders, Inherited; Coagulation Protein Disorders; Hemorrhagic Disorders; Genetic Diseases, Inborn; Blood Coagulation Disorders; Hemophilia A; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antineoplastic Agents, Immunological; Cyclophosphamide; Rituximab
• Other Study ID Numbers: 2011/090/HP