title: Efficacy and safety of rVIII-SingleChain: results of a phase 1/3 multicenter clinical trial in severe hemophilia A.
abstract: Recombinant VIII (rVIII)-SingleChain is a novel B-domain-truncated recombinant factor VIII (rFVIII), comprised of covalently bonded factor VIII (FVIII) heavy and light chains. It was designed to have a higher binding affinity for von Willebrand factor (VWF). This phase 1/3 study investigated the efficacy and safety of rVIII-SingleChain in the treatment of bleeding episodes, routine prophylaxis, and surgical prophylaxis. Participants were ≥12 years of age, with severe hemophilia A (endogenous FVIII <1%). The participants were allocated by the investigator to receive rVIII-SingleChain in either an on-demand or prophylaxis regimen. Of the 175 patients meeting study eligibility criteria, 173 were treated with rVIII-SingleChain, prophylactically (N = 146) or on-demand (N = 27). The total cumulative exposure was 14 306 exposure days (EDs), with 120 participants reaching ≥50 EDs and 52 participants having ≥100 EDs. Hemostatic efficacy was rated by the investigator as excellent or good in 93.8% of the 835 bleeds treated and assessed. Across all prophylaxis regimens, the median annualized spontaneous bleeding rate was 0.00 (Q1, Q3: 0.0, 2.4) and the median overall annualized bleeding rate (ABR) was 1.14 (Q1, Q3: 0.0, 4.2). Surgical hemostasis was rated as excellent/good in 100% of major surgeries by the investigator. No participant developed FVIII inhibitors. In conclusion, rVIII-SingleChain is a novel rFVIII molecule showing excellent hemostatic efficacy in surgery and in the control of bleeding events, low ABR in patients on prophylaxis, and a favorable safety profile in this large clinical study. This trial was registered at www.clinicaltrials.gov as #NCT01486927.
authors.affiliation: Department of Molecular Medicine and Haematology, Faculty of Health Sciences, University of the Witwatersrand, National Health Laboratory Service, Charlotte Maxeke Johannesburg Academic Hospital, Johannesburg, South Africa;
authors.forename: Johnny
authors.initials: J
authors.lastname: Mahlangu
authors.affiliation: Department of Hematology, Blood Neoplasms and Bone Marrow Transplantation, Wroclaw Medical University, Wroclaw, Poland;
authors.forename: Kazimierz
authors.initials: K
authors.lastname: Kuliczkowski
authors.affiliation: Hemophilia Clinic, National Blood Centre, Kuala Lumpur, Malaysia;
authors.forename: Faraizah Abdul
authors.initials: FA
authors.lastname: Karim
authors.affiliation: Institute of Blood Pathology and Transfusion Medicine, National Academy of Medical Sciences of Ukraine, Lviv, Ukraine;
authors.forename: Oleksandra
authors.initials: O
authors.lastname: Stasyshyn
authors.affiliation: Kemerovo Regional Clinical Hospital, Kemerovo, Russia;
authors.forename: Marina V
authors.initials: MV
authors.lastname: Kosinova
authors.affiliation: Perpetual Succour Hospital, Cebu, Philippines;
authors.forename: Lynda Mae
authors.initials: LM
authors.lastname: Lepatan
authors.affiliation: Krakow Medical Centre, Krakow, Poland;
authors.forename: Aleksander
authors.initials: A
authors.lastname: Skotnicki
authors.affiliation: Hemophilia and Thrombophilia Center, Rush University Medical Center, Chicago, IL;
authors.forename: Lisa N
authors.initials: LN
authors.lastname: Boggio
authors.affiliation: Vivantes Clinic Friedrichshain, Berlin, Germany;
authors.forename: Robert
authors.initials: R
authors.lastname: Klamroth
authors.affiliation: Institute of Experimental Haematology and Transfusion Medicine, University Clinic Bonn, Bonn, Germany;
authors.forename: Johannes
authors.initials: J
authors.lastname: Oldenburg
authors.affiliation: Department of Hematology and Transplantation, Medical University of Gdansk, Gdansk, Poland;
authors.forename: Andrzej
authors.initials: A
authors.lastname: Hellmann
authors.affiliation: A. Bianchi Bonomi Hemophilia and Thrombosis Center, IRCCS Ca' Granda Foundation, Maggiore Hospital Policlinico, Milan, Italy;
authors.forename: Elena
authors.initials: E
authors.lastname: Santagostino
authors.affiliation: Western Australian Centre for Thrombosis and Haemostasis, Murdoch University, Perth, Australia;
authors.forename: Ross I
authors.initials: RI
authors.lastname: Baker
authors.affiliation: Van Creveldkliniek, University Medical Center Utrecht, Utrecht, The Netherlands;
authors.forename: Kathelijn
authors.initials: K
authors.lastname: Fischer
authors.affiliation: Blood Center of Wisconsin and Medical College of Wisconsin, Milwaukee, WI;
authors.forename: Joan C
authors.initials: JC
authors.lastname: Gill
authors.affiliation: Royal Perth Hospital, Perth, Australia;
authors.forename: Stephanie
authors.initials: S
authors.lastname: P'Ng
authors.affiliation: Katharine Dormandy Haemophilia Centre and Thrombosis Unit, Royal Free Hospital, London, United Kingdom;
authors.forename: Pratima
authors.initials: P
authors.lastname: Chowdary
authors.affiliation: University of Texas Health Science Center and The Gulf States Hemophilia and Thrombophilia Center, Houston, TX;
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Escobar
authors.affiliation: Lebanon Department of Pediatrics, Hotel Dieu de France Hospital, Beirut, Lebanon;
authors.forename: Claudia Djambas
authors.initials: CD
authors.lastname: Khayat
authors.affiliation: Sanador SRL, Bucharest, Romania;
authors.forename: Luminita
authors.initials: L
authors.lastname: Rusen
authors.affiliation: Clinical Research and Development, CSL Behring, King of Prussia, PA;
authors.forename: Debra
authors.initials: D
authors.lastname: Bensen-Kennedy
authors.affiliation: Clinical Research and Development, CSL Behring, King of Prussia, PA;
authors.forename: Nicole
authors.initials: N
authors.lastname: Blackman
authors.affiliation: Clinical Research and Development, CSL Behring, King of Prussia, PA;
authors.forename: Tharin
authors.initials: T
authors.lastname: Limsakun
authors.affiliation: Clinical Research and Development, CSL Behring, Marburg, Germany; and.
authors.forename: Alex
authors.initials: A
authors.lastname: Veldman
authors.affiliation: Clinical Research and Development, CSL Behring, King of Prussia, PA;
authors.forename: Katie
authors.initials: K
authors.lastname: St Ledger
authors.affiliation: Clinical Division of Haematology and Haemostaseology, Medical Clinic I, Medical University Vienna, Vienna, Austria.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Pabinger
mesh_terms: D061605:Administration, Intravenous; D000293:Adolescent; D000328:Adult; D002648:Child; D003710:Demography; D004305:Dose-Response Relationship, Drug; D005169:Factor VIII / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006467:Hemophilia A / Q000188:drug therapy* / Q000517:prevention & control; D006470:Hemorrhage / Q000188:drug therapy; D006487:Hemostasis / Q000187:drug effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D011994:Recombinant Proteins; D005169:Factor VIII