| アブストラクト | BACKGROUND: Concizumab is an anti-tissue factor pathway inhibitor monoclonal antibody in development as a once-daily, subcutaneous prophylaxis for patients with haemophilia A or haemophilia B with or without inhibitors. We aimed to assess the efficacy and safety of concizumab in patients with haemophilia A or B without inhibitors. Here we report the results from the confirmatory analysis cutoff. METHODS: This prospective, multicentre, open-label, randomised, phase 3a trial (explorer8) was conducted at 69 investigational sites in 31 countries. Eligible patients were male, aged 12 years or older, and had congenital severe haemophilia A or moderate or severe haemophilia B without inhibitors and with documented treatment with clotting factor concentrate in the 24 weeks before screening. The trial was paused because of non-fatal thromboembolic events in three patients (two from this trial [explorer8] and one from a related trial in haemophilia with inhibitors [explorer7; NCT04083781]) and restarted with mitigation measures, including a revised dosing regimen of subcutaneous concizumab at 1.0 mg/kg loading dose on day 1 and subsequent daily doses of 0.20 mg/kg from day 2, with options to decrease to 0.15 mg/kg, stay on 0.20 mg/kg, or increase to 0.25 mg/kg on the basis of concizumab plasma concentration measured after 4 weeks on concizumab. Patients recruited after treatment restart were randomly assigned 1:2 using an interactive web response system to receive no prophylaxis and continue on-demand clotting factor (group 1) or concizumab prophylaxis (group 2). The primary endpoints were the number of treated spontaneous and traumatic bleeding episodes for patients with haemophilia A and haemophilia B separately, assessed at the confirmatory analysis cutoff in randomly assigned patients. Analyses were by intention-to-treat. There were two additional groups containing non-randomly-assigned patients: group 3 contained patients who entered the trial before the trial pause and were receiving concizumab in the phase 2 trial (explorer5; NCT03196297), and group 4 contained patients who received previous clotting factor concentrate prophylaxis or on-demand treatment in the non-interventional trial (explorer6; NCT03741881), patients randomly assigned to groups 1 or 2 before the treatment pause, and patients from explorer5 enrolled after the treatment pause. The safety analysis set contained all patients who received concizumab. Superiority of concizumab over no prophylaxis was established if the two-sided 95% CI of the treatment ratio was less than 1 for haemophilia A and for haemophilia B. This trial is registered with ClinicalTrials.gov, NCT04082429, and its extension part is ongoing. FINDINGS: Patients were recruited between Nov 13, 2019 and Nov 30, 2021; the cutoff date for the analyses presented was July 12, 2022. 173 patients were screened, of whom 148 (86%) were randomly assigned or allocated to the four groups in the study after trial restart on Sept 30, 2020 (nine with haemophilia A and 12 with haemophilia B in group 1; 18 with haemophilia A and 24 with haemophilia B in group 2; nine with haemophilia A in group 3; and 46 with haemophilia A and 30 with haemophilia B in group 4). The estimated mean annualised bleeding rate ratio for treated spontaneous and traumatic bleeding episodes during concizumab prophylaxis versus no prophylaxis was 0.14 (95% CI 0.07-0.29; p<0.0001) for patients with haemophilia A and 0.21 (0.10-0.45; p<0.0001) for patients with haemophilia B. The most frequent adverse events in patients who received concizumab were SARS-CoV-2 infection (19 [13%] of 151 patients), an increase in fibrin D-dimers (12 [8%] patients), and upper respiratory tract infection (ten [7%] patients). There was one fatal adverse event possibly related to treatment (intra-abdominal haemorrhage in a patient from group 4 with haemophilia A with a long-standing history of hypertension). No thromboembolic events were reported between the trial restart and confirmatory analysis cutoff. INTERPRETATION: Concizumab was effective in reducing the bleeding rate compared with no prophylaxis and was considered safe in patients with haemophilia A or B without inhibitors. The results of this trial suggest that concizumab has the potential to be one of the first subcutaneous treatment options for patients with haemophilia B without inhibitors. FUNDING: Novo Nordisk. |
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| 投稿者 | Chowdary, Pratima; Angchaisuksiri, Pantep; Apte, Shashikant; Astermark, Jan; Benson, Gary; Chan, Anthony K C; Jimenez Yuste, Victor; Matsushita, Tadashi; Hogh Nielsen, Amalie Rhode; Sathar, Jameela; Sutton, Christopher; Saulyte Trakymiene, Sonata; Tran, Huyen; Villarreal Martinez, Laura; Wheeler, Allison P; Windyga, Jerzy; Young, Guy; Thaung Zaw, Jay Jay; Eichler, Hermann |
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| 組織名 | Katharine Dormandy Haemophilia and Thrombosis Centre, Royal Free London NHS;Foundation Trust, London, UK. Electronic address: p.chowdary@ucl.ac.uk.;Division of Hematology, Department of Medicine, Ramathibodi Hospital, Mahidol;University, Bangkok, Thailand.;Department of Hematology, Sahyadri Specialty Hospitals, Pune, India.;Institution of Translational Medicine, Lund University, Malmo, Sweden; Department;of Hematology, Oncology and Radiation Physics, Skane University Hospital, Malmo,;Sweden.;Department of Haematology, Belfast Health and Social Care Trust, Belfast, UK.;Department of Pediatrics, McMaster University, Hamilton, ON, Canada.;Hematology Department, La Paz University Hospital, Universidad Autonoma Madrid,;Madrid, Spain.;Department of Transfusion Medicine, Nagoya University Hospital, Nagoya, Japan.;Novo Nordisk, Soborg, Denmark.;Department of Hematology, Ampang Hospital, Kuala Lumpur, Malaysia.;Department of Pediatrics and Child Health, Faculty of Health Sciences, University;of Limpopo and Pietersburg and Mankweng Hospitals, Limpopo, South Africa.;Clinic of Children's Diseases, Faculty of Medicine, Vilnius University Hospital;Santaros Klinikos, Vilnius University, Vilnius, Lithuania.;Ronald Sawyers Haemophilia Centre, The Alfred Hospital, Melbourne, VIC,;Australia; Australian Centre for Blood Diseases, Monash University, Melbourne,;VIC, Australia.;Dr Jose Eleuterio Gonzalez Monterrey University Hospital, Monterrey, Mexico.;Department of Pathology, Microbiology and Immunology, Vanderbilt University;Medical Center, Nashville, TN, USA.;Department of Hemostasis Disorders and Internal Medicine, Laboratory of;Hemostasis and Metabolic Diseases, Institute of Hematology and Transfusion;Medicine, Warsaw, Poland.;Hemostasis and Thrombosis Center, Children's Hospital of Los Angeles, Keck School;of Medicine, University of Southern California, Los Angeles, CA, USA.;Institute of Clinical Hemostaseology and Transfusion Medicine, Saarland;University and University Hospital, Homburg, Germany. |
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