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A multicentre, open-label study of emicizumab given every 2 or 4 weeks in children with severe haemophilia A without inhibitors.

ABSTRACT: INTRODUCTION:Emicizumab is a recombinant humanized bispecific monoclonal antibody mimicking the cofactor function of activated factor VIII. AIM:In this multicentre, open-label study (HOHOEMI), we evaluated the efficacy, safety and pharmacokinetics of emicizumab in Japanese paediatric patients aged <12 years with severe haemophilia A without factor VIII (FVIII) inhibitors. METHODS:Emicizumab was administered subcutaneously, with four loading doses of 3 mg/kg every week followed by maintenance doses of 3 mg/kg every 2 weeks (Q2W) or 6 mg/kg every 4 weeks (Q4W) in 6 and 7 patients, respectively. RESULTS:All patients completed at least 24 weeks of treatment. Baseline ages ranged from 4 months to 10 years, and all patients had been treated with FVIII prophylaxis prior to enrolment except a 4-month-old patient untreated with FVIII previously. In the respective Q2W and Q4W cohorts, 2/6 and 5/7 patients experienced no treated bleeding events, and annualized bleeding rates for treated bleeding events were 1.3 (95% confidence interval [CI], 0.6-2.9) and 0.7 (95% CI, 0.2-2.6). All caregivers preferred emicizumab to the patient's previous treatment. Only one related adverse event (injection site reaction) was observed. There were no thromboembolic events or thrombotic microangiopathy. Individual trough plasma concentrations of emicizumab were within the variability observed in preceding adult/adolescent studies. All patients tested negative for anti-emicizumab antibodies. CONCLUSIONS:Emicizumab administered Q2W or Q4W was efficacious and safe in paediatric patients with severe haemophilia A without inhibitors. This study was registered at http://www.clinicaltrials.jp (JapicCTI-173710).

SUBMITTER: Shima M

PROVIDER: S-EPMC6900083 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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A multicentre, open-label study of emicizumab given every 2 or 4 weeks in children with severe haemophilia A without inhibitors.

Shima Midori M Nogami Keiji K Nagami Sayaka S Yoshida Seitaro S Yoneyama Koichiro K Ishiguro Akira A Suzuki Takashi T Taki Masashi M

Haemophilia : the official journal of the World Federation of Hemophilia 20190912 6

<h4>Introduction</h4>Emicizumab is a recombinant humanized bispecific monoclonal antibody mimicking the cofactor function of activated factor VIII.<h4>Aim</h4>In this multicentre, open-label study (HOHOEMI), we evaluated the efficacy, safety and pharmacokinetics of emicizumab in Japanese paediatric patients aged <12 years with severe haemophilia A without factor VIII (FVIII) inhibitors.<h4>Methods</h4>Emicizumab was administered subcutaneously, with four loading doses of 3 mg/kg every week follo ...[more]

PMID: 31515851

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Project description:IntroductionEmicizumab prophylaxis substantially reduces bleeding episodes in patients with haemophilia A (HA). The haemostatic efficacy of emicizumab in patients with HA is estimated as approximately 15% based on mimic activity of factor (F) VIII. Although it has been proven effective in preventing bleeding, its haemostatic effect during breakthrough bleeding or surgery is considered insufficient. Therefore, haemostatic management of emicizumab-treated patients with HA without inhibitors frequently requires FVIII replacement therapy. In haemostatic management of emicizumab-treated patients with HA, conventional FVIII dosage calculations are used in clinical practice without considering the coagulant effects of emicizumab.Methods and analysisIn the CAGUYAMA study, 100 patients with HA without inhibitors will be enrolled for a maximum duration of 1 year, and samples of 30 events following the concomitant use of FVIII concentrates (30±5 U/kg) with emicizumab will be collected. An 'event' is defined as obtaining blood samples at preadministration and postadministration of FVIII concentrates during a breakthrough bleeding or a surgical procedure. Global coagulation assays will be used to measure the coagulation potential of the obtained samples. Clot waveform analysis (CWA) is used to identify the primary end-point, that is, the degree of improvement in the maximum coagulation rate at preadministration and post-administration of fixed-dose FVIII concentrations. The parameter obtained from CWA, which is triggered by an optimally diluted mixture of prothrombin time reagent and activated partial thromboplastin time reagent, is reported to be an excellent marker for assessing the degree of improvement of the coagulation potential in emicizumab-treated plasmas.Ethics and disseminationThe CAGUYAMA study was approved by the Japan-Certified Review Board of Nara Medical University (Approval ID; nara0031). The study results will be communicated through publication in international scientific journals and presentations at (inter)national conferences.Trial registration numberjRCTs051210137.

Project description:Background: Influenza causes substantial morbidity and mortality despite available treatments. Anecdotal reports suggest that plasma with high antibody titres to influenza might be of benefit in the treatment of severe influenza.Methods: In this randomised, open-label, multicentre, phase 2 trial, 29 academic medical centres in the USA assessed the safety and efficacy of anti-influenza plasma with haemagglutination inhibition antibody titres of 1:80 or more to the infecting strain. Hospitalised children and adults (including pregnant women) with severe influenza A or B (defined as the presence of hypoxia or tachypnoea) were randomly assigned to receive either two units (or paediatric equivalent) of anti-influenza plasma plus standard care, versus standard care alone, and were followed up for 28 days. The primary endpoint was time to normalisation of patients' respiratory status (respiratory rate of ?20 breaths per min for adults or age-defined thresholds of 20-38 breaths per min for children) and a room air oxygen saturation of 93% or more. This study is registered with ClinicalTrials.gov, number NCT01052480.Findings: Between Jan 13, 2011, and March 2, 2015, 113 participants were screened for eligibility and 98 were randomly assigned from 20 out of 29 participating sites. Of the participants with confirmed influenza (by PCR), 28 (67%) of 42 in the plasma plus standard care group normalised their respiratory status by day 28 compared with 24 (53%) of 45 participants on standard care alone (p=0·069). The hazard ratio (HR) comparing plasma plus standard care with standard care alone was 1·71 (95% CI 0·96-3·06). Six participants died, one (2%) from the plasma plus standard care group and five (10%) from the standard care group (HR 0·19 [95% CI 0·02-1·65], p=0·093). Participants in the plasma plus standard care group had non-significant reductions in days in hospital (median 6 days [IQR 4-16] vs 11 days [5-25], p=0·13) and days on mechanical ventilation (median 0 days [IQR 0-6] vs 3 days [0-14], p=0·14). Fewer plasma plus standard care participants had serious adverse events compared with standard care alone recipients (nine [20%] of 46 vs 20 [38%] of 52, p=0·041), the most frequent of which were acute respiratory distress syndrome (one [2%] vs two [4%] patients) and stroke (one [2%] vs two [4%] patients).Interpretation: Although there was no significant effect of plasma treatment on the primary endpoint, the treatment seemed safe and well tolerated. A phase 3 randomised trial is now underway to further assess this intervention.Funding: National Institute of Allergy and Infectious Diseases, US National Institutes of Health.

Project description:IntroductionFor persons with haemophilia A with factor (F) VIII inhibitors (PwHAwI), immune tolerance induction (ITI) therapy is indicated for inhibitor eradication; however, since PwHAwI on ITI were excluded from the emicizumab clinical development programme, there are limited safety data for emicizumab treatment under/immediately after ITI in PwHAwI. Accordingly, there is a need to collect safety and efficacy data on this concomitant treatment strategy. The AKATSUKI study aims to evaluate the safety of emicizumab under/immediately after ITI in PwHAwI; here we report details of the study protocol.Methods and analysisAKATSUKI is an open-label, non-randomised, interventional, multicentre study. Twenty participants with congenital HA with FVIII inhibitors will be enrolled from 17 sites across Japan. Emicizumab will be administered subcutaneously, with an initial loading dose of 3 mg/kg once per week (QW) for the first 4 weeks, followed by a maintenance dose of 1.5 mg/kg QW, 3 mg/kg once every 2 weeks or 6 mg/kg once every 4 weeks. For ITI therapy, 50 IU/kg FVIII will be administered three times per week. For extended half-life FVIII, a dosing frequency of twice per week will be permitted. The primary endpoint is a comprehensive safety evaluation of adverse events (mainly thromboembolic events) and abnormal laboratory values over time. Secondary endpoints are the number of bleeds requiring coagulation factor treatment, the number of participants achieving a partially successful ITI response, FVIII inhibitor titres under/immediately after ITI, quality of life and time to achieve a negative FVIII inhibitor result (<0.6 BU/mL) and partial success in PwHAwI starting ITI after study enrolment.ConclusionsAKATSUKI will evaluate the safety of emicizumab administered under/immediately after ITI, providing reference data to inform treatment strategies in PwHAwI.Ethics and disseminationThe results of this study will be published in a peer-reviewed international journal and presented at national and/or international medical scientific conferences; the major findings of this study will be published on the jRCT registry website (https://jrct.niph.go.jp).Trial registration numberjRCTs041200037.

Dataset Information

A multicentre, open-label study of emicizumab given every 2 or 4 weeks in children with severe haemophilia A without inhibitors.

Publications

A multicentre, open-label study of emicizumab given every 2 or 4 weeks in children with severe haemophilia A without inhibitors.

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