A phase IV, multicentre, open-label study of emicizumab prophylaxis in people with haemophilia A with or without FVIII inhibitors undergoing minor surgical procedures.
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SUBMITTER: Escobar M
PROVIDER: S-EPMC9544354 | biostudies-literature | 2022 Jul
REPOSITORIES: biostudies-literature
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A phase IV, multicentre, open-label study of emicizumab prophylaxis in people with haemophilia A with or without FVIII inhibitors undergoing minor surgical procedures.
Escobar Miguel M Dunn Amy A Quon Doris D Trzaskoma Ben B Lee Lucy L Ko Richard H RH Carpenter Shannon L SL
Haemophilia : the official journal of the World Federation of Hemophilia 20220505 4
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Project description:IntroductionPersons with haemophilia A (PwHA) commonly experience regular bleeding into joints, which may result in joint damage and complications such as degenerative arthritis. Emicizumab has previously demonstrated efficacy in reducing the occurrence of joint bleeds and target joints, along with having a favourable safety profile; however, data on the long-term effects on joint health are lacking. The AOZORA study will evaluate the long-term safety and joint health of paediatric PwHA without factor (F)VIII inhibitors taking emicizumab; here, we report the details of the study protocol and baseline data.Methods and analysisAOZORA is a multicentre, open-label, phase IV clinical study in Japan that aims to enrol approximately 30 PwHA aged <12 years without FVIII inhibitors. The primary endpoints include a long-term safety evaluation of adverse events, laboratory test abnormalities and FVIII inhibitor development; and a long-term joint health assessment using MRI and the Hemophilia Joint Health Score. Exploratory endpoints include characterising participants' physical activities and the number of activity-related bleeds requiring coagulation factor treatment. Currently, 30 participants have been enrolled, including 20 emicizumab-naïve participants and 10 who transferred from HOHOEMI, a previous study in paediatric PwHA.Ethics and disseminationThe AOZORA study was approved by the Institutional Review Boards of Nara Medical University and the St Marianna University Group. The study will be conducted in compliance with the Declaration of Helsinki, the standards stipulated in paragraph 3 of Article 14 and Article 80-2 of the Pharmaceuticals, Medical Devices and Other Therapeutic Products Act, the Ministerial Ordinance on Good Clinical Practice and the Ministerial Ordinance on Good Post-marketing Study Practice. Data will be published in peer-reviewed journals and presented at Global congresses.Trial registration numberJapicCTI-194701.
| S-EPMC9196178 | biostudies-literature
Project description:IntroductionEmicizumab is a recombinant humanized bispecific monoclonal antibody mimicking the cofactor function of activated factor VIII.AimIn 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.MethodsEmicizumab 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.ResultsAll 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.ConclusionsEmicizumab 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).
| S-EPMC6900083 | biostudies-literature
Project description:IntroductionEmicizumab effectively prevents bleeding in people with haemophilia A (PwHA), but is a burden for national healthcare budgets and consequently may limit access. According to the drug label, dosing of emicizumab is based on body weight with fixed intervals of 7, 14 or 28 days, which leads to mean plasma concentrations of 55 µg/mL (SD 15 µg/mL). However, a moderate variability of concentrations and a minimal effective concentration of 30 µg/mL have been suggested in studies. Therefore, a dose of emicizumab that targets a trough concentration of 30 µg/mL is hypothesised to be equally effective as conventional dosing in the prevention of bleeding.Methods and analysisWe designed a phase IV, multicentre, open-label, crossover study to evaluate non-inferiority of bleed control of ≥6 months on conventional dosing in comparison to ≥6 months on dose intervention. This dose intervention consists of reducing the dose of emicizumab to target a trough concentrations of 30 µg/mL using individual pharmacokinetic (PK) parameters. Ninety-five PwHA aged >1 years who received conventional dosing of emicizumab for ≥12 months with good bleeding control during the last 6 months will be recruited from all Dutch haemophilia treatment centres. The study is powered to detect a clinically relevant decrease (risk difference) of 15% in the proportion of patients without treated bleeds during follow-up. Secondary endpoints are spontaneous joint or muscle bleeds, and annualised treated bleeding rates (using negative binomial regression). Cost-effectivity between conventional dosing and individualised PK-guided dosing of emicizumab will be compared.Ethics and disseminationThe DosEmi study was approved by the Medical Ethics Review Committee NedMec of the University Medical Center of Utrecht, The Netherlands. Study results will be communicated through publications in international scientific journals and presentations at (inter)national conferences.Trial registration numberEUCTR2021-004039-10-NL at https://trialsearch.who.int.Protocol versionV.4.1 on 28 October 2022 (DosEmi protocol_V4.1; NL81112.041.22).
| S-EPMC10410934 | biostudies-literature
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.
| S-EPMC10335457 | biostudies-literature
Project description:IntroductionSurgery is frequently required in persons with haemophilia A (PwHA). Emicizumab, a bispecific, humanized monoclonal antibody, bridges activated factor (F) IX and FX. Management of patients undergoing surgery while receiving emicizumab is of clinical interest due to paucity of data.AimReview real-world experience of PwHA with/without FVIII inhibitors who required surgery while receiving emicizumab prophylaxis.MethodsData regarding peri-operative management, including type of surgery, haemostatic agent use and bleeding complications, were collected for PwHA receiving emicizumab undergoing surgery between 25/10/18 and 31/12/19 at the Indiana Hemophilia and Thrombosis Center. Analyses were exploratory and descriptive.ResultsTwenty minor and five major surgeries were performed in 17 and five patients, respectively. Overall, 9/20 minor surgeries were planned to occur with emicizumab as the sole haemostatic agent; of these, four required additional coagulation factor (2 due to haematomas following port removals, 1 due to oozing at port removal site, 1 due to bleeding following squamous cell carcinoma removal). Three of the 11 minor surgeries with planned additional coagulation factor resulted in non-major bleeds; all were safely managed with additional coagulation factor. All five major surgeries were planned with additional haemostatic agents; there was 1 bleed in a patient undergoing elbow synovectomy with nerve transposition, likely triggered by physical/occupational therapy. There were no major bleeds, thrombotic events or deaths.ConclusionsAdditional haemostatic agent use is safe in PwHA undergoing surgery while receiving emicizumab. Additional data are needed to determine the optimal dosing/length of treatment of additional haemostatic agents to lower bleeding risk.
| S-EPMC7898816 | biostudies-literature
Project description:IntroductionSurgery in people with haemophilia and factor VIII inhibitors is typically managed with perioperative administration of haemostatic agents to prevent or control the occurrence of bleeding events. Practical experience of surgery in patients with inhibitors who are receiving treatment with emicizumab is growing; however, the novelty of the situation means that standardised guidelines are lacking with regard to the concomitant administration of haemostatic agents, including dose and laboratory monitoring.AimTo review approaches to haemostatic management during major and minor invasive procedures in patients with haemophilia A and inhibitors, and to provide recommendations for controlling bleeding events.MethodsA search was conducted, limited to the past 4 years (January 2016-April 2020), pertaining to published evidence of surgery for patients receiving emicizumab. Publications identified from the search were manually reviewed to determine studies and case reports relevant for inclusion.ResultsIdentified literature and practical experience of the authors were used to build a consensus of practical recommendations for the concomitant administration of haemostatic agents during the perioperative period for elective surgery in patients with inhibitors who are receiving emicizumab.ConclusionsThe current evidence base indicates that surgery can be successfully performed in patients with inhibitors who are receiving emicizumab and that bypassing agents can be used concomitantly. Data from prospective studies are required to further support recommendations for haemostatic management of surgery in patients receiving emicizumab.
| S-EPMC8359827 | biostudies-literature
Project description:IntroductionEmicizumab is a subcutaneously (SC) administered prophylactic agent for persons with haemophilia A (PwHA). As part of its clinical development, a new instrument was required to measure treatment satisfaction.AimDescribe development of the Satisfaction Questionnaire with Intravenous or Subcutaneous Hemophilia Injection (SQ-ISHI) and its subsequent testing with HAVEN 3 study participants to measure patient satisfaction with emicizumab.MethodsTo develop the SQ-ISHI, we conducted four rounds of in-person interviews at five qualitative research facilities. Participants aged ≥12 years with moderate or severe haemophilia A, receiving intravenous factor VIII (FVIII) prophylaxis, provided feedback to optimize content understanding, ease of completion and item relevance. The final SQ-ISHI was completed by HAVEN 3 participants who previously received FVIII prophylaxis; baseline scores were compared with those at Week 21 or 25 of emicizumab prophylaxis.ResultsSixty-three HAVEN 3 participants were eligible to complete the questionnaire and rate their satisfaction on a scale of 0 ('not at all satisfied') to 10 ('extremely satisfied'). Mean 'overall satisfaction' with previous FVIII prophylaxis at baseline was 6.9 (95% confidence interval [CI]: 6.2 to 7.7) increasing to 8.8 (95% CI: 8.4 to 9.3) at follow-up (Week 21/25 of treatment with emicizumab). The greatest improvement was observed in satisfaction with treatment half-life (mean score at baseline: 5.8 [95% CI: 4.9 to 6.6] vs 8.6 [95% CI: 8.0 to 9.2] at follow-up).ConclusionThese results demonstrate that emicizumab prophylaxis leads to greater treatment satisfaction compared with FVIII prophylaxis, reflecting in part the low treatment burden of emicizumab associated with its infrequent, SC administration.
| S-EPMC8048849 | biostudies-literature
Project description:IntroductionSubcutaneous emicizumab prophylaxis substantially reduces bleeding episodes in patients with haemophilia A (PwHA) and factor VIII inhibitor. However, thrombotic events occurred in some PwHA with inhibitor who had received high cumulative doses of activated prothrombin complex concentrates at their breakthrough bleeds, when they were also given prophylactic emicizumab. After that, although the recommended guidance was proposed for bypassing agents (BPAs) therapy under emicizumab prophylaxis for haemostatic management, detailed investigation(s) is(are) required to elucidate the safe and appropriate dose of BPAs to use concomitantly with emicizumab prophylaxis.Methods and analysisIn the UNEBI Study, 60 PwHA with inhibitor will be enrolled for a maximum duration of 3 years, and samples of 20 events following concomitant use of BPAs with emicizumab will be collected. An 'event' is defined as obtaining blood samples before and after administration of BPA when a breakthrough bleed or a surgical procedure occurs. The coagulation potential in the obtained samples will be measured by global coagulation assays. The primary endpoint is the degree of improvement in the maximum coagulation rate by clot waveform analysis (CWA) before and after administration of fixed-dose BPAs. This parameter obtained from CWA, which is triggered with an optimally diluted mixture of prothrombin time/activated partial thromboplastin time-reagents, is reported to be an excellent marker for assessing the degree of improvement in coagulation potential in emicizumab-treated plasma.Ethics and disseminationThe UNEBI Study was approved by the Japan Certified Review Board of Nara Medical University. The results of the study will be communicated through publication in international scientific journals and presentations at (inter)national conferences.Trial registration numberjRCTs051190119.
| S-EPMC8860020 | biostudies-literature
Project description:Prophylaxis with emicizumab, a subcutaneously administered bispecific humanized monoclonal antibody, promotes effective hemostasis in persons with hemophilia A (PwHAs). The primary efficacy, safety, and pharmacokinetics of emicizumab were reported previously, but long-term data were limited. Here, data from 401 pediatric and adult PwHAs with/without factor VIII (FVIII) inhibitors who were enrolled in the phase 3 HAVEN 1, HAVEN 2, HAVEN 3, and HAVEN 4 studies (NCT02622321, NCT02795767, NCT02847637, NCT03020160) have been pooled to establish a long-term efficacy, safety, and pharmacokinetics profile. Across a median efficacy period of 120.4 weeks (interquartile range, 89.0-164.4) (data cutoff 15 May 2020), the model-based treated annualized bleed rate (ABR) was 1.4 (95% confidence interval [CI], 1.1-1.7). ABRs declined and then stabilized at <1 in an analysis of 24-week treatment intervals; at weeks 121 to 144 (n = 170), the mean treated ABR was 0.7 (95% CI, 0-5.0). During weeks 121 to 144, 82.4% of participants had 0 treated bleeds, 97.6% had ≤3 treated bleeds, and 94.1% reported no treated target joint bleeds. Bleeding into target joints decreased substantially. Emicizumab was well tolerated, and no participant discontinued because of adverse events beyond the 5 previously described. This data cutoff includes the previously reported 3 thrombotic microangiopathies (one in the PwHA with fatal rectal hemorrhage) and 2 thromboembolic events, all associated with activated prothrombin complex concentrate use, as well as a myocardial infarction and a venous device occlusion. With 970.3 patient-years of exposure, emicizumab prophylaxis maintained low bleed rates in PwHAs of all ages with/without FVIII inhibitors and remains well tolerated, with no new safety concerns identified.
| S-EPMC8065240 | biostudies-literature
Project description:BackgroundThe recombinant factor VIII (rFVIII)-IgG1 Fc fusion protein (rFVIII-Fc) was the first available extended half-life rFVIII, shown to prolong dosing intervals of individualised prophylaxis in patients with severe haemophilia A, maintaining low bleeding rates and unchanged or lower FVIII dose versus standard half-life (SHL) rFVIII. Few data are available about real-world experience with rFVIII-Fc, including criteria for patient switching from SHL products, follow up and prophylaxis optimisation.Materials and methodsA single-centre retrospective study was designed to review patients switched to rFVIII-Fc, based on individual needs, after pharmacokinetic (PK) assessment, according to routine clinical practice. In patients with adequate post-switch follow up, data about rFVIII-Fc prophylaxis were compared with those from the last 18-months SHL rFVIII prophylaxis.ResultsOf 25 candidates, 18 patients (15 severe, 3 moderate; aged 9-62 years; 3 with inhibitor history) started rFVIII-Fc regimens, with comparable FVIII weekly dose and reduced infusion frequency (mean -30%) in all 17 patients previously on SHL rFVIII prophylaxis thrice weekly or every other day. Over a mean 18-month follow up in 13 patients, compared with SHL products, further reduced infusion frequency (mean -40%; p<0.001; interval ≥4 days in 9 patients), improved treatment satisfaction (Hemo-sat questionnaires), significantly lower FVIII weekly dose and annual consumption (mean -12%; p=0.019), comparable bleeding rates and FVIII trough levels, and improved management of breakthrough bleeding were observed. von Willebrand Factor Antigen (VWF:Ag) correlated to PK variables and both had relationships with rFVIII-Fc weekly dose, increasing statistical significance over the follow-up period. No inhibitors or drug-related adverse events were recorded.DiscussionIn this real-world series of patients, a switch to rFVIII-Fc, based on careful assessment of clinical needs, PK testing and treatment monitoring, was able to optimise individual convenience, efficacy and costs of prophylaxis.
| S-EPMC7592167 | biostudies-literature