Publications by authors named "Azusa Nagao"

11 Publications

  • Page 1 of 1

Long-term safety and efficacy of emicizumab for up to 5.8 years and patients' perceptions of symptoms and daily life: A phase 1/2 study in patients with severe haemophilia A.

Haemophilia 2021 Jan 24;27(1):81-89. Epub 2020 Nov 24.

Department of Pediatrics, Nara Medical University, Kashihara, Japan.

Introduction: Safety and efficacy results of the phase 1 study and phase 1/2 extension study of the bispecific antibody emicizumab in patients with severe haemophilia A with or without factor VIII inhibitors for up to 2.8 years were reported previously.

Aim: To evaluate further longer-term data including patients' perceptions at study completion.

Methods: Emicizumab was administered subcutaneously once weekly at maintenance doses of 0.3, 1 or 3 mg/kg with potential up-titration. All patients were later switched to the approved maintenance dose of 1.5 mg/kg.

Results: Eighteen patients received emicizumab for up to 5.8 years. Most adverse events were mild and unrelated to emicizumab. Annualized bleeding rates (ABRs) for bleeds treated with coagulation factors decreased from pre-emicizumab rates or remained zero in all patients. The median ABRs were low at 1.25, 0.83 and 0.22 during the 0.3, 1 and 3 mg/kg dosing periods, respectively. Of 8 patients who decreased their doses from 3 to 1.5 mg/kg, ABRs decreased in 4, remained at zero in 2, and increased in 2. Total time spent with symptoms associated with treated bleeds decreased in all patients except 2. All patients answered 'improved' for bleeding severity and time until bleeding stops, except 1 answering 'slightly improved'. Most patients answered 'improved' or 'slightly improved'' for daily life and feelings; in particular, all patients except 1 answered 'improved' or 'slightly improved' for anxiety.

Conclusions: Long-term emicizumab prophylaxis for up to 5.8 years was safe and efficacious, and may improve patients' daily lives and feelings, regardless of inhibitor status.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/hae.14205DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7894561PMC
January 2021

Efficacy and safety of rIX-FP in surgery: An update from a phase 3b extension study.

Thromb Res 2020 09 28;193:139-141. Epub 2020 May 28.

Hôpital Louis Pradel, University Claude Bernard Lyon 1, Lyon, France. Electronic address:

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.thromres.2020.05.046DOI Listing
September 2020

Long-term safety and efficacy of rIX-FP prophylaxis with extended dosing intervals up to 21 days in adults/adolescents with hemophilia B.

J Thromb Haemost 2020 05 30;18(5):1065-1074. Epub 2020 Mar 30.

Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy.

Background: An international, multicenter extension study evaluated recombinant fusion protein linking recombinant coagulation factor IX (FIX) with recombinant human albumin (rIX-FP) in hemophilia B (FIX ≤ 2%) patients previously enrolled in a phase III study or who initiated rIX-FP prophylaxis following surgery.

Objectives: To investigate the long-term safety and efficacy of rIX-FP prophylaxis in adult previously treated patients (PTPs) with hemophilia B.

Methods: Male PTPs were treated with a 7- (35-50 IU/kg), 10- or 14-day regimen (50-75 IU/kg). Patients ≥18 years who were well-controlled on a 14-day regimen for ≥6 months could switch to a 21-day regimen (100 IU/kg).

Results: A total of 59 patients (aged 13-63 years) participated in the study. Following a single dose of 100 IU/kg rIX-FP, in patients eligible for the 21-day regimen, the mean terminal half-life was 143.2 hours. Mean steady-state FIX trough activity levels ranged from 22% with the 7-day regimen to 7.6% with the 21-day regimen. Median (Q1, Q3) annualized spontaneous bleeding rates were 0.00 (0.00, 1.67), 0.28 (0.00, 1.10), 0.37 (0.00, 1.68), and 0.00 (0.00, 0.45) for the 7-, 10-, 14-, and 21-day regimens, respectively. Comparable efficacy was demonstrated for both the 14- and 21-day regimens compared to the 7-day regimen. Overall, 96.5% of bleeding episodes were treated successfully with 1 to 2 rIX-FP infusions. No patients developed an inhibitor and treatment was well tolerated.

Conclusions: rIX-FP extended interval prophylaxis provides dosing flexibility and, in selected patients, a 21-day regimen may provide an alternative option to minimize treatment burden and individualize treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/jth.14778DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7318213PMC
May 2020

Development and Validation of a Population-Pharmacokinetic Model for Rurioctacog Alfa Pegol (Adynovate): A Report on Behalf of the WAPPS-Hemo Investigators Ad Hoc Subgroup.

Clin Pharmacokinet 2020 02;59(2):245-256

Department of Health Research Methods, Evidence, and Impact, McMaster University, 1280 Main Street West, Hamilton, ON, L8S 4K1, Canada.

Background And Objective: Rurioctacog alfa pegol (Adynovate) is a modified recombinant factor VIII concentrate used for treating hemophilia A. Aiming to improve treatment tailoring on the Web-Accessible Population Pharmacokinetic Service-Hemophilia (WAPPS-Hemo) platform for patients of all ages treated with Adynovate, we have developed and evaluated a population pharmacokinetic (PopPK) model. On the platform, PopPK models are used as priors for Bayesian forecasting that derive individual PK of hemophilia patients and are subsequently used for personalized dose regimen design.

Methods: Factor activity measurements and demographic covariate data from patients infused with Adynovate were extracted from the WAPPS-Hemo database. Evaluations testing the appropriateness of Bayesian forecasting included 10-fold cross validation, a limited sampling analysis (LSA), and an external evaluation using additional independent data extracted from the WAPPS-Hemo database at a later date.

Results: The model was constructed using 650 plasma factor activity observations (555 one stage assay and 95 chromogenic assay - 4.6% below limit of quantification) measured in 154 patients from 36 hemophilia centres. A two-compartment model including between subject variability on clearance and central volume was selected as the base model. Covariates were fat free mass on clearance and central volume, age on clearance and assay type on activity. The final model was well-suited to predict PK parameters of new individuals (n = 26) from sparse observations.

Conclusions: The development of a PopPK model for Adynovate using real-world data increases the covariate space (e.g. age) beyond what is possible from clinical trial data. This model is available on the WAPPS-Hemo platform for tailoring treatment in hemophilia A patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s40262-019-00809-6DOI Listing
February 2020

Ischaemic events are rare, and the prevalence of hypertension is not high in Japanese adults with haemophilia: First multicentre study in Asia.

Haemophilia 2019 Jul 2;25(4):e223-e230. Epub 2019 May 2.

Department of Blood Coagulation, Ogikubo Hospital, Tokyo, Japan.

Introduction: With the increasing life expectancy of patients with haemophilia (PWH), the number of PWH with age-related comorbidities, such as ischaemic events, is increasing.

Aim: We conducted this multicentre observational study to identify the risk factors for major ischaemic events in PWH.

Methods: This study was the first multicentre observational study, conducted with the participation of five haemophilia treatment centres in Japan, conducted in ≥30-year-old adult PWH. The latest data recorded in the medical charts between 1 January and 31 December 2016 were reviewed. Healthcare data collected from the National Health and Nutrition Survey were used as the control data.

Results: Data of a total of 711 patients were collected. Only two PWH (0.3%) had a history of ischaemic events. Age-adjusted analysis indicated that the prevalence of hypertension defined as a blood pressure of 140/90 mm Hg or over was similar in the PWH to that in the males of the general population. However, when hypertension was defined more strictly (≥130/85 mm Hg), the prevalence was significantly lower in PWH than in the general male population. The hypertension in PWH was associated with the age, BMI, CKD, HIV infection and inhibitors. In particular, the odds ratio for the presence of inhibitors was high (odds ratio = 7.529).

Conclusion: Whether the present results can be attributed to Japanese ethnicity or to the presence of haemophilia per se remains uncertain. We propose to initiate a prospective study for further investigation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/hae.13749DOI Listing
July 2019

[Successful long-term management of ovarian bleeding and menorrhagia with prothrombin complex concentrate in a patient with congenital factor X deficiency].

Rinsho Ketsueki 2018;59(11):2428-2431

Department of Blood Coagulation, Ogikubo Hospital.

A female patient in her forties exhibited no evidence of abnormal bleeding at birth. At the age of 6 years, she experienced pain in bilateral thighs and knee joints without any occasion. Accordingly, the bleeding tendency was suspected, and the coagulation profile assessment revealed prolongation of the APTT (122 s). Further tests revealed a marked reduction in the factor X activity (FX:C) to 4.5%, and the patient was diagnosed with congenital factor X deficiency; at that time, the case was reported by Mori et al. (The Japanese Society of Hematology 43: 572-586, 1980). At the age of 19 years, she was transferred to our hospital, where both prolongation of the PT and APTT and reduction of FX:C to <1% were reconfirmed. During follow-up observation, the patient developed lower abdominal pain and severe anemia. Gynecological examination revealed ovarian bleeding with menorrhagia. Thus, she was prescribed low-dose pills for menorrhagia, which successfully arrested the progression of anemia for a long term. However, she underwent uterine myomectomy and developed anemia again because of menorrhagia. For controlling menorrhagia-caused severe anemia, we initiated the patient on FX replacement therapy with prothrombin complex concentrate, PPSB-HT "Nichiyaku," by self-infusion on day 1 of each monthly menstrual cycle. Since then, menorrhagia and severe anemia have remained under good control.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.11406/rinketsu.59.2428DOI Listing
May 2019

Clinical outcomes in hemophilia A patients undergoing tailoring of prophylaxis based on population-based pharmacokinetic dosing.

Thromb Res 2019 01 16;173:79-84. Epub 2018 Nov 16.

Department of Blood Coagulation, Ogikubo Hospital, Tokyo, Japan.

Introduction: Standard prophylaxis dosing based on bodyweight may result in over- or under-dosing due to interpatient variability. Adopting individual pharmacokinetic (PK) based tailoring may improve adherence to treatment guideline, and consequently clinical outcomes. Here we report clinical observations performed across the adoption of individual PK based tailoring in a single center in Japan.

Methods: An individual PK study on sparse samples was modeled on myPKFiT or WAPPS-Hemo, depending on concentrate, and used to optimize treatment regimens. Adherence to prophylaxis and bleeding rate were calculated from patient diaries. Radiological joint scores were used to assess arthropathy, and SPSS to perform all the analyses.

Results: Thirty-nine patients underwent PK profiling, and 20 required and accepted a modification of their treatment (8 increases in dose, 5 reductions in frequency, 5 switches to extended half-life (EHL)). Adherence to prophylaxis remained the same in those increasing the dose, whilst increased in all the other groups. Annualized bleeding rate (ABR) and annualized joint bleeding rate (AjBR) decreased in all the groups but reached statistical significance only in those switched to EHL and showed a larger reduction in those patients without baseline arthropathy. Longer time spent above a 1% or 5% threshold was associated with a decrease in the ABR/AjBR.

Conclusions: Our study results suggest that PopPK based tailoring supported changing treatment regimen in nearly half of the patients, and may have contributed to an improvement in the adherence and a reduction in the ABR/AjBR.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.thromres.2018.11.017DOI Listing
January 2019

Brief Report: The Impact of Ledipasvir/Sofosbuvir on HIV-Positive and HIV-Negative Japanese Hemophilia Patients With 1, 4, and Mixed-Genotype HCV.

J Acquir Immune Defic Syndr 2017 04;74(4):418-422

Department of Hematology, Ogikubo Hospital, Tokyo, Japan.

Introduction: Approximately 80% of patients with hemophilia who received nonheated coagulation factor concentrates in the early 1980s were infected with hepatitis C virus (HCV), and approximately 40% of them were infected with HIV.

Aim: We evaluated the efficacy and safety of administering ledipasvir (LDV)/sofosbuvir (SOF) to Japanese patients with hemophilia.

Methods: Forty-three patients with hemophilia with genotype 1 or 4 HCV were treated with LDV/SOF for 12 weeks. The efficacy, safety, and results of the laboratory tests were evaluated.

Results: Twenty patients were coinfected with HIV and HCV. The sustained virological response (SVR) at 12 weeks after therapy was 90% in HIV-positive patients and 100% in HIV-negative patients. The efficacy of LDV/SOF was not significantly different between HIV-positive and HIV-negative patients (P = 0.12). However, the rate of SVR at 12 weeks after therapy in the patients with cirrhosis was significantly lower than that in patients without cirrhosis (P = 0.005). Overall, 20 patients (46%) had adverse events, and while the severity of most was mild to moderate, 3 were serious, including 1 death in the HIV-positive group. All patients completed treatment with no alterations in the antiretroviral regimen. No significant abnormalities in the renal function were detected in patients taking an antiretroviral regimen of tenofovir disoproxil fumarate.

Conclusions: In this cohort study, LDV/SOF was effective and safe, but the SVR in patients with cirrhosis was lower than that in the noncirrhosis group. Thus, patients with hemophilia with genotype 1/4 HCV should be treated as early as possible before the onset of cirrhosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/QAI.0000000000001271DOI Listing
April 2017

Short-term efficacy of the IL6 receptor antibody tocilizumab in patients with HIV-associated multicentric Castleman disease: report of two cases.

J Hematol Oncol 2014 Jan 17;7:10. Epub 2014 Jan 17.

Ogikubo hospital, Imagawa3-1-24, Suginami-ku, Tokyo 167-0035, Japan.

Multicentric Castleman disease (MCD) is a lymphoproliferative disorder caused by human herpesvirus 8 (HHV8) infection HIV associated MCD (HIV-MCD) presents with various clinical symptoms. Many HIV-negative MCD patients are often treated with anti-human interleukin-6 (IL6) receptor monoclonal antibodies (tocilizumab), and successful results have been reported. IL-6 plays an important role in the development of both HIV-positive and HIV-negative MCD; however, the efficacy of tocilizumab in HIV-MCD patients is unknown. We herein report the clinical and biologic courses of two HIV-MCD patients treated with tocilizumab. In both cases, a significant and rapid clinical improvement was observed after the first infusion. However, the treatment efficacy was not maintained for a long period, and relapse occurred at 15 and 22 weeks, respectively. Both patients received rituximab and subsequently achieved complete clinical remission. Our report, in addition to data presented in the literature, suggests that tocilizumab could be an initial treatment option in patients with HIV-MCD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/1756-8722-7-10DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3896700PMC
January 2014