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

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).

Efficacy and safety of tocilizumab in patients with refractory Takayasu arteritis: results from a randomised, double-blind, placebo-controlled, phase 3 trial in Japan (the TAKT study).

OBJECTIVE: To investigate the efficacy and safety of the interleukin-6 receptor antibody tocilizumab in patients with Takayasu arteritis (TAK). METHODS: Patients with TAK who had relapsed within the previous 12 weeks were induced into remission with oral glucocorticoid therapy. In this double-blind, placebo-controlled trial, patients were randomly assigned 1:1 to receive weekly tocilizumab 162 mg or placebo subcutaneously, and oral glucocorticoids were tapered 10 %/week from week 4 to a minimum of 0.1 mg/kg/day until 19 patients relapsed. The primary endpoint was time to relapse of TAK, defined as ≥2 of the following: objective systemic symptoms, subjective systemic symptoms, elevated inflammation markers, vascular signs and symptoms or ischaemic symptoms. RESULTS: The intent-to-treat and safety populations included 18 tocilizumab-treated and 18 placebo-treated patients. The per-protocol set (PPS) included 16 tocilizumab-treated and 17 placebo-treated patients. HRs for time to relapse of TAK were 0.41 (95.41% CI 0.15 to 1.10; p=0.0596) in the intent-to-treat population (primary endpoint) based on relapse in eight tocilizumab-treated and 11 placebo-treated patients and 0.34 (95.41% CI 0.11 to 1.00; p=0.0345) in the PPS. The secondary endpoints, time to relapse assessed by Kerr's definition and clinical symptoms only, were consistent with the primary endpoint. Serious adverse events were reported in one tocilizumab-treated and two placebo-treated patients. There were no serious infections and no deaths. CONCLUSION: Although the primary endpoint was not met, the results suggest favour for tocilizumab over placebo for time to relapse of TAK without new safety concerns. Further investigation is warranted to confirm the efficacy of tocilizumab in patients with refractory TAK. TRIAL REGISTRATION NUMBER: JapicCTI-142616.

Effect of monthly intravenous ibandronate injections on vertebral or non-vertebral fracture risk in Japanese patients with high-risk osteoporosis in the MOVER study.

We examined the efficacy of intravenous (IV) ibandronate 1 mg/month in patient subgroups in the phase III MOVER study. Here we present results of analyses on the incidence of fractures in patients with prevalent vertebral fractures (1 or ≥2, and ≥3) at screening and femoral neck (FN) bone mineral density (BMD) T scores ≥-2.5 or <-2.5, and <-3.0 at baseline. The per-protocol set comprised 1134 patients (ibandronate 0.5 mg/month n = 376; ibandronate 1 mg/month n = 382; risedronate oral 2.5 mg/day n = 376). The incidence of vertebral fractures in patients with 1 or ≥2 prevalent vertebral fractures was 11.2 and 20.4 %, respectively, with ibandronate 1 mg/month, and 12.6 and 22.1 %, respectively, with risedronate. In patients with FN BMD T scores ≥-2.5 or <-2.5, the vertebral fracture incidence was 13.7 and 16.4 %, respectively, with ibandronate 1 mg/month, and 17.3 and 19.1 %, respectively, with risedronate. The incidence of non-vertebral fractures in patients with ≥2 prevalent vertebral fractures or FN BMD T score <-2.5 was 7.6 and 7.6 %, respectively, with ibandronate 1 mg/month, and 9.5 and 9.4 %, respectively, with risedronate. Fracture incidence was consistently lower, but not significant, with ibandronate 1 mg/month than with risedronate in patients with ≥2 prevalent vertebral fractures and FN BMD T score <-2.5. The efficacy of the fracture reduction of monthly IV ibandronate appears consistent and seemingly independent of the number of prevalent vertebral fractures or baseline BMD values.

Higher response with bone mineral density increase with monthly injectable ibandronate 1 mg compared with oral risedronate in the MOVER study.

We examined response to bone mineral density (BMD) gains in the MOVER study following treatment with intravenous (IV) ibandronate 1 mg/month, and investigated the characteristics of a non-responder group. At 1 year, responder rates for patients with BMD increases >0 % were similar with IV ibandronate 0.5 or 1 mg/month and oral risedronate 2.5 mg/day. However, after 3 years, responder rates with BMD increases ≥3 % were highest with ibandronate 1 mg at all bone sites (>80 % at the lumbar spine [L2-L4] and >50 % at all femur sites, which was significantly higher than with risedronate). Non-responders were defined by BMD increases ≤3 % at L2-L4 or ≤0 % at total hip, and ≤50 % reduction in creatinine-corrected urinary collagen type 1 cross-linked C-telopeptide (uCTX) from baseline to 1 year. There were a small number of non-responders in the ibandronate 1 mg group: 3.3 % (10/299) with ≤0 % total hip BMD increase and ≤50 % uCTX reduction from baseline. These non-responders had lower 25-hydroxyvitamin D (25[OH]D) levels than responders, but no differences in kidney function, L2-L4 BMD or bone turnover marker baseline values. Throughout the study, non-responders failed to show any increases in BMD. Our analysis demonstrates significantly higher responder rates with IV ibandronate 1 mg/month than with risedronate at 3 years. A small number of non-responders in the ibandronate group had lower 25(OH)D baseline levels than responders, suggesting that 25(OH)D levels could be a useful indicator of BMD response to therapy.

A double-blind randomized study assessing safety and efficacy following one-year adjunctive treatment with bitopertin, a glycine reuptake inhibitor, in Japanese patients with schizophrenia.

BACKGROUND: Bitopertin, a glycine reuptake inhibitor, was investigated as a novel treatment for schizophrenia. We report all the results of a double-blind randomized study assessing safety and efficacy following 52-week adjunctive treatment with bitopertin in Japanese patients with schizophrenia. METHODS: This study enrolled Japanese outpatients with schizophrenia who met criteria for either "negative symptoms", i.e., patients with persistent, predominant negative symptoms of schizophrenia even after long-term treatment with antipsychotics or "sub-optimally controlled symptoms", i.e., patients with insufficiently improved symptoms of schizophrenia even after long-term treatment with antipsychotics, respectively. One hundred sixty-one patients were randomly assigned to receive 52-week treatments with bitopertin doses of 5, 10, or 20 mg/day at ratio of 1:5:5, where existing antipsychotics were concomitantly administered. Efficacy endpoints included Positive and Negative Syndrome Scale (PANSS), Clinical Global Impression (CGI), and Personal and Social Performance (PSP). The purpose of the present study is primarily to evaluate the safety, and secondarily to investigate the clinical efficacy of bitopertin. RESULTS: One hundred fourteen patients (71 %) completed 52-week treatment with bitopertin. Most of the adverse events were mild or moderate in their severity. The patients in the 20-mg group experienced more adverse events than the patients in the other two groups. Common dose-dependent adverse events were somnolence and insomnia associated with worsening schizophrenia. The blood hemoglobin levels gradually decreased from baseline in a dose-dependent manner, but there were no patients with the decrease below 10 g/dL that would have led to their discontinuation. All the efficacy endpoints gradually improved in all the treatment groups for both of the two symptoms, while there were no clear differences among the three dose groups. CONCLUSIONS: Altogether, bitopertin was found to be generally safe and well-tolerated for the treatment of patients with schizophrenia. All three bitopertin treated groups showed improvements in all the efficacy endpoints for both of the two symptoms, i.e., "negative symptoms" and "sub-optimally controlled symptoms", throughout the duration of the study. TRIAL REGISTRATION: Japan Pharmaceutical Information Center, number JapicCTI-111627 (registered on September 20, 2011).

Increased bone mineral density with monthly intravenous ibandronate contributes to fracture risk reduction in patients with primary osteoporosis: three-year analysis of the MOVER study.

The relationship between gains in bone mineral density (BMD) in the hip and the incidence of vertebral fractures in the MOVER study was examined. Japanese patients from the ibandronate and risedronate treatment groups whose hip BMD had increased during the 3-year treatment period were classified into those with or without vertebral fractures. In both the ibandronate group and the risedronate group, hip BMD gains in the patients who had developed no vertebral fractures during the treatment period were greater than in the patients who developed vertebral fractures. We categorized the gains in hip BMD at 6 months into 3 groups (≤0, >0 to ≤3, and >3%), and used logistic regression analysis to estimate odds ratios and the probabilities of incidence of vertebral fractures at 12, 24, and 36 months. The current study demonstrated that greater gains in hip BMD during the first 6 months of treatment were associated with a reduction in the risk of subsequent vertebral fractures during the duration of treatment, and suggested that measurement of hip BMD gain at that time could lead to a prediction of the risk of the future vertebral fracture incidence.

AOZORA: long-term safety and joint health in paediatric persons with haemophilia A without factor VIII inhibitors receiving emicizumab - protocol for a multicentre, open-label, phase IV clinical study.

INTRODUCTION: Persons 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 ANALYSIS: AOZORA 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 DISSEMINATION: The 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 NUMBER: JapicCTI-194701.

Challenges on Multiple Endpoints in Clinical Trials: An Industry Survey in Japan.

BACKGROUND: Two issues on clinical trials with multiple endpoints were surveyed: (1) the terminology of multiple endpoints, relationship between rare events and endpoints, and differences in multiplicity adjustment between regions; and (2) the current practice on multiplicity adjustment and sample size calculation. This article provides a summary of the results of a survey on the first issue. METHODS: The survey was conducted among 63 members of the Japan Pharmaceutical Manufacturers Association from October to November 2017. RESULTS: Thirty-five companies based in Japan and 12 companies based in other countries, 47 companies in total, responded to the survey. The terms co-primary endpoints, secondary endpoint, and composite endpoint were used in a variety of ways. An endpoint for a clinically most important event that is expected to occur rarely differed between regions. Although the Pharmaceuticals and Medical Devices Agency did not demand multiplicity adjustment, it was considered in clinical trials with multiple endpoints for approval in Japan. CONCLUSIONS: The use of terminology differed from the definition in the Food and Drug Administration guidance and the European Medicines Agency guideline. There remain challenges on a clinically most important event that is expected to occur rarely and multiplicity adjustment in clinical trials with multiple endpoints.

Multiplicity Adjustment and Sample Size Calculation in Clinical Trials with Multiple Endpoints: An Industry Survey of Current Practices in Japan.

BACKGROUND: Two issues in clinical trials with multiple endpoints were surveyed: (1) the terminology of multiple endpoints, the relationship between rare events and endpoints, and the differences in multiplicity adjustment between regions, and (2) the current practice on multiplicity adjustment and sample size calculation. This article summarizes the results of the survey on the second issue. METHODS: Eligible trials for this survey fulfilled the following conditions: (1) confirmatory phase 3 trial; (2) use of multiple primary endpoints, co-primary endpoints, key secondary endpoint(s) or composite endpoint(s); (3) inclusion of Japanese participants; and (4) protocols created in 2010 or later. The survey was conducted at member companies of the Japan Pharmaceutical Manufacturers Association from October 2017 to November 2017. RESULTS: Useable responses were obtained from 78 trials in 13 companies based in Japan and 9 companies based in other countries. The Bonferroni procedure was mostly used in clinical trials with multiple primary endpoints, while multiple testing procedures that consider a hierarchy of endpoints or a structure of hypotheses were used in clinical trials with key secondary endpoint(s). In sample size calculation, we can consider the probability of study success, such as the probability of statistical significance in at least one comparison of primary endpoints; however, other probabilities were also considered. This survey reveals that multiplicity adjustment and the correlation of endpoints were not always considered in sample size calculation. CONCLUSIONS: In clinical trials with multiple endpoints, clinical importance was considered when determining multiple testing procedures. Challenges remain with the definition of power, the consideration of multiple testing procedures and the correlation between endpoints in sample size calculation.

Stroke risk and antihypertensive drug treatment in the general population: the Japan arteriosclerosis longitudinal study.

OBJECTIVE: To evaluate the association between stroke risk and blood pressure (BP) levels with regard to the usage of antihypertensive medications. METHODS: From the Japan arteriosclerosis longitudinal study, 11,371 participants from the four population-based cohort studies (aged 40-89) were followed up for a mean of 9.5 years. A Poisson regression model, adjusting for possible confounding factors, was used to investigate the risk of first stroke among six BP-based categories (BP defined according to recent guidelines), in relation to the use of antihypertensive medications. RESULTS: There were 324 incident cases of first stroke. Among untreated groups, the relative hazard increased linearly with the elevation of BP grade (trend P = 0.0001). The untreated group with normal BP had a significantly higher stroke risk [relative hazard 2.09, 95% confidence interval 1.09-4.01] than the untreated group with optimal BP. There was no stepwise increase in stroke risk observed among treated groups (trend P = 0.1). The stroke risk among treated groups, even among those with optimal BP (relative hazard 4.10, 95% confidence interval 1.17-14.4), was significantly higher than that in the untreated groups with the same BP level. CONCLUSION: Treated individuals with optimal BP had a higher stroke risk than untreated ones with optimal BP. Healthcare providers need to be vigilant for residual cardiovascular risks in treated hypertensive patients.

Challenges on Multiple Endpoints in Clinical Trials: An Industry Survey in Japan.

BACKGROUND: Two issues on clinical trials with multiple endpoints were surveyed: (1) the terminology of multiple endpoints, relationship between rare events and endpoints, and differences in multiplicity adjustment between regions; and (2) the current practice on multiplicity adjustment and sample size calculation. This article provides a summary of the results of a survey on the first issue. METHODS: The survey was conducted among 63 members of the Japan Pharmaceutical Manufacturers Association from October to November 2017. RESULTS: Thirty-five companies based in Japan and 12 companies based in other countries, 47 companies in total, responded to the survey. The terms co-primary endpoints, secondary endpoint, and composite endpoint were used in a variety of ways. An endpoint for a clinically most important event that is expected to occur rarely differed between regions. Although the Pharmaceuticals and Medical Devices Agency did not demand multiplicity adjustment, it was considered in clinical trials with multiple endpoints for approval in Japan. CONCLUSIONS: The use of terminology differed from the definition in the Food and Drug Administration guidance and the European Medicines Agency guideline. There remain challenges on a clinically most important event that is expected to occur rarely and multiplicity adjustment in clinical trials with multiple endpoints.

Current Practice on Multiplicity Adjustment and Sample Size Calculation in Multi-arm Clinical Trials: An Industry Survey in Japan.

BACKGROUND: This study provides the results of a survey on the current practice of multiplicity adjustment and sample size calculation in multi-arm clinical trials. METHODS: The survey was aimed at members of the Japan Pharmaceutical Manufacturers Association (JPMA) and was conducted in 2015. RESULTS: Of the 66 JPMA member companies, effective responses were obtained on 151 trials from 33 companies based in Japan and 11 companies based in other countries. The results from this survey indicate that multiplicity adjustment in confirmatory multi-arm trials is adequate in terms of controlling the familywise error rate. Multiplicity was adjusted in 38.3% of exploratory multi-arm trials. Various multiple comparison procedures (MCPs) were applied, with the fixed sequence procedure being the one applied most frequently. This survey also reveals that there are issues that need to be addressed within sample size calculation. CONCLUSIONS: To adequately design a multi-arm clinical trial, it is important within sample size calculation to consider whether to perform multiplicity adjustment, select MCPs, and define their power.