Molidustat for Renal Anemia in Nondialysis Patients Previously Treated with Erythropoiesis-Stimulating Agents: A Randomized, Open-Label, Phase 3 Study.

INTRODUCTION: Erythropoiesis-stimulating agents (ESAs) are the current standard of care for anemia due to chronic kidney disease (CKD) in patients not undergoing dialysis. Molidustat, an oral hypoxia-inducible factor prolyl hydroxylase inhibitor, is being investigated as an alternative treatment for renal anemia. Molidustat was evaluated in five phase 3 studies, the molidustat once daily improves renal anemia by inducing erythropoietin (MIYABI) program. The present study investigated the safety and efficacy of molidustat in Japanese patients with renal anemia not undergoing dialysis and previously treated with ESAs. METHODS: This was a 52-week, active-controlled, randomized (1:1), open-label, parallel-group, multicenter, phase 3 study in Japanese patients with anemia due to CKD (stages 3-5). Molidustat was initiated at 25 mg or 50 mg once daily according to previous ESA dose. The ESA darbepoetin alfa (darbepoetin) was initiated at a starting dose in accordance with the previous ESA dose and injected subcutaneously once every 2 or 4 weeks. Doses were regularly titrated to maintain hemoglobin (Hb) levels in the target range of 11.0-13.0 g/dL. The primary efficacy outcome was the mean Hb level and its change from baseline during the evaluation period (weeks 30-36). The safety outcomes included evaluation of all adverse events. RESULTS: In total, 164 patients were randomized to receive molidustat (n = 82) or darbepoetin (n = 82). Baseline characteristics were well balanced. Mean (standard deviation) Hb levels at baseline were 11.31 (0.68) g/dL for molidustat and 11.27 (0.64) g/dL for darbepoetin. The mean (95% confidence interval [CI]) for mean Hb levels during the evaluation period for molidustat (11.67 [11.48-11.85] g/dL) and darbepoetin (11.53 [11.31-11.74] g/dL) was within the target range. Based on a noninferiority margin of 1.0 g/dL, molidustat was noninferior to darbepoetin regarding the change in mean Hb level during the evaluation period from baseline, with a least squares mean (95% CI) difference (molidustat-darbepoetin) of 0.13 (-0.15, 0.40) g/dL. The proportion of patients who reported at least 1 treatment-emergent adverse event (TEAE) was 92.7% for molidustat and 96.3% for darbepoetin. TEAEs leading to death were reported in 2 patients (2.4%) in the molidustat group and none in the darbepoetin group; serious TEAEs were reported in 32.9% and 26.8% of patients, respectively. DISCUSSION/CONCLUSION: Molidustat was noninferior to darbepoetin and maintained Hb levels in the prespecified target range in patients with renal anemia not undergoing dialysis and previously treated with ESA. Molidustat was well tolerated, and no new safety signal was observed.

Efficacy and Safety of Molidustat for Anemia in ESA-Naive Nondialysis Patients: A Randomized, Phase 3 Trial.

INTRODUCTION: Molidustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor that predominantly induces renal production of erythropoietin (EPO). Molidustat was evaluated for the treatment of anemia associated with chronic kidney disease (CKD) in the "Molidustat Once Daily Improves Renal Anemia by Inducing EPO" (MIYABI) program, which comprises 5 phase 3 clinical trials. The present MIYABI Non-Dialysis Correction (ND-C) study investigated the efficacy and safety of molidustat in Japanese patients with renal anemia who were not undergoing dialysis and were not receiving erythropoiesis-stimulating agent (ESA) treatment. METHODS: This was a 52-week, randomized (1:1), open-label, active-control, parallel-group, multicenter, phase 3 study in Japanese patients with renal anemia associated with CKD (stages 3-5). Molidustat or the ESA darbepoetin alfa (hereinafter referred to as darbepoetin) were initiated at 25 mg once daily or 30 µg every 2 weeks, respectively, and doses were regularly titrated to correct and to maintain hemoglobin (Hb) levels in the target range of ≥11.0 g/dL and <13.0 g/dL. The primary efficacy outcome was the mean Hb level and its change from baseline during the evaluation period (weeks 30-36). The safety outcomes included evaluation of all adverse events. RESULTS: In total, 162 patients were randomized to receive molidustat (n = 82) or darbepoetin (n = 80). Baseline characteristics were generally well balanced between treatment groups. The mean (standard deviation) Hb levels at baseline were 9.84 (0.64) g/dL for molidustat and 10.00 (0.61) g/dL for darbepoetin. The mean (95% confidence interval [CI]) for mean Hb levels during the evaluation period for molidustat (11.28 [11.07, 11.50] g/dL) and darbepoetin (11.70 [11.50, 11.90] g/dL) was within the target range. Based on a noninferiority margin of 1.0 g/dL, molidustat was noninferior to darbepoetin in the change in mean Hb level during the evaluation period from baseline; the least-squares mean (95% CI) difference (molidustat-darbepoetin) was -0.38 (-0.67, -0.08) g/dL. The proportion of patients who reported at least 1 treatment-emergent adverse event (TEAE) was 93.9% for molidustat and 93.7% for darbepoetin. Most TEAEs were mild (54.9% for molidustat and 63.3% for darbepoetin) or moderate (22.0% for molidustat and 22.8% for darbepoetin) in intensity. There were 3 deaths in the molidustat group and 1 in the darbepoetin group. DISCUSSION/CONCLUSION: In the MIYABI ND-C study, molidustat appeared to be an efficacious and generally well-tolerated alternative to darbepoetin for the treatment of renal anemia in Japanese patients who were not undergoing dialysis and were not receiving ESA treatment.

Efficacy and Safety of Inhaled Iloprost in Japanese Patients With Pulmonary Arterial Hypertension　- Insights From the IBUKI and AIR Studies.

BACKGROUND: Inhaled iloprost is approved for pulmonary arterial hypertension (PAH) in many countries. IBUKI was a phase III, non-randomized, open-label study of the efficacy and safety of inhaled iloprost in Japanese patients with PAH. METHODS AND RESULTS: Adults with PAH who were treatment-naïve or administered endothelin receptor antagonists (ERAs) and/or phosphodiesterase type 5 inhibitors (PDE5-Is) and in NYHA/WHO functional class (FC) III/IV had inhaled iloprost (2.5 µg, increased to 5.0 µg if tolerated) 6-9 times daily for 12 weeks. Eligible patients entered a 40-week extension phase. Endpoints included change from baseline to week 12 in pulmonary vascular resistance (PVR; primary endpoint), other efficacy parameters, and safety. Data were compared with new subgroup analyses of treatment-naïve Western PAH patients from the global phase III AIR study. 27 patients received iloprost: 89% were treated with an ERA and/or PDE5-I; 70% with both. At week 12, PVR improved from baseline by -124 dyn·sec·cm(-5)(95% CI, -177 to -72) and 6-min walking distance increased by 36.0 m (95% CI, 14.9 to 57.1). NYHA/WHO FC improved in 62%; none worsened. Common drug-related adverse events were headache (37%) and cough (15%); 1 patient experienced hypotension; none reported syncope or hemoptysis. There were no deaths and no unexpected long-term safety findings. AIR PAH subgroup analyses showed similar results. CONCLUSIONS: Inhaled iloprost appeared effective and safe in Japanese PAH patients, including ERA- and PDE5-I-treated patients, consistent with findings of the AIR PAH subpopulation and previous iloprost studies.

Efficacy and safety of lanthanum carbonate in pre-dialysis CKD patients with hyperphosphatemia: a randomized trial.

BACKGROUND: Lanthanum carbonate (LC), an effective non-calcium phosphate binder is widely used to manage hyperphosphatemia in patients with chronic kidney disease (CKD) on dialysis. Recently, the additional indication for control of hyperphosphatemia in CKD patients not on dialysis has been approved. METHODS: A multicenter, randomized, double-blind, placebo-controlled trial to confirm the efficacy and safety of LC in Japanese hyperphosphatemic stage 4 - 5 CKD patients not on dialysis. After a 4-week run-in period, 143 eligible subjects with serum phosphate levels of 5.6 - 11.0 mg/dL were randomized (2 : 1) to receive LC or placebo (88 vs. 55) for 8 weeks; 119 subjects completed the study (76 vs. 43). The starting LC dose was 750 mg/day, which was then up-titrated to 2,250 mg/day as needed while tolerated. Primary efficacy analysis was performed on the intent-to-treat (ITT) population of 141 patients (86 vs. 55). RESULTS: LC produced a significantly greater reduction in serum phosphate level compared with placebo after 8 weeks of treatment (difference, 0.97 (95% CI: 0.58, 1.37) mg/ dL; p < 0.0001). The cumulative proportion of subjects with controlled phosphate levels ≤ 4.6 mg/dL was higher in the LC group than the placebo group (59.56% vs. 10.46%). LC caused significantly greater reductions in serum Ca × P product and urinary phosphate excretion compared with placebo. The safety profile of LC was similar to that of placebo. CONCLUSIONS: This study demonstrated the effectiveness of LC to control hyperphosphatemia in pre-dialysis CKD patients.

Molidustat for the treatment of anemia in Japanese patients undergoing peritoneal dialysis: a single-arm, open-label, phase 3 study.

This 36-week, open-label, single-arm, phase 3 study investigated the safety and efficacy of molidustat in Japanese patients with renal anemia undergoing peritoneal dialysis. Molidustat was titrated every 4 weeks to maintain Hb levels within the target range (≥11.0 and <13.0 g/dL). The primary efficacy outcome was the responder rate, defined as the proportion of patients who met all of the following criteria: (1) mean Hb levels in the target range during the evaluation period (Weeks 30-36); (2) ≥50% of Hb values within the target range during the evaluation period; and (3) no rescue treatment before the end of the evaluation period. Overall, 51 patients received molidustat. The responder rate (95% CI) during the evaluation period was 54.9% (40.3, 68.9). Overall, 98.0% of patients experienced at least 1 adverse event during the study. No deaths were reported. Molidustat maintained Hb levels in the prespecified range in more than half of the patients and was well tolerated.

Molidustat for anemia correction in Japanese patients undergoing hemodialysis: a single-arm, phase 3 study.

Molidustat, an orally administered hypoxia-inducible factor prolyl-hydroxylase inhibitor, is under development for the treatment of anemia of CKD. This 24-week, phase 3, single-arm, multicenter study evaluated the efficacy and safety of molidustat in Japanese patients with renal anemia who were undergoing hemodialysis and who were not receiving an erythropoiesis-stimulating agent. Twenty-five patients received molidustat at a starting dose of 75 mg once daily, which was adjusted to maintain a Hb target of ≥10.0 to <12.0 g/dL. The mean rates of Hb increase from baseline and week 0 to the first dose change up to week 8 were -0.030 and 0.080 g/dL/week, respectively. By week 24, 89% of patients had a Hb level within target range. No adverse events of special interest were reported. Treatment with dose-titrated molidustat for 24 weeks was well tolerated in Japanese patients undergoing hemodialysis, and no new safety signal was observed. Clinicaltrials.gov identifier: NCT03351166.

Molidustat for Japanese Patients With Renal Anemia Receiving Dialysis.

INTRODUCTION: Molidustat, a hypoxia-inducible factor prolyl hydroxylase inhibitor for renal anemia treatment, was evaluated in 5 phase 3 studies (MIYABI program). We report the results of the MIYABI hemodialysis-maintenance study. METHODS: This 52-week, randomized, double-blinded, double-dummy study compared the efficacy and safety of molidustat and darbepoetin in Japanese patients receiving hemodialysis and erythropoiesis-stimulating agents. Molidustat (starting dose: 75 mg/day) and darbepoetin were titrated to maintain hemoglobin (Hb) levels in the target range (≥10.0 and <12.0 g/dl). Primary outcomes were mean Hb level during the evaluation period (weeks 33-36) and its change from baseline. Safety outcomes included adverse events. RESULTS: Overall, 229 patients were randomized (molidustat, n = 153; darbepoetin, n = 76). Baseline characteristics were well balanced. Mean baseline Hb level was 10.8 g/dl. Mean (95% confidence interval [CI]) for mean Hb levels during the evaluation period were within the target range in both groups (molidustat: 10.63 [10.42-10.84] g/dl; darbepoetin: 10.77 [10.59-10.95] g/dl). Least-squares mean (95% CI) change in mean Hb level during the evaluation period from baseline was -0.14 (-0.37 to 0.09) g/dl for molidustat and -0.07 (-0.30 to 0.16) g/dl for darbepoetin; molidustat was noninferior to darbepoetin (least-squares mean difference [95% CI] [molidustat-darbepoetin]: -0.13 [-0.46 to 0.19] g/dl), based on a noninferiority margin of 1.0 g/dl. In line with published literature, and as expected in this patient population, most participants had ≥1 treatment-emergent adverse event. CONCLUSION: Molidustat maintained Hb levels throughout the trial in patients receiving dialysis and previously treated with erythropoiesis-stimulating agents, and was noninferior to darbepoetin.

Efficacy and Safety of Intravitreal Aflibercept Treat-and-Extend Regimens in Exudative Age-Related Macular Degeneration: 52- and 96-Week Findings from ALTAIR : A Randomized Controlled Trial.

PURPOSE: To evaluate efficacy and safety of intravitreal injections of aflibercept (IVT-AFL) treat-and-extend (T&E) dosing regimens in treatment-naïve patients with exudative age-related macular degeneration (AMD). METHODS: Adults aged at least 50 years old with exudative AMD and best-corrected visual acuity (BCVA) of 73-25 Early Treatment Diabetic Retinopathy Study (ETDRS) letters were included. Patients received three monthly doses of IVT-AFL 2 mg. At week 16, patients were randomized 1:1 to IVT-AFL T&E with either 2- or 4-week adjustments. The primary endpoint was mean change in BCVA from baseline to week 52. Outcomes were assessed at weeks 52 and 96. RESULTS: Baseline characteristics were comparable between the groups (n = 123 each). Over 52 weeks, mean number of injections was 7.2 and 6.9 and mean last injection interval was 10.7 and 11.8 weeks, for the 2- and 4-week groups, respectively. From baseline, mean change in BCVA was + 9.0 and + 8.4 letters (week 52) and + 7.6 and + 6.1 letters (week 96); mean change in central retinal thickness was - 134.4 µm and - 126.1 µm (week 52) and - 130.5 µm and - 125.3 µm (week 96). Last injection interval before week 52 was at least 12 weeks in 42.3% and 49.6% of patients and 56.9% and 60.2% before week 96. Over 96 weeks, mean number of injections was 10.4 (both groups). The safety profile of IVT-AFL was consistent with previous reports. CONCLUSIONS: IVT-AFL administered using two different T&E regimens for treatment-naïve exudative AMD improved functional and anatomic outcomes at week 52 and outcomes were maintained to week 96. Outcomes were similar between the 2- and 4-week groups. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT02305238.

Molidustat for the treatment of renal anaemia in patients with non-dialysis-dependent chronic kidney disease: design and rationale of two phase III studies.

INTRODUCTION: Anaemia is a common complication of chronic kidney disease (CKD). Owing to the limitations of erythropoiesis-stimulating agents (ESAs), the current standard of care, there is a need to develop new therapies. Hypoxia-inducible factor prolyl-hydroxylase (HIF-PH) inhibitors might be a promising new treatment option. Molidustat is an oral HIF-PH inhibitor that stimulates the endogenous, predominantly renal, production of erythropoietin and was generally well tolerated in phase IIb clinical trials. Here, we report the design and rationale of two studies from the molidustat phase III programme: MolIdustat once dailY improves renal Anaemia By Inducing erythropoietin (MIYABI). METHODS AND ANALYSIS: MIYABI Non-Dialysis-Correction (ND-C) and MIYABI Non-Dialysis-Maintenance (ND-M) are randomised, open-label, parallel-group, multicentre studies that aim to demonstrate the efficacy of molidustat treatment compared with darbepoetin alfa in patients with anaemia and non-dialysis-dependent CKD. The secondary objectives are to assess the safety, pharmacokinetics and pharmacodynamics of molidustat treatment. MIYABI ND-C will recruit patients currently untreated with ESAs, whereas patients treated with an ESA will enter MIYABI ND-M. Each study will recruit 150 patients who will be randomised in a 1:1 ratio to receive either molidustat or darbepoetin alfa for 52 weeks, with efficacy evaluated during weeks 30-36. Study drug doses will be titrated regularly using an interactive voice/web response system with the aim of maintaining the patients' haemoglobin (Hb) levels between ≥110 and <130 g/L. The primary objective will be achieved if, in molidustat-treated patients, the mean Hb level remains within the target range during the evaluation period, and if the change in the mean Hb level at evaluation time points from baseline is non-inferior to darbepoetin alfa. ETHICS AND DISSEMINATION: The protocols were approved by ethics committees at all participating sites. These studies will be conducted in accordance with the Declaration of Helsinki and the Good Clinical Practice guidelines. Results arising from these studies will be published in peer-reviewed journal(s). TRIAL REGISTRATION NUMBERS: NCT03350321; Pre-results, NCT03350347; Pre-results.

Molidustat for the treatment of renal anaemia in patients with dialysis-dependent chronic kidney disease: design and rationale of three phase III studies.

INTRODUCTION: New medications for anaemia associated with chronic kidney disease (CKD) are desirable, owing to the limitations of erythropoiesis-stimulating agents (ESAs), the current standard of care. Molidustat is a novel hypoxia-inducible factor prolyl-hydroxylase inhibitor that stimulates erythropoietin production, predominately in the kidney. We report methodological details of three phase III trials, named MolIdustat once dailY improves renal Anaemia By Inducing erythropoietin (MIYABI), designed primarily to investigate the efficacy of molidustat therapy in adults with renal anaemia and dialysis-dependent CKD. METHODS AND ANALYSIS: MIYABI Haemodialysis-Correction (HD-C) is a single-arm trial (24-week treatment duration) in approximately 25 patients on haemodialysis, currently untreated with ESAs. MIYABI Peritoneal Dialysis (PD) is a single-arm trial (36 week treatment duration) in approximately 50 patients on peritoneal dialysis, treated or untreated with ESAs. MIYABI Haemodialysis-Maintenance (HD-M) is a randomised, active-controlled, double-blinded, double-dummy trial (52-week treatment duration) comparing molidustat with darbepoetin alfa in approximately 225 patients on haemodialysis, treated with ESAs. Molidustat (starting dose 75 mg/day) will be titrated 4-weekly to maintain haemoglobin in predetermined target ranges. The primary objective is to evaluate the efficacy of molidustat, using the following measures: the rate of rise in haemoglobin (g/L/week) at the first dose change up to week 8 (MIYABI HD-C); responder rate (MIYABI HD-C and MIYABI PD); mean haemoglobin level during weeks 33-36 and non-inferiority to darbepoetin alfa shown by change in mean haemoglobin level from baseline (MIYABI HD-M). The secondary objectives are to assess safety, pharmacokinetics and pharmacodynamics. These trials will provide the first evaluations of molidustat therapy in patients receiving either peritoneal dialysis or currently untreated with ESAs on haemodialysis, and provide further evidence in patients treated with ESAs on haemodialysis. ETHICS AND DISSEMINATION: The protocols were approved by ethics committees at all participating sites. The trials will be conducted in accordance with the Declaration of Helsinki and Good Clinical Practice. Results arising from these studies will be published in peer-reviewed journal(s). TRIAL REGISTRATION NUMBERS: NCT03351166; Pre-results, NCT03418168; Pre-results, NCT03543657; Pre-results.

Development and evaluation of the e-learning teaching materials for surgical nursing training.

We investigated e-learning teaching materials with a questionnaire for 55 nursing students. Students thought the materials easy to use. In addition, the teaching materials which we developed gave them the confidence of thinking, "I can do it". We affect training by imaging a nursing procedure and think anxiety to training to be be relieved. However, load of PC became high in these teaching materials to display of two motion pictures simultaneously in one screen, so it would be necessary to produce the teaching materials considered transmission rate.

Structural visualization of expert nursing: Development of an assessment and intervention algorithm for delirium following abdominal and thoracic surgeries.

An assessment and intervention algorithm for delirium following abdominal and thoracic surgeries was developed based upon the current knowledge-base. The sources of information included literature and clinical expertise. The assessment and intervention algorithm was structured and visualized so that patient-tailored and risk-stratified prediction/prevention, assessment, and intervention could be carried out. Accumulation of clinical outcome data is necessary in the future validation study to identify the relative weight of risk factors and clinical utility of the algorithm.

Long-term safety and efficacy of high-dose controlled-release nifedipine (80 mg per day) in Japanese patients with essential hypertension.

High-dose calcium channel blocker (CCB) shows strong blood pressure (BP) lowering effect. Currently available of controlled-release (CR) nifedipine 80 mg per day clinical data are limited to monotherapy and short-term or long-term retrospective studies. We report the safety and efficacy results of a 52-week, prospective open-label study, in which Japanese patients with essential hypertension were treated with CR nifedipine [80 mg per day; 40 mg bis in die (BID; twice daily)] in combination with other antihypertensive drugs. The patients with inadequate BP control despite treatment with CR nifedipine (40 mg once daily) in combination with other antihypertensive drugs were enrolled. The primary objective of this study was to assess the long-term safety of CR nifedipine (80 mg per day). Efficacy variables included changes in the mean sitting BP, the target BP achievement rate and the BP response rate. CR nifedipine (80 mg per day) was generally well tolerated, with the most common drug-related treatment-emergent adverse event being tachycardia (6.9% of patients). Serious treatment-emergent adverse events were reported in three (4.2%) patients. By week 52, the mean reductions in sitting systolic and diastolic BP were 19.4 and 13.6 mm Hg, respectively. The target BP achievement and BP response rates after 52 weeks of treatment were 32.4 and 63.4%, respectively. Based on these findings, long-term treatment with CR nifedipine at 40 mg BID in combination with antihypertensive drugs was well tolerated and effective in Japanese patients with essential hypertension.

Oncology nurses' recognition of long-term cancer survivorship care in Japan.

OBJECTIVE: This study aims to assess the knowledge of definition of cancer survivors among Japanese oncology nurses and their roles in long-term cancer survivorship care. METHODS: A structured self-administered and self-report questionnaire created by the study investigators was given to members of the Japanese Society of Cancer Nursing. The subjects were 81 female oncology nurses. RESULTS: Forty-nine nurses had 11 or more years of nursing experience, while 27 nurses had cancer-related nursing certifications such as, certification in oncology nursing specialist. This study population had rather rich experience in oncology nursing. Sixty-two nurses defined a cancer survivor from the time of diagnosis, while the nurses' recognition of long-term survivorship care was poor, compared with nursing care at the time of diagnosis, during treatment, and end of life. CONCLUSIONS: The nurses were aware of the needs to recognize and address issues faced by long-term cancer survivors and for nursing study, but very few put the effective patient education and interventions into practice. It is because oncology nurses have few chances to see cancer survivors who go out of the hands of healthcare professionals. In increasing the number of long-term survivors, long-term survivorship care is needed in addition to incorporating such education into undergraduate and graduate programs. Further study on the knowledge of long-term cancer survivorship care and nursing practices are required.

Cognition and mental health.

Many theories of mental health agree on the important role played by cognition. They differ however in how and by what process cognition influences mental health. Research in cognitive neuroscience directs our attention to 4 major points as relevant to theories of mental health: (1) monism as a framework, (2) issue of neural plasticity, (3) connection between mental operation and action system (i.e., the control of cognitive and motor activity is shared by the same neural connection.), (4) the issue of the unconscious. On the other hand, research in cross-cultural psychology indicates that cognitive process is strongly influenced by cultural values and norms. Thus, a valid mental health theory should account for all these components. The paper discusses cross-cultural differences in information processing, particularly contrasting East Asian and Western cultural contexts, which may have implications for understanding of mental health and suggests the doctrine of Morita Therapy as a possible integrated theory. It also critiques some therapy techniques on the grounds of both cultural psychology and cognitive science.