Two long-term phase 3 studies of enarodustat (JTZ-951) in Japanese anemic patients with chronic kidney disease not on dialysis or on maintenance hemodialysis: SYMPHONY ND-Long and HD-Long studies.
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SUBMITTER: Akizawa T
PROVIDER: S-EPMC9290460 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:IntroductionEnarodustat (JTZ-951) is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor that might be a new therapeutic approach for managing anemia in patients with chronic kidney disease (CKD). We evaluated the efficacy (noninferiority to darbepoetin alfa [DA]) and safety of enarodustat in Japanese anemic patients with CKD not requiring dialysis.MethodsErythropoiesis-stimulating agent (ESA)-naïve patients and ESA-treated patients were randomized at a 1:1 ratio to receive enarodustat orally once daily or DA subcutaneously every 2 or 4 weeks for 24 weeks, respectively. Subjects in each arm had dose adjustments every 4 weeks to maintain their hemoglobin (Hb) level within the target range (10 to 12 g/dl). The primary endpoint was the difference in the mean Hb level between arms during the evaluation period defined as weeks 20 to 24 (noninferiority margin: -0.75 g/dl).ResultsThe mean Hb level during the evaluation period in the enarodustat arm was 10.96 g/dl (95% confidence interval [CI]: 10.84 to 11.07 g/dl) with a difference of 0.09 g/dl (95% CI: -0.07 to 0.26 g/dl) between arms, establishing its noninferiority to DA. Nearly 90% of subjects in both arms maintained a mean Hb level within the target range. Compared with DA, enarodustat was associated with decreased hepcidin and ferritin, and increased total iron-binding capacity. There were no apparent differences in the incidence of adverse events between arms (65.4% [enarodustat], 82.6% [DA]).ConclusionsThe efficacy of enarodustat was comparable to DA in anemic patients with CKD not requiring dialysis. No new safety concerns were identified compared with DA.
| S-EPMC8258589 | biostudies-literature
Project description:IntroductionEnarodustat (JTZ-951) is a new oral hypoxia-inducible factor-prolyl hydroxylase inhibitor for the treatment of anemia in chronic kidney disease (CKD). We conducted a phase 3 study to compare the efficacy and safety of enarodustat with darbepoetin alfa (DA) in Japanese anemic patients with CKD receiving maintenance hemodialysis.MethodsSubjects receiving maintenance hemodialysis were randomly assigned at a 1:1 ratio to receive oral enarodustat once daily or intravenous DA every week for 24 weeks with dose adjustment every 4 weeks to maintain hemoglobin (Hb) within a target range (≥10.0 to <12.0 g/dL). The primary efficacy endpoint was difference in mean Hb level between arms during the evaluation period defined as weeks 20-24 (noninferiority margin: -1.0 g/dL). Intravenous iron preparations were prohibited during the screening period and during weeks 0-4.ResultsThe mean Hb level of each arm during the evaluation period was 10.73 g/dL (95% confidence interval [CI]: 10.56, 10.91) in the enarodustat arm and 10.85 g/dL (95% CI: 10.72, 10.98) in the DA arm. The difference in the mean Hb level between arms was -0.12 g/dL (95% CI: -0.33, 0.10), confirming the noninferiority of enarodustat to DA. The mean Hb level of each arm was maintained within the target range during the treatment period. Increased total iron-binding capacity and serum iron and decreased hepcidin were observed through week 4 in the enarodustat arm albeit after switching from erythropoiesis-stimulating agents. No apparent safety concerns of enarodustat were observed compared with DA.Discussion/conclusionEnarodustat was noninferior to DA for the treatment of anemia in CKD patients receiving maintenance hemodialysis and was generally well tolerated over 24 weeks.
| S-EPMC8613566 | biostudies-literature
Project description:BACKGROUND:Enarodustat (JTZ-951) is an orally available hypoxia-inducible factor prolyl hydroxylase inhibitor that increases endogenous erythropoietin levels in the treatment of anemia associated with chronic kidney disease (CKD). OBJECTIVE:A phase 2b study of enarodustat to assess the hemoglobin (Hb) response, safety, and maintenance dosage was conducted in Japanese anemic patients with hemodialysis-dependent CKD. METHODS:Subjects receiving a stable dose of an erythropoiesis-stimulating agent were randomized to receive once-daily enarodustat at a dose of 2, 4, or 6 mg or placebo in a double-blind manner for 6 weeks (Period 1) followed by 24-week open treatment with enarodustat, adjusted in the range of 2-8 mg to maintain Hb within a target range (10.0-12.0 g/dL; Period 2). RESULTS:Change in Hb from baseline increased with enarodustat dose in Period 1. In Period 2, the proportion of subjects who maintained their Hb level within the target range at the end of treatment was 65.1%. To maintain Hb levels within the target range over the course of Period 2, approximately 80% of subjects required 2 dose adjustments or fewer. Enarodustat decreased hepcidin and ferritin levels, increased total iron-binding capacity, and was generally well tolerated. CONCLUSIONS:Enarodustat corrected and maintained Hb levels in anemic patients with hemodialysis-dependent CKD. Phase 3 studies of enarodustat are currently ongoing.
| S-EPMC6878752 | biostudies-literature
Project description:BackgroundPatients with end-stage kidney disease (ESKD) treated with hemodialysis (HD) experience many distressing symptoms. One frequently reported symptom is insomnia. There are unique issues about HD treatments and schedules that disrupt regular sleep/wake routines and possibly contribute to the high severity of insomnia. Despite evidence for broad-ranging health effects of insomnia, very few clinical trials have tested the efficacy of treatments for HD patients. Cognitive-behavioral therapy for insomnia (CBT-I) is a recommended first-line therapy but largely inaccessible to HD patients in the United States, partly because they commit considerable amounts of time to thrice-weekly dialysis treatments. Another important reason could be the logistical and reimbursement challenges associated with providing behavioral health care at the dialysis center. CBT-I delivered by telehealth can overcome barriers to access, but its efficacy has never been rigorously tested for these patients. Pharmacotherapy is the most widely used treatment for insomnia; however, some drugs presently used are unsafe as they are associated with a higher risk for death for HD patients (benzodiazepines and zolpidem-like drugs). The efficacy and safety of other medications (trazodone) for the treatment of insomnia has never been tested for patients treated with HD.MethodsThis trial tests the short- and long-term comparative effectiveness of 6-week treatment with telehealth CBT-I, trazodone, or medication placebo. This will be accomplished with a randomized controlled trial (RCT) in which 126 participants treated with HD in community-based dialysis facilities with chronic insomnia will be assigned 1:1:1 to telehealth CBT-I, trazodone, or medication placebo, respectively; short-term effectiveness of each treatment arm will be determined at the end of 6-weeks of treatment and long-term effectiveness at 25-weeks. The primary and secondary patient-reported outcomes will be assessed with computer-based telephone interviewing by research scientists blinded to treatment assignment; additional secondary outcomes will be assessed by participant interview and actigraphy.DiscussionThis clinical RCT will provide the first evidence for the comparative effectiveness of two distinct approaches for treating chronic insomnia and other patient-reported outcomes for patients receiving maintenance HD.Trial registrationNCT03534284 May 23, 2018. SLEEP-HD Protocol Version: 1.3.4 (7/22/2020).
| S-EPMC7574396 | biostudies-literature
Project description:BackgroundPeople receiving in-center hemodialysis (HD) have prioritized the need for more individualized health information and better communication with nephrologists. The most common setting for patient-nephrologist interactions is during the HD treatment, which is a time pressured setting that lacks privacy.ObjectiveTo facilitate effective communication in the hemodialysis (HD) unit, we evaluated the usability of a web application (web app) from both the patient and physician perspective. The main aim of the web app was to support patients in prioritizing their dialysis concerns outside of the clinical HD encounter.DesignMixed method, parallel arm, multi-site, pilot randomized controlled trial.SettingTwo outpatient Canadian HD centers.ParticipantsAdult patients receiving in-center HD and their attending nephrologists.MethodsPatients were randomized to either a web application or an active control (paper form) for logging concerns to be addressed at weekly encounters with the nephrologist over 8 weeks. Topics included: HD treatment, symptoms, modality, and medications. The primary outcome was usability, defined as effectiveness (engagement with the tool, frequency of submitted concerns, whether the concern was satisfactorily addressed) and satisfaction with the tool using a priori thresholds and explored in interviews with patients and nephrologists.Results77 patients (30 women, median age 61, interquartile range [53,67], median 2 years [1,4] on dialysis) and 19 nephrologists (4 women, median age 46 [36,65]) were enrolled. Patient use of a digital device at baseline was low (20%). Engagement with the tool was 70% (web app) and 100% (paper) with a lower proportion of patients in the web app group submitting at least one concern over 8 weeks compared to the paper form group: 56.7% vs 87.9%. Weekly concerns were satisfactorily addressed in both groups and ≥70% of patients would continue to use the tools. For patients, both tools promoted preparation and participation in the encounter; however, only the web app facilitated greater privacy in relaying concerns. For most nephrologists, the tools were disruptive to their workflow and were perceived as unnecessary given existing processes and familiarity with patients. For future versions of the app, patients suggested more features to facilitate self-management and nephrologists suggested integration with health databases and multidisciplinary teams.LimitationsTertiary setting may limit generalizability.ConclusionsBoth tools promoted fundamental components of self-management; however, patients in the paper form group submitted concerns more often and this tool was easier to remember to use. Although modifications would likely enhance web app usability, successful future adoption is limited by physician acceptance.Trial registration ClinicalTrials.gov NCT03605875.
| S-EPMC8323421 | biostudies-literature
Project description:In contrast to the general population, higher body mass index (BMI) is associated with greater survival in patients receiving hemodialysis (HD; "obesity paradox"). We hypothesized that this paradoxical association between BMI and death may be modified by age and dialysis vintage.Retrospective observational study using a large HD patient cohort.123,383 maintenance HD patients treated in DaVita dialysis clinics between July 1, 2001, and June 30, 2006, with follow-up through September 30, 2009.Age, dialysis vintage, and time-averaged BMI. Time-averaged BMI was divided into 6 subgroups; <18.5, 18.5-<23.0, 23.0-<25.0, 25.0-<30.0, 30.0-<35.0, and ?35.0kg/m(2). BMI category of 23-<25kg/m(2) was used as the reference category.All-cause, cardiovascular, and infection-related mortality.Mean BMI of study participants was 27±7kg/m(2). Time-averaged BMI was <18.5 and ?35kg/m(2) in 5% and 11% of patients, respectively. With progressively higher time-averaged BMI, there was progressively lower all-cause, cardiovascular, and infection-related mortality in patients younger than 65 years. In those 65 years or older, even though overweight/obese patients had lower mortality compared with underweight/normal-weight patients, sequential increases in time-averaged BMI?>?25kg/m(2) added no additional benefit. Based on dialysis vintage, incident HD patients had greater all-cause and cardiovascular survival benefit with a higher time-averaged BMI compared with the longer term HD patients.Causality cannot be determined, and residual confounding cannot be excluded given the observational study design.Higher BMI is associated with lower death risk across all age and dialysis vintage groups. This benefit is more pronounced in incident HD patients and those younger than 65 years. Given the robustness of the survival advantage of higher BMI, examining interventions to maintain or even increase dry weight in HD patients irrespective of age and vintage are warranted.
| S-EPMC3969454 | biostudies-literature
Project description:BackgroundThe benefit of alpha-Ketoanalogues (KA) supplementation for chronic kidney disease (CKD) patients that followed low-protein diet (LPD) remains undetermined.MethodsWe extracted longitudinal data for all CKD patients in the Taiwan National Health Insurance from January 1, 2000 through December 31, 2010. A total of 1483 patients with anemic advanced CKD treated with LPD, who started KA supplementation, were enrolled in this study. We analyzed the risks of end stage renal disease and all-cause mortality using Cox proportional hazard models with influential drugs as time-dependent variables.ResultsA total of 1113 events of initiating long-term dialysis and 1228 events of the composite outcome of long-term dialysis or death occurred in patients with advanced CKD after a mean follow-up of 1.57 years. Data analysis suggests KA supplementation is associated with a lower risk for long-term dialysis and the composite outcome when daily dosage is more than 5.5 tablets. The beneficial effect was consistent in subgroup analysis, independent of age, sex, and comorbidities.ConclusionsAmong advanced CKD patients that followed LPD, KA supplementation at an appropriate dosage may substantially reduce the risk of initiating long-term dialysis or of developing the composite outcome. KA supplementation represents an additional therapeutic strategy to slow the progression of CKD.
| S-EPMC5419544 | biostudies-literature
Project description:BACKGROUND:Vascular calcification is seen in most patients on dialysis and is strongly associated with cardiovascular mortality. Vascular calcification is promoted by phosphate, which generally reaches higher levels in hemodialysis than in peritoneal dialysis. However, whether vascular calcification develops less in peritoneal dialysis than in hemodialysis is currently unknown. Therefore, we compared coronary artery calcification (CAC), its progression, and calcification biomarkers between patients on hemodialysis and peritoneal dialysis. METHODS:We measured CAC in 134 patients who had been treated exclusively with hemodialysis (n = 94) or peritoneal dialysis (n = 40) and were transplantation candidates. In 57 of them (34 on hemodialysis and 23 on peritoneal dialysis), we also measured CAC progression annually up to 3 years and the inactive species of desphospho-uncarboxylated matrix Gla protein (dp-ucMGP), fetuin-A, osteoprotegerin. We compared CAC cross-sectionally with Tobit regression. CAC progression was compared in 2 ways: with linear mixed models as the difference in square root transformed volume score per year (?CAC SQRV) and with Tobit mixed models. We adjusted for potential confounders. RESULTS:In the cross-sectional cohort, CAC volume scores were 92 mm3 in hemodialysis and 492 mm3 in peritoneal dialysis (adjusted difference 436 mm3; 95% CI -47 to 919; p = 0.08). In the longitudinal cohort, peritoneal dialysis was associated with significantly more CAC progression defined as ?CAC SQRV (adjusted difference 1.20; 95% CI 0.09 to 2.31; p = 0.03), but not with Tobit mixed models (adjusted difference in CAC score increase per year 106 mm3; 95% CI -140 to 352; p = 0.40). Peritoneal dialysis was associated with higher osteoprotegerin (adjusted p = 0.02) but not with dp-ucMGP or fetuin-A. CONCLUSIONS:Peritoneal dialysis is not associated with less CAC or CAC progression than hemodialysis, and perhaps with even more progression. This indicates that vascular calcification does not develop less in peritoneal dialysis than in hemodialysis.
| S-EPMC6390451 | biostudies-literature
Project description:Evidence-informed decision making in clinical care and policy in nephrology is undermined by trials that selectively report a large number of heterogeneous outcomes, many of which are not patient centered. The Standardized Outcomes in Nephrology-Hemodialysis (SONG-HD) Initiative convened an international consensus workshop on November 7, 2015, to discuss the identification and implementation of a potential core outcome set for all trials in hemodialysis. The purpose of this article is to report qualitative analyses of the workshop discussions, describing the key aspects to consider when establishing core outcomes in trials involving patients on hemodialysis therapy. Key stakeholders including 8 patients/caregivers and 47 health professionals (nephrologists, policymakers, industry, and researchers) attended the workshop. Attendees suggested that identifying core outcomes required equitable stakeholder engagement to ensure relevance across patient populations, flexibility to consider evolving priorities over time, deconstruction of language and meaning for conceptual consistency and clarity, understanding of potential overlap and associations between outcomes, and an assessment of applicability to the range of interventions in hemodialysis. For implementation, they proposed that core outcomes must have simple, inexpensive, and validated outcome measures that could be used in clinical care (quality indicators) and trials (including pragmatic trials) and endorsement by regulatory agencies. Integrating these recommendations may foster acceptance and optimize the uptake and translation of core outcomes in hemodialysis, leading to more informative research, for better treatment and improved patient outcomes.
| S-EPMC5369351 | biostudies-literature
Project description:BACKGROUND Rapid shifting between extracellular and intracellular phosphorus can occur during dialysis sessions, which can cause aberrant intracellular signaling in long-term hemodialysis (LTHD) patients. However, the effect of these intra-dialysis fluctuations of phosphorus on clinical outcomes has not been examined. Therefore, we investigated the relationship between intradialysis serum phosphorus reduction ratio (IDSPRR) and mortality in LTHD patients. MATERIAL AND METHODS This was a retrospective, observational cohort study to assess the predictive power of IDSPRR (>0.63 vs. ?0.63) on mortality in a total of 805 LTHD patients. All these fatal events were analyzed using the Cox proportional hazards regression model. RESULTS After multivariable analysis, baseline IDSPRR higher than 0.63 was significantly predictive of all-cause mortality (hazard ratio [HR]: 1.58; 95% confidence interval [CI]: 1.10-2.26), but not for cardiovascular (CV) mortality (HR: 1.41; 95% CI: 0.91-2.18). However, when time-varied IDSPRRs were applied, a value greater than 0.63 was not only significantly predictive of all-cause mortality (HR: 1.74, 95% CI: 1.16-2.63), but also CV mortality (HR: 2.04, 95% CI: 1.23-3.40). CONCLUSIONS High IDSPRR (>0.63) is independently associated with increased all-cause and CV mortality, which shows the negative effect of rapid intracellular phosphorus-shifting on LTHD patients.
| S-EPMC6354640 | biostudies-literature