A Phase 3, Open‐label, Single‐arm Study of Vadadustat for Anemia in Chronic Kidney Disease for Japanese Patients on Hemodialysis not Receiving Erythropoiesis‐stimulating Agents

Background: Tolvaptan increases free water clearance (aquaresis) and thereby improves hyponatremia. Although hyponatremia on admission is common in patients with congestive heart failure (CHF), little is known regarding the response to tolvaptan in those who also have chronic kidney disease (CKD) with or without hyponatremia. The aim of this subanalysis was to investigate the differences in treatment response between normo- and hyponatremia patients with CHF and CKD stages G3b-5. Methods: The Kanagawa Aquaresis Investigators Trial of Tolvaptan on HF Patients with Renal Impairment (K-STAR) was a multicenter, open-label, randomized, controlled prospective clinical trial that included 81 Japanese patients with CHF and residual signs of congestion despite oral furosemide treatment (≥40 mg/day). All patients were randomly assigned to 7-day treatment with either ≤15 mg/day of new add-on tolvaptan or ≤40 mg/day of increased furosemide. A subanalysis was conducted for 73 patients, who were classified into 2 groups according to their assigned treatment, then further stratified into 2 subgroups according to their serum sodium concentration [Na+]. The differences between the urine and serum parameters from day 1 to 3 were compared between the groups and between the subgroups in each group. Results: The change (Δ) in urine volume (ΔUV) and Δurine osmolality were greater in the tolvaptan group than in the furosemide group; however, ΔUV and Δurine osmolality did not show significant differences between the normonatremia subgroup and the hyponatremia subgroup in each group. In addition, Δserum [Na+] was greater in the tolvaptan group, although the change was not clinically significant. In contrast, Δserum [Na+] did not show significant differences between the normo- and hyponatremia subgroups in each group. Conclusion: Tolvaptan added to furosemide resulted in a greater diuretic effect than increased furosemide, even in normonatremia patients with CHF complicated by CKD stages G3b-5 in the very early treatment phase.

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MO001ROXADUSTAT FOR THE TREATMENT OF ANAEMIA IN CHRONIC KIDNEY DISEASE PATIENTS NOT ON DIALYSIS: A PHASE 3, RANDOMISED, OPEN-LABEL, ACTIVE-CONTROLLED STUDY

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfaa140.mo001 ◽

2020 ◽

Vol 35 (Supplement_3) ◽

Author(s):

Jonathan Barratt ◽

Branislav Andrić ◽

Avtandil Tataradze ◽

Michael Schömig ◽

Michael Reusch ◽

...

Keyword(s):

Chronic Kidney Disease ◽

Kidney Disease ◽

Study Drug ◽

Controlled Study ◽

Open Label ◽

Phase 3 ◽

Study Results ◽

Iv Iron ◽

Change In Mean ◽

To Receive

Abstract Background and Aims Roxadustat is an orally administered hypoxia-inducible factor prolyl hydroxylase inhibitor for the treatment of anaemia in patients (pts) with chronic kidney disease (CKD). Efficacy and safety of roxadustat compared with darbepoetin alfa (DA) for the treatment of anaemia in CKD pts not on dialysis (NDD) was assessed in a randomised, open-label, active-controlled phase 3 study. Results from a protocol-specified interim analysis, performed after pts had either completed ≥36 weeks of treatment or had withdrawn from the study, are presented here. Method This study (CL-0610) enrolled pts with NDD CKD stages 3-5 and anaemia (haemoglobin [Hb] ≤10.5 g/dL) and randomised them to receive roxadustat or DA. Following prescribed initial doses (weight-based), dose adjustments were permitted, with the goal of correcting and maintaining Hb. The primary endpoint was Hb response, defined as Hb ≥11.0 g/dL and an Hb increase from baseline (BL) of ≥1.0 g/dL in pts with BL Hb >8.0 g/dL, or an increase of ≥2.0 g/dL in pts with BL Hb ≤8.0 g/dL, during the first 24 weeks of treatment without rescue therapy. Key secondary endpoints included change in serum lipids, time to first IV iron use, change in mean arterial pressure (MAP), and occurrence of hypertension. Noninferiority of roxadustat to DA was declared if the lower bound of the two-sided 95% confidence interval (CI; roxadustat – DA) for change in Hb was >-0.15. Adverse events (AEs) were assessed across the study and are presented as events/100 patient exposure years (PEY) unless otherwise specified. The full analysis set (FAS) included pts who received ≥1 dose of study drug and had ≥1 post-dose Hb assessment. The per protocol set (PPS) included FAS pts who did not meet exclusion criteria. The safety analysis set (SAF) included pts who received ≥1 dose of study drug. Results As of 15 June 2018, 616 pts were randomised to receive roxadustat (n=323) or DA (n=293); of these 616 pts, 395 pts (roxadustat, n=194; DA, n=201) were still receiving treatment and 89 pts had completed ≥2 years of treatment (roxadustat, n=55; DA, n=34). In the PPS, 89.5% (n=256) of roxadustat pts responded in the first 24 weeks compared with 78.0% (n=213) of DA pts, for a difference of 11.51% (95% CI: 5.66%, 17.36%), thereby establishing roxadustat’s noninferiority to DA. Noninferiority of roxadustat to DA was also demonstrated for MAP and time to occurrence of hypertension. In the FAS, superiority of roxadustat to DA was demonstrated for low-density lipoprotein (LDL) and time to first IV iron use. (Table) In the SAF, overall incidence of AEs was comparable between roxadustat and DA (85.8% and 84.6%, respectively). Conclusion This analysis demonstrates that roxadustat was noninferior to DA in correction of Hb levels during the first 24 weeks of treatment in pts with NDD CKD stages 3-5 and anaemia. Safety profiles were comparable between groups. Final analysis of this study’s data will be presented at the congress.

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

American Journal of Nephrology ◽

10.1159/000518072 ◽

2021 ◽

pp. 1-10

Author(s):

Hiroyasu Yamamoto ◽

Kiyoshi Nobori ◽

Yoshimi Matsuda ◽

Yasuhiro Hayashi ◽

Takanori Hayasaki ◽

...

Keyword(s):

Japanese Patients ◽

Renal Anemia ◽

Target Range ◽

Open Label ◽

Phase 3 ◽

Once Daily ◽

Evaluation Period ◽

Erythropoiesis Stimulating Agents ◽

Previously Treated ◽

The Mean

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.

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Global Phase 3 programme of vadadustat for treatment of anaemia of chronic kidney disease: rationale, study design and baseline characteristics of dialysis-dependent patients in the INNO2VATE trials

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfaa204 ◽

2020 ◽

Author(s):

Kai-Uwe Eckardt ◽

Rajiv Agarwal ◽

Youssef Mk Farag ◽

Alan G Jardine ◽

Zeeshan Khawaja ◽

...

Keyword(s):

Chronic Kidney Disease ◽

Kidney Disease ◽

Open Label ◽

Adverse Cardiovascular Event ◽

Phase 3 ◽

Safety And Efficacy ◽

Endogenous Erythropoietin ◽

Study Results ◽

Long Term Treatment ◽

Baseline Characteristics

Abstract Background Erythropoiesis-stimulating agents (ESAs) are currently the mainstay of treatment for anaemia of chronic kidney disease (CKD). Vadadustat is an investigational oral hypoxia-inducible factor prolyl-hydroxylase inhibitor that stimulates endogenous erythropoietin formation. The INNO2VATE programme comprises two studies designed to evaluate the safety and efficacy of vadadustat versus the ESA darbepoetin alfa in ameliorating anaemia in patients with dialysis-dependent CKD (DD-CKD). Here we describe the trial design along with patient demographics and baseline characteristics. Methods Two Phase 3, open-label, sponsor-blind, active-controlled trials enrolled adults with anaemia of CKD who recently initiated dialysis and had limited ESA exposure (incident DD-CKD trial) or were receiving maintenance dialysis with ESA treatment (prevalent DD-CKD trial). Study periods include correction/conversion (Weeks 0–23), maintenance (Weeks 24–52), long-term treatment (Weeks 53 to end of treatment) and safety follow-up. The primary safety endpoint is the time to the first major adverse cardiovascular event and the primary efficacy endpoint is the change in haemoglobin (baseline to Weeks 24–36). Results A total of 369 and 3554 patients were randomized in the incident DD-CKD and prevalent DD-CKD trials, respectively. Demographics and baseline characteristics were similar among patients in both trials and comparable to those typically observed in DD-CKD. Conclusions The two INNO2VATE trials will provide important information on the safety and efficacy of a novel approach for anaemia management in a diverse DD-CKD population. Demographics and baseline characteristics of enrolled patients suggest that study results will be representative for a large proportion of the DD-CKD population.

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