Head-to-head comparison of the new calcimimetic agent evocalcet with cinacalcet in Japanese hemodialysis patients with secondary hyperparathyroidism

Secondary hyperparathyroidism (SHPT) leads to cardiovascular calcification, which affects survival and quality of life in patients with chronic kidney disease. Cinacalcet is used to control SHPT, but it may induce gastrointestinal symptoms, resulting in lower adherence and insufficient dosages. Therefore, a need exists to develop new calcimimetics that cause fewer gastrointestinal symptoms. Here we conducted a phase 3, randomized, double-blind, double-dummy trial for a head-to-head comparison of the efficacy and safety of evocalcet, a new oral calcimimetic, to the established cinacalcet. Japanese patients with SHPT on hemodialysis were randomized to receive evocalcet or cinacalcet (317 patients each) for 30 weeks. The primary efficacy endpoint was non-inferiority of evocalcet to cinacalcet in the proportion of patients achieving a mean intact parathyroid hormone level of 60 to 240 pg/mL from week 28 to 30 (non-inferiority margin, −15%, per protocol set analyses). In the evocalcet and cinacalcet groups, 72.7% and 76.7%, respectively, achieved the target intact parathyroid hormone level (between-group difference: −4.0% [95% confidence interval −11.4%, 3.5%], for non-inferiority). The incidence of gastrointestinal-related adverse events was 18.6% and 32.8%, respectively (between-group difference: −14.2% [−20.9%, −7.5%], significant for superiority). Thus, the non-inferiority of evocalcet to cinacalcet in suppressing intact parathyroid hormone with fewer gastrointestinal-related adverse events was demonstrated. Hence, evocalcet may be a favorable alternative to existing calcimimetics for management of SHPT. Secondary hyperparathyroidism (SHPT) leads to cardiovascular calcification, which affects survival and quality of life in patients with chronic kidney disease. Cinacalcet is used to control SHPT, but it may induce gastrointestinal symptoms, resulting in lower adherence and insufficient dosages. Therefore, a need exists to develop new calcimimetics that cause fewer gastrointestinal symptoms. Here we conducted a phase 3, randomized, double-blind, double-dummy trial for a head-to-head comparison of the efficacy and safety of evocalcet, a new oral calcimimetic, to the established cinacalcet. Japanese patients with SHPT on hemodialysis were randomized to receive evocalcet or cinacalcet (317 patients each) for 30 weeks. The primary efficacy endpoint was non-inferiority of evocalcet to cinacalcet in the proportion of patients achieving a mean intact parathyroid hormone level of 60 to 240 pg/mL from week 28 to 30 (non-inferiority margin, −15%, per protocol set analyses). In the evocalcet and cinacalcet groups, 72.7% and 76.7%, respectively, achieved the target intact parathyroid hormone level (between-group difference: −4.0% [95% confidence interval −11.4%, 3.5%], for non-inferiority). The incidence of gastrointestinal-related adverse events was 18.6% and 32.8%, respectively (between-group difference: −14.2% [−20.9%, −7.5%], significant for superiority). Thus, the non-inferiority of evocalcet to cinacalcet in suppressing intact parathyroid hormone with fewer gastrointestinal-related adverse events was demonstrated. Hence, evocalcet may be a favorable alternative to existing calcimimetics for management of SHPT. Secondary hyperparathyroidism (SHPT) is one of the most common complications of chronic kidney disease–mineral and bone disorder.1Cunningham J. Locatelli F. Rodriguez M. Secondary hyperparathyroidism: pathogenesis, disease progression, and therapeutic options.Clin J Am Soc Nephrol. 2011; 6: 913-921Crossref PubMed Scopus (380) Google Scholar, 2Komaba H. Kakuta T. Fukagawa M. Diseases of the parathyroid gland in chronic kidney disease.Clin Exp Nephrol. 2011; 15: 797-809Crossref PubMed Scopus (44) Google Scholar Excessive parathyroid hormone (PTH) secretion often causes cardiovascular calcification, which substantially impairs the survival and quality of life of these patients.1Cunningham J. Locatelli F. Rodriguez M. Secondary hyperparathyroidism: pathogenesis, disease progression, and therapeutic options.Clin J Am Soc Nephrol. 2011; 6: 913-921Crossref PubMed Scopus (380) Google Scholar Accordingly, in chronic kidney disease patients it is important to manage intact PTH (iPTH) levels as well as those of serum calcium and phosphorus.3Ketteler M. Block G.A. Evenepoel P. et al.Executive summary of the 2017 KDIGO Chronic Kidney Disease–Mineral and Bone Disorder (CKD-MBD) Guideline Update: what's changed and why it matters.Kidney Int. 2017; 92: 26-36Abstract Full Text Full Text PDF PubMed Scopus (511) Google Scholar For the prevention and management of SHPT, oral phosphate binders and oral or i.v. vitamin D receptor activators have long been used. However, the development of hypercalcemia and hyperphosphatemia was one of the problems associated with vitamin D receptor activator therapy.1Cunningham J. Locatelli F. Rodriguez M. Secondary hyperparathyroidism: pathogenesis, disease progression, and therapeutic options.Clin J Am Soc Nephrol. 2011; 6: 913-921Crossref PubMed Scopus (380) Google Scholar Cinacalcet hydrochloride is an oral calcimimetic agent that acts allosterically on the calcium-sensing receptor on parathyroid cells to suppress PTH secretion. In contrast to vitamin D receptor activators, cinacalcet decreases serum levels of calcium and phosphorus. Thus, cinacalcet therapy has been demonstrated to significantly increase the achievement rate of target levels of serum iPTH, calcium, and phosphorus4Akizawa T. Kido R. Fukagawa M. et al.Decreases in PTH in Japanese hemodialysis patients with secondary hyperparathyroidism: associations with changing practice patterns.Clin J Am Soc Nephrol. 2011; 6: 2280-2288Crossref PubMed Scopus (23) Google Scholar, 5Beladi-Mousavi S.S. Faramarzi M. Calcimimetic agents in the management of secondary hyperparathyroidism among patients with end-stage renal disease; a review article.J Parathyr Dis. 2015; 3: 12-19Google Scholar, 6Fukagawa M. Yumita S. Akizawa T. et al.KRN1493 study group: cinacalcet (KRN1493) effectively decreases the serum intact PTH level with favorable control of the serum phosphorus and calcium levels in Japanese dialysis patients.Nephrol Dial Transplant. 2008; 23: 328-335Crossref PubMed Scopus (106) Google Scholar and has been suggested to decrease the risk of vascular calcification and mortality.7Chertow G.M. Block G.A. et al.EVOLVE Trial InvestigatorsEffect of cinacalcet on cardiovascular disease in patients undergoing dialysis.N Engl J Med. 2012; 367: 2482-2494Crossref PubMed Scopus (686) Google Scholar, 8Akizawa T. Kurita N. Mizobuchi M. et al.PTH-dependence of the effectiveness of cinacalcet in hemodialysis patients with secondary hyperparathyroidism.Sci Rep. 2016; 6: 19612Crossref PubMed Scopus (35) Google Scholar Despite such favorable effects, gastrointestinal (GI) symptoms and drug interactions (cytochrome P450 [CYP]2D6 inhibition and CYP3A4-mediated metabolism) remain important concerns in cinacalcet treatment.9Akizawa T. Koshikawa S. Clinical study of cinacalcet in Japan.Ther Apher Dial. 2008; 12: S13-S15Crossref PubMed Scopus (3) Google Scholar, 10Akiba T. Akizawa T. Tsukamoto Y. et al.Dose determination of cinacalcet hydrochloride in Japanese hemodialysis patients with secondary hyperparathyroidism.Ther Apher Dial. 2008; 12: 117-125Crossref PubMed Scopus (22) Google Scholar GI-related adverse events (AEs) especially are critically responsible for low adherence and insufficient dosage.11Gincherman Y. Moloney K. McKee C. et al.Assessment of adherence to cinacalcet by prescription refill rates in hemodialysis patients.Hemodial Int. 2010; 14: 68-72Crossref PubMed Scopus (51) Google Scholar Etelcalcetide is a new calcimimetic agent for i.v. use developed to improve adherence. However, there remains an unmet need to develop a calcimimetic agent that causes fewer GI symptoms than cinacalcet and etelcalcetide.12Block G.A. Bushinsky D.A. Cheng S. et al.Effect of etelcalcetide vs cinacalcet on serum parathyroid hormone in patients receiving hemodialysis with secondary hyperparathyroidism. A randomized clinical trial.JAMA. 2017; 317: 156-164Crossref PubMed Scopus (144) Google Scholar Evocalcet is another new calcimimetic agent for oral use developed to address the issues reported with cinacalcet use. In addition to suppression of PTH, this agent was selected for further investigation because of its favorable profile by evaluating the effect on gastric emptying in rats and the interaction with CYPs in human liver microsomes.13Kawata T. Tokunaga S. Murai M. et al.A novel calcimimetic agent, evocalcet (MT-4580/KHK7580), suppresses the parathyroid cell function with little effect on the gastrointestinal tract or CYP isozymes in vivo and in vitro.PLoS One. 2018; 3;13: e0195316Google Scholar The present phase 3 clinical trial was conducted with a double-dummy, double-blind design to investigate the efficacy (noninferiority) and safety of evocalcet, with cinacalcet as the comparator. A total of 639 patients were enrolled (320 randomized to receive evocalcet and 319 to receive cinacalcet) from October 2015 to April 2016, with the end-of-participant follow-up in November 2016. The disposition of patients is shown in Figure 1. Five patients discontinued the study before initiating treatment; thus, 634 patients received treatment with evocalcet or cinacalcet (n = 317, each). Of these patients, 526 patients (evocalcet group, 256; cinacalcet group, 270) completed the study. A total of 519 patients (evocalcet group, 253; cinacalcet group, 266) were included in the per-protocol set, 623 patients (evocalcet group, 313; cinacalcet group, 310) were included in the full analysis set, and 634 patients (evocalcet group, 317; cinacalcet group, 317) were included in the safety analysis set. Patient baseline demographic and clinical characteristics are summarized in Table 1. More than 60% of patients in both groups had previously received cinacalcet treatment. More than 20% of patients in both groups had baseline iPTH ≥ 500 pg/ml. Overall, patient characteristics were well balanced between the 2 treatment groups. In the per-protocol set, 153 and 175 patients used cinacalcet before treatment initiation in the evocalcet and cinacalcet groups, respectively, and the mean (SD) duration of cinacalcet treatment before wash-out prior to treatment initiation was comparable: 3.45 (2.55) years and 3.97 (2.62) years. During the evaluation period (28–30 weeks), the median average daily dose (SD) was 3.5 mg (2.4 mg) for evocalcet and 49.20 mg (30.09 mg) for cinacalcet.Table 1Baseline patient demographic and clinical characteristicsPatient characteristicsSafety analysis setPer protocol setEvocalcet(n = 317)Cinacalcet(n = 317)Evocalcet(n = 253)Cinacalcet(n = 266)Male222 (70.0)226 (71.3)177 (70.0)195 (73.3)Age (yr)61.5 (11.3)61.2 (11.0)60.9 (11.4)60.7 (11.1) ≥65 yr148 (46.7)136 (42.9)112 (44.3)108 (40.6)Primary diseaseaFor primary disease and dialysate calcium concentration in the safety analysis set and duration of dialysis in the per-protocol set, the percentages in the evocalcet column do not add up to 100 because of rounding. Diabetic nephropathy85 (26.8)72 (22.7)66 (26.1)63 (23.7) Chronic glomerulonephritis132 (41.6)139 (43.8)104 (41.1)109 (41.0) Other100 (31.5)106 (33.4)83 (32.8)94 (35.3)Duration of dialysis (yr)aFor primary disease and dialysate calcium concentration in the safety analysis set and duration of dialysis in the per-protocol set, the percentages in the evocalcet column do not add up to 100 because of rounding. <570 (22.1)60 (18.9)59 (23.3)50 (18.8) 5–<1097 (30.6)86 (27.1)76 (30.0)71 (26.7) 10–<20117 (36.9)120 (37.9)95 (37.5)105 (39.5) ≥2033 (10.4)51 (16.1)23 (9.1)40 (15.0)Type of dialysis Hemodialysis251 (79.2)244 (77.0)200 (79.1)206 (77.4) Hemodiafiltration66 (20.8)73 (23.0)53 (20.9)60 (22.6)Dialysate calcium concentration (mEq/l)aFor primary disease and dialysate calcium concentration in the safety analysis set and duration of dialysis in the per-protocol set, the percentages in the evocalcet column do not add up to 100 because of rounding. 2.583 (26.2)82 (25.9)71 (28.1)70 (26.3) 2.75114 (36.0)111 (35.0)86 (34.0)92 (34.6) 3.0120 (37.9)124 (39.1)96 (37.9)104 (39.1)History Use of cinacalcet before screening190 (59.9)212 (66.9)155 (61.3)179 (67.3) Use of vitamin D receptor activators at treatment initiation264 (83.3)281 (88.6)217 (85.8)237 (89.1) Use of phosphate binder/calcium preparation at treatment initiation296 (93.4)302 (95.3)236 (93.3)253 (95.1)Baseline intact parathyroid hormone (pg/ml) <500250 (78.9)239 (75.4)198 (78.3)199 (74.8) ≥50067 (21.1)78 (24.6)55 (21.7)67 (25.2)Baseline intact parathyroid hormone (pg/ml)417.4 (175.1)425.8 (189.8)418.3 (176.9)426.8 (195.4)Baseline corrected calcium (mg/dl)9.51 (0.56)9.61 (0.62)9.52 (0.56)9.60 (0.59)Baseline phosphorus (mg/dl)5.77 (1.30)5.56 (1.14)5.75 (1.31)5.54 (1.12)Baseline bone-specific alkaline phosphatase (μg/l)17.56 (9.81)17.78 (9.86)17.58 (9.90)17.38 (9.87)Baseline tartrate-resistant acid phosphatase 5b (mU/dl)790.0 (406.8)884.6 (464.9)783.2 (394.5)859.3 (429.5)Baseline total N-terminal propeptide of type 1 procollagen (μg/l)432.1 (284.0)458.8 (276.4)437.3 (287.5)446.7 (266.9)Data are presented as number (percentage) or mean (SD). SI conversion factors: to convert intact parathyroid hormone to ng/l, multiply values by 1; to convert corrected calcium to mg/l, multiply values by 10; to convert phosphorus to mg/l, multiply values by 10.a For primary disease and dialysate calcium concentration in the safety analysis set and duration of dialysis in the per-protocol set, the percentages in the evocalcet column do not add up to 100 because of rounding. Open table in a new tab Data are presented as number (percentage) or mean (SD). SI conversion factors: to convert intact parathyroid hormone to ng/l, multiply values by 1; to convert corrected calcium to mg/l, multiply values by 10; to convert phosphorus to mg/l, multiply values by 10. Among 519 patients in the per-protocol set (primary analysis set), the number (%) (95% confidence interval [CI]) of patients who achieved the target iPTH level (primary endpoint) was 184 (72.7%) (66.8%, 78.1%) and 204 (76.7%) (71.1%, 81.6%) in the evocalcet and cinacalcet groups, respectively. The difference in the achievement rates between the groups was −4.0% (95% CI −11.4%, 3.5%, P for noninferiority, P = 0.002). Because the lower limit of the 2-sided 95% CI for the difference was −11.4%, which exceeded the noninferiority margin of −15%, the noninferiority of evocalcet to cinacalcet was confirmed. In the full analysis set (secondary analysis set), the nonresponder imputation (assumes participants with missing outcomes are nonresponders) results were not consistent with those of the per-protocol set; however, the results of last observation carried forward and multiple imputation supported the noninferiority confirmed in the per-protocol set (Table 2).Table 2Results of the primary endpointAnalysis setEvocalcet, % (n)Cinacalcet, % (n)Evocalcet – cinacalcet (%)(95% CI)Per-protocol setaPrespecified as primary analysis set.72.7 (184/253)76.7 (204/266)−4.0 (−11.4, 3.5)Full analysis set (nonresponder imputation)59.7 (187/313)67.4 (209/310)−7.7 (−15.2, –0.1)Full analysis set (last observation carried forward)66.5 (208/313)71.6 (222/310)−5.2 (−12.4, 2.1)Full analysis set (multiple imputation)71.275.3−4.2 (−11.6, 3.3)CI, confidence interval.a Prespecified as primary analysis set. Open table in a new tab CI, confidence interval. Regarding secondary endpoints, the number (%) (95% CI) of patients who achieved a ≥30% decrease in iPTH level from baseline was 208 (82.2%) (76.9%, 86.7%) and 235 (88.3%) (83.9%, 91.9%) in the evocalcet and cinacalcet groups, respectively. The mean percent change [SD] in the iPTH level was comparable between the evocalcet and cinacalcet groups (−49.64% [25.87%] and −53.57% [23.00%], respectively). Other endpoints, iPTH, whole PTH, serum-ionized calcium, serum-corrected calcium, serum phosphorus, and intact fibroblast growth factor 23 (FGF23) decreased over time in both groups after study drug administration (Figure 2a–f). The mean levels of the bone turnover markers bone-specific alkaline phosphatase, tartrate-resistant acid phosphatase 5b, and total N-terminal propeptide of type 1 procollagen decreased over time, showing similar trends in both groups (Supplementary Figure S1). Among the 634 patients in the safety analysis set, AEs occurred in 288 patients (90.9%) and 289 patients (91.2%), and adverse drug reactions occurred in 142 patients (44.8%) and 186 patients (58.7%) in the evocalcet and cinacalcet groups, respectively (Table 3). There were no abnormalities associated with vital signs, clinical laboratory measurements, or 12-lead electrocardiography.Table 3Adverse events occurring in 5% of patients or moreAdverse eventEvocalcet(n = 317)Cinacalcet(n = 317)Nasopharyngitis101 (31.9)103 (32.5)Corrected calcium decreased37 (11.7)50 (15.8)Contusion30 (9.5)24 (7.6)Vomiting27 (8.5)37 (11.7)Diarrhea26 (8.2)30 (9.5)Nausea23 (7.3)45 (14.2)Shunt stenosis20 (6.3)12 (3.8)Arthralgia17 (5.4)15 (4.7)Upper respiratory tract inflammation16 (5.0)18 (5.7)Abdominal discomfort14 (4.4)35 (11.0)Blood calcium decreased11 (3.5)24 (7.6)Data are presented as n (%). Open table in a new tab Data are presented as n (%). The overall incidence of GI-related AEs (nausea, vomiting, abdominal discomfort, decreased appetite, and abdominal distension) was lower in the evocalcet group than in the cinacalcet group (59 patients [18.6%; 95% CI 14.5%, 23.3%] vs. 104 patients [32.8%; 95% CI 27.7%, 38.3%], with a between-group difference of −14.2% [95% CI −20.9%, −7.5%], P < 0.001 for superiority) (Figure 3). Such GI-related AEs resulted in dose reduction, interruption, or discontinuation of the drug in 7 patients (11.9%) versus 34 patients (32.7%) (P < 0.001) in the evocalcet and cinacalcet groups, respectively (post hoc analysis). The incidence of calcium decrease–related AEs (classed as MedDRA Preferred Terms "blood calcium decreased," "corrected calcium decreased," and "hypocalcemia") was 18.6% and 24.3% in the evocalcet and cinacalcet groups, respectively. "Corrected calcium decreased" was also the most frequently occurring AE leading to interruption of treatment in both groups (evocalcet group: 28 patients [8.8%]; cinacalcet group: 43 patients [13.6%]). Calcium carbonate was the most frequently used among calcium preparations, and although the dose was increased during the study, the daily dose and the degree of increase were comparable between groups (2689 and 2707 mg/d at week 30 in the evocalcet and cinacalcet groups, respectively). Evocalcet has been developed as a new calcimimetic agent for SHPT with fewer GI symptoms and fewer drug interactions. In this head-to-head comparison study, we compared the efficacy and safety of evocalcet with that of cinacalcet. It was demonstrated that evocalcet was noninferior to cinacalcet in maintaining iPTH levels within the target range. Evocalcet was administered starting from a higher initial dose (2 mg) when the iPTH level was ≥500 pg/ml at 1 week before treatment initiation. In the evaluation period (28–30 weeks), patients treated with evocalcet achieved the target iPTH level as efficiently as those who received cinacalcet (47.5% and 43.3%, respectively). Therefore, with a higher starting dose, evocalcet efficiently suppressed PTH levels in dialysis patients even with severe SHPT. Cinacalcet causes GI symptoms such as nausea and vomiting, which lead to poorer adherence and dosing.11Gincherman Y. Moloney K. McKee C. et al.Assessment of adherence to cinacalcet by prescription refill rates in hemodialysis patients.Hemodial Int. 2010; 14: 68-72Crossref PubMed Scopus (51) Google Scholar In this clinical trial, the incidence of GI-related AEs was lower in the evocalcet group (18.6% [95% CI 14.5%, 23.3%]) than in the cinacalcet group (32.8% [95% CI 27.7%, 38.3%]) (P < 0.001), suggesting a greater potential for therapy continuation with evocalcet than cinacalcet (Figure 3, Supplementary Figure S2). The incidence of GI-related AEs in cinacalcet-naïve patients was lower in the evocalcet group (15.0%) than in the cinacalcet group (31.4%) (P = 0.003) (post hoc analysis). Patients with a history of treatment with cinacalcet were divided into 2 groups, those with and without GI symptoms during previous cinacalcet treatment. Evocalcet-treated patients showed a lower incidence of GI-related AEs in both groups throughout the treatment (P = 0.083 and P = 0.018, respectively). The number of patients who discontinued because of AEs was higher in the evocalcet group compared with the cinacalcet group. However, the number of patients who discontinued because of adverse drug reactions was the same in both groups (evocalcet group, 7; cinacalcet group, 7). Among the patients who discontinued on the basis of the investigator's decision, 6 cases and 1 case were for insufficient efficacy in the evocalcet and cinacalcet groups, respectively. A possible reason for this might be the slower dose escalation of evocalcet compared with that of cinacalcet. Regarding drug interactions, cinacalcet is a potent CYP2D6 inhibitor that increases the exposure of CYP2D6 substrates.14Nakashima D. Takama H. Ogasawara Y. et al.Effect of cinacalcet hydrochloride, a new calcimimetic agent, on the pharmacokinetics of dextromethorphan: in vitro and clinical studies.J Clin Pharmacol. 2007; 47: 1311-1319Crossref PubMed Scopus (50) Google Scholar, 15Harris R.Z. Salfi M. Posvar E. et al.Pharmacokinetics of desipramine HCl when administered with cinacalcet HCl.Eur J Clin Pharmacol. 2007; 63: 159-163Crossref PubMed Scopus (17) Google Scholar Co-administration of a potent CYP3A4 inhibitor has been shown to moderately increase cinacalcet exposure.16Harris R.Z. Salfi M. Sullivan J.T. et al.Pharmacokinetics of cinacalcet hydrochloride when administered with ketoconazole.Clin Pharmacokinet. 2007; 46: 495-501Crossref PubMed Scopus (29) Google Scholar However, in the present clinical trial, no AEs related to drug interactions with CYPs were reported. The efficacy of cinacalcet not only for lowering iPTH but also with respect to prognosis (hard outcome) has been reported in several studies. Cinacalcet did not significantly attenuate the risk of mortality and the primary composite endpoint in the unadjusted analysis, but the adjusted hazard ratio was significant, and there were substantial age-related differences in mortality and the primary composite endpoint in the lag-censoring analysis in the Evaluation of Cinacalcet Hydrochloride Therapy to Lower Cardiovascular Events.7Chertow G.M. Block G.A. et al.EVOLVE Trial InvestigatorsEffect of cinacalcet on cardiovascular disease in patients undergoing dialysis.N Engl J Med. 2012; 367: 2482-2494Crossref PubMed Scopus (686) Google Scholar In addition, cinacalcet decreased mortality risk and cardiovascular events in patients with high iPTH levels in the Mineral and Bone Disorder Outcomes Study for Japanese CKD Stage 5D Patients.8Akizawa T. Kurita N. Mizobuchi M. et al.PTH-dependence of the effectiveness of cinacalcet in hemodialysis patients with secondary hyperparathyroidism.Sci Rep. 2016; 6: 19612Crossref PubMed Scopus (35) Google Scholar Several suggested mechanisms for these favorable effects were also compared in this study, including suppression of serum calcium, serum phosphorus, and intact FGF23. Intact FGF23 decreased over time from treatment initiation in both evocalcet and cinacalcet groups (Figure 2f). No difference was noted in the magnitude of this decrease between these groups. No marked difference was noted in iPTH, whole PTH, serum-corrected calcium, serum-ionized calcium, serum phosphorus, or serum calcium-phosphorus product in either group (Figure 2). Thus, possible beneficial effects on objective outcome measures can be anticipated with evocalcet, which should be confirmed in future clinical studies. There are several limitations in this study, especially those related to regionality. This study was conducted only in Japanese SHPT patients receiving hemodialysis whose iPTH level was controlled to be lower than that of patients in other areas, following the guideline proposed by The Japanese Society for Dialysis Therapy (60–240 pg/ml).17Fukagawa M. Yokoyama K. Koiwa F. et al.CKD-MBD Guideline Working Group; Japanese Society for Dialysis Therapy: clinical practice guideline for the management of chronic kidney disease-mineral and bone disorder.Ther Apheresis Dial. 2013; 17: 247-288Crossref PubMed Scopus (259) Google Scholar Furthermore, the incidence of parathyroidectomy and the number of severe SHPT patients are lower in Japan than in other countries18Tentori F. Wang M. Bieber B.A. et al.Recent changes in therapeutic approaches and association with outcomes among patients with secondary hyperparathyroidism on chronic hemodialysis: the DOPPS study.Clin J Am Soc Nephrol. 2015; 10: 98-109Crossref PubMed Scopus (199) Google Scholar; therefore, the results cannot be generalized to other ethnic populations. In summary, in this head-to-head comparison study, evocalcet was found to be noninferior to cinacalcet in suppressing iPTH levels in hemodialysis patients, with fewer GI-related AEs and no presumed drug interactions. Thus, our results suggest that evocalcet may be a potent alternative to existing calcimimetics for the management of SHPT, with fewer GI-related AEs. This study was conducted in 89 facilities in Japan (Supplementary Material S3, List of Collaborators). The study protocol was approved by the institutional review board at each center. All study procedures were conducted in accordance with the Declaration of Helsinki and in compliance with the Pharmaceuticals and Medical Devices Act, Ministerial Ordinance on Good Clinical Practice and its partial amendments. The study was registered at ClinicalTrials.gov (NCT02549391) and JAPIC (JapicCTI-153013). Written informed consent was obtained from all patients. Cinacalcet was washed out within ≥2 weeks before the screening period. Other treatments, such as vitamin D receptor activator, phosphate binders, calcium preparations, and dialysis conditions, including dialysate calcium level, were not changed. The inclusion criteria were age ≥20 years, hemodialysis 3 times per week for ≥12 weeks, iPTH level of >240 pg/ml (average of the values measured at 2 weeks and 1 week before the study initiation), and serum calcium level corrected for albumin ≥ 9.0 mg/dl. Detailed exclusion criteria are listed in Supplementary Material S4, Detailed Exclusion Criteria. This was a multicenter, active-controlled, randomized, double-blind, double-dummy, intra-subject dose-adjustment, parallel-group study of evocalcet in SHPT patients receiving hemodialysis. Cinacalcet was used as the active control. The study design is shown in Figure 4. The study included a dose adjustment period of 28 weeks and an evaluation period of 2 weeks. Patients who fulfilled all of the eligibility criteria were randomized in a 1:1 ratio either to the evocalcet group or to the cinacalcet group using a dynamic allocation procedure. The investigative site and iPTH level (<500 pg/ml or ≥500 pg/ml) at 1 week before treatment initiation were used as stratification factors. Randomization was performed using an interactive web response system. For administration of the study drug, we applied a double-dummy technique and ensured concealment of allocation sequence and blindness. The evocalcet group received evocalcet and the cinacalcet placebo, and the cinacalcet group received cinacalcet and the evocalcet placebo, orally once daily for 30 weeks. The dosage and administration of evocalcet were based on previous clinical trials. In the dose adjustment period, evocalcet was administered at an initial dose of 1 mg if the iPTH level was <500 pg/ml or 2 mg if the iPTH level was ≥500 pg/ml at 1 week before treatment initiation. Cinacalcet was administered at an initial dose of 25 mg for all patients, regardless of the iPTH level. Then the dose was adjusted to achieve the target iPTH level range proposed by The Japanese Society for Dialysis Therapy (60–240 pg/ml).17Fukagawa M. Yokoyama K. Koiwa F. et al.CKD-MBD Guideline Working Group; Japanese Society for Dialysis Therapy: clinical practice guideline for the management of chronic kidney disease-mineral and bone disorder.Ther Apheresis Dial. 2013; 17: 247-288Crossref PubMed Scopus (259) Google Scholar The doses of evocalcet and cinacalcet were increased by 1 mg and 25 mg, or reduced by 1 mg and 12.5–25 mg, respectively. The maximum dose was set at 8 mg for evocalcet and 100 mg for cinacalcet. During the evaluation period, the dose at the end of the dose adjustment period was maintained except for dose reduction and interruption of treatment. The dose escalation criteria were as follows: maintenance of the current dose for at least 3 weeks; an iPTH level > 240 pg/ml or dose escalation judged as possible by the investigators even if the iPTH level was ≤240 pg/ml (but not lower than 150 pg/ml); a serum-corrected calcium level ≥ 8.4 mg/dl; and dose escalation judged as possible by the investigators without affecting the safety of the study subject. When all the dose escalation criteria were met, the dose was increased on the dialysis day by 1 mg for evocalcet and by 25 mg for cinacalcet. When the cinacalcet dose reached 87.5 mg (except for a dose reduction from 100 mg) or 100 mg, the dose was increased only for evocalcet. The dose was reduced if the iPTH level decreased to <60 pg/ml or if a dose reduction was judged by the investigators as necessary because of AEs. If any of the dose reduction criteria were met, the dose reduction was set at 1 mg for evocalcet and at 25 mg for cinacalcet. In some cases, however, a dose reduction of 12.5 mg for cinacalcet was permitted. In addition, if the dose of cinacalcet was 25 mg, the dose was reduced to 12.5 mg. The dose was interrupted if the serum-corrected calcium level (centrally measured) decreased to ≤7.5 mg/dl, or if the investigator determined that dose interruption was necessary because of AEs. All clinical examinations were performed in central laboratories. iPTH was measured by electrochemiluminescence assay (ECLusys PTH; Roche Diagnostics, Tokyo, Japan). Intact FGF23 was measured by enzyme-linked immunosorbent assay (FGF-23 ELISA Kit; KAINOS Laboratories, Tokyo, Japan). The primary endpoint was the proportion of patients who achieved a mean iPTH level of 60–240 pg/ml during the evaluation period. The noninferiority of evocalcet to cinacalcet was evaluated. The secondary endpoints included the proportion of patients achieving a decrease in iPTH level of ≥30% from baseline and the mean percent change in iPTH level from baseline. Other endpoints included the time-course changes of iPTH, whole PTH, serum calcium level corrected for albumin, serum-ionized calcium, serum phosphorus, and intact FGF23. Serum markers of bone turnover (bone-specific alkaline phosphatase, tartrate-resistant acid phosphatase 5b, and total N-terminal propeptide of type 1 procollagen) were also evaluated. The safety profile was characterized by AEs, vital signs, clinical laboratory measurements, and 12-lead electrocardiography for patients who received at least 1 dose of either study drug. AEs were summarized by frequency and categorized according to Preferred Term (MedDRA version 19.0). Because dialysis patients in Japan are usually monitored by doctors as well as other medical staff 3 times per week at each dialysis session, AEs, including those related to GI symptoms, were assessed by investigators' interviews or patients' self-reports at those times. AEs were assessed and compared between the 2 groups. AEs related to GI symptoms were prespecified as a combination of the following 5 events: nausea, vomiting, abdominal discomfort, decreased appetite, and abdominal distension, on the basis of the safety profile of a previous cinacalcet phase 3 study.6Fukagawa M. Yumita S. Akizawa T. et al.KRN1493 study group: cinacalcet (KRN1493) effectively decreases the serum intact PTH level with favorable control of the serum phosphorus and calcium levels in Japanese dialysis patients.Nephrol Dial Transplant. 2008; 23: 328-335Crossref PubMed Scopus (106) Google Scholar AEs were categorized according to Preferred Term (MedDRA version 19.0). The target number of patients (231 per group) was calculated using the z test, with a percentage of patients achieving an iPTH level of ≥60 pg/ml and ≤240 pg/ml of 60% for each group, a noninferiority margin of 15%, a 1-sided significance level of 2.5%, and a power of 90%. Given that approximately 20% of patients could drop out or be excluded from the per-protocol set, the target number of patients receiving study treatment was set at 300 per group. The definitions of the analysis sets are described in Supplementary Material S5, Study Analysis Sets. The proportion of patients who achieved target levels of iPTH and ≥30% decreases in iPTH levels from baseline and exact 95% CIs were calculated for each group. The difference in the achievement rates between the groups (evocalcet group − cinacalcet group) and a 2-sided 95% CI (normal approximation) for the difference were calculated. The per-protocol set was prespecified as the primary analysis set. The noninferiority of evocalcet to cinacalcet was verified when the lower limit of the 2-sided 95% CI for the difference in the achievement rates between the groups exceeded a noninferiority margin of −15%, on the basis of a previous phase 3 study of cinacalcet.6Fukagawa M. Yumita S. Akizawa T. et al.KRN1493 study group: cinacalcet (KRN1493) effectively decreases the serum intact PTH level with favorable control of the serum phosphorus and calcium levels in Japanese dialysis patients.Nephrol Dial Transplant. 2008; 23: 328-335Crossref PubMed Scopus (106) Google Scholar As a secondary analysis set, the full analysis set (nonresponder imputation) was prespecified. In addition, data for withdrawn patients were handled by last observation carried forward and multiple imputation to supplement the missing values for the primary endpoint. For a discontinued subject, the mean iPTH concentration during the evaluation period was imputed by last observation carried forward using the mean iPTH concentration at 3 time points closest to the day of discontinuation. In addition, missing data were imputed by multiple imputation using Markov chain Monte Carlo methods, under the assumption of a normal distribution for log-transformed iPTH concentrations from baseline to week 30 in each subject. By inverse transformation (exponential transformation), the mean iPTH concentration during the evaluation period was derived for each subject. The number of imputations performed was 100. In general, categorical data are summarized by frequency and percentage, and continuous data are summarized using descriptive statistics (number of patients, mean, and SD). Statistical significance was set at P < 0.05. The statistical analysis was performed using SAS 9.4 (SAS Institute, Cary, NC). MF has received consulting fees from Kyowa Hakko Kirin (KHK) Co., Ltd. and Ono Pharmaceutical Co., Ltd.; lecture fees from KHK Co., Ltd., Bayer Yakuhin, Ltd., Torii Pharmaceutical Co., Ltd., and Ono Pharmaceutical Co., Ltd.; and grants from KHK Co., Ltd. and Bayer Yakuhin, Ltd. TA has received consulting fees from KHK Co., Ltd., Astellas Pharma Inc., Bayer Yakuhin, Ltd., Fuso Pharmaceutical Industries, Ltd., Japan Tobacco Inc., Ono Pharmaceutical Co., Ltd., and NIPRO Industry; and lecture fees from KHK Co., Ltd., Chugai Pharmaceutical Co., Ltd., Bayer Yakuhin, Ltd., Kissei Pharmaceutical Co., Ltd., Torii Pharmaceutical Co., Ltd., and Ono Pharmaceutical Co., Ltd. RS is employed by KHK, which funded this research. All the other collaborators listed in Supplementary Material S3 are the members of Evocalcet study group and were paid by KHK for participating in this study. The results of this study were presented in poster format at Kidney Week 2017 (New Orleans, LA, October 31–November 5, 2017). The authors wish to thank Michelle Belanger, MD, of Edanz Medical Writing for providing medical writing assistance. This trial was sponsored by Kyowa Hakko Kirin (KHK). KHK participated in and approved the design and conduct of the study. KHK was involved in the collection, management, analysis, and interpretation of the data; preparation, review, and approval of the manuscript; and decision to submit the manuscript for publication. All authors designed the study and contributed to acquisition, analysis, and interpretation of data; MF drafted the manuscript; MF, RS, and TA revised the manuscript critically for important intellectual content. All authors approved the final version of the manuscript. Download .doc (.18 MB) Help with doc files Figure S1Changes in markers of bone turnover. (A) Bone-specific alkaline phosphatase (BAP), (B) tartrate-resistant acid phosphatase 5b (TRACP-5b), and (C) total N-terminal propeptide of type 1 procollagen (P1NP). Download .doc (.09 MB) Help with doc files Figure S2Kaplan-Meier plots of the cumulative incidence of gastrointestinal-related adverse events at the first occurrence. Download .docx (.02 MB) Help with docx files Supplemental Material S3List of Collaborators. Download .docx (.01 MB) Help with docx files Supplemental Material S4Detailed Exclusion Criteria. Download .docx (.01 MB) Help with docx files Supplemental Material S5Study Analysis Sets. Evocalcet in the management of secondary hyperparathyroidism in dialysis patientsKidney InternationalVol. 94Issue 4PreviewUse of calcimimetics will be influenced not only by assessment of benefits and harms in individual patients but also by cost and by national guidelines. The Japanese Society for Dialysis Therapy has a lower PTH threshold for PTH control than other countries. The current RCT, despite its limitations, provides a rationale for use of evocalcet in the management of secondary hyperPTH. Full-Text PDF Open ArchiveIn this issueKidney InternationalVol. 94Issue 4PreviewThe enzyme renin is produced exclusively by juxtaglomerular cells in the kidney; until now, its only known substrate was angiotensinogen. Békássy and colleagues showed that renin can cleave complement component C3 into C3a and C3b, thereby activating the alternative pathway. Renin cleaves C3 in the same place as the C3 convertase, and with similar activity. Renin-mediated complement activation was blocked by aliskiren, a renin inhibitor approved for the treatment of hypertension. Békássy's team then treated 3 patients who had dense deposit disease with aliskiren and showed that systemic C3 levels improved, suggesting less C3 cleavage. Full-Text PDF Open Archive