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1.
Evocalcet with vitamin D receptor activator treatment for secondary hyperparathyroidism.
Shigematsu, T, Asada, S, Endo, Y, Kawata, T, Fukagawa, M, Akizawa, T
PloS one. 2022;(2):e0262829
Abstract
This ad hoc analysis of a previously conducted phase 3 head-to-head comparison study of evocalcet and cinacalcet in secondary hyperparathyroidism patients undergoing maintenance hemodialysis evaluated the efficacy and safety of combined once-daily oral evocalcet and intravenous vitamin D receptor activator treatment stratified by weekly vitamin D receptor activator dose (117, 45, and 91 patients in no, low [< 1.5 μg], and high [≥ 1.5 μg] dose groups, respectively). Effects of vitamin D receptor activator were assessed on the basis of intact parathyroid hormone, corrected calcium, phosphorus, and fibroblast growth factor-23 levels; percent changes from baseline; proportions of patients who achieved target intact parathyroid hormone, corrected calcium, and phosphorus at Weeks 28-30; and adverse drug reactions. Intact parathyroid hormone, corrected calcium, phosphorus, and fibroblast growth factor-23 levels decreased in all groups; phosphorus and fibroblast growth factor-23 levels remained high in the high dose group. In the low and high dose groups, greater proportions of patients achieved the corrected calcium target compared with the no dose group (p = 0.043). Ratios of intact-to-C-terminal fibroblast growth factor-23 decreased in all groups. In low and high dose groups, hypocalcemia was less common than in the no dose group (p = 0.014). Evocalcet with concomitant vitamin D receptor activator demonstrated benefits such that more patients achieved the corrected calcium target and exhibited decreased fibroblast growth factor-23 synthesis; the incidence of hypocalcemia also decreased. Clinical trial registration: ClinicalTrials.gov (NCT02549391) and JAPIC (JapicCTI-153013).
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2.
Paricalcitol- or cinacalcet-centred therapy affects markers of bone mineral disease in patients with secondary hyperparathyroidism receiving haemodialysis: results of the IMPACT-SHPT study.
Cozzolino, M, Ketteler, M, Martin, KJ, Sharma, A, Goldsmith, D, Khan, S
Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 2014;(4):899-905
Abstract
BACKGROUND In this Phase 4 international study, efficacy and safety of paricalcitol-centred therapy were compared with that of cinacalcet-centred therapy for the treatment of chronic kidney disease (CKD)-associated secondary hyperparathyroidism (SHPT) in patients undergoing haemodialysis (ClinicalTrials.gov identifier NCT00977080). METHODS Patients ≥ 18 years of age with Stage 5 CKD and SHPT [intact parathyroid hormone (iPTH) level of 300-800 pg/mL, calcium level of 8.4-10.0 mg/dL and phosphate concentration of ≤ 6.5 mg/dL] who were undergoing haemodialysis were included. Patients were randomized by mode of paricalcitol administration [i.e. intravenous (IV) or oral strata] to receive paricalcitol- or cinacalcet-centred therapy for ≤ 28 weeks. Changes in metabolic markers [total alkaline phosphatase (AP), bone-specific AP and fibroblast growth factor-23 (FGF-23)] and the proportion of patients in each treatment group who achieved an iPTH level of 150-300 pg/mL during Weeks 8, 16 and 21-28 as a composite value were evaluated. RESULTS Compared with cinacalcet-centred therapy, levels of both bone turnover markers were significantly reduced from baseline with IV and oral paricalcitol-centred treatment (P < 0.05 for both dosing strata) at Weeks 8, 16 and 28. Levels of FGF-23 were increased with paricalcitol versus cinacalcet-centred treatment. A greater proportion of patients receiving paricalcitol-centred therapy achieved target iPTH levels (i.e. 150-300 pg/mL) throughout the study in the IV and oral dosing strata compared with patients receiving cinacalcet-centred treatment. CONCLUSIONS In patients with CKD and SHPT undergoing haemodialysis, paricalcitol-centred therapy reduced circulating bone turnover markers and iPTH levels and increased FGF-23 levels compared with cinacalcet-centred treatment. TRIAL REGISTRATION ClinicalTrials.gov identifier NCT00977080.
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3.
Cinacalcet treatment decreases plasma fibroblast growth factor 23 concentration in haemodialysed patients with chronic kidney disease and secondary hyperparathyroidism.
Kuczera, P, Adamczak, M, Wiecek, A
Clinical endocrinology. 2014;(4):607-12
Abstract
OBJECTIVE Recent clinical studies suggest that fibroblast growth factor 23 (FGF23) is important in the pathogenesis of calcium-phosphate abnormalities in patients with chronic kidney disease and that increased plasma FGF23 concentration is a cardiovascular risk factor in these patients. The aim of this prospective, single-arm, open-label clinical study was to assess the influence of 6-month cinacalcet treatment on plasma FGF23 concentration in haemodialysed patients with secondary hyperparathyroidism (sHPT). DESIGN, PATIENTS AND MEASUREMENTS In 58 haemodialysed patients with sHPT (parathormone PTH > 300 ng/l), serum PTH, FGF23, calcium and phosphate concentrations were assessed before the first dose of cinacalcet and after 3 and 6 months of treatment. RESULTS Serum PTH concentration decreased significantly after 3 and 6 months of treatment, and the mean serum calcium and phosphate concentrations remained stable during the treatment period. Plasma FGF23 concentration (geometric mean with 95% confidence index) decreased after 3 and 6 months of treatment from 354 (261-481) ng/l to 295 (204-428) ng/l; P = 0·099 and to 183 (117-285) ng/l; P = 0·015, respectively. FGF23 concentration decreased in 52% of patients. In multivariate regression analysis, plasma FGF23 concentration changes were explained by the changes in serum phosphate, but not by serum PTH or calcium changes or by the dose of cinacalcet. CONCLUSIONS 1. Cinacalcet treatment decreases plasma FGF23 concentration in haemodialysed patients with secondary hyperparathyroidism. 2. The decrease in plasma FGF23 concentration seems to be related to the decrease in serum phosphate concentration.
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Efficacy of cinacalcet with low-dose vitamin D in incident haemodialysis subjects with secondary hyperparathyroidism.
Ureña-Torres, P, Bridges, I, Christiano, C, Cournoyer, SH, Cooper, K, Farouk, M, Kopyt, NP, Rodriguez, M, Zehnder, D, Covic, A
Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 2013;(5):1241-54
Abstract
BACKGROUND Treatment with cinacalcet improves the control of secondary hyperparathyroidism (SHPT) and the achievement of calcium and phosphorus targets. Most data come from subjects receiving cinacalcet after several years of dialysis treatment. We therefore compared the efficacy of treatment with cinacalcet and low doses of active vitamin D to flexible doses of active vitamin D alone for the management of SHPT in patients recently initiating haemodialysis. METHODS This open-label trial randomized subjects (n = 309) with parathyroid hormone (PTH) >300 pg/mL on dialysis for 3-12 months to either cinacalcet with low-dose active vitamin D, if prescribed (cinacalcet); or usual care without cinacalcet (control). Randomized subjects were stratified by PTH at screening (300-450, >450-600, >600 pg/mL) and by the use of active vitamin D at enrolment. Treatment duration was 12 months, with primary efficacy endpoint (mean PTH reduction ≥ 30% from baseline) assessed at 6 months. RESULTS The mean [standard deviation (SD)] haemodialysis vintage at enrolment was 7.2 (2.7) months; 53% of subjects were not receiving active vitamin D at enrolment. There was a significant difference in the achievement of the primary endpoint (≥ 30% PTH reduction at 6 months) between cinacalcet-treated subjects and controls in both the entire cohort (63 versus 38%; n = 304; P < 0.0001) and the subgroup of subjects not receiving active vitamin D at enrolment (70 versus 44%; n = 161; P < 0.01). Hypocalcaemia and gastrointestinal adverse events were more commonly observed in cinacalcet-treated subjects. CONCLUSIONS These results indicate that cinacalcet with low-dose active vitamin D, if prescribed, provides a more effective treatment approach than usual care without cinacalcet for SHPT in incident haemodialysis patients, even in relatively treatment-naive patients.
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Cinacalcet treatment and serum FGF23 levels in haemodialysis patients with secondary hyperparathyroidism.
Koizumi, M, Komaba, H, Nakanishi, S, Fujimori, A, Fukagawa, M
Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 2012;(2):784-90
Abstract
BACKGROUND Elevated fibroblast growth factor 23 (FGF23) is associated with adverse clinical outcomes and development of secondary hyperparathyroidism (SHPT) refractory to active vitamin D. Cinacalcet hydrochloride is effective in treating SHPT, but little is known as to whether treatment with cinacalcet alters these levels and whether pretreatment FGF23 levels predict response to this therapy. METHODS We measured serum full-length FGF23 levels in 55 haemodialysis patients, who participated and completed the 52-week, multicentre, open-label single-arm trial that examined the effectiveness of cinacalcet for treating SHPT. In the study, alteration of vitamin D dosage was not permitted except for the case in which serum calcium could not be managed by calcium carbonate adjustment alone. RESULTS After 12 weeks of cinacalcet treatment, FGF23 levels decreased significantly concomitantly with a significant reduction in intact parathyroid hormone (PTH) levels. These responses were sustained >52 weeks. In multivariate regression analyses, changes from baseline in serum FGF23 were associated with changes in serum calcium and phosphorus but not with intact PTH at each time point of measurements (Week-12, Week-24 and Week-52). Baseline FGF23 was not associated with the likelihood of achieving an intact PTH <180 pg/mL at the study end. CONCLUSIONS Cinacalcet lowers serum FGF23 in haemodialysis patients with SHPT independently of the effects of active vitamin D. Pretreatment FGF23 cannot predict treatment response to cinacalcet in this setting. The precise mechanism of FGF23 reduction by cinacalcet and its clinical impact on outcomes in patients remain to be investigated.
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Cinacalcet improves endothelial dysfunction and cardiac hypertrophy in patients on hemodialysis with secondary hyperparathyroidism.
Choi, SR, Lim, JH, Kim, MY, Hong, YA, Chung, BH, Chung, S, Choi, BS, Yang, CW, Kim, YS, Chang, YS, et al
Nephron. Clinical practice. 2012;(1-2):1-8
Abstract
BACKGROUND Secondary hyperparathyroidism (SHPT) in patients on hemodialysis is strongly associated with cardio-vascular morbidity and mortality. Treatment of SHPT with cinacalcet decreases circulating parathyroid hormone (PTH) concentrations and lowers serum calcium and phosphorus concentrations. Therefore, we investigated the cardiovascular effects of cinacalcet in hemodialysis patients with SHPT. METHODS We studied 12 hemodialysis patients with SPHT [serum intact PTH (iPTH) >300 pg/ml]. The study consisted of three phases: an initial run-in period of 16 weeks, including a wash-out period of 4 weeks (pretreatment), a cinacalcet treatment period of 20 weeks (treatment), and 20-week follow-up after suspension of cinacalcet treatment (posttreatment). In this study, vitamin D sterols were not prescribed to all the study subjects for at least 1 year during the pretreatment period. RESULTS Cinacalcet significantly decreased serum iPTH (pretreatment vs. treatment; 628.2 ± 250.8 vs. 251.7 ± 237.4 pg/ml, p < 0.01), calcium, phosphorus, and calcium × phosphorus product (p < 0.01), all of which returned to baseline levels after treatment. There was no change in C-reactive protein during the study period. There was significantly improvement in brachial flow-mediated dilatation (p < 0.01) and enhanced cardio-ankle vascular index (p < 0.01) with cinacalcet treatment. Moreover, cinacalcet significantly improved diastolic function (E/e' ratio, p < 0.05) and the left ventricular mass index (p < 0.05). Cinacalcet also increased serum NO x (p < 0.05) and decreased serum isoprostane (p < 0.05) and soluble intercellular adhesion molecule-1 concentrations (p < 0.05). All of these biochemical parameters returned to their pretreatment concentrations after withdrawal of cinacalcet. CONCLUSIONS Cinacalcet hydrochloride without vitamin D might ameliorate endothelial dysfunction, diastolic dysfunction, and cardiac hypertrophy by decreasing oxidative stress and increasing the serum nitric oxide production in hemodialysis patients with SHPT.
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Self-reported symptoms in patients on hemodialysis with moderate to severe secondary hyperparathyroidism receiving combined therapy with cinacalcet and low-dose vitamin D sterols.
Chertow, GM, Lu, ZJ, Xu, X, Knight, TG, Goodman, WG, Bushinsky, DA, Block, GA
Hemodialysis international. International Symposium on Home Hemodialysis. 2012;(2):188-97
Abstract
Patients with secondary hyperparathyroidism experience a variety of clinical symptoms which may adversely affect physical and mental function. As part of a multicenter, open-label clinical trial, subjects completed a questionnaire that included the Medical Outcomes Study Short Form-36 and 14 kidney disease-related symptoms at multiple time points during the study. Out of the 567 subjects who received at least one dose of cinacalcet, 528 to 535 (93.8-94.4%) completed all or portions of the questionnaire at baseline. The median bioactive parathyroid hormone (PTH) was 294 pg/mL (10%, 90% range, 172-655 pg/mL). Following treatment with cinacalcet and low-dose vitamin D sterols, subjects reported significant improvement in the frequency of pain in muscles, joints and bones, stiff joints, dry skin, itchy skin, excessive thirst, and trouble with memory. At end of the efficacy assessment phase (Weeks 16 to 22), the magnitude of improvement was the greatest in joint pain, bone pain, dry skin, and excessive thirst (>5 on a 0-100 scale; P < 0.001). There were no clinically or statistically significant changes in any of the Short Form-36 subscales or in the physical or mental health composite scores. Among patients on hemodialysis with moderate to severe secondary hyperparathyroidism, treatment with cinacalcet and low-dose vitamin D sterols results in significant improvement in pain in the muscles, joints and bones, joint stiffness, dry and itchy skin, excessive thirst, and trouble with memory.
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Effects of cinacalcet treatment on serum soluble Klotho levels in haemodialysis patients with secondary hyperparathyroidism.
Komaba, H, Koizumi, M, Tanaka, H, Takahashi, H, Sawada, K, Kakuta, T, Fukagawa, M
Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 2012;(5):1967-9
Abstract
BACKGROUND Klotho is a transmembrane protein that acts as a cofactor for fibroblast growth factor 23 (FGF23). Klotho also exists as a soluble circulating protein, but its role in secondary hyperparathyroidism (SHPT) is largely unknown. METHODS We measured serum soluble Klotho levels in 51 haemodialysis patients, who participated and completed a 52-week, multicentre, open-label single-arm trial that examined the effectiveness of cinacalcet for treating SHPT. RESULTS After 12 weeks of cinacalcet treatment, serum soluble Klotho decreased significantly (P = 0.03) but only marginally from 398 pg/mL [interquartile range (IQR), 268-588 pg/mL] to 378 pg/mL (IQR, 266-568 pg/mL) and returned to baseline levels. There were no significant associations between the changes in soluble Klotho levels and changes in any other parameters of mineral metabolism, including serum calcium, phosphorus, intact parathyroid hormone and FGF23. CONCLUSION Despite significant alterations in mineral and bone metabolism during treatment with cinacalcet, this resulted in only small and transient reductions in serum levels of soluble Klotho.
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A computerized treatment algorithm trial to optimize mineral metabolism in ESRD.
Spiegel, DM, McPhatter, L, Allison, A, Drumheller, JC, Lockridge, R
Clinical journal of the American Society of Nephrology : CJASN. 2012;(4):632-9
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Abstract
BACKGROUND AND OBJECTIVES Achievement of mineral targets in patients receiving dialysis remains challenging. This study sought to evaluate outcomes for phosphorus, calcium, and parathyroid hormone when a dialysis population was switched from a predominantly active vitamin D analogue treatment regimen to a computerized algorithm incorporating both cinacalcet and active vitamin D as potential first-line therapies. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS This longitudinal prospective trial enrolled 92 patients undergoing maintenance hemodialysis. Baseline measures (the average of the 3 months before computerized algorithm implementation) were compared with the proportion of patients achieving the prespecified targets at 6 and 12 months. RESULTS After 6 months there was a statistically significant improvement in the percentage of patients achieving the primary and secondary phosphorus targets (primary: phosphorus ≤ 5.5 mg/dl, increase from 41% to 75%, P<0.001; secondary: phosphorus 3.0-4.6 mg/dl, increase from 16% to 38%; P=0.005). These improvements were sustained at 12 months. There was a statistically significant improvement in the percentage of patients achieving all three prespecified secondary endpoints (an increase from 12.8% to 25.6% at 12 months; P=0.04); however, this was mainly driven by improved phosphorus control. The proportion of patients achieving the primary or secondary parathyroid hormone targets did not improve. CONCLUSIONS A greater proportion of dialysis patients achieved improved phosphorus but not parathyroid hormone control by switching from a predominantly active vitamin D analogue-based treatment regimen for mineral and bone disorder to a computer-driven algorithm that incorporated cinacalcet and low-dose active vitamin D analogues as first-line therapy.
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Cinacalcet HCl reduces hypercalcemia in primary hyperparathyroidism across a wide spectrum of disease severity.
Peacock, M, Bilezikian, JP, Bolognese, MA, Borofsky, M, Scumpia, S, Sterling, LR, Cheng, S, Shoback, D
The Journal of clinical endocrinology and metabolism. 2011;(1):E9-18
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Abstract
CONTEXT Primary hyperparathyroidism (PHPT) is characterized by elevated serum calcium (Ca) and increased PTH concentrations. OBJECTIVE The objective of the investigation was to establish the efficacy of cinacalcet in reducing serum Ca in patients with PHPT across a wide spectrum of disease severity. DESIGN AND SETTING The study was a pooled analysis of data from three multicenter clinical trials of cinacalcet in PHPT. PATIENTS Patients were grouped into three disease categories for analysis based on the following: 1) history of failed parathyroidectomy (n = 29); 2) meeting one or more criteria for parathyroidectomy but without prior surgery (n = 37); and 3) mild asymptomatic PHPT without meeting criteria for either above category (n = 15). INTERVENTION The intervention in this study was treatment with cinacalcet for up to 4.5 yr. OUTCOMES Measurements in the study included serum Ca, PTH, phosphate, and bone-specific alkaline phosphatase, and areal bone mineral density (aBMD). Vital signs, safety biochemical and hematological indices, and adverse events were monitored throughout the study period. RESULTS The extent of cinacalcet-induced serum Ca reduction, proportion of patients achieving normal serum Ca (≤10.3 mg/dl), reduction in serum PTH, and increase in serum phosphate were similar across all three categories. Except for decreased aBMD at the total femur indicated for parathyroidectomy group at 1 yr, no significant changes in aBMD occurred. The efficacy of cinacalcet was maintained for up to 4.5 yr of follow-up. AEs were mild and similar across the three categories. CONCLUSIONS Cinacalcet is equally effective in the medical management of PHPT patients across a broad spectrum of disease severity, and overall cinacalcet is well tolerated.