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Paricalcitol Versus Cinacalcet Plus Low-Dose Vitamin D for the Treatment

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Paricalcitol Versus Cinacalcet Plus Low-Dose Vitamin D for the Treatment Nephrol Dial Transplant (2012) 27: 1942–1949 doi: 10.1093/ndt/gfr531 Advance Access publication 19 September 2011 Paricalcitol versus cinacalcet plus low-dose vitamin D for the treatment of secondary hyperparathyroidism in patients receiving haemodialysis: study design and baseline characteristics of the IMPACT SHPT study Markus Ketteler1, Kevin J. Martin2, Mario Cozzolino3, David Goldsmith4, Amit Sharma5, Samina Khan6, Emily Dumas6, Michael Amdahl6, Steven Marx6 and Paul Audhya6 1Division of Nephrology, Klinikum Coburg, Coburg, Germany, 2Department of Internal Medicine, Division of Nephrology, Saint Louis University, St Louis, MO, USA, 3Department of Medicine, Surgery and Dentistry, University of Milan, Renal Division, Hospital San Paolo, Milan, Italy, 4Renal and Transplantation Department, Guy’s Hospital, London, UK, 5Boise Kidney and Hypertension Institute, Boise, ID, USA and 6Abbott Laboratories, Abbott Park, IL, USA Correspondence and offprint requests to: Markus Ketteler; E-mail: [email protected] Abstract Introduction Background. Paricalcitol and cinacalcet are common thera- pies for patients on haemodialysis with secondary Secondary hyperparathyroidism (SHPT) is a major compli- hyperparathyroidism (SHPT). We conducted a multi-centre cation of chronic kidney disease (CKD) [1] resulting from study in 12 countries to compare the safety and efficacy of impaired calcium and phosphate homeostasis and a lack of paricalcitol and cinacalcet for the treatment of SHPT. vitamin D receptor (VDR) activation secondary to active Methods. Patients aged 18 years with Stage 5 chronic kidney disease receiving maintenance haemodialysis and vitamin D deficiency [2, 3]. SHPT is characterized by with intact parathyroid hormone (iPTH) 300–800 pg/mL, increased parathyroid hormone (PTH) synthesis and secre- calcium 8.4–10.0 mg/dL (2.09–2.49 mmol/L) and phospho- tion and progressive parathyroid gland hyperplasia [2]. rus 6.5 mg/dL (2.09 mmol/L) were randomized within two Important pathogenic factors in SHPT include phosphate strata defined by the mode of paricalcitol administration to retention, hypocalcaemia, low levels of active vitamin D treatment with paricalcitol- (intra-venous, US and Russian (1,25-dihydroxycholecalciferol, calcitriol) [3], high levels sites, IV stratum; oral, non-US and non-Russian sites, oral of fibroblast growth factor 23 (FGF23) [4], parathyroid stratum) or cinacalcet-centred therapy. The primary endpoint resistance to inhibition by calcium, vitamin D [5] and is the proportion of patients in each treatment group who FGF23 [6, 7] and skeletal resistance to PTH [3]. achieve a mean iPTH value of 150–300 pg/mL during Severe SHPT is associated with a high risk of unfavour- Weeks 21–28 of treatment. Assuming efficacy response rates able clinical outcomes, particularly cardiovascular compli- of 36 and 66% for cinacalcet and paricalcitol, respectively, cations [1, 8] and high-turnover metabolic bone disease [3]. and a 20% discontinuation rate, 124 subjects in each A strong association between vitamin D deficiency and stratum were estimated to provide 81% power to detect a cardiovascular disease is well established for the general 30% absolute difference in the primary endpoint. population [9] and for patients on haemodialysis [10]. Results. Of 746 patients screened, 272 (mean age, 63 years; Other risk factors for mortality in patients on haemodialysis mean iPTH, 509 pg/mL) were randomized. Mean duration of include hypocalcaemia, hyperphosphataemia [11] and high haemodialysis at baseline was 3.7 years. Comorbidities in- FGF23 [12]. Control of the levels of intact PTH (iPTH), cluded hypertension (90.4%), Type 2 diabetes (40.4%), con- calcium and phosphate is an important therapeutic goal in gestive heart failure (17.3%), coronary artery disease (34.6%) treating patients with SHPT on haemodialysis. For patients and gastrointestinal disorders (75%). with Stage 5 CKD on haemodialysis, the 2003 guidelines Conclusions. The study participants are representative of of the Kidney Disease Outcomes Quality Initiative a multinational cohort of patients on haemodialysis with (KDOQI) of the National Kidney Foundation recommend elevated iPTH. The study results will provide valuable specific targets for these parameters, including serum iPTH information on the best available treatment of SHPT in concentrations of 150–300 pg/mL [13]. In contrast, the patients on haemodialysis. 2009 Kidney Disease—Improving Global Outcomes (KDIGO) guidelines recommend maintaining PTH Keywords: cinacalcet hydrochloride; haemodialysis; hyperparathyroidism; kidney disease; paricalcitol between two and nine times the upper limit of normal [14], which corresponds to a range of 130–600 pg/mL [15]. The KDIGO guidelines further recommend that a clinically Ó The Author 2011. Published by Oxford University Press on behalf of ERA-EDTA. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0), which permits unrestricted non-commercial use, distribution and reproduction in any medium, provided the original work is properly cited. Study design: paricalcitol- versus cinacalcet-based therapy 1943 relevant trend towards marked increase (or decrease) in iPTH a mean calcium <8.4 mg/dL (2.09 mmol/L) or >10.5 mg/dL (2.61 mmol/ levels should prompt initiation of or change in therapy to L) during Weeks 21–28. Safety will be evaluated through adverse events reporting and assessment of changes in complete chemistry avoid progression to levels outside of this range. and haematology measurements and vital signs. Additional laboratory A variety of treatments for SHPT are currently available tests will be conducted to assess changes in FGF23, bone-specific alka- including non-selective (calcitriol, alfacalcidol, doxercalci- line phosphatase (BSAP), alkaline phosphatase, phosphate, PTH- ferol) and selective VDR activators (paricalcitol and maxa- related peptide and 25-hydroxy vitamin D. Ibis testing, which combines calcitol) and the calcimimetic cinacalcet. Paricalcitol [16, 17] polymerase chain reaction and mass spectrometry to detect DNA in biological samples, will be used to identify the presence of viral and is approved for the treatment of patients with SHPT with microbial pathogens [33]. Stages 3–5 of CKD, whereas cinacalcet [18] is approved For each study site, the protocol was approved by an Institutional Re- for the treatment of patients with SHPT on dialysis. A draw- view Board or Independent Ethics Committee. The study is being con- back of calcitriol and other non-selective VDR activators is ducted in accordance with the protocol, International Conference on Harmonization guidelines, applicable regulations and guidelines govern- that high doses may cause hypercalcaemia [19], which is ing clinical study conduct and the ethical principles established in the associated with increased mortality in patients on haemodial- Declaration of Helsinki. All study participants provided written informed ysis [20]. The risk of hypercalcaemia associated with VDR consent before undergoing any study-related procedures. activators can be reduced by using a selective VDR activator Enrolment has been completed. After an initial screening period, eligi- such as paricalcitol, which causes lesser hypercalcaemia due ble participants underwent a 4-week washout period during which they discontinued prior VDR activator and cinacalcet therapy and after which to smaller increases in intestinal calcium absorption than they were re-evaluated for eligibility (Figure 1). A stratified randomization other VDR activators [21–23], or by using cinacalcet, scheme was used. Random assignment at a ratio of 1:1 to paricalcitol or which allosterically activates the calcium-sensing recep- cinacalcet occurred within each of two strata defined by the mode of tor to reduce PTH secretion [19]. Adding cinacalcet to paricalcitol administration (oral or intra-venous). The randomization schedule was generated by the Clinical Statistics Department at Abbott conventional care or to low-dose VDR activator therapy Laboratories (Abbott Park, IL) before the start of the study. Treatment in patients on haemodialysis has been shown to reduce the group assignment occurred at the Day 1 visit and was implemented serum levels of calcium, phosphate, PTH [24–27]and through an interactive voice response system. FGF23 [28]. Randomized controlled studies also demon- Randomized patients receive one of two treatments for 28 weeks strated that intra-venous and oral paricalcitol effectively (Figure 1). Patients assigned to paricalcitol will receive intra-venous paricalcitol (US and Russian sites) or oral paricalcitol (non-US and non- reduce iPTH in patients with Stage 5 CKD without sig- Russian sites). The mean absolute bioavailability of paricalcitol capsules nificantly increasing the risk of hypercalcaemia or hyper- under low-fat diet conditions ranges from 72 to 86% in healthy subjects phosphatemia [29, 30]. Data from large observational and in CKD Stage 5 patients on haemodialysis. studies suggest that paricalcitol compared with calcitriol In the paricalcitol arm, cinacalcet will be administered as supplemental medication if serum calcium is 10.5 mg/dL (2.61 mmol/L) in samples of is associated with a significantly lower risk of all-cause two consecutive blood tests. Doses of paricalcitol will be adjusted as mortality [31] and that increasing doses of paricalcitol per shown in Figure 2. Patients assigned to the cinacalcet arm will
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