A Randomized Trial of Cinacalcet versus Vitamin D Analogs as Monotherapy in Secondary Hyperparathyroidism (PARADIGM)

Abstract

Background and objectives Direct comparison of cinacalcet and vitamin D analogs as monotherapies to lower parathyroid hormone (PTH) levels has not been undertaken.Design, setting, participants, & measurements This was a prospective, multicenter, phase 4, randomized, openlabel study that enrolled participants from 2010 to 2012. Adult participants (n=312) on hemodialysis with PTH .450 pg/ml were randomized 1:1 to 12 months of treatment with either cinacalcet (n=155) or vitamin D analogs (n=157) to evaluate the mean percentage change in plasma PTH level (primary end point) and the proportion of participants achieving plasma PTH ,300 pg/ml or a $30% decrease in PTH (secondary end points). A preplanned analysis to determine whether there were important region-by-treatment interactions was also undertaken.Results Baseline mean PTH was 846 pg/ml (n=155) for cinacalcet and 816 pg/ml (n=157) for vitamin D analog therapy. The mean (95% confidence interval) percentage change from baseline in PTH was 212.1% (220.0% to 24.1%) in the cinacalcet arm and 27.0% (214.9% to 0.8%) in the vitamin D analog arm, a difference of 25.0% (215.4% to 5.4%) (P=0.35). Similarly, there was no difference in achievement of secondary efficacy end points between arms (19.4% and 15.3% of participants with PTH#300 pg/ml and 42.6% and 33.8% of participants had a PTH reduction .30% in the cinacalcet and vitamin D analog arms, respectively). A prespecified analysis revealed a large treatment-by-region interaction, with nominally greater response to cinacalcet compared with vitamin D analogs in non-United States participants (US versus non-US participants, P,0.001). Hypocalcemia was more common in the cinacalcet arm, whereas hypercalcemia and hyperphosphatemia occurred more often in the vitamin D analog arm.Conclusions Participants had similar modest reductions in PTH with either cinacalcet or vitamin D analog monotherapy over 52 weeks of treatment, but effects varied by region. Treatments differed with regard to effect on calcium and phosphorus levels.

Clinical and Practical Use of Calcimimetics in Dialysis Patients With Secondary Hyperparathyroidism

“…On the other hand, surgical parathyroidectomy is not exempt from important, sometimes neglected, risks, as recently reported (5,28). Fortunately, with the advent of calcimimetics, enormous progress has been made in extending the armamentarium against SHPT, although we acknowledge that there is insufficient high-grade evidence on whether any treatment or a combination thereof should be preferred to control SHPT in dialysis patients (29,30).…”

“…As a consequence of its unique mode of action, cinacalcet may cause hypocalcemia instead of the hypercalcemia associated with vitamin D derivatives (3,17,24,29,68). The decreases in serum Ca levels mainly occur during the first 2 weeks of treatment and are significantly greater among patients with relatively higher baseline or pretreatment PTH values.…”

Optimal management of bone mineral disorders in chronic kidney disease and end stage renal disease

“…Cinacalcet continues to be used for management of SHPT and its secondary effects on bone in ESRD. In the PARADIGM trial, Wetmore et al [30] noted only modest reductions in PTH with cinacalcet (−12%) and vitamin D analogs (−7%) as monotherapy. In an exploratory analysis of PARADIGM, cinacalcet use was associated with hypocalcemia and reduced FGF-23, while vitamin D analogs were associated with hypercalcemia, hyperphosphatemia and increased FGF23 [31].…”

The Efficacy of Cinacalcet in the Treatment of Hyperparathyroidism in Turkish Hemodialysis Patient Population

“…The decreased renal production of vitamin D, phosphorus retention, hypocalcemia, and increased fibroblast growth factor 23 (FGF-23) play a role in the pathogenesis of CKD-MBD (4). Active vitamin D preparations or analogues are usually used in order to control the increase in parathormone (PTH) but treatment goals cannot usually be reached due to side effects such as hypercalcemia and hyperphosphatemia caused by these treatments (5,6). The levels of PTH were found to be below 300 pg/ml in only 50% of the patients according to 2013 registry data of the Turkish Society of Nephrology (7).…”