A randomized, double-blind, placebo-controlled study to assess the efficacy and safety of cinacalcet HCl in participants with CKD not receiving dialysis
Am J Kidney Dis 2009;53:197-207
To determine whether cinacalcet was more effective than placebo in controlling hyperparathyroidism in stage 3 & 4 CKD. To evaluate the safety profile of cinacalcet in this population
Study design and study population:
A multi-centre, international placebo controlled phase 3 study. Patients were enrolled if iPTH levels were >100 pg/mL (stage 3) and > 160 pg/mL (stage) – higher than the K/DOQI recommendations (70 pg/mL [~ 7.7 pmol/L] stage 3: 110 pg/mL [~ 12.1 pmol/L] stage 4). There was a 16 week dose titration phase and a 16 week efficacy, safety assessment phase. Patients were excluded if their vitamin D sterol dose had been changed within the prior 30 days. 404 of 623 patients screened were enrolled in a 3:1 cinacalcet: placebo ratio.
Patients were stratified by CKD stage. Cinacalcet dose began at 30 mg/dy and was titrated in 30 mg increments to a maximum of 180 mg/dy each 4 weeks to achieve K/DOQI iPTH targets (70 pg/mL [~ 7.7 pmol/L] stage 3: 110 pg/mL [~ 12.1 pmol/L] stage 4). Safety rules for hypocalcemia and over suppression of iPTH were in place. Vitamin D sterol dose could be increased for hypocalcemia < 8.8 mg/dL (~ 2.2 mmol/L) or if iPTH increased by more than 50%. Calcium supplementation was permitted for hypocalcemia and calcium containing phosphate binders were permitted for elevations of serum phosphate above 5.0 mg/dL (~ 1.67 mmol/L)
Primary and Secondary End-points
The primary efficacy end-point was the proportion of patients achieving a > 30% decrease in iPTH. Secondary efficacy end points were changes in iPTH from baseline and percentage of patients achieving the K/DOQI stage specific iPTH targets
Safety end points were clinical adverse events, serum and urinary biochemical parameters and hematologic parameters.
Cinacalcet was superior to placebo in the primary end-point of > reduction in iPTH (74% vs 28%) and in the proportion achieving the K/DOQI targets for both stage 3 (49% vs 7%) and stage 4 (42% vs 3%). The effect was independent of active vitamin D sterol use.
In terms of safety, calcium concentrations fell by ~ 10% incinacalcet treated patients and were essentially stable in the placebo group. Albumin corrected calcium levels < 8.0 mg/dL (~ 2.0 mmol/L) were seen in 25% of the cinacalcet group (1% placebo) and < 7.5 mg/dL (~ 1.85 mmol/L) in 3% (none in the placebo). Phosphorus concentrations rose in the cinacalcet group (presumably due to loss of phosphaturic effect of PTH). As commonly seen in CKD trials, clinical adverse events were high in both groups. GI side effects and muscle spasms were higher in the cinacalcet group
The international, multicentre design of this randomized, placebo controlled trial is strong. The study provides conclusive evidence that cinacalcet is superior to placebo in the lowering of iPTH in CKD stage 3 & 4 patients. No hard end points, (e.g. clinical or bone biopsy appearance) were evaluated in the study, which was of intermediate duration (32 weeks).
While cinacalcet is effective in lowering iPTH in this population, it is unclear whether this will be of long term benefit. The rise in phosphate levels is a little concerning given the epidemiologic associative data with elevated phosphate and mortality both in the general population and the end stage renal failure population. Patients on cinacalcet also received more calcium, which may not be beneficial, and more vitamin D, which might be beneficial. Longer term studies with hard outcome data, or stronger associative data in the CKD stage 3 & 4 patient population is required.