Adults

The safety and efficacy of ZEMPLAR capsules were evaluated in three, 24-week, double blind, placebo-controlled, randomized, multicenter, Phase 3 clinical studies in CKD Stages 3 and 4 patients. Two studies used an identical three times a week dosing design, and one study used a daily dosing design. A total of 107 patients received ZEMPLAR capsules and 113 patients received placebo. The mean age of the patients was 63 years, 68% were male, 71% were Caucasian, and 26% were African-American. The average baseline iPTH was 274 pg/mL (range: 145-856 pg/mL). The average duration of CKD prior to study entry was 5.7 years. At study entry 22% were receiving calcium based phosphate binders and/or calcium supplements. Baseline 25-hydroxyvitamin D levels were not measured. 

The initial dose of ZEMPLAR capsules was based on baseline iPTH. If iPTH was ≤ 500 pg/mL, ZEMPLAR capsules were administered 1 mcg daily or 2 mcg three times a week, not more than every other day. If iPTH was > 500 pg/mL, ZEMPLAR capsules were administered 2 mcg daily or 4 mcg three times a week, not more than every other day. The dose was increased by 1 mcg daily or 2 mcg three times a week every 2 to 4 weeks until iPTH levels were reduced by at least 30% from baseline. The overall average weekly dose of ZEMPLAR capsules was 9.6 mcg/week in the daily regimen and 9.5 mcg/week in the three times a week regimen. 

In the clinical studies, doses were titrated for any of the following reasons: if iPTH fell to < 60 pg/mL, or decreased > 60% from baseline, the dose was reduced or temporarily withheld; if iPTH decreased < 30% from baseline and serum calcium was ≤ 10.3 mg/dL and serum phosphorus was ≤ 5.5 mg/dL, the dose was increased; and if iPTH decreased between 30 to 60% from baseline and serum calcium and phosphorus were ≤ 10.3 mg/dL and ≤ 5.5 mg/dL, respectively, the dose was maintained. Additionally, if serum calcium was between 10.4 to 11.0 mg/dL, the dose was reduced irrespective of iPTH, and the dose was withheld if serum calcium was > 11.0 mg/dL. If serum phosphorus was > 5.5 mg/dL, dietary counseling was provided, and phosphate binders could have been initiated or increased. If the elevation persisted, the ZEMPLAR capsules dose was decreased. Seventy-seven percent (77%) of the ZEMPLAR capsules treated patients and 82% of the placebo treated patients completed the 24-week treatment. The primary efficacy endpoint of at least two consecutive ≥ 30% reductions from baseline iPTH was achieved by 91% of ZEMPLAR capsules treated patients and 13% of the placebo treated patients (p < 0.001). The proportion of ZEMPLAR capsules treated patients achieving two consecutive ≥ 30% reductions was similar between the daily and the three times a week regimens (daily: 30/33, 91%; three times a week: 62/68, 91%). 

The incidence of hypercalcemia (defined as two consecutive serum calcium values > 10.5 mg/dL), and hyperphosphatemia in ZEMPLAR capsules treated patients was similar to placebo. There were no treatment related adverse events associated with hypercalcemia or hyperphosphatemia in the ZEMPLAR capsules group. No increases in urinary calcium or phosphorous were detected in ZEMPLAR capsules treated patients compared to placebo. 

The pattern of change in the mean values for serum iPTH during the studies is shown in Figure 1. 

Figure 1. Mean Values for Serum iPTH Over Time in the Three Double-Blind, Placebo-Controlled, Phase 3, CKD Stages 3 and 4 Studies Combined

The mean changes from baseline to final treatment visit in serum iPTH, calcium, phosphorus, and bone-specific alkaline phosphatase are shown in Table 9. 

Pediatric patients 10 to 16 years of age

The safety and efficacy of ZEMPLAR capsules were evaluated in a 12-week, double-blind, placebo-controlled, randomized, multicenter study in pediatric patients ages 10 to 16 years with CKD Stages 3 and 4. A total of 18 patients received ZEMPLAR capsules and 18 patients received placebo during the blinded phase of the study. The mean age of the patients was 13.6 years, 69% were male, 86% were Caucasian, and 8% were Asian. 

The initial dose of ZEMPLAR capsules was 1 mcg three times a week. Serum iPTH, calcium, and phosphorus levels were monitored every 2-4 weeks with a goal to maintain levels within target ranges: iPTH 35 to 70pg/mL for CKD stage 3, iPTH 70 to 110pg/mL for CKD stage 4, calcium < 10.2mg/dL, phosphorous < 5.8mg/dL. Starting at Treatment Week 4 and every 4 weeks thereafter, doses may have been increased in 1 mcg increments three times a week (e.g., increase from 1 mcg three times per week to 2 mcg three times per week) based upon safety observations and blood chemistry evaluations. Each administered dose could be decreased in 1 mcg increments three times a week, or held if the patient was receiving a 1 mcg dose, as appropriate at any time. The average cumulative weekly dose of ZEMPLAR was 4mcg/week during the 12 week blinded treatment period. 

The primary efficacy endpoint, the proportion of Stage 3 and 4 patients achieving two consecutive ≥ 30% reductions from baseline in iPTH levels, was statistically significant during the 12-week blinded phase. Results are shown in Table 10.