Dose-response Study of Paricalcitol Injection in Chronic Kidney Disease Patients Receiving Hemodialysis

• The proportion of subjects with >=50% decrease from baseline in iPTH [ Time Frame: Final visit ] [ Designated as safety issue: No ]
• The incident rate of hypercalcemia [ Time Frame: During the study ] [ Designated as safety issue: Yes ]
• The incident rate of hyperphosphatemia [ Time Frame: During the study ] [ Designated as safety issue: Yes ]

• Mean Change From Baseline in Intact Parathyroid Hormone (iPTH) Level [ Time Frame: Baseline to Week 13 (Final Visit) ] [ Designated as safety issue: No ]
• Percentage of Subjects With Intact Parathyroid Hormone (iPTH) ≤ 180 Picograms/Milliliter (pg/mL) [ Time Frame: Baseline to Week 13 (Final Visit) ] [ Designated as safety issue: No ]
• Percentage of Subjects With 2 or More Decreases of ≥ 50% From Baseline in Intact Parathyroid Hormone (iPTH) Level [ Time Frame: Through Week 13 ] [ Designated as safety issue: No ]
• Duration of 2 Consecutive Decreases of ≥ 50% From Baseline in Intact Parathyroid Hormone (iPTH) Values [ Time Frame: Through Week 13 ] [ Designated as safety issue: No ]
• Duration of 2 Consecutive Intact Parathyroid Hormone (iPTH) Values ≤ 180 pg/mL [ Time Frame: Through Week 13 ] [ Designated as safety issue: No ]

• The mean change of iPTH [ Time Frame: Final visit ] [ Designated as safety issue: No ]
• The proportion of subjects with iPTH <=180 pg/mL [ Time Frame: Final visit ] [ Designated as safety issue: No ]
• The proprortion of subjects with two or more >=50% decrease from baseline in iPTH. The time course change of iPTH. [ Time Frame: During the study ] [ Designated as safety issue: No ]
• The duration of two consecutive iPTH >=50% or < 180 pg/mL [ Time Frame: During the study ] [ Designated as safety issue: No ]

The purpose of this study was to investigate the initial dose and dose adjustment range for paricalcitol injection in patients with chronic kidney disease on hemodialysis who have secondary hyperparathyroidism.

This multicenter, randomized, open-label trial consisted of 4 dose-adjustment regimens for paricalcitol injection (initial doses and dose adjustment ranges were 2 ± 1 µg, 2 ± 2 µg, 4 ± 1 µg, and 4 ± 2 µg) and 1 maxacalcitol regimen (initial dose and dose adjustment range was 5 µg ± 2.5 µg or 10 µg ± 2.5 µg) as a reference group. Subjects who met the inclusion criteria were randomized equally to 1 of the treatment groups with iPTH values at screening (< 500 pg/mL or ≥ 500 pg/mL) as a dynamic allocation factor. Study drugs were administered 3 times weekly (every other day) from the venous end of the hemodialysis circuit just before completion of the dialysis session. The initial doses were continued for 2 weeks, followed by dose adjustments (increase, maintenance, decrease, suspension, or resumption) by 1 µg or 2 µg units for the paricalcitol groups and by 2.5 µg units for the maxacalcitol group based on iPTH, calcium (adjusted), and phosphorus values every 2 weeks.

Subjects in the paricalcitol groups were to be suspended from treatment if their iPTH value decreased to < 60 pg/mL in accordance with the guidelines proposed by the Japanese Society of Dialysis Therapy for the treatment of secondary hyperparathyroidism in chronic dialysis patients (control goal value of 60-180 pg/mL for iPTH). The dose adjustment criteria based on iPTH values for the maxacalcitol group were set according to the prescribing information for maxacalcitol (suspended when iPTH decreased to ≤ 150 pg/mL).

• Chronic Kidney Disease on Hemodialysis
• Secondary Hyperparathyroidism

• Drug: Maxacalcitol
  Study drug was administered 3 times per week (no more frequently than every other day) intravenously immediately before the completion of hemodialysis. The initial dosage was administered for 2 weeks, with subsequent dosage adjustment based on the subject's iPTH, calcium (adjusted), and phosphorus levels every 2 weeks. Total duration of treatment was 12 weeks.
  Other Name: maxacalcitol
• Drug: Paricalcitol
  Study drug was administered 3 times per week (no more frequently than every other day) intravenously immediately before the completion of hemodialysis. The initial dosage was administered for 2 weeks, with subsequent dosage adjustment based on the subject's iPTH, calcium (adjusted), and phosphorus levels every 2 weeks. Total duration of treatment was 12 weeks.
  Other Names:

  • ABT-358
  • Zemplar
  • paricalcitol

• Experimental: Paricalcitol 2 µg ± 1 µg
  Paricalcitol initial dosage 2 micrograms (µg) with incremental adjustment of 1 µg
  Intervention: Drug: Paricalcitol
• Experimental: Paricalcitol 2 µg ± 2 µg
  Paricalcitol initial dosage 2 µg with incremental adjustment of 2 µg
  Intervention: Drug: Paricalcitol
• Experimental: Paricalcitol 4 µg ± 1 µg
  Paricalcitol initial dosage 4 µg with incremental adjustment of 1 µg
  Intervention: Drug: Paricalcitol
• Experimental: Paricalcitol 4 µg ± 2 µg
  Paricalcitol initial dosage 4 µg with incremental adjustment of 2 µg
  Intervention: Drug: Paricalcitol
• Maxacalcitol 5 or 10 µg ± 2.5 µg
  Maxacalcitol initial dosage 5 or 10 µg with incremental adjustment of 2.5 µg
  Intervention: Drug: Maxacalcitol

Inclusion Criteria:

• Diagnosed with chronic kidney disease receiving hemodialysis 3 times a week for at least 3 months prior to obtaining the informed consent and scheduled to be receiving the same hemodialysis during the study period.
• Using dialysate with constant concentration of calcium for 4 weeks prior to obtaining informed consent and phosphate binder with constant dose regimen for 2 weeks prior to obtaining informed consent.
• Intact parathyroid hormone level (iPTH) ≥ 300 pg/mL
• Calcium (adjusted) 8.4-10.2 milligrams/deciliter (mg/dL)
• Phosphorus ≤ 6.5 mg/dL
• Age ≥ 20 years

Exclusion Criteria:

• History of allergic reaction or significant sensitivity to vitamin D or vitamin D related compounds
• Parathyroidectomy or ethanol infusion within past year
• Progressive malignancy or clinically significant hepatic diseases, severe cerebral/cardiovascular diseases, severe hypertension, or uncontrolled diabetes mellitus
• Drug or alcohol abuse within past 6 months
• Taking calcitonin, maintenance intravenous or oral glucocorticoids, cinacalcet, bisphosphonates, selective estrogen-receptor modulator (SERM), vitamin D compounds (other than study drug), or other drugs that may affect calcium or bone metabolism (other than estrogen or progestin, vitamin K2)
• Will need to take chronic dose (≥ 2 consecutive weeks) of cytochrome P450 (CYP3A) inhibitors (e.g., clarithromycin, grapefruit products) or inducers (e.g., carbamazepine, rifampicin)
• Taking aluminum containing products (2 weeks prior to consent)