Extended-Release Calcifediol Normalized 1,25-Dihydroxyvitamin D and Prevented Progression of Secondary Hyperparathyroidism in Hemodialysis Patients in a Randomized Clinical Trial.

Introduction: Serum concentrations of 25-hydroxyvitamin D (25D) and 1,25-dihydroxyvitamin D (1,25D) decline as chronic kidney disease (CKD) advances, becoming insufficient without effective vitamin D repletion and driving onset of secondary hyperparathyroidism (SHPT). Randomized controlled trials (RCTs) in non-dialysis CKD patients have established that extended-release calcifediol (ERC) effectively raises 25D and 1,25D and reduces elevated intact parathyroid hormone (iPTH) despite the progressive loss of renal cytochrome P450 25D-1α-hydroxylase (CYP27B1), suggesting its potential efficacy in treating SHPT in end-stage kidney disease (ESKD).

Methods: This pilot RCT explored the safety and efficacy of oral ERC to raise serum total 25D to ≥50 ng/mL, normalize circulating 1,25D and reduce elevated iPTH in ESKD patients requiring regular hemodialysis (HD). Forty-four adults from 27 United States clinics requiring HD three times per week were washed out from iPTH-lowering therapies and randomized 3:1 to 26 weeks of treatment with ERC (300 µg/HD) or placebo. Participants had a mean age of 56.4±11.6 years, body mass index of 32.7±8.1 kg/m2, 46% were female, 68% Black, 30% White, 24% Hispanic. At randomization, iPTH had to be 300-<1,200 pg/mL, 25D <50 ng/mL, corrected serum calcium <9.8 mg/dL and phosphorus <6.5 mg/dL. These parameters were monitored weekly or biweekly, and 1,25D quarterly.

Results: Mean (±SE) serum total 25D rose with ERC treatment from 24.1±1.7 ng/mL at baseline (BL) to steady-state levels of 157.7±10.4 (p<0.001) after 12 weeks, with all individual levels exceeding 50 ng/mL but varying inversely with body weight. Serum 25D levels declined with placebo treatment from 36.0±5.3 to 30.6±5.5 ng/mL. Mean 1,25D rose from 9.4±1.2 to 50.7±7.8 pg/mL (p<0.001) with ERC and concentrations surpassed 19.9 pg/mL (lower limit of normal) in 93% of participants. Mean iPTH increased 19.8±10.6% from BL with placebo (497.6±69.2 to 593.1±95.1 pg/mL) but decreased 1.7±4.7% (p<0.05) with ERC (530.4±29.4 to 529.6±43.7 pg/mL) . A strong correlation was observed between serum 1,25D and 25D (r2 = 0.8248; p<0.001) with ERC treatment indicating that, on average, 1,25D normalized as 25D reached ≥50 ng/mL. Increases in mean serum calcium or phosphorus, episodes of hypercalcemia or adverse events were not observed with ERC treatment.

Conclusion: ERC safely raised serum total 25D, normalized low serum 1,25D and stabilized elevated plasma iPTH in this pilot placebo-controlled RCT involving ESKD patients requiring regular HD. The observed increases in 1,25D indicated that ERC restored adequate endogenous vitamin D hormone production via substrate-driven conversion to calcitriol in extra-renal tissues expressing CYP27B1, thereby preventing SHPT progression.