Comparison of Paricalcitol With Maxacalcitol Injection in Japanese Hemodialysis Patients With Secondary Hyperparathyroidism

Secondary hyperparathyroidism (SHPT) is one of the major complications of chronic kidney disease (CKD) and is associated with elevated serum intact parathyroid hormone (iPTH). Calcitriol, a non‐selective vitamin D receptor agonist (VDRA) that suppresses iPTH is used for SHPT treatment, but its use is frequently complicated by hypercalcemia. Paricalcitol, a selective VDRA, demonstrated efficacy in iPTH suppression compared to maxacalcitol in a Phase 2 study (M11‐609) in Japanese subjects. The current larger Phase 3 study (M11‐517), evaluated the efficacy of intravenous paricalcitol injection compared to intravenous maxacalcitol injection with respect to iPTH and calcium control using a non‐inferiority primary endpoint. In this double‐blind, double‐dummy, parallel‐group study, eligible Japanese CKD subjects with SHPT on hemodialysis were randomized 1:1 to receive intravenous paricalcitol or intravenous maxacalcitol injections for 12 weeks. Dynamic allocation of subjects on the basis of screening iPTH levels was used to ensure equal distribution of subjects with iPTH <500 pg/mL and ≥500 pg/mL into the two treatment groups. 255 subjects were randomized to receive paricalcitol (N = 127) or maxacalcitol (N = 128). Primary efficacy analysis indicated that 27.7% in the paricalcitol group vs. 30.5% in the maxacalcitol group (95% CI −14.34% to 8.79%, P = 0.353) achieved target iPTH in the last 3 weeks without hypercalcemia during treatment, failing to achieve the non‐inferiority margin of −5% that was set based upon agreement with the PMDA. Both intravenous paricalcitol and maxacalcitol were effective in reducing iPTH and provided similar safety profiles; however, non‐inferiority for paricalcitol vs. maxacalcitol was not demonstrated.

[1]  K. Iseki,et al.  Clinical Practice Guideline for the Management of Chronic Kidney Disease‐Mineral and Bone Disorder , 2013, Therapeutic apheresis and dialysis : official peer-reviewed journal of the International Society for Apheresis, the Japanese Society for Apheresis, the Japanese Society for Dialysis Therapy.

[2]  E. Nemeth,et al.  The calcium-sensing receptor: a key factor in the pathogenesis of secondary hyperparathyroidism. , 2005, American journal of physiology. Renal physiology.

[3]  M. Wolf,et al.  Survival of patients undergoing hemodialysis with paricalcitol or calcitriol therapy. , 2003, The New England journal of medicine.

[4]  D. Batlle,et al.  Paricalcitol versus calcitriol in the treatment of secondary hyperparathyroidism. , 2003, Kidney international.

[5]  Alex J. Brown,et al.  Vitamin D analogues for secondary hyperparathyroidism. , 2002, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[6]  J. Takahashi,et al.  Effects of 1,25-dihydroxy-22-oxavitamin D3 on parathyroid gland function in haemodialysis patients with secondary hyperparathyroidism , 2002 .

[7]  M. Fukagawa,et al.  [A comparison between 1,25-dihydroxy-22-oxavitamin D3 and 1,25-dihydroxyvitamin D3 regarding suppression of parathyroid hormone secretion and calcemic action]. , 2002, Clinical calcium.

[8]  D. Batlle,et al.  Suppression of parathyroid hormone secretion in hemodialysis patients: comparison of paricalcitol with calcitriol. , 2001, American journal of kidney diseases : the official journal of the National Kidney Foundation.

[9]  Alex J. Brown,et al.  The noncalcemic analogue of vitamin D, 22-oxacalcitriol, suppresses parathyroid hormone synthesis and secretion. , 1989, Contributions to nephrology.

[10]  D. Andress Nonclassical Aspects of Differential Vitamin D Receptor Activation , 2012, Drugs.

[11]  M. Fukagawa,et al.  A comparison between 1,25-dihydroxy-22-oxavitamin D(3) and 1,25-dihydroxyvitamin D(3) regarding suppression of parathyroid hormone secretion and calcaemic action. , 2002, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.