ArticlesEfficacy and safety of recombinant human parathyroid hormone (1–84) in hypoparathyroidism (REPLACE): a double-blind, placebo-controlled, randomised, phase 3 study
Introduction
Hypoparathyroidism is a rare disorder characterised by absent or deficient production of parathyroid hormone (PTH). PTH deficiency is responsible for impaired mineral homoeostasis, which is disrupted in several ways: calcium absorption is impaired due to reduced renal conversion of 25-hydroxyvitamin D to active 1,25-dihydroxyvitamin D; hypercalciuria results from reduced PTH-dependent renal calcium reabsorption; and bone turnover is decreased.1, 2, 3 Hormone deficiency states are usually treated by replacing the deficient hormone; however, this disorder is currently managed with large doses of oral calcium and active vitamin D metabolites or analogues, an approach that does not always provide adequate or consistent control of biochemical and clinical aspects of the disease. Adverse short-term and long-term complications include large swings in serum calcium concentrations and risks of calcifications in the kidney, brain, and elsewhere.4 Without the calcium-conserving effects of PTH in the distal renal tubule, hypercalciuria, kidney stones, and reduced renal function can occur.5, 6
Human PTH(1–34), an active fragment of full length endogenous PTH(1–84), has been studied as a PTH replacement therapy in hypoparathyroidism.7, 8, 9, 10, 11, 12 Winer and colleagues7, 8, 9, 10, 11, 12 have shown the feasibility of PTH replacement therapy; however, PTH(1–34) has a short half-life and has not been approved for this indication. By contrast, recombinant human (rh)PTH(1–84), which is identical in structure to the full-length endogenous hormone, is associated with a longer calcaemic effect when injected into the thigh13 than is rhPTH(1–34) injected into the abdomen.14 Serum calcium returns to baseline concentrations 24 h after administration of rhPTH(1–84), making this compound suitable for once-daily administration for hypoparathyroidism.15, 16, 17, 18
In the REPLACE study, we aimed to test the efficacy, safety, and tolerability of a once-daily flexible dose (50 μg, 75 μg, or 100 μg) regimen of rhPTH(1–84) in adults with hypoparathyroidism, to assess whether rhPTH(1–84) is an effective replacement therapy in this population of patients.
Section snippets
Study design and patients
In this randomised, placebo-controlled, double-blind registration trial, we recruited patients aged 18–85 years who had well documented hypoparathyroidism for 18 months or longer from 33 outpatient sites in eight countries: USA (20), Canada (3), Denmark (3), Hungary (3), Belgium (1), France (1), Italy (1), and the UK (1). Hypoparathyroidism was defined as hypocalcaemia (calcium concentration below the lower limit of normal) and documented PTH concentrations below the lower limit of the normal
Results
Between June 23, 2009, and Feb 28, 2011, 196 patients were screened, of whom 134 were eligible for random assignment to the rhPTH(1–84) (n=90) or placebo groups (n=44; figure 1). All 134 patients were included in the primary efficacy and safety analyses. Patient demographics, baseline characteristics, and laboratory values were similar between the rhPTH(1–84) and placebo groups (table 1). Most patients were women (78%), and the mean age of all patients was 47·5 years (SD 12·71). The most common
Discussion
This randomised controlled trial provides evidence that rhPTH(1–84) replacement therapy is effective in treating hypoparathyroidism when compared with oral calcium and active vitamin D alone (placebo group). More than half the patients in the rhPTH(1–84) group (53%) reached the primary endpoint, compared with only 2% in the placebo group.
Patients recruited for this trial were representative of the disorder in that even after optimisation of their calcium and vitamin D regimen, 89 (66%) patients
References (22)
- et al.
Hypoparathyroidism in the adult: epidemiology, diagnosis, pathophysiology, target-organ involvement, treatment, and challenges for future research
J Bone Miner Res
(2011) Clinical practice. Hypoparathyroidism
N Engl J Med
(2008)- et al.
PTH replacement therapy of hypoparathyroidism
Osteoporos Int
(2013) - et al.
Prevalence and progression of basal ganglia calcification and its pathogenic mechanism in patients with idiopathic hypoparathyroidism
Clin Endocrinol (Oxf)
(2012) - et al.
Nephrocalcinosis in children and adolescents: sonographic evaluation during long-term treatment with 1,25-dihydroxycholecalciferol
Child Nephrol Urol
(1988) - et al.
Long-term follow-up of patients with hypoparathyroidism
J Clin Endocrinol Metab
(2012) - et al.
Synthetic human parathyroid hormone 1-34 vs calcitriol and calcium in the treatment of hypoparathyroidism
JAMA
(1996) - et al.
A randomized, cross-over trial of once-daily versus twice-daily parathyroid hormone 1-34 in treatment of hypoparathyroidism
J Clin Endocrinol Metab
(1998) - et al.
Long-term treatment of hypoparathyroidism: a randomized controlled study comparing parathyroid hormone-(1-34) versus calcitriol and calcium
J Clin Endocrinol Metab
(2003) - et al.
Effects of once versus twice-daily parathyroid hormone 1–34 therapy in children with hypoparathyroidism
J Clin Endocrinol Metab
(2008)