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Efficacy and safety of recombinant human parathyroid hormone (1–84) in hypoparathyroidism (REPLACE): a double-blind, placebo-controlled, randomised, phase 3 study

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Summary

Background

Hypoparathyroidism results in impaired mineral homoeostasis, including hypocalcaemia and hyperphosphataemia. Treatment with high-dose oral calcium and active vitamin D does not provide adequate or consistent control of biochemical indices and can lead to serious long-term complications. We aimed to test the efficacy, safety, and tolerability of once-daily recombinant human parathyroid hormone 1–84 (rhPTH[1–84]) in adults with hypoparathyroidism.

Methods

In this double-blind, placebo-controlled, randomised phase 3 study (REPLACE), we recruited patients with hypoparathyroidism (≥18 months duration) aged 18–85 years from 33 sites in eight countries. After an optimisation period, during which calcium and active vitamin D doses were adjusted to achieve consistent albumin-corrected serum calcium, patients were randomly assigned (2:1) via an interactive voice response system to 50 μg per day of rhPTH(1–84) or placebo for 24 weeks. Active vitamin D and calcium were progressively reduced, while rhPTH(1–84) could be titrated up from 50 μg to 75 μg and then 100 μg (weeks 0–5). The primary endpoint was the proportion of patients at week 24 who achieved a 50% or greater reduction from baseline in their daily dose of oral calcium and active vitamin D while maintaining a serum calcium concentration greater than or the same as baseline concentrations and less than or equal to the upper limit of normal, analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00732615.

Findings

Between June 23, 2009, and Feb 28, 2011, 134 eligible patients were recruited and randomly assigned to rhPTH(1–84) (n=90) or placebo (n=44). Six patients in the rhPTH(1–84) group and seven in the placebo group discontinued before study end. 48 (53%) patients in the rhPTH(1–84) group achieved the primary endpoint compared with one (2%) patient in the placebo group (percentage difference 51·1%, 95% CI 39·9–62·3; p<0·0001). The proportions of patients who had at least one adverse event were similar between groups (84 [93%] patients in the rhPTH[1–84] group vs 44 [100%] patients in the placebo group), with hypocalcaemia, muscle spasm, paraesthesias, headache, and nausea being the most common adverse events. The proportions of patients with serious adverse events were also similar between the rhPTH(1–84) group (ten [11%] patients) and the placebo group (four [9%] patients).

Interpretation

50 μg, 75 μg, or 100 μg per day of rhPTH(1–84), administered subcutaneously in the outpatient setting, is efficacious and well tolerated as a PTH replacement therapy for patients with hypoparathyroidism.

Funding

NPS Pharmaceuticals.

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

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