Efficacy and safety of recombinant human parathyroid hormone (1-84) in hypoparathyroidism (REPLACE)

A double-blind, placebo-controlled, randomised, phase 3 study

Michael Mannstadt, Bart L. Clarke, Tamara Vokes, Maria Luisa Brandi, Lakshminarayan Ranganath, William D. Fraser, P. Lakatos, L. Bajnok, Roger Garceau, Leif Mosekilde, Hjalmar Lagast, Dolores Shoback, John P. Bilezikian

Research output: Contribution to journalArticle

108 Citations (Scopus)

Abstract

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

Original languageEnglish
Pages (from-to)275-283
Number of pages9
JournalThe Lancet Diabetes and Endocrinology
Volume1
Issue number4
DOIs
Publication statusPublished - Dec 2013

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Hypoparathyroidism
Placebos
Safety
Calcium
Vitamin D
Hypocalcemia
human PTH protein
Double-Blind Method
Serum Albumin
Minerals
Homeostasis
Serum

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Internal Medicine
  • Endocrinology

Cite this

Efficacy and safety of recombinant human parathyroid hormone (1-84) in hypoparathyroidism (REPLACE) : A double-blind, placebo-controlled, randomised, phase 3 study. / Mannstadt, Michael; Clarke, Bart L.; Vokes, Tamara; Brandi, Maria Luisa; Ranganath, Lakshminarayan; Fraser, William D.; Lakatos, P.; Bajnok, L.; Garceau, Roger; Mosekilde, Leif; Lagast, Hjalmar; Shoback, Dolores; Bilezikian, John P.

In: The Lancet Diabetes and Endocrinology, Vol. 1, No. 4, 12.2013, p. 275-283.

Research output: Contribution to journalArticle

Mannstadt, M, Clarke, BL, Vokes, T, Brandi, ML, Ranganath, L, Fraser, WD, Lakatos, P, Bajnok, L, Garceau, R, Mosekilde, L, Lagast, H, Shoback, D & Bilezikian, JP 2013, 'Efficacy and safety of recombinant human parathyroid hormone (1-84) in hypoparathyroidism (REPLACE): A double-blind, placebo-controlled, randomised, phase 3 study', The Lancet Diabetes and Endocrinology, vol. 1, no. 4, pp. 275-283. https://doi.org/10.1016/S2213-8587(13)70106-2
Mannstadt, Michael ; Clarke, Bart L. ; Vokes, Tamara ; Brandi, Maria Luisa ; Ranganath, Lakshminarayan ; Fraser, William D. ; Lakatos, P. ; Bajnok, L. ; Garceau, Roger ; Mosekilde, Leif ; Lagast, Hjalmar ; Shoback, Dolores ; Bilezikian, John P. / Efficacy and safety of recombinant human parathyroid hormone (1-84) in hypoparathyroidism (REPLACE) : A double-blind, placebo-controlled, randomised, phase 3 study. In: The Lancet Diabetes and Endocrinology. 2013 ; Vol. 1, No. 4. pp. 275-283.
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AU - Brandi, Maria Luisa

AU - Ranganath, Lakshminarayan

AU - Fraser, William D.

AU - Lakatos, P.

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