title: Efficacy and safety of recombinant human parathyroid hormone (1-84) in hypoparathyroidism (REPLACE): a double-blind, placebo-controlled, randomised, phase 3 study.
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.
  
  
  RESULTS
  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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. Electronic address: mmannstadt@partners.org.
authors.forename: Michael
authors.initials: M
authors.lastname: Mannstadt
authors.affiliation: Division of Endocrinology, Diabetes, Metabolism and Nutrition, Mayo Clinic, Rochester, MN, USA.
authors.forename: Bart L
authors.initials: BL
authors.lastname: Clarke
authors.affiliation: Section of Endocrinology, University of Chicago Medicine, Chicago, IL, USA.
authors.forename: Tamara
authors.initials: T
authors.lastname: Vokes
authors.affiliation: Department of Internal Medicine, University of Florence, Florence, Italy.
authors.forename: Maria Luisa
authors.initials: ML
authors.lastname: Brandi
authors.affiliation: Department of Clinical Biochemistry and Metabolic Medicine, Royal Liverpool University Hospital, Liverpool, UK.
authors.forename: Lakshminarayan
authors.initials: L
authors.lastname: Ranganath
authors.affiliation: Department of Medicine, Norwich Medical School, University of East Anglia, Norwich, UK.
authors.forename: William D
authors.initials: WD
authors.lastname: Fraser
authors.affiliation: 1st Department of Internal Medicine, Semmelweis University, Budapest, Hungary.
authors.forename: Peter
authors.initials: P
authors.lastname: Lakatos
authors.affiliation: 1st Department of Internal Medicine, University of Pécs Medical School, Pécs, Hungary.
authors.forename: Laszlo
authors.initials: L
authors.lastname: Bajnok
authors.affiliation: NPS Pharmaceuticals, Bedminster, NJ, USA.
authors.forename: Roger
authors.initials: R
authors.lastname: Garceau
authors.affiliation: Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Leif
authors.initials: L
authors.lastname: Mosekilde
authors.affiliation: NPS Pharmaceuticals, Bedminster, NJ, USA.
authors.forename: Hjalmar
authors.initials: H
authors.lastname: Lagast
authors.affiliation: Endocrine Research Unit, San Francisco Veterans Affairs Medical Center, University of California, San Francisco, CA, USA.
authors.forename: Dolores
authors.initials: D
authors.lastname: Shoback
authors.affiliation: Division of Endocrinology, College of Physicians and Surgeons, Columbia University, New York, NY, USA.
authors.forename: John P
authors.initials: JP
authors.lastname: Bilezikian
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019355:Calcium Citrate / Q000008:administration & dosage; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D006261:Headache / Q000139:chemically induced / Q000175:diagnosis; D006801:Humans; D007011:Hypoparathyroidism / Q000175:diagnosis* / Q000188:drug therapy* / Q000453:epidemiology; D007279:Injections, Subcutaneous; D008297:Male; D008875:Middle Aged; D010281:Parathyroid Hormone / Q000008:administration & dosage* / Q000009:adverse effects*; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000009:adverse effects; D013035:Spasm / Q000139:chemically induced / Q000175:diagnosis; D016896:Treatment Outcome; D014807:Vitamin D / Q000008:administration & dosage; D055815:Young Adult
chemical_list: C470125:PTH protein, human; D010281:Parathyroid Hormone; D011994:Recombinant Proteins; D014807:Vitamin D; D019355:Calcium Citrate