Michael Mannstadt1, Bart L Clarke2, Tamara Vokes3, Maria Luisa Brandi4, Lakshminarayan Ranganath5, William D Fraser6, Peter Lakatos7, Laszlo Bajnok8, Roger Garceau9, Leif Mosekilde10, Hjalmar Lagast9, Dolores Shoback11, John P Bilezikian12. 1. Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. Electronic address: mmannstadt@partners.org. 2. Division of Endocrinology, Diabetes, Metabolism and Nutrition, Mayo Clinic, Rochester, MN, USA. 3. Section of Endocrinology, University of Chicago Medicine, Chicago, IL, USA. 4. Department of Internal Medicine, University of Florence, Florence, Italy. 5. Department of Clinical Biochemistry and Metabolic Medicine, Royal Liverpool University Hospital, Liverpool, UK. 6. Department of Medicine, Norwich Medical School, University of East Anglia, Norwich, UK. 7. 1st Department of Internal Medicine, Semmelweis University, Budapest, Hungary. 8. 1st Department of Internal Medicine, University of Pécs Medical School, Pécs, Hungary. 9. NPS Pharmaceuticals, Bedminster, NJ, USA. 10. Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark. 11. Endocrine Research Unit, San Francisco Veterans Affairs Medical Center, University of California, San Francisco, CA, USA. 12. Division of Endocrinology, College of Physicians and Surgeons, Columbia University, New York, NY, USA.
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) orplacebo (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.
RCT Entities:
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 humanparathyroid 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.
Authors: Karen K Winer; Andrea Kelly; Alicia Johns; Bo Zhang; Karen Dowdy; Lauren Kim; James C Reynolds; Paul S Albert; Gordon B Cutler Journal: J Pediatr Date: 2018-12 Impact factor: 4.406