Use of NPSP558 in the Treatment of Hypoparathyroidism (REPLACE)

A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study to Investigate the Use of NPSP558, a Recombinant Human Parathyroid Hormone (rhPTH[1-84]) for the Treatment of Adults With Hypoparathyroidism

Use of PTH (1-84) a recombinant hormone in escalating doses for the treatment of adults with hypoparathyroidism. The use of PTH should result in a decrease of calcium and vitamin D supplements.

Study Overview

• Status: Completed
• Conditions: Hypoparathyroidism
• Intervention / Treatment: Drug: Placebo; Drug: NPSP558

Detailed Description

Patients with a history of hypoparathyroidism will be randomized to receive placebo or study drug for 24 weeks, which will be injected daily in either thigh. During that time they will be monitored for safety (specifically, calcium levels in the blood and urine). In addition, the patients' intake of Vitamin D and calcium will be measured.

• Study Type: Interventional
• Enrollment (Actual): 124
• Phase: Phase 3

Contacts and Locations

Study Locations

• Belgium
  • Liege, Belgium, BE-4000
    • Chetre Hospitalier Universitaire de Liege
• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2N 4Z6
      • Heritage Medical Research Clinic
  • Nova Scotia
    • Halifax, Nova Scotia, Canada, B3H 2Y9
      • Capital District Health Authority, QEII Health Sciences Centre
  • Ontario
    • Oakville, Ontario, Canada, L6J 1X8
      • Oakville Bone Center
• Denmark
  • Aarhus, Denmark, DK-8000
    • Aarhus University Hospital
  • Odense, Denmark, DK-5000
    • Odense University Hospital
• France
  • Paris, France, F-75015
    • Hôpital Européen Georges Pompidou
• Hungary
  • Budapest, Hungary
    • Semmelweis University Medical School
  • Pécs, Hungary
    • University of Pécs, School of Medicine
  • Szeged, Hungary
    • University of Szeged
• Italy
  • Firenze, Italy, I - 50134
    • University Hospital of Careggi
• United Kingdom
  • Liverpool, United Kingdom, L69 3GA
    • Royal Liverpool University Hospital
• United States
  • Arizona
    • Scottsdale, Arizona, United States, 85259
      • Mayo Clinic-Scottsdale
  • California
    • Lakewood, California, United States, 90712
      • Advance Medical Research LLC
    • Orange, California, United States, 92868
      • Diabetes Associates
    • San Francisco, California, United States, 94127
      • University of California-San Francisco VA Medical Center
  • Florida
    • Hialeah, Florida, United States, 33012
      • Palm Springs Research Institute
    • Jacksonville, Florida, United States, 32224
      • Mayo Clinic Jacksonville
  • Illinois
    • Chicago, Illinois, United States, 60637
      • University of Chicago Medical Center
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University School of Medicine
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
  • Michigan
    • Detroit, Michigan, United States, 48236
      • Michigan Bone and Mineral Clinic PC
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic Rochester
  • New York
    • New York, New York, United States, 10032
      • Columbia University Medical Center
    • Staten Island, New York, United States, 10301
      • University Physicians Group
  • North Carolina
    • Greenville, North Carolina, United States, 27834
      • Physicians East
  • Ohio
    • Cincinnati, Ohio, United States, 45219
      • University of Cincinnati Bone Health and Osteoporosis Center
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Children's Hospital of Philadelphia
  • Texas
    • San Antonio, Texas, United States, 78229
      • Cetero Research DGD Research Inc.
    • Waco, Texas, United States, 76708
      • Hillcrest Family Health Center
  • Washington
    • Vancouver, Washington, United States, 98664
      • The Vancouver Clinic

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria

Patients who meet all of the following inclusion criteria can be enrolled and potentially randomized into this study:

• Adult males or females 18 to 85 years of age (prior to screening)
• History of hypoparathyroidism for ≥ 18 months
• Requirement for vitamin D metabolite/analog therapy with calcitriol ≥0.25 μg per day or alphacalcidol ≥0.50 μg per day prior to randomization. Requirement for supplemental oral calcium treatment ≥ 1000 mg per day over and above normal dietary calcium intake
• Serum thyroid function tests within normal laboratory limits at screening
• Serum magnesium levels within laboratory normal limits
• Serum 25-hydroxyvitamin D [25(OH)D] level ≤ 1.5-fold the laboratory upper limit of normal
• Creatinine clearance > 30 mL/min on two separate measurements OR creatinine clearance > 60 mL/min AND serum creatinine < 1.5 mg/dL
• With regard to female patients: women who are postmenopausal and women who are surgically sterilized can be enrolled. Women of childbearing potential must have a negative pregnancy test at Randomization and be willing to use two medically acceptable methods of contraception for the duration of the study.

Exclusion Criteria

Patients who have any of the following during the screening visit are not eligible for enrollment in this study:

• Known history of hypoparathyroidism resulting from an activating mutation in the CaSR gene or impaired responsiveness to PTH (pseudohypoparathyroidism)
• Any disease that might affect calcium metabolism or calcium-phosphate homeostasis other than hypoparathyroidism, such as active hyperthyroidism, Paget's disease, insulin dependent diabetes mellitus (IDDM) or poorly controlled Type II diabetes mellitus (HbA1C > 8%), severe and chronic cardiac, liver or renal disease, Cushing's syndrome, neuromuscular disease such as rheumatoid arthritis, myeloma, pancreatitis, malnutrition, rickets, recent prolonged immobility, active malignancy, primary or secondary hyperparathyroidism, a history of parathyroid carcinoma, hypopituitarism, acromegaly, or multiple endocrine neoplasia types I and II
• Patients with a history of thyroid cancer must be documented to be disease-free for a period of at least 5 years
• Patients dependent on regular parenteral calcium infusions (eg calcium gluconate) to maintain calcium homeostasis
• Patients that have undergone gastric resection or have active peptic ulcer disease requiring medical therapy
• Use of prohibited medications such as loop and thiazide diuretics, raloxifene hydrochloride, lithium, estrogens and progestins for hormone replacement therapy,methotrexate, or systemic corticosteroids within respective prohibited periods
• Previous treatment with PTH-like drugs, including PTH(1-84), PTH(1-34) or other N-terminal fragments or analogs of PTH or PTH-related protein within 6 months prior to screening
• Other drugs known to influence calcium and bone metabolism, such as calcitonin, fluoride tablets, or cinacalcet hydrochloride within the prohibited period
• Use of oral bisphosphonates within the previous 6 months or IV bisphosphonate preparations within the previous 12 months prior to screening
• Seizure disorder/epilepsy with a history of a seizure within the previous 6 months prior to screening
• Presence of open epiphyses
• Irradiation (radiotherapy) to the skeleton within 5 years
• Serum 25-hydroxyvitamin D levels greater than 1.5-fold the laboratory upper limit of normal
• Participation in any other investigational trial in which receipt of investigational drug or device occurred within 6 months prior to screening for this study
• Pregnant or lactating women
• History of diagnosed drug or alcohol dependence within the previous 3 years
• Clinical history of renal calculi within the past 12 months
• History of gout
• Disease processes that may adversely affect gastrointestinal absorption, including but not limited to short bowel syndrome, bowel resection, tropical sprue, celiac disease, ulcerative colitis, and Crohn's disease
• Chronic/severe cardiac disease including but not limited to cardiac insufficiency, arrhythmias, bradycardia (resting heart rate < 60 beats/minute), or hypotension (systolic and diastolic blood pressures < 100 and 60 mmHg, respectively)
• History of cerebrovascular accident (CVA).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Sterile water for injection	Drug: Placebo; Placebo for subcutaneous injection
Experimental: 50, 75, 100 mcg NPSP558; Initial dose of 50mcg, to be titrated up to 75mcg and then 100mcg dependent upon response	Drug: NPSP558; Parathyroid hormone 50, 75, or 100 mcg injectable subcutaneously daily

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The Percentage of Subjects Who Met the Triple Efficacy Endpoint Criteria at Week 24.	The triple efficacy endpoint criteria were defined as at least a 50% reduction from the baseline in oral calcium dose and at least a 50% reduction from the baseline in active vitamin D dose and an albumin-corrected total serum calcium concentration that was maintained or normalized compared to the baseline value (≥ 7.5 mg/dL) and did not exceed the upper limit of the laboratory normal range. The analysis of primary efficacy endpoint was based on investigator prescribed data.	Week 24 of dosing

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage Changes From Baseline in Daily Calcium Dose at Week 24.	The analysis of this endpoint was based on investigator prescribed data.	24 Weeks
Proportion of Subjects Who Achieved Independence From Active Vitamin D and an Oral Calcium Dose of ≤ 500 mg/Day at Week 24.	Subjects Who Achieved Independence from Active Vitamin D Usage and with Calcium Dose of 500 mg/day or less. This analysis was based on Investigator Prescribed Data.	24 Weeks
Percentage of Subjects With Any Clinical Symptoms of Hypocalcemia During Weeks 16-24.	Clinical symptoms were a selected group of adverse events that occurred during study weeks 16 through 24. The group of terms were defined by key opinion leaders and documented in study protocol.	8 Weeks

Collaborators and Investigators

• Sponsor: Shire

Publications and helpful links

General Publications

• Ayodele O, Mu F, Berman R, Swallow E, Rejnmark L, Gosmanova EO, Kaul S. Lower Risk of Cardiovascular Events in Adult Patients with Chronic Hypoparathyroidism Treated with rhPTH(1-84): A Retrospective Cohort Study. Adv Ther. 2022 Aug;39(8):3845-3856. doi: 10.1007/s12325-022-02198-y. Epub 2022 Jun 11.
• Chen KS, Gosmanova EO, Curhan GC, Ketteler M, Rubin M, Swallow E, Zhao J, Wang J, Sherry N, Krasner A, Bilezikian JP. Five-year Estimated Glomerular Filtration Rate in Patients With Hypoparathyroidism Treated With and Without rhPTH(1-84). J Clin Endocrinol Metab. 2020 Oct 1;105(10):e3557-65. doi: 10.1210/clinem/dgaa490.
• Vokes TJ, Mannstadt M, Levine MA, Clarke BL, Lakatos P, Chen K, Piccolo R, Krasner A, Shoback DM, Bilezikian JP. Recombinant Human Parathyroid Hormone Effect on Health-Related Quality of Life in Adults With Chronic Hypoparathyroidism. J Clin Endocrinol Metab. 2018 Feb 1;103(2):722-731. doi: 10.1210/jc.2017-01471.
• 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. Efficacy and safety of recombinant human parathyroid hormone (1-84) in hypoparathyroidism (REPLACE): a double-blind, placebo-controlled, randomised, phase 3 study. Lancet Diabetes Endocrinol. 2013 Dec;1(4):275-83. doi: 10.1016/S2213-8587(13)70106-2. Epub 2013 Oct 7. Erratum In: Lancet Diabetes Endocrinol. 2014 Jan;2(1):e3. Dosage error in article text.

Study record dates

Study Major Dates

• Study Start (Actual): December 18, 2008
• Primary Completion (Actual): September 28, 2011
• Study Completion (Actual): September 28, 2011

Study Registration Dates

• First Submitted: August 8, 2008
• First Submitted That Met QC Criteria: August 11, 2008
• First Posted (Estimate): August 12, 2008

Study Record Updates

• Last Update Posted (Actual): June 3, 2021
• Last Update Submitted That Met QC Criteria: May 13, 2021
• Last Verified: May 1, 2021

More Information

Terms related to this study

• Keywords: Hypoparathyroidism
• Additional Relevant MeSH Terms: Endocrine System Diseases; Parathyroid Diseases; Hypoparathyroidism
• Other Study ID Numbers: CL1-11-040; 2008-005063-34 (EudraCT Number)