Clinical trial NCT00732615: Use of NPSP558 in the Treatment of Hypoparathyroidism
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Hypoparathyroidism
Keywords: Hypoparathyroidism
Lead sponsor: Takeda
Sponsor class: INDUSTRY
First posted: 2008-08-12
Enrollment: 124
Sex: ALL
Minimum age (years): 18
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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).

Primary outcomes:
measure: The Percentage of Subjects Who Met the Triple Efficacy Endpoint Criteria at Week 24.
timeFrame: Week 24 of dosing
Secondary outcomes:
measure: Percentage Changes From Baseline in Daily Calcium Dose at Week 24.
timeFrame: 24 Weeks
measure: Proportion of Subjects Who Achieved Independence From Active Vitamin D and an Oral Calcium Dose of ≤ 500 mg/Day at Week 24.
timeFrame: 24 Weeks
measure: Percentage of Subjects With Any Clinical Symptoms of Hypocalcemia During Weeks 16-24.
timeFrame: 8 Weeks
Other outcomes:
Locations:
city: Scottsdale
country: United States
facility: Mayo Clinic-Scottsdale
state: Arizona
city: Lakewood
country: United States
facility: Advance Medical Research LLC
state: California
city: Orange
country: United States
facility: Diabetes Associates
state: California
city: San Francisco
country: United States
facility: University of California-San Francisco VA Medical Center
state: California
city: Hialeah
country: United States
facility: Palm Springs Research Institute
state: Florida
city: Jacksonville
country: United States
facility: Mayo Clinic Jacksonville
state: Florida
city: Chicago
country: United States
facility: University of Chicago Medical Center
state: Illinois
city: Indianapolis
country: United States
facility: Indiana University School of Medicine
state: Indiana
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Detroit
country: United States
facility: Michigan Bone and Mineral Clinic PC
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic Rochester
state: Minnesota
city: New York
country: United States
facility: Columbia University Medical Center
state: New York
city: Staten Island
country: United States
facility: University Physicians Group
state: New York
city: Greenville
country: United States
facility: Physicians East
state: North Carolina
city: Cincinnati
country: United States
facility: University of Cincinnati Bone Health and Osteoporosis Center
state: Ohio
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: San Antonio
country: United States
facility: Cetero Research DGD Research Inc.
state: Texas
city: Waco
country: United States
facility: Hillcrest Family Health Center
state: Texas
city: Vancouver
country: United States
facility: The Vancouver Clinic
state: Washington
city: Liege
country: Belgium
facility: Chetre Hospitalier Universitaire de Liege
city: Calgary
country: Canada
facility: Heritage Medical Research Clinic
state: Alberta
city: Halifax
country: Canada
facility: Capital District Health Authority, QEII Health Sciences Centre
state: Nova Scotia
city: Oakville
country: Canada
facility: Oakville Bone Center
state: Ontario
city: Aarhus
country: Denmark
facility: Aarhus University Hospital
city: Odense
country: Denmark
facility: Odense University Hospital
city: Paris
country: France
facility: Hôpital Européen Georges Pompidou
city: Budapest
country: Hungary
facility: Semmelweis University Medical School
city: Pécs
country: Hungary
facility: University of Pécs, School of Medicine
city: Szeged
country: Hungary
facility: University of Szeged
city: Firenze
country: Italy
facility: University Hospital of Careggi
city: Liverpool
country: United Kingdom
facility: Royal Liverpool University Hospital
Study officials:
affiliation: Takeda
name: Study Director
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.