Hypoparathyroidism
Conditions
Keywords
Hypoparathyroidism
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.
Interventions
DRUGPlacebo
Placebo for subcutaneous injection
DRUGNPSP558
Parathyroid hormone 50, 75, or 100 mcg injectable subcutaneously daily
Sponsors
Shire
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 85 Years
Healthy volunteers
No
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).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Percentage of Subjects Who Met the Triple Efficacy Endpoint Criteria at Week 24. | Week 24 of dosing | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage Changes From Baseline in Daily Calcium Dose at Week 24. | 24 Weeks | The analysis of this endpoint was based on investigator prescribed data. |
| Proportion of Subjects Who Achieved Independence From Active Vitamin D and an Oral Calcium Dose of ≤ 500 mg/Day at Week 24. | 24 Weeks | 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. |
| Percentage of Subjects With Any Clinical Symptoms of Hypocalcemia During Weeks 16-24. | 8 Weeks | 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. |
Countries
Belgium, Canada, Denmark, France, Hungary, Italy, United Kingdom, United States
Participant flow
Recruitment details
124 Subjects were enrolled between 12/2008 and 9/2011 at 28 clinical sites in North America, Western Europe and Hungary.
Pre-assignment details
Subjects underwent a screening and stabilization period (optimization) of up to 16 weeks prior to enrollment. Please note: Data for 10 subjects were excluded.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Matching Placebo: Placebo for subcutaneous injection | 40 |
| NPSP558 NPSP558: Recombinant Human Parathyroid hormone (rhPTH\[1-84\]) 50, 75, or 100 mcg subcutaneously daily | 84 |
| Total | 124 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 2 |
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | Non-Compliance, Subject/Physician Dec. | 1 | 1 |
| Overall Study | Physician Decision | 3 | 0 |
| Overall Study | Withdrawal by Subject | 3 | 1 |
Baseline characteristics
| Characteristic | Placebo | NPSP558 | Total |
|---|---|---|---|
| Age, Customized 45 to 64 years | 23 Participants | 45 Participants | 68 Participants |
| Age, Customized < 45 years | 13 Participants | 35 Participants | 48 Participants |
| Age, Customized > = 65 years | 4 Participants | 4 Participants | 8 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 2 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 40 Participants | 82 Participants | 122 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) White | 39 Participants | 80 Participants | 119 Participants |
| Region of Enrollment Europe | 12 Participants | 25 Participants | 37 Participants |
| Region of Enrollment Hungary | 7 Participants | 16 Participants | 23 Participants |
| Region of Enrollment North America | 21 Participants | 43 Participants | 64 Participants |
| Sex: Female, Male Female | 33 Participants | 65 Participants | 98 Participants |
| Sex: Female, Male Male | 7 Participants | 19 Participants | 26 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 38 / 40 | 69 / 84 |
| serious Total, serious adverse events | 4 / 40 | 9 / 84 |
Outcome results
Primary
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.
Time frame: Week 24 of dosing
Population: Intent to Treat (ITT) population, which includes all randomized subjects who received at least 1 dose of study drug and had at least 1 post-baseline efficacy assessment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | The Percentage of Subjects Who Met the Triple Efficacy Endpoint Criteria at Week 24. | 2.5 percentage of participants |
| NPSP558 | The Percentage of Subjects Who Met the Triple Efficacy Endpoint Criteria at Week 24. | 54.8 percentage of participants |
Comparison: The null hypothesis is that the % of subjects meeting primary efficacy endpoint criteria are the same for both tmt arms. The sample size was determined based on the assumption that 40% and 10% of subjects for NPSP558 and pbo arms would meet the endpt criteria, respectively. Based on 2-tailed test, alpha of 0.05 and 2-to-1 randomization ratio, 84 (56 NPSP558, 28 pbo) subjects who completing the study would achieve 80% statistical power. Adjusted for dropouts, planned enrollment was 110 subjects.p-value: <0.00195% CI: [40.6, 64]Fisher Exact
Secondary
Percentage Changes From Baseline in Daily Calcium Dose at Week 24.
The analysis of this endpoint was based on investigator prescribed data.
Time frame: 24 Weeks
Population: Intent to Treat (ITT) population subjects with Baseline and Week 24 data
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Percentage Changes From Baseline in Daily Calcium Dose at Week 24. | 2.4 percentage change from baseline | Standard Deviation 38.37 |
| NPSP558 | Percentage Changes From Baseline in Daily Calcium Dose at Week 24. | -51.8 percentage change from baseline | Standard Deviation 45.71 |
Comparison: The null hypothesis is that there is no difference between the percentage changes from baseline for the two treatment arms.p-value: <0.001ANCOVA
Secondary
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.
Time frame: 8 Weeks
Population: Intent to Treat (ITT) population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Subjects With Any Clinical Symptoms of Hypocalcemia During Weeks 16-24. | 37.5 percentage of participants |
| NPSP558 | Percentage of Subjects With Any Clinical Symptoms of Hypocalcemia During Weeks 16-24. | 34.5 percentage of participants |
Comparison: The null hypothesis is that the percentages of subjects with any reported clinical symptoms for the two treatment arms are the same.p-value: 0.74795% CI: [0.402, 1.922]Cochran-Mantel-Haenszel
Secondary
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.
Time frame: 24 Weeks
Population: Intent to Treat (ITT) population subjects with Baseline and Week 24 data.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Proportion of Subjects Who Achieved Independence From Active Vitamin D and an Oral Calcium Dose of ≤ 500 mg/Day at Week 24. | 6.1 percentage of participants |
| NPSP558 | Proportion of Subjects Who Achieved Independence From Active Vitamin D and an Oral Calcium Dose of ≤ 500 mg/Day at Week 24. | 43.0 percentage of participants |
Comparison: The null hypothesis is that there is no difference between the proportions of subjects (who achieved this secondary endpoint) from the two treatment arms.p-value: <0.00195% CI: [2.619, 52.363]Cochran-Mantel-Haenszel