Hypercalcemia, Hyperparathyroidism, Primary
Conditions
Keywords
Primary hyperparathyroidism, Parathyroidectomy, Hypercalcemia
Brief summary
This study is designed to demonstrate the efficacy and to assess the safety of cinacalcet for the reduction of hypercalcemia in patients with primary hyperparathyroidism for whom parathyroidectomy is indicated on the basis of an elevated corrected total serum calcium, but who are unable to undergo parathyroidectomy.
Detailed description
The study will consist of a 30-day screening phase, a 12-week placebo-controlled dose-titration phase, and a 16-week placebo-controlled efficacy assessment phase (EAP). Participants who complete 28 weeks on study will continue into an open-label safety extension phase for 24 weeks of investigational cinacalcet treatment.
Interventions
DRUGCinacalcet
Administered orally at a starting dose of 30 mg twice a day (BID). Participants will be eligible for a dose titration once every 3 weeks during the placebo-controlled dose titration phase based on corrected total serum calcium concentration and safety assessments obtained the previous week. Doses may be sequentially increased to 60 mg BID, 90 mg BID, and 90 mg 3 times a day (TID).
DRUGPlacebo
Administered orally following the same tiitration regimen as the experimental arm.
Sponsors
Amgen
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 No maximum
Healthy volunteers
No
Inclusion criteria
* age ≥ 18 years * diagnosis of primary hyperparathyroidism (HPT) * subjects must have the following laboratory values: 1. local/historical laboratory result showing a corrected total serum calcium \> 1 mg/dL (0.25 mmol/L) above the upper limit of normal and ≤ 12.5 mg/dL (3.12 mmol/L) within the past 12 months, and * local/historical laboratory result showing a plasma parathyroid horone (PTH) \> 75% of upper limit of normal within the past 12 months, and * one central laboratory draw at the screen visit showing a corrected total serum calcium \> 11.3 mg/dL (2.82 mmol/L) and ≤ 12.5 mg/dL (3.12 mmol/L), and * one central laboratory draw at the screen visit showing a plasma PTH \> 55 pg/mL (5.8 pmol/L) OR 2. two central laboratory draws performed during the screening period at least 7 days apart, showing a * corrected total serum calcium \> 11.3 mg/dL (2.82 mmol/L) and ≤ 12.5 mg/dL (3.12 mmol/L), and * plasma PTH \> 55 pg/mL (5.8 pmol/L) * not able to undergo parathyroidectomy for ≥ 1 of the following reasons: * failed parathyroidectomy * comorbid conditions contraindicating parathyroidectomy * parathyroidectomy not considered appropriate or is not feasible by primary physician and subject * before any study-specific procedure is performed, the appropriate written informed consent must be obtained
Exclusion criteria
* symptoms attributable to hypercalcemia, requiring immediate medical intervention, as judged by the investigator (including acute kidney stone, nausea and vomiting requiring intravenous hydration, confusion, lethargy, stupor, or coma) * unstable medical condition, defined as having been hospitalized within 30 days before the date of informed consent, or otherwise unstable in the judgment of the investigator * administration of drugs that increase serum calcium concentration, including but not limited to thiazide diuretics or lithium * initiated bisphosphonate therapy or changed bisphosphonate dose within 12 weeks before the date of informed consent * current administration of drugs for ventricular arrhythmia * unable to provide informed consent, or is at risk for poor compliance with study procedures * currently enrolled in another investigational device or drug study(s), or completed such study within 30 days before the date of informed consent * known hypersensitivity to or unable to tolerate cinacalcet * received treatment with cinacalcet within 60 days before the date of informed consent * history of seizures or an adjustment of anti-seizure medication within 12 weeks before the date of informed consent * family history or diagnosis a genetic syndrome, such as familial benign hypocalciuric hypercalcemia (FBHH) or multiple endocrine neoplasia type 1 (MEN1) and type 2 (MEN2), where primary HPT is one of the clinical manifestations of familial benign hypocalciuric hypercalcemia (FBHH) * refused to use highly effective contraceptive measures (as determined by the investigator) throughout the study * pregnant or breastfeeding
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Percentage of Participants With Mean Corrected Total Serum Calcium Concentration ≤ 10.3 mg/dL (2.57 mmol/L) During the EAP | Efficacy assessment phase (study visits at Weeks 16, 20, 24, and 28) |
Secondary
| Measure | Time frame |
|---|---|
| Percentage of Participants With a ≥ 1 mg/dL (0.25 mmol/L) Decrease From Baseline in Mean Corrected Total Serum Calcium Concentration During the EAP | Baseline and the EAP (mean of Weeks 16, 20, 24, and 28) |
| Percent Change From Baseline in Corrected Total Serum Calcium Concentration During the EAP | Baseline and the EAP (mean of Weeks 16, 20, 24, and 28) |
| Percent Change From Baseline in Plasma Parathyroid Hormone Level During the EAP | Baseline and the EAP (mean of Weeks 16, 20, 24, and 28) |
Countries
Australia, Canada, Hungary, Poland, Portugal, Russia, United States
Participant flow
Recruitment details
The study was conducted at 29 centers in United States, Australia, Canada, Hungary, Poland, Portugal, and Russian Federation. The first participant enrolled on 10 March 2010 and the last participant enrolled on 28 December 2011.
Pre-assignment details
This study consisted of a 12-week placebo-controlled dose-titration phase, a 16-week placebo-controlled efficacy assessment phase (EAP), and an open-label safety extension phase for 24 weeks of cinacalcet treatment. Participants were randomized in a 1:1 ratio to cinacalcet or placebo stratified by bisphosphonate use.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants received placebo orally twice a day (BID) for 12 weeks during the dose titration phase and for another 16 weeks during the efficacy assessment phase. Participants then continued into the open-label extension phase and received cinacalcet at a starting dose of 30 mg BID for 24 weeks. The dose of cinacalcet could have been increased or decreased as needed to maintain a corrected total serum calcium concentration within the normal range through Week 52. | 34 |
| Cinacalcet Participants received cinacalcet at a starting dose of 30 mg orally BID and were eligible for a dose titration once every 3 weeks during the 12-week dose-titration phase based on corrected total serum calcium concentration and safety assessments. Participants continued to receive cinacalcet for another 16 weeks during the efficacy assessment phase and then continued into the open-label extension phase and received cinacalcet at a starting dose of 30 mg BID for 24 weeks. The dose of cinacalcet could have been increased or decreased as needed to maintain a corrected total serum calcium concentration within the normal range through Week 52. | 33 |
| Total | 67 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Efficacy Assessment Phase (Weeks 13-28) | Lost to Follow-up | 0 | 1 |
| Open-label Extension Phase (Weeks 29-52) | Adverse Event | 1 | 1 |
| Open-label Extension Phase (Weeks 29-52) | Withdrawal by Subject | 1 | 0 |
| Titration Phase (Weeks 1-12) | Other | 0 | 1 |
| Titration Phase (Weeks 1-12) | Requirement for alternative therapy | 1 | 0 |
| Titration Phase (Weeks 1-12) | Withdrawal by Subject | 2 | 3 |
Baseline characteristics
| Characteristic | Placebo | Cinacalcet | Total |
|---|---|---|---|
| Age, Continuous | 75.0 years STANDARD_DEVIATION 8.9 | 69.5 years STANDARD_DEVIATION 13 | 72.3 years STANDARD_DEVIATION 11.4 |
| Albumin-corrected Calcium | 11.80 mg/dL STANDARD_DEVIATION 0.48 | 11.73 mg/dL STANDARD_DEVIATION 0.45 | 11.77 mg/dL STANDARD_DEVIATION 0.46 |
| Bisphosphonate Use No | 24 participants | 24 participants | 48 participants |
| Bisphosphonate Use Yes | 10 participants | 9 participants | 19 participants |
| Intact Parathyroid Hormone (iPTH) | 238.6 pg/mL STANDARD_DEVIATION 212.2 | 179.0 pg/mL STANDARD_DEVIATION 98 | 209.7 pg/mL STANDARD_DEVIATION 168.4 |
| Race/Ethnicity, Customized Black or African American | 1 participants | 4 participants | 5 participants |
| Race/Ethnicity, Customized Hispanic or Latino | 0 participants | 1 participants | 1 participants |
| Race/Ethnicity, Customized White or Caucasian | 33 participants | 28 participants | 61 participants |
| Sex: Female, Male Female | 27 Participants | 25 Participants | 52 Participants |
| Sex: Female, Male Male | 7 Participants | 8 Participants | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 15 / 34 | 25 / 33 | 15 / 29 | 10 / 28 |
| serious Total, serious adverse events | 4 / 34 | 3 / 33 | 7 / 29 | 1 / 28 |
Outcome results
Primary
Percentage of Participants With Mean Corrected Total Serum Calcium Concentration ≤ 10.3 mg/dL (2.57 mmol/L) During the EAP
Time frame: Efficacy assessment phase (study visits at Weeks 16, 20, 24, and 28)
Population: Full analysis set (all participants randomized to treatment). For participants with no data for the EAP, the last post-baseline value from the titration phase was used to impute the missing EAP values (last value carried forward (LVCF) imputation). Participants with only baseline information were counted as non-responders.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With Mean Corrected Total Serum Calcium Concentration ≤ 10.3 mg/dL (2.57 mmol/L) During the EAP | 0.0 percentage of participants |
| Cinacalcet | Percentage of Participants With Mean Corrected Total Serum Calcium Concentration ≤ 10.3 mg/dL (2.57 mmol/L) During the EAP | 75.8 percentage of participants |
p-value: <0.001Cochran-Mantel-Haenszel
Secondary
Percentage of Participants With a ≥ 1 mg/dL (0.25 mmol/L) Decrease From Baseline in Mean Corrected Total Serum Calcium Concentration During the EAP
Time frame: Baseline and the EAP (mean of Weeks 16, 20, 24, and 28)
Population: Full analysis set (all participants randomized to treatment). For participants with no data for the EAP, the last post-baseline value from the titration phase was used to impute the missing EAP values (last value carried forward (LVCF) imputation). Participants with only baseline information were counted as non-responders.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With a ≥ 1 mg/dL (0.25 mmol/L) Decrease From Baseline in Mean Corrected Total Serum Calcium Concentration During the EAP | 5.9 percentage of participants |
| Cinacalcet | Percentage of Participants With a ≥ 1 mg/dL (0.25 mmol/L) Decrease From Baseline in Mean Corrected Total Serum Calcium Concentration During the EAP | 84.8 percentage of participants |
p-value: <0.001Cochran-Mantel-Haenszel
Secondary
Percent Change From Baseline in Corrected Total Serum Calcium Concentration During the EAP
Time frame: Baseline and the EAP (mean of Weeks 16, 20, 24, and 28)
Population: Full analysis set with at least 1 post-baseline measurement; for participants with no data for the EAP, the last post-baseline value from the titration phase was used to impute the missing EAP values (LVCF imputation).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Percent Change From Baseline in Corrected Total Serum Calcium Concentration During the EAP | -1.66 percent change | Standard Error 0.99 |
| Cinacalcet | Percent Change From Baseline in Corrected Total Serum Calcium Concentration During the EAP | -15.21 percent change | Standard Error 1 |
p-value: <0.00195% CI: [-16.23, -10.88]ANCOVA
Secondary
Percent Change From Baseline in Plasma Parathyroid Hormone Level During the EAP
Time frame: Baseline and the EAP (mean of Weeks 16, 20, 24, and 28)
Population: Full analysis set with at least 1 post-baseline measurement; for participants with no data for the EAP, the last post-baseline value from the titration phase was used to impute the missing EAP values (LVCF imputation).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Percent Change From Baseline in Plasma Parathyroid Hormone Level During the EAP | -1.01 percent change | Standard Error 4.05 |
| Cinacalcet | Percent Change From Baseline in Plasma Parathyroid Hormone Level During the EAP | -23.80 percent change | Standard Error 4.18 |
p-value: <0.00195% CI: [-34.01, -11.57]ANCOVA