Hyperparathyroidism, Secondary
Conditions
Keywords
Secondary Hyperparathyroidism (SHPT), chronic kidney disease (CKD), hemodialysis, parathyroid hormone (PTH), hypocalcemia, bone and mineral metabolism
Brief summary
This study is designed to assess the efficacy and safety of etelcalcetide (AMG 416) compared with placebo in the treatment of SHPT in CKD patients receiving hemodialysis.
Interventions
DRUGEtelcalcetide
Administered intravenously three times per week. The starting dose was 5 mg. The dose may have been increased at weeks 5, 9, 13, and 17 (4-week intervals) by 2.5 mg or 5 mg on the basis of the predialysis parathyroid hormone and corrected calcium concentrations obtained in the prior week. The minimum dose was 2.5 mg and the maximum dose was 15 mg.
DRUGPlacebo
Administered intravenously (IV) three times per week.
Sponsors
Amgen
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 100 Years
Healthy volunteers
No
Inclusion criteria
* Subject understands the study procedures and agrees to participate in the study by giving written informed consent. * Subject is 18 years of age or older. * Subject agrees to not participate in another study of an investigational agent during the study. * Subject must be receiving hemodialysis 3 times weekly for at least 3 months * Other Inclusion Criteria may apply
Exclusion criteria
* Currently receiving treatment in another investigational device or drug study, or ended treatment on another investigational device or drug study(s) within 8 weeks prior to screening. * Other investigational procedures while participating in this study are excluded. * Anticipated or scheduled parathyroidectomy during the study period. * Subject has received a parathyroidectomy within 3 months prior to dosing. * Anticipated or scheduled kidney transplant during the study period. * Subject has known sensitivity to any of the products or components to be administered during dosing. * Subject has participated in a prior clinical trial of AMG 416 * Subject has an unstable medical condition based on medical history, physical examination, and routine laboratory tests, or is otherwise unstable in the judgment of the Investigator. * Subject has a history of any illness that, in the opinion of the Investigator, might confound the results of the study or pose additional risk to the subject. * Other
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With > 30% Decrease From Baseline in Mean PTH During the Efficacy Assessment Phase | Baseline and the efficacy assessment phase (EAP; defined as Weeks 20 to 27, inclusive). | Participants who did not have any scheduled assessments during the EAP were considered non-responders. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Mean Predialysis Parathyroid Hormone ≤ 300 pg/mL During the Efficacy Assessment Phase | Baseline and the efficacy assessment phase (Week 20 to Week 27) | Participants who had no scheduled assessments during the EAP were considered non-responders. |
| Percent Change From Baseline in Predialysis PTH During the Efficacy Assessment Phase | Baseline and the Efficacy Assessment Phase (Week 20 to Week 27) | — |
| Percent Change From Baseline in Predialysis Corrected Calcium During the Efficacy Assessment Phase | Baseline and the efficacy assessment phase (Week 20 to Week 27) | — |
| Percent Change From Baseline in Predialysis Corrected Calcium Phosphorus Product (cCa x P) During the Efficacy Assessment Phase | Baseline and the efficacy assessment phase (Week 20 to Week 27) | — |
| Percent Change From Baseline in Predialysis Phosphorus During the Efficacy Assessment Phase | Baseline and the efficacy assessment phase (Week 20 to Week 27) | — |
Countries
Australia, Belgium, Canada, Czechia, France, Germany, Hungary, Israel, Italy, Netherlands, Poland, Russia, Spain, Sweden, United States
Participant flow
Recruitment details
This study was conducted at 97 centers in the US, Canada, Europe, Israel, the Russian Federation, and Australia. The first participant was enrolled on 12 March 2013, and the last participant 07 October 2013.
Pre-assignment details
Eligible participants were randomized 1:1 to etelcalcetide or placebo. Randomization was stratified by screening parathyroid hormone (PTH) (\< 600 pg/mL, 600 to ≤ 1000 pg/mL, and \> 1000 pg/mL), prior cinacalcet use and region (North America or non-North America).
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants received placebo administered by intravenous bolus injection at the end of each hemodialysis session, three times per week (TIW) for 26 weeks. | 260 |
| Etelcalcetide Participants received etelcalcetide administered by intravenous bolus injection at the end of each hemodialysis session TIW for 26 weeks. | 255 |
| Total | 515 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 7 | 5 |
| Overall Study | Lost to Follow-up | 12 | 19 |
| Overall Study | Protocol Specified Criteria | 25 | 1 |
| Overall Study | Withdrawal by Subject | 12 | 12 |
Baseline characteristics
| Characteristic | Placebo | Etelcalcetide | Total |
|---|---|---|---|
| Age, Continuous | 59.0 years STANDARD_DEVIATION 13.9 | 58.4 years STANDARD_DEVIATION 14.6 | 58.7 years STANDARD_DEVIATION 14.3 |
| Corrected Calcium (cCa) | 9.70 mg/dL STANDARD_DEVIATION 0.69 | 9.63 mg/dL STANDARD_DEVIATION 0.65 | 9.66 mg/dL STANDARD_DEVIATION 0.67 |
| Corrected Calcium Phosphorus Product (cCa x P) | 56.37 mg²/dL² STANDARD_DEVIATION 14.5 | 55.30 mg²/dL² STANDARD_DEVIATION 15.27 | 55.84 mg²/dL² STANDARD_DEVIATION 14.88 |
| Parathyroid Hormone | 851.7 pg/mL STANDARD_DEVIATION 552 | 845.0 pg/mL STANDARD_DEVIATION 464.3 | 848.4 pg/mL STANDARD_DEVIATION 510 |
| Phosphorus | 5.83 mg/dL STANDARD_DEVIATION 1.45 | 5.76 mg/dL STANDARD_DEVIATION 1.6 | 5.79 mg/dL STANDARD_DEVIATION 1.53 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 participants | 0 participants | 0 participants |
| Race/Ethnicity, Customized Asian | 6 participants | 13 participants | 19 participants |
| Race/Ethnicity, Customized Black (or African American) | 80 participants | 64 participants | 144 participants |
| Race/Ethnicity, Customized Hispanic/Latino | 33 participants | 32 participants | 65 participants |
| Race/Ethnicity, Customized Missing | 0 participants | 2 participants | 2 participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 3 participants | 7 participants | 10 participants |
| Race/Ethnicity, Customized Not Hispanic/Latino | 227 participants | 221 participants | 448 participants |
| Race/Ethnicity, Customized Other | 2 participants | 6 participants | 8 participants |
| Race/Ethnicity, Customized White | 169 participants | 163 participants | 332 participants |
| Sex: Female, Male Female | 95 Participants | 93 Participants | 188 Participants |
| Sex: Female, Male Male | 165 Participants | 162 Participants | 327 Participants |
| Stratification Factor: Cinacalcet Use Within 8 Weeks of Randomization No | 227 participants | 226 participants | 453 participants |
| Stratification Factor: Cinacalcet Use Within 8 Weeks of Randomization Yes | 33 participants | 29 participants | 62 participants |
| Stratification Factor: Region Non-North America | 110 participants | 109 participants | 219 participants |
| Stratification Factor: Region North America | 150 participants | 146 participants | 296 participants |
| Stratification Factor: Screening Serum Parathroid Hormone > 1000 pg/mL | 55 participants | 53 participants | 108 participants |
| Stratification Factor: Screening Serum Parathroid Hormone < 600 pg/mL | 84 participants | 84 participants | 168 participants |
| Stratification Factor: Screening Serum Parathroid Hormone ≥ 600 to ≤ 1000 pg/mL | 121 participants | 118 participants | 239 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 132 / 259 | 199 / 252 |
| serious Total, serious adverse events | 71 / 259 | 62 / 252 |
Outcome results
Primary
Percentage of Participants With > 30% Decrease From Baseline in Mean PTH During the Efficacy Assessment Phase
Participants who did not have any scheduled assessments during the EAP were considered non-responders.
Time frame: Baseline and the efficacy assessment phase (EAP; defined as Weeks 20 to 27, inclusive).
Population: The full analysis set, consisting of all randomized participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With > 30% Decrease From Baseline in Mean PTH During the Efficacy Assessment Phase | 9.6 percentage of participants |
| Etelcalcetide | Percentage of Participants With > 30% Decrease From Baseline in Mean PTH During the Efficacy Assessment Phase | 75.3 percentage of participants |
Comparison: A Cochran-Mantel-Haenszel test stratified by screening PTH category (\< 600, ≥ 600 to ≤ 1000, and \> 1000 pg/mL), recent cinacalcet use within 8 weeks before randomization (yes and no), and region (North America and non-North America) was used to compare the primary endpoint of percentage of participants with \> 30% reduction from baseline in PTH during the EAP between etelcalcetide and placebo.p-value: <0.00195% CI: [18.18, 52.17]Cochran-Mantel-Haenszel
Secondary
Percentage of Participants With Mean Predialysis Parathyroid Hormone ≤ 300 pg/mL During the Efficacy Assessment Phase
Participants who had no scheduled assessments during the EAP were considered non-responders.
Time frame: Baseline and the efficacy assessment phase (Week 20 to Week 27)
Population: Full analysis set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With Mean Predialysis Parathyroid Hormone ≤ 300 pg/mL During the Efficacy Assessment Phase | 4.6 percentage of participants |
| Etelcalcetide | Percentage of Participants With Mean Predialysis Parathyroid Hormone ≤ 300 pg/mL During the Efficacy Assessment Phase | 53.3 percentage of participants |
p-value: <0.00195% CI: [16.35, 70.37]Cochran-Mantel-Haenszel
Secondary
Percent Change From Baseline in Predialysis Corrected Calcium During the Efficacy Assessment Phase
Time frame: Baseline and the efficacy assessment phase (Week 20 to Week 27)
Population: Full analysis set participants with observed data
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Percent Change From Baseline in Predialysis Corrected Calcium During the Efficacy Assessment Phase | 0.58 percent change | Standard Error 0.29 |
| Etelcalcetide | Percent Change From Baseline in Predialysis Corrected Calcium During the Efficacy Assessment Phase | -6.69 percent change | Standard Error 0.55 |
p-value: <0.00195% CI: [-8.38, -6.03]Repeated Measures Mixed Effects Model
Secondary
Percent Change From Baseline in Predialysis Corrected Calcium Phosphorus Product (cCa x P) During the Efficacy Assessment Phase
Time frame: Baseline and the efficacy assessment phase (Week 20 to Week 27)
Population: Full analysis set participants with observed data
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Percent Change From Baseline in Predialysis Corrected Calcium Phosphorus Product (cCa x P) During the Efficacy Assessment Phase | -1.06 percent change | Standard Error 1.42 |
| Etelcalcetide | Percent Change From Baseline in Predialysis Corrected Calcium Phosphorus Product (cCa x P) During the Efficacy Assessment Phase | -15.84 percent change | Standard Error 1.57 |
p-value: <0.00195% CI: [-18.65, -10.51]Repeated Measures Mixed Effects Model
Secondary
Percent Change From Baseline in Predialysis Phosphorus During the Efficacy Assessment Phase
Time frame: Baseline and the efficacy assessment phase (Week 20 to Week 27)
Population: Full analysis set participants with observed data
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Percent Change From Baseline in Predialysis Phosphorus During the Efficacy Assessment Phase | -1.60 percent change | Standard Error 1.42 |
| Etelcalcetide | Percent Change From Baseline in Predialysis Phosphorus During the Efficacy Assessment Phase | -9.63 percent change | Standard Error 1.61 |
p-value: <0.00195% CI: [-12.15, -3.92]Repeated Measures Mixed Effects Model
Secondary
Percent Change From Baseline in Predialysis PTH During the Efficacy Assessment Phase
Time frame: Baseline and the Efficacy Assessment Phase (Week 20 to Week 27)
Population: Full analysis set participants with observed data
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Percent Change From Baseline in Predialysis PTH During the Efficacy Assessment Phase | 13.72 percent change | Standard Error 2.5 |
| Etelcalcetide | Percent Change From Baseline in Predialysis PTH During the Efficacy Assessment Phase | -57.39 percent change | Standard Error 1.91 |
p-value: <0.00195% CI: [-77.53, -65.14]Repeated Measures Mixed Effects Model