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 compared with placebo in the treatment of SHPT in patients with chronic kidney disease (CKD) receiving hemodialysis.
Interventions
DRUGEtelcalcetide
Administered intravenously three times per week. The starting dose was 5 mg. The dose may have been increased at 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 must be receiving hemodialysis 3 times weekly for at least 3 months * Subject agrees to not participate in another study of an investigational agent during the study. * 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 (also referred to as KAI-4169). * Subject has received cinacalcet within the 4 weeks prior to screening labs (treatment with cinacalcet is prohibited during the study). * 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. * Other
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With a > 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 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, Austria, Belgium, Canada, Czechia, France, Germany, Hungary, Israel, Italy, Poland, Russia, Spain, United Kingdom, United States
Participant flow
Recruitment details
This study was conducted at 111 centers in the US, Canada, Europe, Israel, Russian Federation, and Australia. The first participant was enrolled on 12 March 2013 and the last participant enrolled on 08 November 2013.
Pre-assignment details
Eligible participants were randomized in a 1:1 ratio to etelcalcetide or placebo. Randomization was stratified by mean 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. | 254 |
| Etelcalcetide Participants received etelcalcetide administered by intravenous bolus injection at the end of each hemodialysis session, TIW, for 26 weeks. The starting dose was 5 mg and may have been increased at weeks 5, 9, 13 and 17 to achieve a predialysis PTH ≤ 300 pg/mL. | 254 |
| Total | 508 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 7 | 9 |
| Overall Study | Lost to Follow-up | 10 | 11 |
| Overall Study | Protocol Specified Criteria | 29 | 1 |
| Overall Study | Sponsor Decision | 0 | 1 |
| Overall Study | Withdrawal by Subject | 15 | 12 |
Baseline characteristics
| Characteristic | Etelcalcetide | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 58.4 years STANDARD_DEVIATION 14.6 | 57.1 years STANDARD_DEVIATION 14.5 | 57.7 years STANDARD_DEVIATION 14.6 |
| Corrected Calcium | 9.65 mg/dL STANDARD_DEVIATION 0.66 | 9.61 mg/dL STANDARD_DEVIATION 0.6 | 9.63 mg/dL STANDARD_DEVIATION 0.63 |
| Corrected Calcium Phosphorus Product (cCa x P) | 57.37 mg²/dL² STANDARD_DEVIATION 15.51 | 55.54 mg²/dL² STANDARD_DEVIATION 15.81 | 56.46 mg²/dL² STANDARD_DEVIATION 15.67 |
| Parathyroid Hormone (PTH) | 848.7 pg/mL STANDARD_DEVIATION 520.4 | 819.7 pg/mL STANDARD_DEVIATION 386 | 834.2 pg/mL STANDARD_DEVIATION 457.9 |
| Phosphorus | 5.95 mg/dL STANDARD_DEVIATION 1.59 | 5.78 mg/dL STANDARD_DEVIATION 1.6 | 5.87 mg/dL STANDARD_DEVIATION 1.59 |
| Race American Indian or Alaska Native | 0 participants | 0 participants | 0 participants |
| Race Asian | 5 participants | 3 participants | 8 participants |
| Race Black (or African American) | 72 participants | 69 participants | 141 participants |
| Race Missing | 0 participants | 1 participants | 1 participants |
| Race Native Hawaiian or Other Pacific Islander | 0 participants | 2 participants | 2 participants |
| Race Other | 4 participants | 4 participants | 8 participants |
| Race White | 173 participants | 175 participants | 348 participants |
| Sex: Female, Male Female | 103 Participants | 114 Participants | 217 Participants |
| Sex: Female, Male Male | 151 Participants | 140 Participants | 291 Participants |
| Stratification Factor: Cinacalcet Use Within 8 Weeks of Randomization No | 221 participants | 220 participants | 441 participants |
| Stratification Factor: Cinacalcet Use Within 8 Weeks of Randomization Yes | 33 participants | 34 participants | 67 participants |
| Stratification Factor: Mean Screening Serum Parathyroid Hormone (PTH) > 1000 pg/mL | 52 participants | 56 participants | 108 participants |
| Stratification Factor: Mean Screening Serum Parathyroid Hormone (PTH) < 600 pg/mL | 87 participants | 84 participants | 171 participants |
| Stratification Factor: Mean Screening Serum Parathyroid Hormone (PTH) ≥ 600 to ≤ 1000 pg/mL | 115 participants | 114 participants | 229 participants |
| Stratification Factor: Region Non-North America | 122 participants | 125 participants | 247 participants |
| Stratification Factor: Region North America | 132 participants | 129 participants | 261 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 110 / 254 | 194 / 251 |
| serious Total, serious adverse events | 78 / 254 | 68 / 251 |
Outcome results
Primary
Percentage of Participants With a > 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 a > 30% Decrease From Baseline in Mean PTH During the Efficacy Assessment Phase | 8.3 percentage of participants |
| Etelcalcetide | Percentage of Participants With a > 30% Decrease From Baseline in Mean PTH During the Efficacy Assessment Phase | 74.0 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 proportion of participants with \> 30% reduction from baseline in PTH during the EAP between etelcalcetide and placebo.p-value: <0.00195% CI: [18.71, 56.31]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 | 5.1 percentage of participants |
| Etelcalcetide | Percentage of Participants With Mean Predialysis Parathyroid Hormone ≤ 300 pg/mL During the Efficacy Assessment Phase | 49.6 percentage of participants |
p-value: <0.00195% CI: [11.47, 42.48]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 | 1.18 percent change | Standard Error 0.29 |
| Etelcalcetide | Percent Change From Baseline in Predialysis Corrected Calcium During the Efficacy Assessment Phase | -7.29 percent change | Standard Error 0.53 |
p-value: <0.00195% CI: [-9.52, -7.23]Repeated Measures Mixed Effects Model
Secondary
Percent Change From Baseline in Predialysis Corrected Calcium Phosphorus Product 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 During the Efficacy Assessment Phase | -0.19 percent change | Standard Error 1.44 |
| Etelcalcetide | Percent Change From Baseline in Predialysis Corrected Calcium Phosphorus Product During the Efficacy Assessment Phase | -14.34 percent change | Standard Error 2.06 |
p-value: <0.00195% CI: [-19.73, -10.25]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 | -1.31 percent change | Standard Deviation 1.42 |
| Etelcalcetide | Percent Change From Baseline in Predialysis Phosphorus During the Efficacy Assessment Phase | -7.71 percent change | Standard Deviation 2.16 |
p-value: 0.00395% CI: [-12.31, -2.59]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 | 13.00 percent change | Standard Error 2.81 |
| Etelcalcetide | Percent Change From Baseline in Predialysis PTH During the Efficacy Assessment Phase | -55.11 percent change | Standard Error 1.94 |
p-value: <0.00195% CI: [-77.77, -64.46]Repeated Measures Mixed Effects Model