Chronic Kidney Disease, Secondary Hyperparathyroidism
Conditions
Keywords
Secondary Hyperparathyroidism, renal, kidney, kidneys, dialysis, hemodialysis, chronic kidney disease, CKD, SHPT
Brief summary
The purpose of this study is to demonstrate that treatment with etelcalcetide (AMG 416) is not inferior to treatment with cinacalcet for lowering serum parathyroid hormone (PTH) levels by \> 30% from baseline among patients with chronic kidney disease (CKD) and secondary hyperparathyroidism (SHPT) who require management with hemodialysis.
Interventions
DRUGEtelcalcetide
Administered intravenously three times per week. The starting dose was 5 mg, titrated up to 15 mg based on serum PTH and corrected calcium levels.
DRUGCinacalcet
Cinacalcet was administered orally once a day. The starting dose was 30 mg daily, titrated up to 180 mg daily based on serum PTH and corrected calcium levels.
DRUGOral Placebo
Administered orally once a day.
DRUGIntravenous Placebo
Administered intravenously (IV) three times per week.
Sponsors
Amgen
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
* Eligible subjects must be receiving adequate thrice weekly maintenance hemodialysis with a dialysate calcium concentration ≥ 2.5 mEq/L for at least 3 months prior to screening laboratory assessments * Subjects must have SHPT as defined by one central laboratory screening predialysis serum PTH value \> 500 pg/mL, measured on separate days within 2 weeks prior to randomization * Subjects must have one serum cCa value ≥ 8.3 mg/dL obtained before dialysis within 2 weeks of the date of randomization * Subjects receiving calcium supplements must have no more than a maximum dose change of 50% within 2 weeks before screening laboratory assessments are obtained, and the dose must remain unchanged through randomization
Exclusion criteria
* Eligible subjects cannot have received cinacalcet during the 3 months preceding the first screening laboratory assessment * Other criteria may apply
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Percentage of Participants With > 30% Reduction From Baseline in Mean Parathyroid Hormone During the Efficacy Assessment Phase - Non-inferiority Analysis | Baseline and the efficacy assessment phase (EAP; defined as Weeks 20 to 27, inclusive). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With > 50% Reduction From Baseline in Mean PTH During the Efficacy Assessment Phase | Baseline and the efficacy assessment phase (Weeks 20 to 27, inclusive). | — |
| Percentage of Participants With > 30% Reduction From Baseline in Mean PTH During the Efficacy Assessment Phase | Baseline and the efficacy assessment phase (Week 20 to Week 27) | — |
| Mean Number of Days of Vomiting or Nausea Per Week in the First 8 Weeks | First 8 weeks | Participants completed the Nausea/Vomiting Symptom Assessment (NVSA) questionnaire daily. This questionnaire asked participants to indicate the severity of nausea on a scale from 0 (no nausea) to 10 (as severe as can be imagined) and if they had vomited in the past 24 hours. A day of vomiting or nausea was defined as those where the severity of nausea score was \> 0 or where the episodes of vomiting score was \> 0. |
| Percent Change From Baseline in Mean Corrected Calcium During the Efficacy Assessment Phase | Baseline and the efficacy assessment phase (weeks 20 - 27) | — |
| Percentage of Participants With Mean Predialysis Serum Phosphorus ≤ 4.5 mg/dL During the Efficacy Assessment Phase | Efficacy assessment phase (weeks 20 - 27) | — |
| Mean Severity of Nausea in the First 8 Weeks | First 8 weeks | Severity of nausea was assessed using the Nausea and Vomiting Symptom Assessment questionnaire which asked participants to rate the severity of nausea on a scale from 0 (no nausea) to 10 (as severe as can be imagined). For each participant, the mean severity of nausea was calculated by averaging all available daily severities (including zeroes) reported in the first 8 weeks. |
| Mean Number of Episodes of Vomiting Per Week in the First 8 Weeks | First 8 weeks | The number of vomiting episodes was assessed using the Nausea and Vomiting Symptom Assessment questionnaire which asks participants on a daily basis how many times they vomited in the past 24 hours. The number of episodes in a week is the sum of all reported daily episodes in the week. For participants providing less than 7 days of responses to NVSA questions in any given week, data from that week did not contribute to the analysis. |
Countries
Austria, Belgium, Canada, Czechia, Denmark, Estonia, France, Germany, Greece, Hungary, Italy, Latvia, Lithuania, New Zealand, Poland, Portugal, Russia, Spain, Sweden, Switzerland, Turkey (Türkiye), United States
Participant flow
Recruitment details
This study was conducted at 164 centers in Austria, Belgium, Canada, the Czech Republic, Denmark, Estonia, France, Germany, Greece, Hungary, Italy, Latvia, Lithuania, New Zealand, Poland, Portugal, Russia, Spain, Sweden, Switzerland, Turkey, and the United States. Participants were enrolled from 13 August 2013 to 16 May 2014.
Pre-assignment details
Eligible participants were stratified by screening serum parathyroid hormone (PTH) level (\< 900 or ≥ 900 pg/mL) and region (North America or non-North America) and were randomized 1:1 to receive etelcalcetide intravenously (IV) plus oral placebo or oral cinacalcet plus placebo IV.
Participants by arm
| Arm | Count |
|---|---|
| Cinacalcet Participants were randomized to receive oral cinacalcet once daily and placebo intravenous bolus injection at the end of each hemodialysis session, three times per week (TIW) for 26 weeks. The starting dose of cinacalcet was 30 mg daily and could have been titrated at weeks 5, 9, 13, and 17 to target predialysis serum PTH ≤ 300 pg/mL but no lower than 100 pg/mL while maintaining corrected calcium (cCa) ≥ 8.3 mg/dL. | 343 |
| Etelcalcetide Participants were randomized to receive etelcalcetide administered by intravenous bolus injection at the end of each hemodialysis session TIW, and daily oral doses of placebo tablets for 26 weeks. The starting dose of etelcalcetide was 5 mg, and could have been titrated at weeks 5, 9, 13, and 17 to target predialysis serum PTH ≤ 300 pg/mL but no lower than 100 pg/mL while maintaining cCa ≥ 8.3 mg/dL. | 340 |
| Total | 683 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 6 | 10 |
| Overall Study | Lost to Follow-up | 9 | 12 |
| Overall Study | Sponsor Decision | 2 | 0 |
| Overall Study | Withdrawal by Subject | 32 | 31 |
Baseline characteristics
| Characteristic | Etelcalcetide | Total | Cinacalcet |
|---|---|---|---|
| Age, Continuous | 54.0 years STANDARD_DEVIATION 13.8 | 54.7 years STANDARD_DEVIATION 14.1 | 55.3 years STANDARD_DEVIATION 14.4 |
| Age, Customized < 65 years | 262 participants | 505 participants | 243 participants |
| Age, Customized ≥ 65 years | 78 participants | 178 participants | 100 participants |
| Corrected Calcium | 9.67 mg/dL STANDARD_DEVIATION 0.71 | 9.62 mg/dL STANDARD_DEVIATION 0.69 | 9.58 mg/dL STANDARD_DEVIATION 0.67 |
| Corrected Calcium Phosphorus Product (cCa x P) | 56.36 mg²/dL² STANDARD_DEVIATION 17.15 | 56.00 mg²/dL² STANDARD_DEVIATION 16.27 | 55.65 mg²/dL² STANDARD_DEVIATION 15.37 |
| Ethnicity Hispanic/Latino | 38 participants | 79 participants | 41 participants |
| Ethnicity Not Hispanic/Latino | 302 participants | 604 participants | 302 participants |
| Parathyroid Hormone | 1092.12 pg/mL STANDARD_DEVIATION 622.81 | 1115.52 pg/mL STANDARD_DEVIATION 666.22 | 1138.71 pg/mL STANDARD_DEVIATION 706.77 |
| Phosphorus | 5.81 mg/dL STANDARD_DEVIATION 1.69 | 5.81 mg/dL STANDARD_DEVIATION 1.63 | 5.82 mg/dL STANDARD_DEVIATION 1.58 |
| Race Asian | 9 participants | 16 participants | 7 participants |
| Race Black | 54 participants | 106 participants | 52 participants |
| Race Native Hawaiian or Other Pacific Islander | 6 participants | 9 participants | 3 participants |
| Race Other | 10 participants | 14 participants | 4 participants |
| Race White | 261 participants | 538 participants | 277 participants |
| Sex: Female, Male Female | 148 Participants | 299 Participants | 151 Participants |
| Sex: Female, Male Male | 192 Participants | 384 Participants | 192 Participants |
| Stratification Factor: Region Non-North America | 237 participants | 475 participants | 238 participants |
| Stratification Factor: Region North America | 103 participants | 208 participants | 105 participants |
| Stratification Factor: Screening Serum Parathyroid Hormone (PTH) < 900 pg/mL | 169 participants | 340 participants | 171 participants |
| Stratification Factor: Screening Serum Parathyroid Hormone (PTH) ≥ 900 pg/mL | 171 participants | 343 participants | 172 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 259 / 341 | 278 / 338 |
| serious Total, serious adverse events | 93 / 341 | 85 / 338 |
Outcome results
Primary
Percentage of Participants With > 30% Reduction From Baseline in Mean Parathyroid Hormone During the Efficacy Assessment Phase - Non-inferiority Analysis
Time frame: Baseline and the efficacy assessment phase (EAP; defined as Weeks 20 to 27, inclusive).
Population: Full analysis set participants with PTH data during the EAP
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cinacalcet | Percentage of Participants With > 30% Reduction From Baseline in Mean Parathyroid Hormone During the Efficacy Assessment Phase - Non-inferiority Analysis | 63.9 percentage of participants |
| Etelcalcetide | Percentage of Participants With > 30% Reduction From Baseline in Mean Parathyroid Hormone During the Efficacy Assessment Phase - Non-inferiority Analysis | 77.9 percentage of participants |
Comparison: The analysis was conducted on the Full Analysis Set (683 participants). Imputation under the non-inferiority null method was applied to participants who did not have PTH data during the EAP.~The Mantel-Haenszel estimator was used to calculate the treatment difference between the proportions (Cinacalcet - Etelcalcetide) stratified by screening PTH level and region.95% CI: [-17.45, -3.51]
Secondary
Mean Number of Days of Vomiting or Nausea Per Week in the First 8 Weeks
Participants completed the Nausea/Vomiting Symptom Assessment (NVSA) questionnaire daily. This questionnaire asked participants to indicate the severity of nausea on a scale from 0 (no nausea) to 10 (as severe as can be imagined) and if they had vomited in the past 24 hours. A day of vomiting or nausea was defined as those where the severity of nausea score was \> 0 or where the episodes of vomiting score was \> 0.
Time frame: First 8 weeks
Population: Full analysis set with available data. For participants providing less than 7 days of responses to NVSA questions in any given week, data from that week did not contribute to the analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Cinacalcet | Mean Number of Days of Vomiting or Nausea Per Week in the First 8 Weeks | 0.3 days of vomiting or nausea per week | Standard Error 0.03 |
| Etelcalcetide | Mean Number of Days of Vomiting or Nausea Per Week in the First 8 Weeks | 0.4 days of vomiting or nausea per week | Standard Error 0.04 |
Comparison: Analyzed using a generalized linear mixed model with Poisson regression, including screening value of the number of days of nausea and vomiting, treatment, stratification factors (screening PTH level and region), study weeks, and treatment by study weeks as covariates.~Superiority of etelcalcetide compared with cinacalcet was tested at the 5% significance level (2-sided).p-value: 0.2795% CI: [0.89, 1.49]Generalized Linear Mixed Model
Secondary
Mean Number of Episodes of Vomiting Per Week in the First 8 Weeks
The number of vomiting episodes was assessed using the Nausea and Vomiting Symptom Assessment questionnaire which asks participants on a daily basis how many times they vomited in the past 24 hours. The number of episodes in a week is the sum of all reported daily episodes in the week. For participants providing less than 7 days of responses to NVSA questions in any given week, data from that week did not contribute to the analysis.
Time frame: First 8 weeks
Population: Full analysis set with available data. For participants providing less than 7 days of responses to NVSA questions in any given week, data from that week did not contribute to the analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Cinacalcet | Mean Number of Episodes of Vomiting Per Week in the First 8 Weeks | 0.1 vomiting episodes per week | Standard Error 0.02 |
| Etelcalcetide | Mean Number of Episodes of Vomiting Per Week in the First 8 Weeks | 0.2 vomiting episodes per week | Standard Error 0.02 |
Comparison: This analysis was conducted using a generalized linear mixed model with Poisson regression including screening value of the number of episodes of vomiting, treatment, stratification factors (screening PTH level and region), study weeks, and treatment by study weeks as covariates.95% CI: [0.86, 1.72]
Secondary
Mean Severity of Nausea in the First 8 Weeks
Severity of nausea was assessed using the Nausea and Vomiting Symptom Assessment questionnaire which asked participants to rate the severity of nausea on a scale from 0 (no nausea) to 10 (as severe as can be imagined). For each participant, the mean severity of nausea was calculated by averaging all available daily severities (including zeroes) reported in the first 8 weeks.
Time frame: First 8 weeks
Population: Full analysis set with available data
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Cinacalcet | Mean Severity of Nausea in the First 8 Weeks | 0.48 units on a scale | Standard Error 0.06 |
| Etelcalcetide | Mean Severity of Nausea in the First 8 Weeks | 0.45 units on a scale | Standard Error 0.06 |
Comparison: Analyzed using an analysis of covariance (ANCOVA) model adjusted for screening PTH level and region.95% CI: [-0.18, 0.12]
Secondary
Percentage of Participants With > 30% Reduction From Baseline in Mean PTH During the Efficacy Assessment Phase
Time frame: Baseline and the efficacy assessment phase (Week 20 to Week 27)
Population: Full analysis set; participants were considered non-responders if they did not have PTH data during the EAP (ie, non-responder imputation).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cinacalcet | Percentage of Participants With > 30% Reduction From Baseline in Mean PTH During the Efficacy Assessment Phase | 57.7 percentage of participants |
| Etelcalcetide | Percentage of Participants With > 30% Reduction From Baseline in Mean PTH During the Efficacy Assessment Phase | 68.2 percentage of participants |
Comparison: Achievement of \> 30% reduction in mean predialysis serum PTH from baseline during the EAP was analyzed using the Cochran-Mantel-Haenszel test stratified by screening PTH level and region.~Superiority of etelcalcetide compared with cinacalcet was tested at the 5% significance level (2-sided).p-value: 0.00495% CI: [1.16, 2.17]Cochran-Mantel-Haenszel
Secondary
Percentage of Participants With > 50% Reduction From Baseline in Mean PTH During the Efficacy Assessment Phase
Time frame: Baseline and the efficacy assessment phase (Weeks 20 to 27, inclusive).
Population: Full analysis set; participants were considered non-responders if they did not have PTH data during the EAP (ie, non-responder imputation).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cinacalcet | Percentage of Participants With > 50% Reduction From Baseline in Mean PTH During the Efficacy Assessment Phase | 40.2 percentage of participants |
| Etelcalcetide | Percentage of Participants With > 50% Reduction From Baseline in Mean PTH During the Efficacy Assessment Phase | 52.4 percentage of participants |
Comparison: Achievement of \> 50% reduction in mean predialysis serum PTH from baseline during the EAP was analyzed using the Cochran-Mantel-Haenszel (CMH) test stratified by screening PTH level and region.~Superiority of etelcalcetide compared with cinacalcet was tested at the 5% significance level (2-sided).p-value: 0.00195% CI: [1.21, 2.23]Cochran-Mantel-Haenszel
Secondary
Percentage of Participants With Mean Predialysis Serum Phosphorus ≤ 4.5 mg/dL During the Efficacy Assessment Phase
Time frame: Efficacy assessment phase (weeks 20 - 27)
Population: Full analysis set; participants with no phosphorus assessments during the EAP were considered non-responders.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cinacalcet | Percentage of Participants With Mean Predialysis Serum Phosphorus ≤ 4.5 mg/dL During the Efficacy Assessment Phase | 29.2 percentage of participants |
| Etelcalcetide | Percentage of Participants With Mean Predialysis Serum Phosphorus ≤ 4.5 mg/dL During the Efficacy Assessment Phase | 32.1 percentage of participants |
Comparison: Analyzed using the Cochran-Mantel-Haenszel method stratified by screening PTH level and region.95% CI: [0.83, 1.59]
Secondary
Percent Change From Baseline in Mean Corrected Calcium During the Efficacy Assessment Phase
Time frame: Baseline and the efficacy assessment phase (weeks 20 - 27)
Population: Full analysis set with available data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cinacalcet | Percent Change From Baseline in Mean Corrected Calcium During the Efficacy Assessment Phase | -6.28 percent change | Standard Error 0.44 |
| Etelcalcetide | Percent Change From Baseline in Mean Corrected Calcium During the Efficacy Assessment Phase | -9.83 percent change | Standard Error 0.49 |
Comparison: Analyzed using a repeated measures mixed effects model, including treatment group, randomization stratification factors (screening PTH level and region), study week, and study week by treatment as fixed effects.95% CI: [-4.76, -2.21]