Chronic Kidney Disease, Hyperparathyroidism, Hyperparathyroidism, Secondary, Kidney Disease, Secondary Hyperparathyroidism
Conditions
Keywords
dialysis, sensipar, mimpara, hemodialysis, peritoneal dialysis, renal, parathyroid hormone, pediatric
Brief summary
The purpose of this study is to assess the safety and efficacy of adding cinacalcet to the current treatment of secondary hyperparathyroidism in children currently receiving dialysis compared to a treatment regimen that does not include cinacalcet.
Detailed description
Secondary hyperparathyroidism (SHPT) is a condition that can develop early in patients with chronic kidney disease (CKD), usually gets worse over time, and is known to cause problems for patients on dialysis. Children on dialysis can have a wide range of bone and growth issues, and common treatments have a chance of making these things worse by increasing serum calcium and serum phosphorus. Cinacalcet has been shown to be effective in controlling parathyroid hormone (PTH), calcium and phosphorus in adults. The purpose of this study is to show that including cinacalcet in the treatment of SHPT will lower the levels of intact parathyroid hormone (iPTH) in a larger number of pediatric patients with CKD who are receiving dialysis, compared to a treatment regimen that does not include cinacalcet.
Interventions
DRUGcinacalcet capsule
Cinacalcet was prepared for oral administration as both capsules for sprinkling and film coated tablets for swallowing.
DRUGplacebo
Placebo tablets and capsules for sprinkling identical to active treatment.
DRUGStandard of Care
All participants, regardless of treatment assignment, will receive standard of care with vitamin D sterols (calcitriol and its analogs), as prescribed by the treating physician.
Sponsors
Amgen
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
6 Years to 17 Years
Healthy volunteers
No
Inclusion criteria
* Age 6 to less than 18 years at screening * Diagnosed with CKD and SHPT receiving hemodialysis or peritoneal dialysis for ≥ 2 months before randomization * Dry weight ≥ 12.5 kg at screening * iPTH obtained from the central laboratory must be \> 300 pg/mL (31.8 pmol/L) * Serum calcium (corrected) obtained from the central laboratory must be ≥ 8.8 mg/dL (2.2 mmol/L) * Serum phosphorus obtained from the central laboratory ≥ 4.0 mg/dL (1.3 mmol/L) for children 6 to less than 12 years old, or ≥ 3.5 mg/dL (1.1 mmol/L) for children 12 to less than 18 years old * Subjects already receiving vitamin D sterols (either calcitriol or a synthetic analog), a stable dose within the last 2 months prior to randomization * Subjects taking growth hormone, a stable dose defined as no change \> than 20% in the last 2 months prior to randomization * Subjects on anti-convulsant medication must be on a stable dose for 3 months, and have a therapeutic blood level of the anti-convulsant at the time of randomization * Subjects must be on a dialysate calcium concentration of ≥ 2.5 mEq/L (1.25 mmol/L) for at least 2 months prior to randomization
Exclusion criteria
* Underwent parathyroidectomy in the last 6 months * Anticipated parathyroidectomy within 6 months after randomization * Received therapy with cinacalcet (sensipar/mimpara) within the last month * A new onset of seizure or worsening of a pre-existing seizure disorder within the last 3 months * Scheduled date for kidney transplant from a known living donor that makes completion of the study unlikely
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Achieving ≥ 30% Reduction in Mean iPTH From Baseline to the Efficacy Assessment Phase | From Baseline to the Efficacy Assessment Phase, Weeks 25-30 | The efficacy assessment value is based on the scheduled assessment(s) taken during the efficacy assessment phase (EAP; Weeks 25 - 30). When multiple assessments were available, the average of those was used. If an efficacy measurement during the EAP was missing, the mean of the last 2 available post-baseline values in the dose-titration phase was used. If only one post-baseline value was available, this single value was used. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline in Mean Corrected Total Serum Calcium During the Efficacy Assessment Period | From Baseline to the Efficacy Assessment Phase, Weeks 25-30. | Serum calcium was reported as a corrected value by the central laboratory based on calcium and albumin concentrations: Corrected total calcium (mg/dL) = measured total serum calcium (mg/dL) + 0.8 (4.0 - Serum albumin (g/dL)). The efficacy assessment value is based on the scheduled assessment(s) taken during the efficacy assessment phase. When multiple assessments were available, the average of those was used. If an efficacy measurement during the EAP was missing, the mean of the last 2 available postbaseline values in the dose-titration phase was used. If only one post-baseline value was available, this single value was used. |
| Percent Change From Baseline in Mean Serum Phosphorus During the Efficacy Assessment Phase | From Baseline to the Efficacy Assessment Phase, Weeks 25-30. | The efficacy assessment value is based on the scheduled assessment(s) taken during the efficacy assessment phase. When multiple assessments were available, the average of those was used. If an efficacy measurement during the EAP was missing, the mean of the last 2 available postbaseline values in the dose-titration phase was used. If only one post-baseline value was available, this single value was used. |
| Percent Change From Baseline in Mean Phosphorous Product (Ca x P) During the Efficacy Assessment Phase | From Baseline to end of Efficacy Assessment Period, assessed up to 30 weeks | The efficacy assessment value is based on the scheduled assessment(s) taken during the efficacy assessment phase. When multiple assessments were available, the average of those was used. If an efficacy measurement during the EAP was missing, the mean of the last 2 available postbaseline values in the dose-titration phase was used. If only one post-baseline value was available, this single value was used. |
| Percentage of Participants Achieving Mean iPTH ≤ 300 pg/mL (31.8 Pmol/L) During the Efficacy Assessment Phase | From Baseline to the Efficacy Assessment Phase (EAP), Weeks 25-30 | The efficacy assessment value is based on the scheduled assessment(s) taken during the efficacy assessment phase. When multiple assessments were available, the average of those was used. If an efficacy measurement during the EAP was missing, the mean of the last 2 available postbaseline values in the dose-titration phase was used. If only one post-baseline value was available, this single value was used. |
| Growth Velocity From End of Double-blind Phase to End of Open-label Phase | End of double-blind phase (Week 30) until end of the open-label phase (Week 60) | Linear growth velocity (cm/year) = 52 x change in height (cm) / number of weeks between the two assessments. End of open-label phase visit was at Week 60 by design but the last assessment in the open-label phase was used due to the early termination of the study. |
| Percent Change From Baseline in Mean Ionized Calcium During the Efficacy Assessment Phase | From Baseline to the Efficacy Assessment Phase, Weeks 25-30. | The efficacy assessment value is based on the scheduled assessment(s) taken during the efficacy assessment phase. When multiple assessments were available, the average of those was used. If an efficacy measurement during the EAP was missing, the mean of the last 2 available postbaseline values in the dose-titration phase was used. If only one post-baseline value was available, this single value was used. |
| Growth Velocity From Baseline to End of Double-blind Phase | From Baseline to end of Efficacy Assessment at Week 30 | Linear growth velocity (cm/year) = 52 x change in height (cm) / number of weeks between the two assessments. End of double-blind phase visit was at Week 30 by design but the last assessment in the double-blind phase was used due to the early termination of the study. |
Countries
Australia, Belgium, Germany, Hungary, Mexico, Poland, Russia, Slovakia, Spain, United States
Participant flow
Recruitment details
The first patient was enrolled on 28 June 2011 and the last patient enrolled was on 15 January 2013. Eligible participants were between the ages of 6 to less than 18 years old who had chronic kidney (CKD) and secondary hyperparathyroidism treated with either hemodialysis or peritoneal dialysis for ≥ 2 months.
Pre-assignment details
This study consisted of a 30-week randomized, double-blind phase followed by a 30-week open-label phase. Participants were randomized 1:1 to receive either cinacalcet or placebo in the double-blind phase. All participants received cinacalcet in the open-label phase.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants received standard of care and placebo once daily for 30 weeks during the double-blind phase. During the open-label phase, participants received cinacalcet with standard of care for an additional 30 weeks. The starting dose of cinacalcet was ≤ 0.20 mg/kg based on dry weight, and could be titrated up according to plasma iPTH and serum calcium levels every 4 weeks up to Week 54 to a maximum dose of 4.2 mg/kg. | 21 |
| Cinacalcet Participants received standard of care and cinacalcet once daily for 30 weeks during the double-blind phase. The starting dose of cinacalcet was ≤ 0.20 mg/kg based on dry weight, and could be titrated up according to plasma iPTH and serum calcium levels every 4 weeks until Week 24 to a maximum dose of 4.2 mg/kg. During the open-label phase participants continued to receive cinacalcet with standard of care for an additional 30 weeks. Regardless of the titration level reached at the last dose of IP in the double-blind phase, all participants started titration at ≤ 0.20 mg/kg based on dry weight. | 22 |
| Total | 43 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Double-blind Phase | Administrative decision | 7 | 9 |
| Double-blind Phase | Adverse Event | 1 | 0 |
| Double-blind Phase | Death | 0 | 1 |
| Double-blind Phase | Non-compliance | 0 | 1 |
| Double-blind Phase | Other | 1 | 1 |
| Double-blind Phase | Protocol-specified criteria | 2 | 6 |
| Double-blind Phase | Withdrawal by Subject | 2 | 0 |
| Open-label Phase | Administrative decision | 4 | 3 |
| Open-label Phase | Never received investigational product | 2 | 0 |
| Open-label Phase | Protocol-specified criteria | 1 | 0 |
Baseline characteristics
| Characteristic | Placebo | Cinacalcet | Total |
|---|---|---|---|
| Age, Continuous | 13.2 years STANDARD_DEVIATION 2.9 | 13.3 years STANDARD_DEVIATION 3.6 | 13.2 years STANDARD_DEVIATION 3.3 |
| Age, Customized 12 to < 18 years | 16 participants | 16 participants | 32 participants |
| Age, Customized 6 to < 12 years | 5 participants | 6 participants | 11 participants |
| Corrected Total Serum Calcium | 9.88 mg/dL STANDARD_DEVIATION 0.62 | 9.91 mg/dL STANDARD_DEVIATION 0.54 | 9.90 mg/dL STANDARD_DEVIATION 0.58 |
| Intact Parathyroid Hormone (iPTH) | 795.8 pg/mL STANDARD_DEVIATION 537.9 | 757.1 pg/mL STANDARD_DEVIATION 440.1 | 776.0 pg/mL STANDARD_DEVIATION 484.8 |
| Race/Ethnicity, Customized Black or African American | 6 participants | 5 participants | 11 participants |
| Race/Ethnicity, Customized Hispanic or Latino | 5 participants | 3 participants | 8 participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 16 participants | 19 participants | 35 participants |
| Race/Ethnicity, Customized Other | 0 participants | 1 participants | 1 participants |
| Race/Ethnicity, Customized White | 15 participants | 16 participants | 31 participants |
| Serum Phosphorous | 6.37 mg/dL STANDARD_DEVIATION 1.48 | 6.68 mg/dL STANDARD_DEVIATION 1.78 | 6.53 mg/dL STANDARD_DEVIATION 1.63 |
| Sex: Female, Male Female | 10 Participants | 12 Participants | 22 Participants |
| Sex: Female, Male Male | 11 Participants | 10 Participants | 21 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 | 17 / 21 | 16 / 22 | 6 / 6 | 3 / 4 |
| serious Total, serious adverse events | 9 / 21 | 9 / 22 | 3 / 6 | 1 / 4 |
Outcome results
Primary
Percentage of Participants Achieving ≥ 30% Reduction in Mean iPTH From Baseline to the Efficacy Assessment Phase
The efficacy assessment value is based on the scheduled assessment(s) taken during the efficacy assessment phase (EAP; Weeks 25 - 30). When multiple assessments were available, the average of those was used. If an efficacy measurement during the EAP was missing, the mean of the last 2 available post-baseline values in the dose-titration phase was used. If only one post-baseline value was available, this single value was used.
Time frame: From Baseline to the Efficacy Assessment Phase, Weeks 25-30
Population: Full analysis set, which includes all randomized participants with at least 1 post-baseline assessment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants Achieving ≥ 30% Reduction in Mean iPTH From Baseline to the Efficacy Assessment Phase | 19.0 percentage of participants |
| Cinacalcet | Percentage of Participants Achieving ≥ 30% Reduction in Mean iPTH From Baseline to the Efficacy Assessment Phase | 54.5 percentage of participants |
Comparison: A hierarchical testing procedure was used to test the primary and biochemical secondary endpoints (Outcome Measures 1-5). The primary endpoint was tested at a significance level of 0.05. The four biochemical secondary endpoints were to be tested using Holm's method at 0.05 should the primary endpoint achieve a significant result.p-value: 0.01795% CI: [8.76, 62.24]Cochran-Mantel-Haenszel
Secondary
Growth Velocity From Baseline to End of Double-blind Phase
Linear growth velocity (cm/year) = 52 x change in height (cm) / number of weeks between the two assessments. End of double-blind phase visit was at Week 30 by design but the last assessment in the double-blind phase was used due to the early termination of the study.
Time frame: From Baseline to end of Efficacy Assessment at Week 30
Population: Full analysis set; the last assessment in the double-blind phase was used due to the early termination of the study. Only participants with available data are included in the analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo | Growth Velocity From Baseline to End of Double-blind Phase | 3.1 cm/year |
| Cinacalcet | Growth Velocity From Baseline to End of Double-blind Phase | 3.3 cm/year |
p-value: 0.89695% CI: [-3.1, 3.6]ANCOVA
Secondary
Growth Velocity From End of Double-blind Phase to End of Open-label Phase
Linear growth velocity (cm/year) = 52 x change in height (cm) / number of weeks between the two assessments. End of open-label phase visit was at Week 60 by design but the last assessment in the open-label phase was used due to the early termination of the study.
Time frame: End of double-blind phase (Week 30) until end of the open-label phase (Week 60)
Population: Full analysis set. Only participants with available data were included in the anaysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Growth Velocity From End of Double-blind Phase to End of Open-label Phase | 2.75 cm/year | Standard Deviation 3.23 |
| Cinacalcet | Growth Velocity From End of Double-blind Phase to End of Open-label Phase | 1.21 cm/year | Standard Deviation 1.31 |
Secondary
Percentage of Participants Achieving Mean iPTH ≤ 300 pg/mL (31.8 Pmol/L) During the Efficacy Assessment Phase
The efficacy assessment value is based on the scheduled assessment(s) taken during the efficacy assessment phase. When multiple assessments were available, the average of those was used. If an efficacy measurement during the EAP was missing, the mean of the last 2 available postbaseline values in the dose-titration phase was used. If only one post-baseline value was available, this single value was used.
Time frame: From Baseline to the Efficacy Assessment Phase (EAP), Weeks 25-30
Population: Full analysis set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants Achieving Mean iPTH ≤ 300 pg/mL (31.8 Pmol/L) During the Efficacy Assessment Phase | 23.8 pecentage of participants |
| Cinacalcet | Percentage of Participants Achieving Mean iPTH ≤ 300 pg/mL (31.8 Pmol/L) During the Efficacy Assessment Phase | 27.3 pecentage of participants |
Comparison: The secondary endpoint with the smallest p-value was first compared at a significance level of 0.0125. If the p-value was \> 0.0125, all 4 secondary endpoints were non-significant; if ≤ 0.0125, the null hypothesis for that endpoint was rejected. Next, the 2nd smallest p-value was compared at a level of 0.0167; if \> 0.0167, the remaining 3 endpoints were not significant, or, the null hypothesis of that endpoint was rejected. The other 2 endpoints were analyzed similarly, at 0.025 and 0.05.p-value: 0.82695% CI: [-22.58, 29.51]Cochran-Mantel-Haenszel
Secondary
Percent Change From Baseline in Mean Corrected Total Serum Calcium During the Efficacy Assessment Period
Serum calcium was reported as a corrected value by the central laboratory based on calcium and albumin concentrations: Corrected total calcium (mg/dL) = measured total serum calcium (mg/dL) + 0.8 (4.0 - Serum albumin (g/dL)). The efficacy assessment value is based on the scheduled assessment(s) taken during the efficacy assessment phase. When multiple assessments were available, the average of those was used. If an efficacy measurement during the EAP was missing, the mean of the last 2 available postbaseline values in the dose-titration phase was used. If only one post-baseline value was available, this single value was used.
Time frame: From Baseline to the Efficacy Assessment Phase, Weeks 25-30.
Population: Full analysis set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Percent Change From Baseline in Mean Corrected Total Serum Calcium During the Efficacy Assessment Period | -1.0 percent change | 95% Confidence Interval 1.91 |
| Cinacalcet | Percent Change From Baseline in Mean Corrected Total Serum Calcium During the Efficacy Assessment Period | -4.6 percent change | 95% Confidence Interval 1.84 |
Comparison: The secondary endpoint with the smallest p-value was first compared at a significance level of 0.0125. If the p-value was \> 0.0125, all 4 secondary endpoints were non-significant; if ≤ 0.0125, the null hypothesis for that endpoint was rejected. Next, the 2nd smallest p-value was compared at a level of 0.0167; if \> 0.0167, the remaining 3 endpoints were not significant, or, the null hypothesis of that endpoint was rejected. The other 2 endpoints were analyzed similarly, at 0.025 and 0.05.p-value: 0.14795% CI: [-8.6, 1.3]ANCOVA
Secondary
Percent Change From Baseline in Mean Ionized Calcium During the Efficacy Assessment Phase
The efficacy assessment value is based on the scheduled assessment(s) taken during the efficacy assessment phase. When multiple assessments were available, the average of those was used. If an efficacy measurement during the EAP was missing, the mean of the last 2 available postbaseline values in the dose-titration phase was used. If only one post-baseline value was available, this single value was used.
Time frame: From Baseline to the Efficacy Assessment Phase, Weeks 25-30.
Population: Full analysis set; only participants with available data were included in the analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo | Percent Change From Baseline in Mean Ionized Calcium During the Efficacy Assessment Phase | -1.5 percent change |
| Cinacalcet | Percent Change From Baseline in Mean Ionized Calcium During the Efficacy Assessment Phase | -2.3 percent change |
p-value: 0.85495% CI: [-9.4, 7.9]ANCOVA
Secondary
Percent Change From Baseline in Mean Phosphorous Product (Ca x P) During the Efficacy Assessment Phase
The efficacy assessment value is based on the scheduled assessment(s) taken during the efficacy assessment phase. When multiple assessments were available, the average of those was used. If an efficacy measurement during the EAP was missing, the mean of the last 2 available postbaseline values in the dose-titration phase was used. If only one post-baseline value was available, this single value was used.
Time frame: From Baseline to end of Efficacy Assessment Period, assessed up to 30 weeks
Population: Full analysis set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo | Percent Change From Baseline in Mean Phosphorous Product (Ca x P) During the Efficacy Assessment Phase | 8.0 percent change |
| Cinacalcet | Percent Change From Baseline in Mean Phosphorous Product (Ca x P) During the Efficacy Assessment Phase | -2.0 percent change |
Comparison: The secondary endpoint with the smallest p-value was first compared at a significance level of 0.0125. If the p-value was \> 0.0125, all 4 secondary endpoints were non-significant; if ≤ 0.0125, the null hypothesis for that endpoint was rejected. Next, the 2nd smallest p-value was compared at a level of 0.0167; if \> 0.0167, the remaining 3 endpoints were not significant, or, the null hypothesis of that endpoint was rejected. The other 2 endpoints were analyzed similarly, at 0.025 and 0.05.p-value: 0.11795% CI: [-22.5, 2.6]ANCOVA
Secondary
Percent Change From Baseline in Mean Serum Phosphorus During the Efficacy Assessment Phase
The efficacy assessment value is based on the scheduled assessment(s) taken during the efficacy assessment phase. When multiple assessments were available, the average of those was used. If an efficacy measurement during the EAP was missing, the mean of the last 2 available postbaseline values in the dose-titration phase was used. If only one post-baseline value was available, this single value was used.
Time frame: From Baseline to the Efficacy Assessment Phase, Weeks 25-30.
Population: Full analysis set; data for one participant in the Placebo group were not available.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo | Percent Change From Baseline in Mean Serum Phosphorus During the Efficacy Assessment Phase | 10.2 percent change |
| Cinacalcet | Percent Change From Baseline in Mean Serum Phosphorus During the Efficacy Assessment Phase | 4.9 percent change |
Comparison: The secondary endpoint with the smallest p-value was first compared at a significance level of 0.0125. If the p-value was \> 0.0125, all 4 secondary endpoints were non-significant; if ≤ 0.0125, the null hypothesis for that endpoint was rejected. Next, the 2nd smallest p-value was compared at a level of 0.0167; if \> 0.0167, the remaining 3 endpoints were not significant, or, the null hypothesis of that endpoint was rejected. The other 2 endpoints were analyzed similarly, at 0.025 and 0.05.p-value: 0.45495% CI: [-19.4, 8.9]ANCOVA