Chronic Kidney Disease, Secondary Hyperparathyroidism
Conditions
Keywords
Chronic Kidney Disease, Secondary Hyperparathyroidism, Dialysis, Pediatric
Brief summary
The primary objective was to evaluate the efficacy of cinacalcet for reducing the plasma intact parathyroid hormone (iPTH) level by ≥ 30%.
Detailed description
This was a 24-week, randomized, multicenter, open-label, controlled study. Participants were randomized into one of two treatment arms; oral administration of cinacalcet daily in addition to standard of care treatment, or standard of care alone. Randomization was stratified by age group (6 to \< 12 and 12 to \< 18 years of age). All participants received standard of care which could include therapy with Vitamin D sterols, calcium supplementation, and phosphate binders. Participants in both treatment groups who completed the 20-week treatment period and those who ended the study due to study closure were eligible to enroll in an open-label extension study (20140159; NCT02341417) for further safety follow-up.
Interventions
DRUGCinacalcet HCl
Capsules were opened and either sprinkled onto soft food (≥ 5 mg dose) or suspended into a sucrose syrup (≥ 2.5 mg dose) to create a liquid suspension for administration. Tablets were used for doses of 30 mg and higher in participants who could swallow tablets.
DIETARY_SUPPLEMENTStandard of Care
Standard of care therapy included the use of vitamin D sterols, calcium supplementation, and phosphate binders.
Sponsors
Amgen
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
6 Years to 17 Years
Healthy volunteers
No
Inclusion criteria
* Age 6 - \< 18 years * Diagnosis of SHPT with the mean of the two consecutive central laboratory iPTH values ≥ 300 pg/mL during screening * Corrected calcium value of ≥ 8.8 mg/dL during screening * Diagnosis of CKD, receiving either hemodialysis or peritoneal dialysis, for ≥ 30 days prior to screening * Parent or legally acceptable representative has provided written informed consent and subject has provided written assent when required by institutional guidelines
Exclusion criteria
* History of congenital long QT syndrome, second or third degree heart block, ventricular tachyarrhythmias or other conditions associated with prolonged QT interval * Corrected QT interval (QTc) \> 500 ms, using Bazett's formula * QTc ≥ 450 to ≤ 500 ms, using Bazett's formula, unless written permission to enroll is provided by the investigator after consultation with a pediatric cardiologist * Use of grapefruit juice, herbal medications, or potent cytochrome P450 3A4 (CYP3A4) inhibitors (eg, erythromycin, clarithromycin, ketoconazole, itraconazole) * Use of concomitant medications that may prolong the QTc interval (eg, ondansetron, albuterol)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Who Achieved a ≥ 30% Reduction From Baseline In Mean Plasma iPTH During Weeks 11 to 15 | Baseline and weeks 11 to 15 | Intact parathyroid hormone (iPTH) levels were measured at weeks 11 and 15; the mean value from these 2 measurements was calculated. This endpoint was the primary endpoint in the US only. |
| Percentage of Participants Who Achieved a ≥ 30% Reduction From Baseline in Mean Plasma Intact Parathyroid Hormone During the Efficacy Assessment Period | Baseline and the efficacy assessment period (EAP), weeks 17 to 20 | Intact parathyroid hormone (iPTH) levels were measured at weeks 17, 18, 19 and 20; the mean value from these measurements was calculated. This endpoint was specified as the the primary endpoint in all countries except the United States (US). In the US this endpoint was specified as a secondary efficacy endpoint. |
Secondary
| Measure | Time frame |
|---|---|
| Percentage of Participants Who Achieved a Mean iPTH ≤ 300 pg/mL (31.8 Pmol/L) During Weeks 17 to 20 | Efficacy assessment period, weeks 17 to 20 |
| Percent Change in iPTH From Baseline to the Mean Value During Weeks 17 to 20 | Baseline and weeks 17 to 20 |
| Change in Corrected Serum Calcium From Baseline to the Mean Value During Weeks 17 to 20 | Baseline and weeks 17 to 20 |
| Change in Serum Phosphorus From Baseline to the Mean Value During Weeks 17 to 20 | Baseline and weeks 17 to 20 |
Countries
Belgium, Czechia, France, Germany, Greece, Hungary, Italy, Lithuania, New Zealand, Poland, Portugal, Russia, Slovakia, Spain, Ukraine, United States
Participant flow
Recruitment details
This study was conducted at 32 centers in Belgium, Czech Republic, France, Germany, Greece, Hungary, Lithuania, Poland, Portugal, Russia Federation, Slovakia, Spain, Ukraine, and the United States.
Pre-assignment details
Eligible participants were randomized to 1 of 2 treatment groups in a 1:1 ratio: cinacalcet daily in addition to standard of care (SOC) therapy or SOC therapy alone. Randomization was stratified by age group (6 to \< 12 and 12 to \< 18 years). Participants remained on treatment for 20 weeks or until the time of renal transplant or parathyroidectomy.
Participants by arm
| Arm | Count |
|---|---|
| Standard of Care Standard of care therapy included the use of vitamin D sterols, calcium supplementation, and phosphate binders. | 28 |
| Cinacalcet In addition to standard of care participants received cinacalcet at a starting dose (based on dry body weight) of 0.20 mg/kg administered once a day by mouth. Dose adjustments and withholding were based on ionized calcium levels, plasma iPTH, and corrected calcium levels. | 27 |
| Total | 55 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Study Closure | 7 | 6 |
| Overall Study | Withdrawal by Subject | 1 | 5 |
Baseline characteristics
| Characteristic | Standard of Care | Cinacalcet | Total |
|---|---|---|---|
| Age, Continuous | 12.4 years STANDARD_DEVIATION 3.5 | 12.8 years STANDARD_DEVIATION 3.9 | 12.6 years STANDARD_DEVIATION 3.6 |
| Age, Customized 12 to < 18 years | 19 participants | 18 participants | 37 participants |
| Age, Customized 6 to < 12 years | 9 participants | 9 participants | 18 participants |
| Intact Parathyroid Hormone Level | 1228.43 pg/mL STANDARD_DEVIATION 732.08 | 945.72 pg/mL STANDARD_DEVIATION 635.35 | 1092.31 pg/mL STANDARD_DEVIATION 695.53 |
| Race/Ethnicity, Customized Black (or African American) | 4 participants | 5 participants | 9 participants |
| Race/Ethnicity, Customized Hispanic/Latino | 4 participants | 0 participants | 4 participants |
| Race/Ethnicity, Customized Mixed Race | 0 participants | 1 participants | 1 participants |
| Race/Ethnicity, Customized Not Hispanic/Latino | 24 participants | 27 participants | 51 participants |
| Race/Ethnicity, Customized Other | 1 participants | 2 participants | 3 participants |
| Race/Ethnicity, Customized White | 23 participants | 19 participants | 42 participants |
| Sex: Female, Male Female | 15 Participants | 12 Participants | 27 Participants |
| Sex: Female, Male Male | 13 Participants | 15 Participants | 28 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 17 / 30 | 20 / 25 |
| serious Total, serious adverse events | 2 / 30 | 4 / 25 |
Outcome results
Primary
Percentage of Participants Who Achieved a ≥ 30% Reduction From Baseline in Mean Plasma Intact Parathyroid Hormone During the Efficacy Assessment Period
Intact parathyroid hormone (iPTH) levels were measured at weeks 17, 18, 19 and 20; the mean value from these measurements was calculated. This endpoint was specified as the the primary endpoint in all countries except the United States (US). In the US this endpoint was specified as a secondary efficacy endpoint.
Time frame: Baseline and the efficacy assessment period (EAP), weeks 17 to 20
Population: The full analysis set (all randomized participants) was used for this analysis. For participants with no iPTH values in the EAP, the mean of the last 2 available postbaseline values was used. If only 1 postbaseline value was available, this value was used. If no postbaseline value was available, the participant was considered a non-responder.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Standard of Care | Percentage of Participants Who Achieved a ≥ 30% Reduction From Baseline in Mean Plasma Intact Parathyroid Hormone During the Efficacy Assessment Period | 32.1 percentage of participants |
| Cinacalcet | Percentage of Participants Who Achieved a ≥ 30% Reduction From Baseline in Mean Plasma Intact Parathyroid Hormone During the Efficacy Assessment Period | 22.2 percentage of participants |
Comparison: A hierarchical testing procedure was used to test the primary and biochemical secondary endpoints. The primary endpoint was tested at a 2-sided significance level of 0.05. The secondary endpoints were tested using Holm's method at 0.05 (2-sided) should the primary endpoint achieve a significant result.p-value: 0.4295% CI: [-33.3, 13.4]Cochran-Mantel-Haenszel
Primary
Percentage of Participants Who Achieved a ≥ 30% Reduction From Baseline In Mean Plasma iPTH During Weeks 11 to 15
Intact parathyroid hormone (iPTH) levels were measured at weeks 11 and 15; the mean value from these 2 measurements was calculated. This endpoint was the primary endpoint in the US only.
Time frame: Baseline and weeks 11 to 15
Population: The analysis was conducted using the full analysis set; participants who had no week 11 or 15 iPTH values were considered non-responders (non-responder imputation).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Standard of Care | Percentage of Participants Who Achieved a ≥ 30% Reduction From Baseline In Mean Plasma iPTH During Weeks 11 to 15 | 17.9 percentage of participants |
| Cinacalcet | Percentage of Participants Who Achieved a ≥ 30% Reduction From Baseline In Mean Plasma iPTH During Weeks 11 to 15 | 25.9 percentage of participants |
p-value: 0.4895% CI: [-13.7, 29.9]Cochran-Mantel-Haenszel
Secondary
Change in Corrected Serum Calcium From Baseline to the Mean Value During Weeks 17 to 20
Time frame: Baseline and weeks 17 to 20
Population: This analysis was conducted using the full analysis set using last value carried forward imputation. Participants with no post-baseline values available were excluded from the analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Standard of Care | Change in Corrected Serum Calcium From Baseline to the Mean Value During Weeks 17 to 20 | 0.06 mg/dL | Standard Error 0.126 |
| Cinacalcet | Change in Corrected Serum Calcium From Baseline to the Mean Value During Weeks 17 to 20 | -0.28 mg/dL | Standard Error 0.135 |
p-value: 0.05995% CI: [-0.7, 0.01]ANCOVA
Secondary
Change in Serum Phosphorus From Baseline to the Mean Value During Weeks 17 to 20
Time frame: Baseline and weeks 17 to 20
Population: This analysis was conducted using the full analysis set using last value carried forward imputation. Participants with no post-baseline values available were excluded from the analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Standard of Care | Change in Serum Phosphorus From Baseline to the Mean Value During Weeks 17 to 20 | -0.09 mg/dL | Standard Error 0.258 |
| Cinacalcet | Change in Serum Phosphorus From Baseline to the Mean Value During Weeks 17 to 20 | 0.67 mg/dL | Standard Error 0.266 |
p-value: 0.03995% CI: [0.04, 1.48]ANCOVA
Secondary
Percentage of Participants Who Achieved a Mean iPTH ≤ 300 pg/mL (31.8 Pmol/L) During Weeks 17 to 20
Time frame: Efficacy assessment period, weeks 17 to 20
Population: This analysis was conducted using the full analysis set. For participants with no iPTH values in the EAP, the mean of the last 2 available postbaseline values was used. If only 1 postbaseline value was available, this value was used. If no postbaseline value was available, the participant was considered a non-responder.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Standard of Care | Percentage of Participants Who Achieved a Mean iPTH ≤ 300 pg/mL (31.8 Pmol/L) During Weeks 17 to 20 | 17.9 percentage of participants |
| Cinacalcet | Percentage of Participants Who Achieved a Mean iPTH ≤ 300 pg/mL (31.8 Pmol/L) During Weeks 17 to 20 | 7.4 percentage of participants |
p-value: 0.2595% CI: [-27.7, 6.8]Cochran-Mantel-Haenszel
Secondary
Percent Change in iPTH From Baseline to the Mean Value During Weeks 17 to 20
Time frame: Baseline and weeks 17 to 20
Population: This analysis was conducted using the full analysis set using last value carried forward imputation. Participants with no post-baseline values available were excluded from the analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Standard of Care | Percent Change in iPTH From Baseline to the Mean Value During Weeks 17 to 20 | -11.3 percent change | Standard Error 11.1 |
| Cinacalcet | Percent Change in iPTH From Baseline to the Mean Value During Weeks 17 to 20 | 7.7 percent change | Standard Error 11.73 |
p-value: 0.2395% CI: [-12.5, 50.5]ANCOVA