Chronic Allograft Nephropathy, Chronic Kidney Disease, Chronic Renal Failure, Disordered Mineral Metabolism, End Stage Renal Disease, Hyperparathyroidism, Hypophosphatemia, Kidney Disease, Kidney Transplantation, Post Renal Transplantation
Conditions
Keywords
Intervention, Cinacalcet, Sensipar, Mimpara, hyperparathyroidism, calcium, osteodystrophy, hypercalcemia, renal, transplant, acute rejection, kidney transplant failure, hypophosphatemia
Brief summary
Hyperparathyroidism (HPT) is common in people with a kidney transplant. Patients with HPT often have high parathyroid hormone (PTH) levels and may have large parathyroid glands in the neck. Patients with HPT can develop bone disease (osteodystrophy). This bone disease can cause bone pain, fractures, and poor formation of red blood cells. Other problems from HPT may include increases in blood levels of calcium (hypercalcemia) and low blood levels of phosphorus (hypophosphatemia). The high calcium levels may cause calcium to deposit in body tissues. Calcium deposits can cause arthritis (joint pain and swelling), muscle inflammation, itching, gangrene (death of soft tissue), heart and lung problems or kidney transplant dysfunction (worsening of kidney transplant function). The purpose of this study is to evaluate the effects of cinacalcet (Sensipar/Mimpara) on high calcium levels in the blood in patients with HPT after a kidney transplant.
Interventions
DRUGCinacalcet
Possible sequential doses are 30, 60, 90, 120, and 180 mg.
DRUGPlacebo
Administered orally following the same dosing regimen as the experimental arm.
Sponsors
Amgen
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Received a kidney transplant ≥ 9 weeks at time of Screening and ≤ 24 months before first dose * May be the first kidney transplant or a repeat kidney transplant. * Subjects with a functional, stable kidney transplant, defined as MDRD estimated glomerular filtration rate (eGFR) ≥ 30 mL/min/1.73 m² (chromic kidney disease stage 3 or better) at Screening. * Men or women ≥ 18 years at the start of Screening (ie, time of informed consent). * Corrected total serum calcium \> 10.5 mg/dL (2.63 mmol/L), defined as the mean of 2 values in Screening period. * iPTH \> 100 pg/mL (10.6 pmol/L), during the Screening period (obtained at either Screen 1 or Screen 2).
Exclusion criteria
* Received cinacalcet therapy post-transplant for more than 14 days cumulatively post-transplant. If cinacalcet therapy was received for a total of 14 days or less post-transplant, there must be a 4-week washout before subject is eligible for screening (Note: This does not exclude pre-transplant use of cinacalcet). * Anticipated parathyroidectomy within 6 to12 months after Randomization. * Ongoing therapy with bisphosphonates or use within 6 months prior to Screening. * Ongoing use of 1,25-dihydroxyvitamin D3 (including other active vitamin D metabolites or analogues) or use within 30 days prior to Screening. * Ongoing use of calcium supplements or use within 30 days prior to Screening. * Ongoing use of phosphate binders (calcium or non-calcium containing) or use within 30 days prior to Screening. * Ongoing use of a thiazide diuretic. * Subjects with a history of seizures who had a seizure within the 3 months prior to Randomization, which required adjustments to the seizure medication. * Acute Kidney Injury (AKI) or renal biopsy within 6 weeks prior to Screening, unless it is an institutional protocol-driven biopsy.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Percentage of Participants With a Mean Corrected Total Serum Calcium Value < 10.2 mg/dL (2.55 mmol/L) During the Efficacy Assessment Phase (EAP) | Weeks 21 to 26 (EAP) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to the EAP in Mean Serum Phosphorus | Baseline and the EAP (mean of Weeks 22, 24, and 26) | — |
| Change From Baseline to Week 52 in eGFR | Baseline and Week 52 | eGFR was calculated using the Modification of Diet in Renal Disease (MDRD) formula. |
| Change From Baseline to the EAP in Corrected Total Calcium | Baseline and the EAP (mean of Weeks 22, 24, and 26) | — |
| Percent Change From Baseline to Week 52 in Bone Mineral Density at the Femoral Neck | Baseline and Week 52 | Bone mineral density (BMD) was measured using dual X-ray absorptiometry (DXA). |
| Change From Baseline to the EAP in Urine Phosphorus | Baseline and the EAP (mean of Weeks 22, 24, and 26) | — |
| Percentage of Participants With a Parathyroidectomy | 56 weeks | — |
| Time to Parathyroidectomy | 56 weeks | — |
| Change From Baseline to the EAP in Intact Parathyroid Hormone (iPTH) | Baseline and the EAP (mean of Weeks 22, 24, and 26) | — |
Countries
Australia, Austria, Belgium, Canada, France, Germany, Italy, Poland, Spain, Switzerland, United States
Participant flow
Recruitment details
This study was conducted at 33 centers in 11 countries (Australia, Austria, Belgium, Canada, France, Germany, Italy, Poland, Spain, Switzerland, and USA). First patient enrolled on 15 October 2009 and last patient enrolled on 07 March 2012.
Pre-assignment details
The study consisted of a 20-week titration phase, a 6-week efficacy assessment phase (EAP), a 26-week blinded maintenance phase and a 4-week follow-up phase. Randomization was stratified by corrected total serum calcium (Ca); enrollment into the low Ca stratum was limited to ≤70% of patients to ensure at least 30% enrollment in the high Ca stratum.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants received placebo orally once daily for 52 weeks. | 57 |
| Cinacalcet Participants received cinacalcet at a starting dose of 30 mg orally once daily for 52 weeks. Cinacalcet dose was titrated every 4 weeks during the dose-titration phase and during study visits in the maintenance phase based on the iPTH values, corrected total serum calcium values, and safety assessments. | 57 |
| Total | 114 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 1 |
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | Non-compliance | 0 | 1 |
| Overall Study | Other | 1 | 0 |
| Overall Study | Protocol-specified Criteria | 1 | 0 |
| Overall Study | Withdrawal by Subject | 2 | 2 |
Baseline characteristics
| Characteristic | Cinacalcet | Total | Placebo |
|---|---|---|---|
| Age, Continuous | 53.0 years STANDARD_DEVIATION 10.7 | 52.3 years STANDARD_DEVIATION 10.3 | 51.7 years STANDARD_DEVIATION 9.9 |
| Corrected Total Serum Calcium | 11.28 mg/dL STANDARD_DEVIATION 0.41 | 11.29 mg/dL STANDARD_DEVIATION 0.45 | 11.31 mg/dL STANDARD_DEVIATION 0.5 |
| Estimated Glomerular Filtration Rate (eGFR) | 57.00 mL/min/1.73 m² STANDARD_DEVIATION 17.31 | 55.84 mL/min/1.73 m² STANDARD_DEVIATION 16.07 | 54.68 mL/min/1.73 m² STANDARD_DEVIATION 14.79 |
| Intact Parathyroid Hormone | 327.7 pg/mL STANDARD_DEVIATION 262.6 | 317.6 pg/mL STANDARD_DEVIATION 224.5 | 307.5 pg/mL STANDARD_DEVIATION 180.5 |
| Race/Ethnicity, Customized Asian | 2 participants | 5 participants | 3 participants |
| Race/Ethnicity, Customized Black or African American | 5 participants | 9 participants | 4 participants |
| Race/Ethnicity, Customized Hispanic or Latino | 2 participants | 3 participants | 1 participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 participants | 2 participants | 2 participants |
| Race/Ethnicity, Customized Other | 1 participants | 2 participants | 1 participants |
| Race/Ethnicity, Customized White or Caucasian | 47 participants | 93 participants | 46 participants |
| Serum Phosphorus | 2.66 mg/dL STANDARD_DEVIATION 0.54 | 2.57 mg/dL STANDARD_DEVIATION 0.54 | 2.48 mg/dL STANDARD_DEVIATION 0.52 |
| Sex: Female, Male Female | 26 Participants | 51 Participants | 25 Participants |
| Sex: Female, Male Male | 31 Participants | 63 Participants | 32 Participants |
| Stratification Factor: Albumin-corrected Calcium Level Corrected calcium ≤ 11.2 mg/dL | 23 participants | 45 participants | 22 participants |
| Stratification Factor: Albumin-corrected Calcium Level Corrected calcium > 11.2 mg/dL | 34 participants | 69 participants | 35 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 45 / 57 | 45 / 57 |
| serious Total, serious adverse events | 19 / 57 | 15 / 57 |
Outcome results
Primary
Percentage of Participants With a Mean Corrected Total Serum Calcium Value < 10.2 mg/dL (2.55 mmol/L) During the Efficacy Assessment Phase (EAP)
Time frame: Weeks 21 to 26 (EAP)
Population: Full analysis set (all randomized participants excluding participants determined to have graft failure prior to week 26)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With a Mean Corrected Total Serum Calcium Value < 10.2 mg/dL (2.55 mmol/L) During the Efficacy Assessment Phase (EAP) | 3.5 percentage of participants |
| Cinacalcet | Percentage of Participants With a Mean Corrected Total Serum Calcium Value < 10.2 mg/dL (2.55 mmol/L) During the Efficacy Assessment Phase (EAP) | 78.9 percentage of participants |
Comparison: The primary endpoint was tested at a significance level of 0.05.p-value: <0.001Cochran-Mantel-Haenszel
95% CI: [18.76, 445.41]
95% CI: [63.83, 87.05]
Secondary
Change From Baseline to the EAP in Corrected Total Calcium
Time frame: Baseline and the EAP (mean of Weeks 22, 24, and 26)
Population: Full analysis set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline to the EAP in Corrected Total Calcium | -0.14 mg/dL | Standard Deviation 0.51 |
| Cinacalcet | Change From Baseline to the EAP in Corrected Total Calcium | -1.53 mg/dL | Standard Deviation 0.74 |
p-value: <0.00195% CI: [-1.62, -1.16]ANCOVA
Secondary
Change From Baseline to the EAP in Intact Parathyroid Hormone (iPTH)
Time frame: Baseline and the EAP (mean of Weeks 22, 24, and 26)
Population: Full analysis set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline to the EAP in Intact Parathyroid Hormone (iPTH) | -10.6 pg/mL | Standard Deviation 106.4 |
| Cinacalcet | Change From Baseline to the EAP in Intact Parathyroid Hormone (iPTH) | -127.9 pg/mL | Standard Deviation 254.2 |
p-value: 0.00295% CI: [-189.88, -44.55]ANCOVA
Secondary
Change From Baseline to the EAP in Mean Serum Phosphorus
Time frame: Baseline and the EAP (mean of Weeks 22, 24, and 26)
Population: Full analysis set with available data
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline to the EAP in Mean Serum Phosphorus | 0.07 mg/dL | Standard Deviation 0.48 |
| Cinacalcet | Change From Baseline to the EAP in Mean Serum Phosphorus | 0.52 mg/dL | Standard Deviation 0.54 |
p-value: <0.00195% CI: [0.26, 0.64]ANCOVA
Secondary
Change From Baseline to the EAP in Urine Phosphorus
Time frame: Baseline and the EAP (mean of Weeks 22, 24, and 26)
Population: Full analysis set with available data
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline to the EAP in Urine Phosphorus | -1.47 mg/dL | Standard Deviation 31.51 |
| Cinacalcet | Change From Baseline to the EAP in Urine Phosphorus | -2.62 mg/dL | Standard Deviation 43.93 |
p-value: 0.84695% CI: [-15.91, 13.06]ANCOVA
Secondary
Change From Baseline to Week 52 in eGFR
eGFR was calculated using the Modification of Diet in Renal Disease (MDRD) formula.
Time frame: Baseline and Week 52
Population: Full analysis set with available data
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline to Week 52 in eGFR | 0.06 mL/min/1.73 m² | Standard Deviation 8.7 |
| Cinacalcet | Change From Baseline to Week 52 in eGFR | -0.37 mL/min/1.73 m² | Standard Deviation 11.69 |
p-value: 0.84295% CI: [-4.37, 3.57]ANCOVA
Secondary
Percentage of Participants With a Parathyroidectomy
Time frame: 56 weeks
Population: Full analysis set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With a Parathyroidectomy | 0.0 percentage of participants |
| Cinacalcet | Percentage of Participants With a Parathyroidectomy | 0.0 percentage of participants |
Secondary
Percent Change From Baseline to Week 52 in Bone Mineral Density at the Femoral Neck
Bone mineral density (BMD) was measured using dual X-ray absorptiometry (DXA).
Time frame: Baseline and Week 52
Population: Full analysis set with available data
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Percent Change From Baseline to Week 52 in Bone Mineral Density at the Femoral Neck | 1.05 percent change |
| Cinacalcet | Percent Change From Baseline to Week 52 in Bone Mineral Density at the Femoral Neck | 1.24 percent change |
p-value: 0.26695% CI: [-1.1, 3.93]ANCOVA
Secondary
Time to Parathyroidectomy
Time frame: 56 weeks
Population: Full analysis set who underwent a parathyroidectomy