Chronic Kidney Disease, Secondary Hyperparathyroidism
Conditions
Keywords
Cinacalcet HCl, Cinacalcet, AMG 073, Sensipar, Mimpara, Calcimimetic, Hemodialysis, CKD, Secondary hyperparathyroidism (HPT)
Brief summary
The purpose of this study is to evaluate the effects of cinacalcet (cinacalcet HCl or Sensipar®/Mimpara®) on cardiovascular events and death in chronic kidney disease (CKD) patients with secondary hyperparathyroidism (HPT) who are receiving dialysis.
Detailed description
Secondary HPT is common in people with CKD. Patients with secondary HPT often have high parathyroid hormone (PTH) levels and may develop large parathyroid glands in the neck. Patients with secondary HPT may have bone disease (osteodystrophy). This bone disease may cause bone pain, fractures, and poor formation of red blood cells. Other problems from secondary HPT may include increases in blood levels of calcium and phosphorus. These 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), or heart and lung problems. New evidence suggests that secondary HPT is associated with cardiovascular disease and increased death risk. The purpose of this study is to evaluate the effects of cinacalcet (cinacalcet HCl or Sensipar®/Mimpara®) on cardiovascular events (having to do with the heart and its blood vessels) and death in chronic kidney disease (CKD) patients with secondary hyperparathyroidism (HPT) who are receiving dialysis. These events include death from any reason, heart attack and episodes where the heart does not get enough oxygen, peripheral vascular disease (narrowing of vessels that carry blood to the legs, arms, stomach or kidneys), and heart failure (a condition that occurs when the heart is unable to pump enough blood to meet the need's of the body's tissues)
Interventions
DRUGCinacalcet
Possible doses: 30, 60, 90, 120, and 180 mg using tablet strengths of 30, 60, or 90 mg. Sequential titration starting at 30 mg daily (QD), once every 4 weeks for the first 20 weeks and once every 8 weeks after Week 20. Titration increases or decreases based on PTH values, serum calcium, and safety. Daily dosing unless temporary hold criteria or withdrawal criteria is met, or until study completion; estimated 2.5 to 4 years of intervention.
DRUGPlacebo
Possible doses: 30, 60, 90, 120, and 180 mg using tablet strengths of 30, 60, or 90 mg. Sequential titration starting at 30 mg QD, once every 4 weeks for the first 20 weeks and once every 8 weeks after Week 20. Titration increases or decreases based on PTH values, serum calcium, and safety. Daily dosing unless temporary hold criteria or withdrawal criteria is met, or until study completion; estimated 2.5 to 4 years of intervention.
Sponsors
Amgen
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Inclusion:≥ 18 years of age * Treated with maintenance hemodialysis - PTH ≥ 300 pg/mL (31.8 pmol/L) * serum calcium ≥ 8.4mg/dL (2.1 mmol/L) * Ca x P ≥ 45 mg2\*/dL2 (3.63 mmol2/L2)
Exclusion criteria
- Exclusion: * Parathyroidectomy in the 12 weeks before the date of informed consent * Received therapy with cinacalcet within 3 months of randomization * Hospitalization within 12 weeks of randomization for any of the following events: a. Myocardial ischemia b. Unstable angina c. Heart Failure (HF) (including any unplanned presentation to a health care facility that would require mechanical intervention \[i.e., unplanned dialysis treatment\]) d. Peripheral vascular disease (other than dialysis vascular access revision) e. Stroke * History of seizure within 12 weeks prior to randomization * Scheduled date for kidney transplant from a known living donor * Anticipated parathyroidectomy within 6 months after randomization * in all instances, the 2 refers to squared.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to Primary Composite Endpoint (All-cause Mortality, Myocardial Infarction, Hospitalization for Unstable Angina, Heart Failure or Peripheral Vascular Event) | From date of randomization until date of first confirmed primary composite endpoint event, assessed up to 5.4 years | Time to Primary Composite Endpoint (All-cause Mortality, Myocardial Infarction, Hospitalization for Unstable Angina, Heart Failure or Peripheral Vascular Event). Stratified by history of diabetes and country. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Myocardial Infarction | From date of randomization until date of first confirmed myocardial infarction endpoint event, assessed up to 5.4 years | Time to Myocardial Infarction. Stratified by history of diabetes and country. |
| Time to Hospitalization for Unstable Angina | From date of randomization until date of first confirmed hospitalization for unstable angina endpoint event, assessed up to 5.4 years | Time to Hospitalization for Unstable Angina. Stratified by history of diabetes and country. |
| Time to Heart Failure | From date of randomization until date of first confirmed heart failure endpoint event, assessed up to 5.4 years | Time to Heart Failure. Stratified by history of diabetes and country. |
| Time to Peripheral Vascular Event | From date of randomization until date of first confirmed peripheral vascular endpoint event, assessed up to 5.4 years | Time to Peripheral Vascular Event. Stratified by history of diabetes and country. |
| Time to All-cause Mortality | From date of randomization until date of confirmed all-cause mortality endpoint event, assessed up to 5.4 years | Time to All-cause Mortality. Stratified by history of diabetes and country. |
| Time to Stroke | From date of randomization until date of first confirmed stroke endpoint event, assessed up to 5.4 years | Time to Stroke. Stratified by history of diabetes and country. |
| Time to Bone Fracture | From date of randomization until date of first confirmed bone fracture endpoint event, assessed up to 5.4 years | Time to Bone Fracture. Stratified by history of diabetes and country. |
| Time to Parathyroidectomy | From date of randomization until date of first confirmed parathyroidectomy endpoint event, assessed up to 5.4 years | Time to Parathyroidectomy. Stratified by history of diabetes and country. |
| Time to Cardiovascular Mortality | From date of randomization until date of first confirmed cardiovascular mortality endpoint event, assessed up to 5.4 years | Time to Cardiovascular Mortality. Stratified by history of diabetes and country. |
Participant flow
Recruitment details
Participants were recruited from dialysis clinics and hospitals between August 2006 to Jan 2008 from 22 countries.
Pre-assignment details
Participants were screened over a 30 day period.
Participants by arm
| Arm | Count |
|---|---|
| Cinacalcet Cinacalcet administered orally in doses of 30, 60, 90, 120 or 180 mg per day. Participants could be titrated up to maximum dose based on PTH (parathyroid hormone), serum calcium and safety assessments. | 1,948 |
| Placebo Participants were given matching placebo tablets compared to the cinacalcet group. | 1,935 |
| Total | 3,883 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 58 | 61 |
| Overall Study | Withdrawal by Subject | 91 | 98 |
Baseline characteristics
| Characteristic | Cinacalcet | Total | Placebo |
|---|---|---|---|
| Age, Continuous | 54.8 Years STANDARD_DEVIATION 14.5 | 54.4 Years STANDARD_DEVIATION 14.4 | 54.0 Years STANDARD_DEVIATION 14.2 |
| Country stratification factor Argentina | 171 Participants | 341 Participants | 170 Participants |
| Country stratification factor Australia | 74 Participants | 149 Participants | 75 Participants |
| Country stratification factor Austria | 31 Participants | 60 Participants | 29 Participants |
| Country stratification factor Belgium | 50 Participants | 100 Participants | 50 Participants |
| Country stratification factor Brazil | 151 Participants | 301 Participants | 150 Participants |
| Country stratification factor Canada | 73 Participants | 146 Participants | 73 Participants |
| Country stratification factor Denmark | 8 Participants | 19 Participants | 11 Participants |
| Country stratification factor France | 40 Participants | 80 Participants | 40 Participants |
| Country stratification factor Germany | 81 Participants | 162 Participants | 81 Participants |
| Country stratification factor Hungary | 66 Participants | 133 Participants | 67 Participants |
| Country stratification factor Ireland | 5 Participants | 11 Participants | 6 Participants |
| Country stratification factor Italy | 69 Participants | 137 Participants | 68 Participants |
| Country stratification factor Mexico | 23 Participants | 45 Participants | 22 Participants |
| Country stratification factor Netherlands | 15 Participants | 29 Participants | 14 Participants |
| Country stratification factor Poland | 59 Participants | 116 Participants | 57 Participants |
| Country stratification factor Portugal | 22 Participants | 43 Participants | 21 Participants |
| Country stratification factor Russia | 143 Participants | 283 Participants | 140 Participants |
| Country stratification factor Spain | 40 Participants | 78 Participants | 38 Participants |
| Country stratification factor Sweden | 13 Participants | 23 Participants | 10 Participants |
| Country stratification factor Switzerland | 18 Participants | 37 Participants | 19 Participants |
| Country stratification factor United Kingdom | 81 Participants | 160 Participants | 79 Participants |
| Country stratification factor United States | 715 Participants | 1430 Participants | 715 Participants |
| History of Diabetes Stratification Factor Diabetes | 619 Participants | 1233 Participants | 614 Participants |
| History of Diabetes Stratification Factor No Diabetes | 1329 Participants | 2650 Participants | 1321 Participants |
| Race/Ethnicity, Customized Aborigine | 1 Participants | 5 Participants | 4 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 5 Participants | 12 Participants | 7 Participants |
| Race/Ethnicity, Customized Asian | 47 Participants | 85 Participants | 38 Participants |
| Race/Ethnicity, Customized Black or African American | 409 Participants | 837 Participants | 428 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 317 Participants | 627 Participants | 310 Participants |
| Race/Ethnicity, Customized Japanese | 4 Participants | 5 Participants | 1 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 12 Participants | 21 Participants | 9 Participants |
| Race/Ethnicity, Customized Other | 29 Participants | 51 Participants | 22 Participants |
| Race/Ethnicity, Customized White or Caucasian | 1124 Participants | 2240 Participants | 1116 Participants |
| Sex: Female, Male Female | 809 Participants | 1578 Participants | 769 Participants |
| Sex: Female, Male Male | 1139 Participants | 2305 Participants | 1166 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 1,220 / 1,923 | 1,444 / 1,938 |
| serious Total, serious adverse events | 1,351 / 1,923 | 1,338 / 1,938 |
Outcome results
Primary
Time to Primary Composite Endpoint (All-cause Mortality, Myocardial Infarction, Hospitalization for Unstable Angina, Heart Failure or Peripheral Vascular Event)
Time to Primary Composite Endpoint (All-cause Mortality, Myocardial Infarction, Hospitalization for Unstable Angina, Heart Failure or Peripheral Vascular Event). Stratified by history of diabetes and country.
Time frame: From date of randomization until date of first confirmed primary composite endpoint event, assessed up to 5.4 years
Population: Utilizes the Efficacy Analysis Set which includes all randomized participants. Participants were analyzed in the treatment group as randomized using the Intent-to-treat (ITT) method.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cinacalcet | Time to Primary Composite Endpoint (All-cause Mortality, Myocardial Infarction, Hospitalization for Unstable Angina, Heart Failure or Peripheral Vascular Event) | 55.0 Months |
| Placebo | Time to Primary Composite Endpoint (All-cause Mortality, Myocardial Infarction, Hospitalization for Unstable Angina, Heart Failure or Peripheral Vascular Event) | 53.0 Months |
p-value: 0.112Log Rank
95% CI: [0.85, 1.02]Regression, Cox
Secondary
Time to All-cause Mortality
Time to All-cause Mortality. Stratified by history of diabetes and country.
Time frame: From date of randomization until date of confirmed all-cause mortality endpoint event, assessed up to 5.4 years
Population: Utilizes the Efficacy Analysis Set which includes all randomized participants. Participants were analyzed in the treatment group as randomized using the Intent-to-treat (ITT) method.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cinacalcet | Time to All-cause Mortality | NA Months |
| Placebo | Time to All-cause Mortality | NA Months |
p-value: 0.249Log Rank
95% CI: [0.85, 1.04]Regression, Cox
Secondary
Time to Bone Fracture
Time to Bone Fracture. Stratified by history of diabetes and country.
Time frame: From date of randomization until date of first confirmed bone fracture endpoint event, assessed up to 5.4 years
Population: Utilizes the Efficacy Analysis Set which includes all randomized participants. Participants were analyzed in the treatment group as randomized using the Intent-to-treat (ITT) method.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cinacalcet | Time to Bone Fracture | NA Months |
| Placebo | Time to Bone Fracture | NA Months |
p-value: 0.218Log Rank
95% CI: [0.75, 1.07]Regression, Cox
Secondary
Time to Cardiovascular Mortality
Time to Cardiovascular Mortality. Stratified by history of diabetes and country.
Time frame: From date of randomization until date of first confirmed cardiovascular mortality endpoint event, assessed up to 5.4 years
Population: Utilizes the Efficacy Analysis Set which includes all randomized participants. Participants were analyzed in the treatment group as randomized using the Intent-to-treat (ITT) method.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cinacalcet | Time to Cardiovascular Mortality | NA Months |
| Placebo | Time to Cardiovascular Mortality | NA Months |
p-value: 0.277Log Rank
95% CI: [0.8, 1.07]Regression, Cox
Secondary
Time to Heart Failure
Time to Heart Failure. Stratified by history of diabetes and country.
Time frame: From date of randomization until date of first confirmed heart failure endpoint event, assessed up to 5.4 years
Population: Utilizes the Efficacy Analysis Set which includes all randomized participants. Participants were analyzed in the treatment group as randomized using the Intent-to-treat (ITT) method.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cinacalcet | Time to Heart Failure | NA Months |
| Placebo | Time to Heart Failure | NA Months |
p-value: 0.034Log Rank
95% CI: [0.68, 0.99]Regression, Cox
Secondary
Time to Hospitalization for Unstable Angina
Time to Hospitalization for Unstable Angina. Stratified by history of diabetes and country.
Time frame: From date of randomization until date of first confirmed hospitalization for unstable angina endpoint event, assessed up to 5.4 years
Population: Utilizes the Efficacy Analysis Set which includes all randomized participants. Participants were analyzed in the treatment group as randomized using the Intent-to-treat (ITT) method.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cinacalcet | Time to Hospitalization for Unstable Angina | NA Months |
| Placebo | Time to Hospitalization for Unstable Angina | NA Months |
p-value: 0.283Log Rank
95% CI: [0.58, 1.18]Regression, Cox
Secondary
Time to Myocardial Infarction
Time to Myocardial Infarction. Stratified by history of diabetes and country.
Time frame: From date of randomization until date of first confirmed myocardial infarction endpoint event, assessed up to 5.4 years
Population: Utilizes the Efficacy Analysis Set which includes all randomized participants. Participants were analyzed in the treatment group as randomized using the Intent-to-treat (ITT) method.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cinacalcet | Time to Myocardial Infarction | NA Months |
| Placebo | Time to Myocardial Infarction | NA Months |
p-value: 0.8Log Rank
95% CI: [0.79, 1.19]Regression, Cox
Secondary
Time to Parathyroidectomy
Time to Parathyroidectomy. Stratified by history of diabetes and country.
Time frame: From date of randomization until date of first confirmed parathyroidectomy endpoint event, assessed up to 5.4 years
Population: Utilizes the Efficacy Analysis Set which includes all randomized participants. Participants were analyzed in the treatment group as randomized using the Intent-to-treat (ITT) method.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cinacalcet | Time to Parathyroidectomy | NA Months |
| Placebo | Time to Parathyroidectomy | NA Months |
95% CI: [0.36, 0.54]Regression, Cox
p-value: <0.001Log Rank
Secondary
Time to Peripheral Vascular Event
Time to Peripheral Vascular Event. Stratified by history of diabetes and country.
Time frame: From date of randomization until date of first confirmed peripheral vascular endpoint event, assessed up to 5.4 years
Population: Utilizes the Efficacy Analysis Set which includes all randomized participants. Participants were analyzed in the treatment group as randomized using the Intent-to-treat (ITT) method.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cinacalcet | Time to Peripheral Vascular Event | NA Months |
| Placebo | Time to Peripheral Vascular Event | NA Months |
p-value: 0.19Log Rank
95% CI: [0.72, 1.07]Regression, Cox
Secondary
Time to Stroke
Time to Stroke. Stratified by history of diabetes and country.
Time frame: From date of randomization until date of first confirmed stroke endpoint event, assessed up to 5.4 years
Population: Utilizes the Efficacy Analysis Set which includes all randomized participants. Participants were analyzed in the treatment group as randomized using the Intent-to-treat (ITT) method.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cinacalcet | Time to Stroke | NA Months |
| Placebo | Time to Stroke | NA Months |
p-value: 0.607Log Rank
95% CI: [0.82, 1.4]Regression, Cox