Chronic Kidney Disease on Hemodialysis, Secondary Hyperparathyroidism
Conditions
Keywords
chronic kidney disease, secondary hyperparathyroidism, hemodialysis, paricalcitol, maxacalcitol
Brief summary
The purpose of this study was to investigate the initial dose and dose adjustment range for paricalcitol injection in patients with chronic kidney disease on hemodialysis who have secondary hyperparathyroidism.
Detailed description
This multicenter, randomized, open-label trial consisted of 4 dose-adjustment regimens for paricalcitol injection (initial doses and dose adjustment ranges were 2 ± 1 µg, 2 ± 2 µg, 4 ± 1 µg, and 4 ± 2 µg) and 1 maxacalcitol regimen (initial dose and dose adjustment range was 5 µg ± 2.5 µg or 10 µg ± 2.5 µg) as a reference group. Subjects who met the inclusion criteria were randomized equally to 1 of the treatment groups with iPTH values at screening (\< 500 pg/mL or ≥ 500 pg/mL) as a dynamic allocation factor. Study drugs were administered 3 times weekly (every other day) from the venous end of the hemodialysis circuit just before completion of the dialysis session. The initial doses were continued for 2 weeks, followed by dose adjustments (increase, maintenance, decrease, suspension, or resumption) by 1 µg or 2 µg units for the paricalcitol groups and by 2.5 µg units for the maxacalcitol group based on iPTH, calcium (adjusted), and phosphorus values every 2 weeks. Subjects in the paricalcitol groups were to be suspended from treatment if their iPTH value decreased to \< 60 pg/mL in accordance with the guidelines proposed by the Japanese Society of Dialysis Therapy for the treatment of secondary hyperparathyroidism in chronic dialysis patients (control goal value of 60-180 pg/mL for iPTH). The dose adjustment criteria based on iPTH values for the maxacalcitol group were set according to the prescribing information for maxacalcitol (suspended when iPTH decreased to ≤ 150 pg/mL).
Interventions
DRUGMaxacalcitol
Study drug was administered 3 times per week (no more frequently than every other day) intravenously immediately before the completion of hemodialysis. The initial dosage was administered for 2 weeks, with subsequent dosage adjustment based on the subject's iPTH, calcium (adjusted), and phosphorus levels every 2 weeks. Total duration of treatment was 12 weeks.
DRUGParicalcitol
Study drug was administered 3 times per week (no more frequently than every other day) intravenously immediately before the completion of hemodialysis. The initial dosage was administered for 2 weeks, with subsequent dosage adjustment based on the subject's iPTH, calcium (adjusted), and phosphorus levels every 2 weeks. Total duration of treatment was 12 weeks.
Sponsors
Abbott Japan Co.,Ltd
Abbott
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
20 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Diagnosed with chronic kidney disease receiving hemodialysis 3 times a week for at least 3 months prior to obtaining the informed consent and scheduled to be receiving the same hemodialysis during the study period. * Using dialysate with constant concentration of calcium for 4 weeks prior to obtaining informed consent and phosphate binder with constant dose regimen for 2 weeks prior to obtaining informed consent. * Intact parathyroid hormone level (iPTH) ≥ 300 pg/mL * Calcium (adjusted) 8.4-10.2 milligrams/deciliter (mg/dL) * Phosphorus ≤ 6.5 mg/dL * Age ≥ 20 years
Exclusion criteria
* History of allergic reaction or significant sensitivity to vitamin D or vitamin D related compounds * Parathyroidectomy or ethanol infusion within past year * Progressive malignancy or clinically significant hepatic diseases, severe cerebral/cardiovascular diseases, severe hypertension, or uncontrolled diabetes mellitus * Drug or alcohol abuse within past 6 months * Taking calcitonin, maintenance intravenous or oral glucocorticoids, cinacalcet, bisphosphonates, selective estrogen-receptor modulator (SERM), vitamin D compounds (other than study drug), or other drugs that may affect calcium or bone metabolism (other than estrogen or progestin, vitamin K2) * Will need to take chronic dose (≥ 2 consecutive weeks) of cytochrome P450 (CYP3A) inhibitors (e.g., clarithromycin, grapefruit products) or inducers (e.g., carbamazepine, rifampicin) * Taking aluminum containing products (2 weeks prior to consent)
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Percentage of Subjects With ≥ 50% Decrease From Baseline in Intact Parathyroid Hormone (iPTH) Serum Level | Baseline to Week 13 (Final Visit) |
Secondary
| Measure | Time frame |
|---|---|
| Mean Change From Baseline in Intact Parathyroid Hormone (iPTH) Level | Baseline to Week 13 (Final Visit) |
| Percentage of Subjects With Intact Parathyroid Hormone (iPTH) ≤ 180 Picograms/Milliliter (pg/mL) | Baseline to Week 13 (Final Visit) |
| Percentage of Subjects With 2 or More Decreases of ≥ 50% From Baseline in Intact Parathyroid Hormone (iPTH) Level | Through Week 13 |
| Duration of 2 Consecutive Decreases of ≥ 50% From Baseline in Intact Parathyroid Hormone (iPTH) Values | Through Week 13 |
| Duration of 2 Consecutive Intact Parathyroid Hormone (iPTH) Values ≤ 180 pg/mL | Through Week 13 |
Other
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Subjects With Hypercalcemia | Through Week 13 | Hypercalcemia was defined as at least 1 adjusted calcium value \> 11.5 mg/dL or at least 2 consecutive adjusted calcium values ≥ 11.0 mg/dL |
| Percentage of Subjects With Hyperphosphatemia | Through Week 13 | Hyperphosphatemia was defined as at least 2 consecutive phosphorus values ≥ 7.0 mg/dL |
Countries
Japan
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Paricalcitol 2 µg ± 1 µg Paricalcitol initial dosage 2 µg with incremental adjustment of 1 µg | 30 |
| Paricalcitol 2 µg ± 2 µg Paricalcitol initial dosage 2 µg with incremental adjustment of 2 µg | 31 |
| Paricalcitol 4 µg ± 1 µg Paricalcitol initial dosage 4 µg with incremental adjustment of 1 µg | 31 |
| Paricalcitol 4 µg ± 2 µg Paricalcitol initial dosage 4 µg with incremental adjustment of 2 µg | 31 |
| Maxacalcitol 5 or 10 µg ± 2.5 µg Maxacalcitol initial dosage 5 or 10 µg with incremental adjustment of 2.5 µg | 30 |
| Total | 153 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 1 | 0 | 0 | 0 |
| Overall Study | Lost to Follow-up | 0 | 0 | 1 | 0 | 0 |
| Overall Study | Missed Visit | 0 | 0 | 0 | 1 | 0 |
| Overall Study | Physician Decision | 0 | 0 | 0 | 1 | 0 |
| Overall Study | Protocol Violation | 0 | 0 | 0 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 0 | 1 | 1 | 1 |
Baseline characteristics
| Characteristic | Paricalcitol 2 µg ± 2 µg | Paricalcitol 4 µg ± 1 µg | Paricalcitol 4 µg ± 2 µg | Paricalcitol 2 µg ± 1 µg | Maxacalcitol 5 or 10 µg ± 2.5 µg | Total |
|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 13 Participants | 12 Participants | 12 Participants | 11 Participants | 18 Participants | 66 Participants |
| Age, Categorical Between 18 and 65 years | 18 Participants | 19 Participants | 19 Participants | 19 Participants | 12 Participants | 87 Participants |
| Age Continuous | 60.7 years STANDARD_DEVIATION 11.8 | 58.1 years STANDARD_DEVIATION 12.35 | 61.5 years STANDARD_DEVIATION 11.17 | 62.1 years STANDARD_DEVIATION 11.94 | 64.1 years STANDARD_DEVIATION 11.98 | 61.3 years STANDARD_DEVIATION 11.86 |
| Region of Enrollment Japan | 31 participants | 31 participants | 31 participants | 30 participants | 30 participants | 153 participants |
| Sex: Female, Male Female | 14 Participants | 11 Participants | 14 Participants | 18 Participants | 7 Participants | 64 Participants |
| Sex: Female, Male Male | 17 Participants | 20 Participants | 17 Participants | 12 Participants | 23 Participants | 89 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 30 / 30 | 29 / 31 | 30 / 31 | 28 / 31 | 29 / 30 |
| serious Total, serious adverse events | 1 / 30 | 2 / 31 | 3 / 31 | 2 / 31 | 2 / 30 |
Outcome results
Primary
Percentage of Subjects With ≥ 50% Decrease From Baseline in Intact Parathyroid Hormone (iPTH) Serum Level
Time frame: Baseline to Week 13 (Final Visit)
Population: The efficacy analysis was performed on the full analysis set (FAS). The FAS included all treated patients, except for 1 subject from the paricalcitol 4 ± 2 µg group who discontinued the study without measurement of iPTH after the first drug injection. Missing data were not imputed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Paricalcitol 2 µg ± 1 µg | Percentage of Subjects With ≥ 50% Decrease From Baseline in Intact Parathyroid Hormone (iPTH) Serum Level | 53.3 Percentage of participants |
| Paricalcitol 2 µg ± 2 µg | Percentage of Subjects With ≥ 50% Decrease From Baseline in Intact Parathyroid Hormone (iPTH) Serum Level | 41.9 Percentage of participants |
| Paricalcitol 4 µg ± 1 µg | Percentage of Subjects With ≥ 50% Decrease From Baseline in Intact Parathyroid Hormone (iPTH) Serum Level | 38.7 Percentage of participants |
| Paricalcitol 4 µg ± 2 µg | Percentage of Subjects With ≥ 50% Decrease From Baseline in Intact Parathyroid Hormone (iPTH) Serum Level | 56.7 Percentage of participants |
| Maxacalcitol 5 or 10 µg ± 2.5 µg | Percentage of Subjects With ≥ 50% Decrease From Baseline in Intact Parathyroid Hormone (iPTH) Serum Level | 43.3 Percentage of participants |
Secondary
Duration of 2 Consecutive Decreases of ≥ 50% From Baseline in Intact Parathyroid Hormone (iPTH) Values
Time frame: Through Week 13
Population: Includes subjects from the Full Analysis Set (FAS) who had 2 consecutive iPTH decreases of ≥ 50% from baseline. Missing data were not imputed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Paricalcitol 2 µg ± 1 µg | Duration of 2 Consecutive Decreases of ≥ 50% From Baseline in Intact Parathyroid Hormone (iPTH) Values | 23.8 days | Standard Deviation 14.34 |
| Paricalcitol 2 µg ± 2 µg | Duration of 2 Consecutive Decreases of ≥ 50% From Baseline in Intact Parathyroid Hormone (iPTH) Values | 27.7 days | Standard Deviation 14.6 |
| Paricalcitol 4 µg ± 1 µg | Duration of 2 Consecutive Decreases of ≥ 50% From Baseline in Intact Parathyroid Hormone (iPTH) Values | 29.0 days | Standard Deviation 15.26 |
| Paricalcitol 4 µg ± 2 µg | Duration of 2 Consecutive Decreases of ≥ 50% From Baseline in Intact Parathyroid Hormone (iPTH) Values | 25.2 days | Standard Deviation 18.21 |
| Maxacalcitol 5 or 10 µg ± 2.5 µg | Duration of 2 Consecutive Decreases of ≥ 50% From Baseline in Intact Parathyroid Hormone (iPTH) Values | 10.9 days | Standard Deviation 12.18 |
Secondary
Duration of 2 Consecutive Intact Parathyroid Hormone (iPTH) Values ≤ 180 pg/mL
Time frame: Through Week 13
Population: Includes subjects from the Full Analysis Set (FAS) who had 2 consecutive iPTH values ≤ 180 pg/mL. Missing data were not imputed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Paricalcitol 2 µg ± 1 µg | Duration of 2 Consecutive Intact Parathyroid Hormone (iPTH) Values ≤ 180 pg/mL | 22.0 days | Standard Deviation 12.23 |
| Paricalcitol 2 µg ± 2 µg | Duration of 2 Consecutive Intact Parathyroid Hormone (iPTH) Values ≤ 180 pg/mL | 26.1 days | Standard Deviation 15.36 |
| Paricalcitol 4 µg ± 1 µg | Duration of 2 Consecutive Intact Parathyroid Hormone (iPTH) Values ≤ 180 pg/mL | 19.7 days | Standard Deviation 13.32 |
| Paricalcitol 4 µg ± 2 µg | Duration of 2 Consecutive Intact Parathyroid Hormone (iPTH) Values ≤ 180 pg/mL | 17.2 days | Standard Deviation 15.52 |
| Maxacalcitol 5 or 10 µg ± 2.5 µg | Duration of 2 Consecutive Intact Parathyroid Hormone (iPTH) Values ≤ 180 pg/mL | 3.1 days | Standard Deviation 3.29 |
Secondary
Mean Change From Baseline in Intact Parathyroid Hormone (iPTH) Level
Time frame: Baseline to Week 13 (Final Visit)
Population: The efficacy analysis was performed on the full analysis set (FAS). The FAS included all treated patients, except for 1 subject from the paricalcitol 4 ± 2 µg group who discontinued the study without measurement of iPTH after the first drug injection. Missing data were not imputed.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Paricalcitol 2 µg ± 1 µg | Mean Change From Baseline in Intact Parathyroid Hormone (iPTH) Level | -233.2 pg/mL |
| Paricalcitol 2 µg ± 2 µg | Mean Change From Baseline in Intact Parathyroid Hormone (iPTH) Level | -260.8 pg/mL |
| Paricalcitol 4 µg ± 1 µg | Mean Change From Baseline in Intact Parathyroid Hormone (iPTH) Level | -178.2 pg/mL |
| Paricalcitol 4 µg ± 2 µg | Mean Change From Baseline in Intact Parathyroid Hormone (iPTH) Level | -211.7 pg/mL |
| Maxacalcitol 5 or 10 µg ± 2.5 µg | Mean Change From Baseline in Intact Parathyroid Hormone (iPTH) Level | -236.6 pg/mL |
Secondary
Percentage of Subjects With 2 or More Decreases of ≥ 50% From Baseline in Intact Parathyroid Hormone (iPTH) Level
Time frame: Through Week 13
Population: The efficacy analysis was performed on the full analysis set (FAS). The FAS included all treated subjects, except for 1 subject from the paricalcitol 4 ± 2 µg group who discontinued the study without measurement of iPTH after the first drug injection. Missing data were not imputed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Paricalcitol 2 µg ± 1 µg | Percentage of Subjects With 2 or More Decreases of ≥ 50% From Baseline in Intact Parathyroid Hormone (iPTH) Level | 90.0 Percentage of participants |
| Paricalcitol 2 µg ± 2 µg | Percentage of Subjects With 2 or More Decreases of ≥ 50% From Baseline in Intact Parathyroid Hormone (iPTH) Level | 100 Percentage of participants |
| Paricalcitol 4 µg ± 1 µg | Percentage of Subjects With 2 or More Decreases of ≥ 50% From Baseline in Intact Parathyroid Hormone (iPTH) Level | 90.3 Percentage of participants |
| Paricalcitol 4 µg ± 2 µg | Percentage of Subjects With 2 or More Decreases of ≥ 50% From Baseline in Intact Parathyroid Hormone (iPTH) Level | 90.0 Percentage of participants |
| Maxacalcitol 5 or 10 µg ± 2.5 µg | Percentage of Subjects With 2 or More Decreases of ≥ 50% From Baseline in Intact Parathyroid Hormone (iPTH) Level | 93.3 Percentage of participants |
Secondary
Percentage of Subjects With Intact Parathyroid Hormone (iPTH) ≤ 180 Picograms/Milliliter (pg/mL)
Time frame: Baseline to Week 13 (Final Visit)
Population: The efficacy analysis was performed on the full analysis set (FAS). The FAS included all treated patients, except for 1 subject from the paricalcitol 4 ± 2 µg group who discontinued the study without measurement of iPTH after the first drug injection. Missing data were not imputed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Paricalcitol 2 µg ± 1 µg | Percentage of Subjects With Intact Parathyroid Hormone (iPTH) ≤ 180 Picograms/Milliliter (pg/mL) | 36.7 Percentage of participants |
| Paricalcitol 2 µg ± 2 µg | Percentage of Subjects With Intact Parathyroid Hormone (iPTH) ≤ 180 Picograms/Milliliter (pg/mL) | 32.3 Percentage of participants |
| Paricalcitol 4 µg ± 1 µg | Percentage of Subjects With Intact Parathyroid Hormone (iPTH) ≤ 180 Picograms/Milliliter (pg/mL) | 32.3 Percentage of participants |
| Paricalcitol 4 µg ± 2 µg | Percentage of Subjects With Intact Parathyroid Hormone (iPTH) ≤ 180 Picograms/Milliliter (pg/mL) | 36.7 Percentage of participants |
| Maxacalcitol 5 or 10 µg ± 2.5 µg | Percentage of Subjects With Intact Parathyroid Hormone (iPTH) ≤ 180 Picograms/Milliliter (pg/mL) | 33.3 Percentage of participants |
Other Pre-specified
Percentage of Subjects With Hypercalcemia
Hypercalcemia was defined as at least 1 adjusted calcium value \> 11.5 mg/dL or at least 2 consecutive adjusted calcium values ≥ 11.0 mg/dL
Time frame: Through Week 13
Population: Safety analysis was performed on the Safety Set, which included all subjects who received at least 1 dose of study drug. Missing data were not imputed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Paricalcitol 2 µg ± 1 µg | Percentage of Subjects With Hypercalcemia | 30.0 Percentage of participants |
| Paricalcitol 2 µg ± 2 µg | Percentage of Subjects With Hypercalcemia | 48.4 Percentage of participants |
| Paricalcitol 4 µg ± 1 µg | Percentage of Subjects With Hypercalcemia | 45.2 Percentage of participants |
| Paricalcitol 4 µg ± 2 µg | Percentage of Subjects With Hypercalcemia | 58.1 Percentage of participants |
| Maxacalcitol 5 or 10 µg ± 2.5 µg | Percentage of Subjects With Hypercalcemia | 30.0 Percentage of participants |
Other Pre-specified
Percentage of Subjects With Hyperphosphatemia
Hyperphosphatemia was defined as at least 2 consecutive phosphorus values ≥ 7.0 mg/dL
Time frame: Through Week 13
Population: Safety analysis was performed on the Safety Set, which included all subjects who received at least 1 dose of study drug. Missing data were not imputed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Paricalcitol 2 µg ± 1 µg | Percentage of Subjects With Hyperphosphatemia | 10.0 Percentage of participants |
| Paricalcitol 2 µg ± 2 µg | Percentage of Subjects With Hyperphosphatemia | 9.7 Percentage of participants |
| Paricalcitol 4 µg ± 1 µg | Percentage of Subjects With Hyperphosphatemia | 9.7 Percentage of participants |
| Paricalcitol 4 µg ± 2 µg | Percentage of Subjects With Hyperphosphatemia | 19.4 Percentage of participants |
| Maxacalcitol 5 or 10 µg ± 2.5 µg | Percentage of Subjects With Hyperphosphatemia | 13.3 Percentage of participants |