Chronic Kidney Disease Stage 3 and 4
Conditions
Keywords
Reduction of parathyroid hormone levels in pediatric patients with Chronic Kidney Disease Stage 3 and 4
Brief summary
Part 1: To determine the safety, tolerability, and pharmacokinetics of a single dose of 3 μg paricalcitol capsules in children ages 10 to 16 years with moderate to severe chronic kidney disease (CKD Stages 3 and 4). Part 2: To determine the safety and efficacy of paricalcitol capsules as compared to placebo in decreasing serum intact parathyroid hormone (iPTH) in children ages 10 to 16 years with moderate to severe chronic kidney disease with an initial 12 weeks of double-blinded study drug followed by a minimum of 12 weeks of open-label active drug.
Detailed description
The study consists of two parts. Part 1 is an open-label single-dose, non-fasting, multicenter study to evaluate the pharmacokinetics (PK) of paricalcitol capsules in 12 children ages 10 to 16 years with CKD Stages 3 and 4. Part 2 of this study will be conducted as a 12 week randomized double-blind, placebo-controlled study, followed by 12 weeks open-label treatment. Participants active or enrolled under amendment 5 will enter a follow-up period and have study visits every 4 weeks until the final participant reaches Week 24.
Interventions
DRUGParicalcitol
Paricalcitol capsules taken with water.
DRUGPlacebo
Placebo capsules taken with water
Sponsors
AbbVie (prior sponsor, Abbott)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
10 Years to 16 Years
Healthy volunteers
No
Inclusion criteria
* Subject has chronic kidney disease Stage 3 or 4 as determined by estimated glomerular filtration rate (15 to 59 mL/min/1.73 m²) at Screening. * Subject is not expected to begin dialysis for at least 6 months (in the opinion of the investigator). * For entry into the Washout Period (for subjects who are currently on a vitamin D receptor activator \[VDRA\] and need to complete a 2 to 4 week washout), the subject must satisfy the following criteria based on the Screening laboratory values: * estimated glomerular filtration rate between 15 to 59 mL/min/1.73 m². * iPTH measurement that is greater than or equal to 60 pg/mL (Stage 3 subjects) or greater than or equal to 90 pg/mL (Stage 4 subjects). * An adjusted serum calcium value greater than or equal to 8.2 mg/dL (2.05 mmol/L) to less than or equal to 10.5 mg/dL (2.63 mmol/L). * A serum phosphorus value greater than or equal to 2.0 mg/dL (0.65 mmol/L but less than or equal to 6.0 mg/dL (1.94 mmol/L). * For entry into the Treatment Phase (vitamin D receptor activator naïve subjects and those that have completed a 4 week washout), the subject must have: * iPTH measurement that is greater than or equal to 75 pg/mL (Stage 3 subjects) or greater than or equal to 110 pg/mL (Stage 4 subjects). * An adjusted serum calcium value greater than or equal to 8.4 mg/dL (2.10 mmol/L) but less than or equal to 10.2 mg/dL (2.55 mmol/L). * A serum phosphorus value greater than or equal to 2.5 mg/dL (0.81 mmol/L) but less than or equal to 5.8 mg/dL (1.87 mmol/L). * Must have 25-hydroxyvitamin D levels ≥ 30 ng/mL prior to washout, if not VDRA naïve, or treatment in Part II of the study.
Exclusion criteria
* All subjects that have had a small bowel transplant will be excluded from the study. * Subject has had acute kidney failure within 12 weeks of the Screening Phase (defined as an acute rise in serum creatinine). * Subject has had symptomatic or significant hypocalcemia requiring active vitamin D therapy (for example, calcitriol, paricalcitol, doxercalciferol or alfacalcidol) within 6 months prior to the Screening Phase. * Subject has a history of active kidney stones (6 months prior to screening). * Subject has chronic gastrointestinal disease, which in the investigator's opinion may cause significant gastrointestinal malabsorption. * Subject is taking maintenance calcitonin, bisphosphonates, cinacalcet, glucocorticoids in an equivalent dose of greater than 5 mg prednisone daily, or other drugs known to affect calcium or bone metabolism within 4 weeks prior to treatment.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part 1: Paricalcitol Maximum Observed Plasma Concentration (Cmax) | Blood samples were collected at hour 0, 1, 2, 4, 6, 8, 12, 24, 36, and 48 hours after dosing. | — |
| Part 1: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity (AUC0-∞) | Blood samples were collected at hour 0, 1, 2, 4, 6, 8, 12, 24, 36, and 48 hours after dosing. | — |
| Part 2: Percentage of Participants Achieving Two Consecutive Reductions at Least 30% From Baseline in iPTH | 12-week double-blind treatment period | The primary efficacy endpoint was the percentage of participants who achieved two consecutive ≥ 30% reductions from baseline in intact parathyroid hormone (iPTH) levels during the 12 week double-blind portion of the study regardless of CKD stage. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Part 2: Percentage of Participants Achieving Final Phosphorus Levels Within KDOQI Target Ranges | Week 12 | The KDOQI target ranges of serum phosphorus are to maintain at or above age appropriate lower limits and no higher than the age-appropriate upper limits: Age 6 - 12: 3.6 - 5.8 mg/dL (1.16 - 1.87 mmol/L); Age 13 - 20: 2.3 - 4.5 mg/dL (0.74 - 1.45 mmol/L). |
| Part 2: Percentage of Participants Achieving a Final iPTH Within KDOQI Target Ranges | Week 12 | The Kidney Disease Outcomes Quality Initiatives (KDOQI) Pediatric Subcommittee on Practice Guidelines for Bone Metabolism and Disease in Children with CKD target range for intact parathyroid hormone (iPTH) is as follows:: CKD Stage 3: 35 - 69 pg/mL; CKD Stage 4: 70 - 110 pg/mL. |
| Part 2: Change From Baseline in First Morning Void (FMV) Urinary Albumin to Creatinine Ratio (UACR) | Baseline and Weeks 4, 8 and 12 | The mean change from Baseline in FMV UACR on a log scale to each post baseline visit. |
| Part 2: Change From Baseline in iPTH to Each Post-baseline Visit | Baseline and Weeks 2, 4, 8 and 12 | — |
| Part 2: Percentage of Participants Achieving Final Calcium Levels Within KDOQI Target Ranges | Week 12 | KDOQI recommends serum calcium is maintained within age appropriate normal ranges: Age 6 - 12: 9.4 - 10.2 mg/dL (2.35 - 2.55 mmol/L); Age 13 - 20: 8.8 - 10.2 mg/dL (2.20 - 2.55 mmol/L). |
Participant flow
Recruitment details
Part 1 was an open-label, single-dose study evaluating the pharmacokinetics of paricalcitol capsules in children with moderate to severe chronic kidney disease (CKD). Part 2 consisted of a double-blind, placebo-controlled study to evaluate safety and efficacy of paricalcitol and an open-label phase where all participants received paricalcitol.
Pre-assignment details
Two participants enrolled in Part 2 after completing Part 1 of the study, hence the actual total number of enrolled participants is equal to 47.
Participants by arm
| Arm | Count |
|---|---|
| Part 1: Paricalcitol Participants received a single 3 µg dose of paricalcitol capsules on Study Day 1. | 12 |
| Part 2: Placebo Participants received placebo capsules three times a week (TIW) for 12 weeks during the double-blind treatment phase. From Weeks 12 to 24 participants received open-label paricalcitol at an initial dose of 1 µg three times a week. Doses could be increased in 1 μg increments every 4 weeks based on chemistry evaluations to target Kidney Disease Outcomes Quality Initiatives (KDOQI) target levels. | 18 |
| Part 2: Paricalcitol Participants received paricalcitol three times a week for 12 weeks during the double-blind treatment period and during the open-label period (Weeks 12-24). The initial dose of paricalcitol was 1 µg TIW. Doses could be increased in 1 μg increments every 4 weeks based on chemistry evaluations to target KDOQI target levels. | 19 |
| Total | 49 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Part 2 Double-blind Treatment Period | Adverse Event | 0 | 2 | 1 |
| Part 2 Double-blind Treatment Period | Randomized in Error | 0 | 0 | 1 |
| Part 2 Double-blind Treatment Period | Required a Dose Reduction | 0 | 0 | 3 |
| Part 2 Double-blind Treatment Period | Withdrawal by Subject | 0 | 0 | 1 |
| Part 2 Open-label Period | Adverse Event | 0 | 4 | 1 |
Baseline characteristics
| Characteristic | Part 1: Paricalcitol | Total | Part 2: Placebo | Part 2: Paricalcitol |
|---|---|---|---|---|
| Age, Continuous Part 1 | 13.5 years STANDARD_DEVIATION 1.98 | 13.5 years STANDARD_DEVIATION 1.98 | — | — |
| Age, Continuous Part 2 | — | 13.6 years STANDARD_DEVIATION 1.78 | 13.3 years STANDARD_DEVIATION 1.75 | 13.9 years STANDARD_DEVIATION 1.81 |
| Chronic Kidney Disease Stage Missing | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Chronic Kidney Disease Stage Stage 3 | 6 Participants | 27 Participants | 11 Participants | 10 Participants |
| Chronic Kidney Disease Stage Stage 4 | 6 Participants | 21 Participants | 7 Participants | 8 Participants |
| Race/Ethnicity, Customized American Indian/Alaska Native | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 0 Participants | 4 Participants | 0 Participants | 4 Participants |
| Race/Ethnicity, Customized Black | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Native Hawaiian or other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Other | 0 Participants | 2 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 10 Participants | 41 Participants | 17 Participants | 14 Participants |
| Sex: Female, Male Female | 3 Participants | 14 Participants | 5 Participants | 6 Participants |
| Sex: Female, Male Male | 9 Participants | 35 Participants | 13 Participants | 13 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 | 2 / 12 | 15 / 18 | 7 / 18 | 12 / 16 | 5 / 13 |
| serious Total, serious adverse events | 0 / 12 | 2 / 18 | 0 / 18 | 1 / 16 | 1 / 13 |
Outcome results
Primary
Part 1: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity (AUC0-∞)
Time frame: Blood samples were collected at hour 0, 1, 2, 4, 6, 8, 12, 24, 36, and 48 hours after dosing.
Population: All participants enrolled and administered paricalcitol for the PK Portion, Part 1
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Paricalcitol | Part 1: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity (AUC0-∞) | 2.87 ng*hr/mL | Standard Deviation 0.84 |
Primary
Part 1: Paricalcitol Maximum Observed Plasma Concentration (Cmax)
Time frame: Blood samples were collected at hour 0, 1, 2, 4, 6, 8, 12, 24, 36, and 48 hours after dosing.
Population: All participants enrolled and administered paricalcitol for the pharmacokinetic (PK) period, Part 1
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Paricalcitol | Part 1: Paricalcitol Maximum Observed Plasma Concentration (Cmax) | 0.13 ng/mL | Standard Deviation 0.052 |
Primary
Part 2: Percentage of Participants Achieving Two Consecutive Reductions at Least 30% From Baseline in iPTH
The primary efficacy endpoint was the percentage of participants who achieved two consecutive ≥ 30% reductions from baseline in intact parathyroid hormone (iPTH) levels during the 12 week double-blind portion of the study regardless of CKD stage.
Time frame: 12-week double-blind treatment period
Population: The Intent-To-Treat (ITT) Dataset, defined as the set of all randomized participants who took at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1: Paricalcitol | Part 2: Percentage of Participants Achieving Two Consecutive Reductions at Least 30% From Baseline in iPTH | 0 percentage of participants |
| Part 2: Paricalcitol | Part 2: Percentage of Participants Achieving Two Consecutive Reductions at Least 30% From Baseline in iPTH | 27.8 percentage of participants |
Comparison: Treatment effects were evaluated based on a two-sided significance level of 0.050. The primary efficacy analysis was a comparison between the paricalcitol capsules and placebo groups in the percentage of participants achieving 2 consecutive ≥ 30% reductions in iPTH from baseline regardless of CKD stage conducted using Fisher's exact test.p-value: 0.04595% CI: [7.5, 52.8]Fisher Exact
Secondary
Part 2: Change From Baseline in First Morning Void (FMV) Urinary Albumin to Creatinine Ratio (UACR)
The mean change from Baseline in FMV UACR on a log scale to each post baseline visit.
Time frame: Baseline and Weeks 4, 8 and 12
Population: Intent-to-treat dataset with available Baseline data, and available data at each time point
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1: Paricalcitol | Part 2: Change From Baseline in First Morning Void (FMV) Urinary Albumin to Creatinine Ratio (UACR) | Week 4 | -0.12 mg/g | Standard Error 0.126 |
| Part 1: Paricalcitol | Part 2: Change From Baseline in First Morning Void (FMV) Urinary Albumin to Creatinine Ratio (UACR) | Week 8 | -0.13 mg/g | Standard Error 0.141 |
| Part 1: Paricalcitol | Part 2: Change From Baseline in First Morning Void (FMV) Urinary Albumin to Creatinine Ratio (UACR) | Week 12 | -0.08 mg/g | Standard Error 0.259 |
| Part 2: Paricalcitol | Part 2: Change From Baseline in First Morning Void (FMV) Urinary Albumin to Creatinine Ratio (UACR) | Week 4 | -0.13 mg/g | Standard Error 0.132 |
| Part 2: Paricalcitol | Part 2: Change From Baseline in First Morning Void (FMV) Urinary Albumin to Creatinine Ratio (UACR) | Week 8 | -0.01 mg/g | Standard Error 0.155 |
| Part 2: Paricalcitol | Part 2: Change From Baseline in First Morning Void (FMV) Urinary Albumin to Creatinine Ratio (UACR) | Week 12 | 0.22 mg/g | Standard Error 0.292 |
Comparison: Overall Comparison (all time points): a mixed effects repeated measures analysis using all the longitudinal observations across the visits including the fixed categorical effects of treatment, visit, and treatment-by-visit interaction, and the continuous covariate of baseline measurementp-value: 0.46995% CI: [-0.25, 0.53]Mixed Models Analysis
Comparison: Week 4 Comparison: a mixed effects repeated measures analysis using all the longitudinal observations across the visits including the fixed categorical effects of treatment, visit, and treatment-by-visit interaction, and the continuous covariate of baseline measurement.p-value: 0.97595% CI: [-0.39, 0.37]Mixed Models Analysis
Comparison: Week 8 Comparison: a mixed effects repeated measures analysis using all the longitudinal observations across the visits including the fixed categorical effects of treatment, visit, and treatment-by-visit interaction, and the continuous covariate of baseline measurementp-value: 0.56795% CI: [-0.32, 0.56]Mixed Models Analysis
Comparison: Week 12 Comparison: a mixed effects repeated measures analysis using all the longitudinal observations across the visits including the fixed categorical effects of treatment, visit, and treatment-by-visit interaction, and the continuous covariate of baseline measurementp-value: 0.46295% CI: [-0.53, 1.12]Mixed Models Analysis
Secondary
Part 2: Change From Baseline in iPTH to Each Post-baseline Visit
Time frame: Baseline and Weeks 2, 4, 8 and 12
Population: Intent to treat dataset with available data at each time point
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1: Paricalcitol | Part 2: Change From Baseline in iPTH to Each Post-baseline Visit | Week 2 | 50.39 pg/mL | Standard Error 15.186 |
| Part 1: Paricalcitol | Part 2: Change From Baseline in iPTH to Each Post-baseline Visit | Week 4 | 57.16 pg/mL | Standard Error 20.813 |
| Part 1: Paricalcitol | Part 2: Change From Baseline in iPTH to Each Post-baseline Visit | Week 8 | 57.31 pg/mL | Standard Error 22.099 |
| Part 1: Paricalcitol | Part 2: Change From Baseline in iPTH to Each Post-baseline Visit | Week 12 | 71.47 pg/mL | Standard Error 17.661 |
| Part 2: Paricalcitol | Part 2: Change From Baseline in iPTH to Each Post-baseline Visit | Week 12 | -17.05 pg/mL | Standard Error 19.186 |
| Part 2: Paricalcitol | Part 2: Change From Baseline in iPTH to Each Post-baseline Visit | Week 2 | -12.16 pg/mL | Standard Error 14.695 |
| Part 2: Paricalcitol | Part 2: Change From Baseline in iPTH to Each Post-baseline Visit | Week 8 | -12.79 pg/mL | Standard Error 24.814 |
| Part 2: Paricalcitol | Part 2: Change From Baseline in iPTH to Each Post-baseline Visit | Week 4 | -11.27 pg/mL | Standard Error 22.117 |
Comparison: Overall Comparison (all time points): A mixed effects repeated measures analysis using all the longitudinal observations across the visits including the fixed categorical effects of treatment, visit, and treatment-by-visit interaction, and the continuous covariate of baseline measurement.p-value: <0.00195% CI: [-108.05, -36.75]Mixed Models Analysis
Comparison: Week 2 Comparison: a mixed effects repeated measures analysis using all the longitudinal observations across the visits including the fixed categorical effects of treatment, visit, and treatment-by-visit interaction, and the continuous covariate of baseline measurement.p-value: 0.00695% CI: [-105.6, -19.49]Mixed Models Analysis
Comparison: Week 4 Comparison: a mixed effects repeated measures analysis using all the longitudinal observations across the visits including the fixed categorical effects of treatment, visit, and treatment-by-visit interaction, and the continuous covariate of baseline measurement.p-value: 0.03295% CI: [-130.39, -6.47]Mixed Models Analysis
Comparison: Week 8 Comparison: A mixed effects repeated measures analysis using all the longitudinal observations across the visits including the fixed categorical effects of treatment, visit, and treatment-by-visit interaction, and the continuous covariate of baseline measurement.p-value: 0.04395% CI: [-137.82, -2.37]Mixed Models Analysis
Comparison: Week 12 Comparison: A mixed effects repeated measures analysis using all the longitudinal observations across the visits including the fixed categorical effects of treatment, visit, and treatment-by-visit interaction, and the continuous covariate of baseline measurement.p-value: 0.00295% CI: [-142.04, -35.01]Mixed Models Analysis
Secondary
Part 2: Percentage of Participants Achieving a Final iPTH Within KDOQI Target Ranges
The Kidney Disease Outcomes Quality Initiatives (KDOQI) Pediatric Subcommittee on Practice Guidelines for Bone Metabolism and Disease in Children with CKD target range for intact parathyroid hormone (iPTH) is as follows:: CKD Stage 3: 35 - 69 pg/mL; CKD Stage 4: 70 - 110 pg/mL.
Time frame: Week 12
Population: Intent to treat dataset
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1: Paricalcitol | Part 2: Percentage of Participants Achieving a Final iPTH Within KDOQI Target Ranges | 11.1 percentage of participants |
| Part 2: Paricalcitol | Part 2: Percentage of Participants Achieving a Final iPTH Within KDOQI Target Ranges | 33.3 percentage of participants |
p-value: 0.128Cochran-Mantel-Haenszel
Secondary
Part 2: Percentage of Participants Achieving Final Calcium Levels Within KDOQI Target Ranges
KDOQI recommends serum calcium is maintained within age appropriate normal ranges: Age 6 - 12: 9.4 - 10.2 mg/dL (2.35 - 2.55 mmol/L); Age 13 - 20: 8.8 - 10.2 mg/dL (2.20 - 2.55 mmol/L).
Time frame: Week 12
Population: Intent to treat dataset
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1: Paricalcitol | Part 2: Percentage of Participants Achieving Final Calcium Levels Within KDOQI Target Ranges | 94.4 percentage of participants |
| Part 2: Paricalcitol | Part 2: Percentage of Participants Achieving Final Calcium Levels Within KDOQI Target Ranges | 83.3 percentage of participants |
p-value: 0.327Cochran-Mantel-Haenszel
Secondary
Part 2: Percentage of Participants Achieving Final Phosphorus Levels Within KDOQI Target Ranges
The KDOQI target ranges of serum phosphorus are to maintain at or above age appropriate lower limits and no higher than the age-appropriate upper limits: Age 6 - 12: 3.6 - 5.8 mg/dL (1.16 - 1.87 mmol/L); Age 13 - 20: 2.3 - 4.5 mg/dL (0.74 - 1.45 mmol/L).
Time frame: Week 12
Population: Intent to treat dataset
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1: Paricalcitol | Part 2: Percentage of Participants Achieving Final Phosphorus Levels Within KDOQI Target Ranges | 72.2 percentage of participants |
| Part 2: Paricalcitol | Part 2: Percentage of Participants Achieving Final Phosphorus Levels Within KDOQI Target Ranges | 50.0 percentage of participants |
p-value: 0.194Cochran-Mantel-Haenszel