Safety and Efficacy of Paricalcitol Capsules in Decreasing Serum Parathyroid Hormone Levels in Children Aged 10-16 With Chronic Kidney Disease (CKD)

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Phase 3, Prospective, Randomized, Double-blind, Placebo-controlled Multicenter Study to Evaluate the Pharmacokinetics, Safety and Efficacy of Paricalcitol Capsules in Decreasing Serum Intact Parathyroid Hormone Levels in Pediatric Subjects Ages 10 to 16 Years With Moderate to Severe Chronic Kidney Disease

Conditions
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Chronic Kidney Disease Stage 3 and 4

Intervention / Treatment
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* Drug: Paricalcitol
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 10 Years
Maximum Age: 16 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1: Paricalcitol<br>Participants received a single 3 µg dose of paricalcitol capsules on Study Day 1. | Drug: Paricalcitol<br>* Paricalcitol capsules taken with water.<br>* Other names: Zemplar;|
| Placebo Comparator: Part 2: Placebo<br>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. | Drug: Paricalcitol<br>* Paricalcitol capsules taken with water.<br>* Other names: Zemplar;Drug: Placebo<br>* Placebo capsules taken with water<br>|
| Experimental: Part 2: Paricalcitol<br>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. | Drug: Paricalcitol<br>* Paricalcitol capsules taken with water.<br>* Other names: Zemplar;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 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. | 12-week double-blind treatment period | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Week 12 | 
| 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 | 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). | Week 12 | 
| 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). | Week 12 | 
| 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. | Baseline and Weeks 4, 8 and 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Reduction of parathyroid hormone levels in pediatric patients with Chronic Kidney Disease Stage 3 and 4