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Hyperparathyroidism, Secondary

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Renal Insufficiency

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Female Urogenital Diseases and Pregnancy Complications

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Bone Density Conservation Agents

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Cinacalcet

Vitamin D

Cholecalciferol

Calcium

Calcium, Dietary

Hormones

Hormone Antagonists

Vitamin D3

Calciferol

Phytosterol

Standard of care therapy included the use of vitamin D sterols, calcium supplementation, and phosphate binders.

In addition to standard of care participants received cinacalcet at a starting dose (based on dry body weight) of 0.20 mg/kg administered once a day by mouth. Dose adjustments and withholding were based on ionized calcium levels, plasma iPTH, and corrected calcium levels.

Capsules were opened and either sprinkled onto soft food (≥ 5 mg dose) or suspended into a sucrose syrup (≥ 2.5 mg dose) to create a liquid suspension for administration. Tablets were used for doses of 30 mg and higher in participants who could swallow tablets.

Cinacalcet HCl

Standard of Care

The primary objective was to evaluate the efficacy of cinacalcet for reducing the plasma intact parathyroid hormone (iPTH) level by ≥ 30%.

This was a 24-week, randomized, multicenter, open-label, controlled study. Participants were randomized into one of two treatment arms; oral administration of cinacalcet daily in addition to standard of care treatment, or standard of care alone. Randomization was stratified by age group (6 to \< 12 and 12 to \< 18 years of age). All participants received standard of care which could include therapy with Vitamin D sterols, calcium supplementation, and phosphate binders.

Participants in both treatment groups who completed the 20-week treatment period and those who ended the study due to study closure were eligible to enroll in an open-label extension study (20140159; NCT02341417) for further safety follow-up.

Efficacy and Safety of Cinacalcet in Pediatric Patients With Secondary Hyperparathyroidism (SHPT) and Chronic Kidney Disease (CKD) on Dialysis

A Randomized, Open-label, Controlled Study to Assess the Efficacy and Safety of Cinacalcet HCl in Pediatric Subjects With Secondary Hyperparathyroidism and Chronic Kidney Disease Receiving Dialysis

Intact parathyroid hormone (iPTH) levels were measured at weeks 11 and 15; the mean value from these 2 measurements was calculated.

This endpoint was the primary endpoint in the US only.

Intact parathyroid hormone (iPTH) levels were measured at weeks 17, 18, 19 and 20; the mean value from these measurements was calculated.

This endpoint was specified as the the primary endpoint in all countries except the United States (US). In the US this endpoint was specified as a secondary efficacy endpoint.

Amgen

Two participants who were randomized to the cinacalcet group but did not receive cinacalcet were included in the Standard of Care group for safety analysis.

Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.

Total

Age, Continuous

6 to < 12 years

12 to < 18 years

Age, Customized

Sex: Female, Male

Black (or African American)

White

Mixed Race

Other

Race/Ethnicity, Customized

Hispanic/Latino

Not Hispanic/Latino

Intact Parathyroid Hormone Level

Study Director

The analysis was conducted using the full analysis set; participants who had no week 11 or 15 iPTH values were considered non-responders (non-responder imputation).

Percentage of Participants Who Achieved a ≥ 30% Reduction From Baseline In Mean Plasma iPTH During Weeks 11 to 15

A hierarchical testing procedure was used to test the primary and biochemical secondary endpoints. The primary endpoint was tested at a 2-sided significance level of 0.05. The secondary endpoints were tested using Holm's method at 0.05 (2-sided) should the primary endpoint achieve a significant result.

The full analysis set (all randomized participants) was used for this analysis. For participants with no iPTH values in the EAP, the mean of the last 2 available postbaseline values was used. If only 1 postbaseline value was available, this value was used. If no postbaseline value was available, the participant was considered a non-responder.

Percentage of Participants Who Achieved a ≥ 30% Reduction From Baseline in Mean Plasma Intact Parathyroid Hormone During the Efficacy Assessment Period

This analysis was conducted using the full analysis set. For participants with no iPTH values in the EAP, the mean of the last 2 available postbaseline values was used. If only 1 postbaseline value was available, this value was used. If no postbaseline value was available, the participant was considered a non-responder.

Percentage of Participants Who Achieved a Mean iPTH ≤ 300 pg/mL (31.8 Pmol/L) During Weeks 17 to 20

This analysis was conducted using the full analysis set using last value carried forward imputation. Participants with no post-baseline values available were excluded from the analysis.

Percent Change in iPTH From Baseline to the Mean Value During Weeks 17 to 20

Change in Corrected Serum Calcium From Baseline to the Mean Value During Weeks 17 to 20

Change in Serum Phosphorus From Baseline to the Mean Value During Weeks 17 to 20

Overall Study

Participants received a single, intravenous (IV) bolus administration of 0.035 mg/kg etelcalcetide at the end of hemodialysis on study day 1.

A single IV-bolus dose of 0.035 mg/kg etelcalcetide into the venous line of the dialysis circuit at the end of a hemodialysis session.

Etelcalcetide

This is a study to evaluate the safety and pharmacokinetics in pediatric patients with secondary hyperparathyroidism receiving a single dose of etelcalcetide at the end of hemodialysis.

A Single-dose Study in Paediatric Patients Aged 2 to Less Than 18 Years With Secondary Hyperparathyroidism (sHPT) Receiving Haemodialysis

An Open-label, Single-dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Etelcalcetide (AMG 416) in Paediatric Subjects Aged 2 to Less Than 18 Years With Secondary Hyperparathyroidism (sHPT) Receiving Maintenance Haemodialysis

De-identified individual patient data for variables necessary to address the specific research question in an approved data sharing request.

A treatment-emergent adverse event is any adverse event (AE) that begins or worsens after the initial dose of study drug (etelcalcetide) and up to 30 days after the last dose.

Common adverse events were defined as adverse events occurring in at least 2 participants.

The Medical Dictionary for Regulatory Activities (MedDRA) version 21.0 was used for coding all adverse events.

When albumin was less than 4.0 mg/dL, the calcium concentration was corrected according to the formula: cCa (mmol/L) = measured total serum calcium (mmol/L) + 0.02 (40 - serum albumin \[g/L\]).

Plasma etelcalcetide concentrations were measured using a validated high performance liquid chromatography assay. The lower limit of quantitation was 0.200 ng/mL.

Plasma etelcalcetide concentrations were measured using a validated high performance liquid chromatography assay. The lower limit of quantitation was 0.200 ng/mL.

Area under the curve for plasma etelcalcetide from time zero to the last quantifiable concentration (AUClast) was estimated using the linear trapezoidal method.

Plasma etelcalcetide concentrations were measured using a validated high performance liquid chromatography assay. The lower limit of quantitation was 0.200 ng/mL.

Area under the concentration-time curve from time zero to infinite time (AUCinf) was estimated using the linear trapezoidal method.

Plasma etelcalcetide concentrations were measured using a validated high performance liquid chromatography assay. The lower limit of quantitation was 0.200 ng/mL.

Terminal half life of plasma etelcalcetide (t1/2,z) was calculated as t1/2,z = ln(2)/λz, where λz is the first-order terminal rate constant estimated by linear regression of the terminal log-linear phase.

Samples were collected predose and at end of study (day 30) and tested for anti etelcalcetide binding antibodies using a validated immunoassay.

Developing antibody binding was defined as participants who were binding antibody positive postbaseline with a negative result at baseline.

A treatment-emergent adverse event is any adverse event that begins or worsens after the initial dose of study drug (etelcalcetide) and up to 30 days after the last dose. The severity of each adverse event was graded using the National Cancer Institute-Common Terminology Criteria for Adverse Events (CTCAE) version 4.0, where Grade 1 = Mild (asymptomatic or mild symptoms), Grade 2 = Moderate (minimal, local or noninvasive intervention indicated), Grade 3 = Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated, Grade 4 = Life-threatening consequences; urgent intervention indicated, and Grade 5 = Death related to AE.

Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.

Participants received a single, intravenous bolus administration of 0.035 mg/kg etelcalcetide at the end of hemodialysis on study day 1.

Ethnicity (NIH/OMB)

Serum Corrected Calcium Concentration

Serum Phosphorus Concentration

Serum Potassium Concentration

Serum Intact Parathyroid Hormone Concentration

Serum Calcium Concentration

Serum Ionized Calcium Concentration

Heart Rate

Temperature

Systolic blood pressure

Diastolic blood pressure

Blood Pressure

The PR interval is measured using electrocardiography (ECG) and is the period from the beginning of the P wave (the onset of atrial depolarization) until the beginning of the QRS complex (the onset of ventricular depolarization); it is normally between 120 and 200 milliseconds (ms) in duration.

PR Interval

The QRS interval measured during ECG, denotes depolarization of the ventricles, between the beginning of the Q wave and the end of the S wave.

QRS Interval

The QT interval measured during ECG is a measure of the time between the start of the Q wave and the end of the T wave in the heart's electrical cycle. The QT interval represents electrical depolarization and repolarization of the ventricles.

QT Interval

Corrected (Bazett) QT Interval (QTcB)

Corrected (Fridericia) QT Interval (QTcF)

Headache

Calcium ionised decreased

Hypotension

Participants who received at least 1 dose of etelcalcetide (safety analysis set)

Common Treatment-emergent Adverse Events

Day 1, 4 hours

Day 3

Day 8

Day 10

Day 30

Treated participants with available data at each time point.

Change From Baseline in Serum Corrected Calcium Concentration Over Time

Change From Baseline in Serum Phosphorus Concentration at End of Study

Change From Baseline in Serum Potassium Concentration at End of Study

Change From Baseline in Intact Parathyroid Hormone (iPTH) Levels Over Time

Change From Baseline in Heart Rate at End of Study

Change From Baseline in Temperature at End of Study

Change From Baseline in Blood Pressure at End of Study

Change From Baseline in PR Interval at End of Study

Change From Baseline in QRS Interval at End of Study

Change From Baseline in QT Interval at End of Study

Change From Baseline in Corrected (Bazett) QT Interval at End of Study

Change From Baseline in Corrected (Fridericia) QT Interval at End of Study

Change From Baseline in Serum Total Calcium Concentration

Change From Baseline in Serum Ionized Calcium Concentration

Maximum Observed Plasma Concentration (Cmax) of Etelcalcetide

The pharmacokinetic concentration analysis set was composed of all participants who received etelcalcetide and had at least 1 pharmacokinetic sample collected.

Time to Maximum Concentration (Tmax) of Etelcalcetide

Area Under the Plasma Etelcalcetide Concentration-Time Curve From Time Zero to Time of Last Quantifiable Concentration (AUClast)

Pharmacokinetic analysis set with available AUCinf data

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Efficacy and Safety of Cinacalcet in Pediatric Patients With Secondary Hyperparathyroidism (SHPT) and Chronic Kidney Disease (CKD) on Dialysis	NCT02138838	Chronic Kidney ...	Cinacalcet HCl Standard of Car...	6 Years - 17 Years	Amgen
A Single-dose Study in Paediatric Patients Aged 2 to Less Than 18 Years With Secondary Hyperparathyroidism (sHPT) Receiving Haemodialysis	NCT02833857	Chronic Kidney ...	Etelcalcetide	2 Years - 17 Years	Amgen
Efficacy and Safety of Cinacalcet in Pediatric Patients With Secondary Hyperparathyroidism (SHPT) and Chronic Kidney Disease (CKD) on Dialysis	NCT02138838	Chronic Kidney ...	Cinacalcet HCl Standard of Car...	6 Years - 17 Years	Amgen

Spots Global Cancer Trial Database for chronic kidney disease, secondary hyperparathyroidism