A Study of Etelcalcetide in Pediatric Subjects With Secondary Hyperparathyroidism and Chronic Kidney Disease on Hemodialysis

Study Overview
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Brief Summary
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This is a Phase 3 Study of Etelcalcetide in Pediatric Subjects With Secondary Hyperparathyroidism and Chronic Kidney Disease on Hemodialysis

Detailed Description
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SHPT is a common and serious co-morbidity that develops relatively early in the course of CKD, worsens with declining kidney function, and is associated with serious complications in children on dialysis. Children on dialysis experience a wide spectrum of bone abnormalities and growth retardation, in addition to increased risk for cardiovascular morbidity and mortality that manifests early in their adulthood. Traditional therapies for SHPT (eg, vitamin D sterols) are widely used in the pediatric dialysis population, and have the potential to aggravate complications of the disease by increasing serum calcium (Ca), serum phosphorus, and serum Ca times serum phosphorus product. Etelcalcetide has been shown to be safe and efficacious in treating adult CKD patients with SHPT by simultaneously controlling intact parathyroid hormone (iPTH), Ca, and phosphorus and has recently been approved for use in adult patients with SHPT treated with hemodialysis in both the United States and Europe. Although no previous studies have been conducted in pediatric patients with etelcalcetide (one single dose pharmacokinetic [PK] study is currently ongoing),Amgen anticipates minimal to moderate risk with a possibility of direct benefit to the pediatric subjects (age 28 days to 18 years) in this study. The burden of complications of SHPT in the pediatric dialysis population and the limitations of current standard therapy, underscore the need for studies of etelcalcetide in these patients to address this unmet medical need and inform the pediatric nephrology community of the potential use of etelcalcetide in children on hemodialysis with critical safety and efficacy data.

Official Title
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Phase 3, Randomized, Open-label, Controlled, Multiple Dose, Efficacy, Safety, Pharmacokinetic, and Pharmacodynamic Study of Etelcalcetide in Pediatric Subjects 28 Days to < 18 Years of Age With Secondary Hyperparathyroidism and Chronic Kidney Disease Receiving Maintenance Hemodialysis

Conditions
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Secondary Hyperparathyroidism, Chronic Kidney Disease

Intervention / Treatment
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* Drug: Etelcalcetide


Participation Criteria
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Eligibility Criteria
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Inclusion criteria Age of 28 days or older and less than 18 years Dry weight ≥ 7 kg during screening. Diagnosed with CKD and SHPT undergoing hemodialysis at the time of screening. Diagnosis of SHPT with the mean of the 2 consecutive central laboratory iPTH values ≥ 400 pg/mL (42 pmol/L) during screening, on separate days and within 2 weeks of enrolment. Serum cCa value ≥ 9.0 mg/dL (2.25 mmol/L) for subjects ≥ 2 years of age and older and serum cCa value ≥ 9.6 mg/dL (2.4 mmol/L) for subjects 28 days to < 2 years of age obtained from the central laboratory during screening. Dialysate Ca level ≥ 2.5 mEq/L during screening for at least 4 weeks prior to screening and throughout the duration of the study. No more than a maximum prescribed dose change of 50% for active vitamin D sterols/phosphate binders/Ca supplements within the 2 weeks prior to screening assessments and remain stable. SHPT not due to vitamin D deficiency, per investigator assessment. Exclusion Criteria Disease Related History of congenital long QT syndrome, second or third degree heart block, ventricular tachyarrhythmia's or other conditions associated with prolonged QT interval. Anticipated or scheduled parathyroidectomy during the study period. Anticipated or scheduled kidney transplant during the study period. Subject has received a parathyroidectomy within 6 months prior to randomization. Other Medical Conditions History of other malignancy, except non-melanoma skin cancers, cervical or breast ductal carcinoma in situ within the last 5 years. Prior/Concomitant Therapy Use of concomitant medications that may prolong the corrected QT interval (eg, ondansetron, albuterol, sotalol, amiodarone, erythromycin, or clarithromycin). Refer to CredibleMeds.org for guidance. Receipt of cinacalcet therapy within 30 days prior to screening assessments and through randomization. Receipt of etelcalcetide within 6 months prior to screening assessments and through randomization. All herbal medicines (eg, St. John's wort), vitamins, and supplements consumed by the subject within the 30 days prior to randomization, and continuing use if applicable, will be reviewed by the Principal Investigator and the Amgen Medical Monitor. Written documentation of the review and Amgen acknowledgment is required for subject participation. Use of any over-the-counter or prescription medications within the 14 days or 5 half-lives (whichever is longer) prior to randomization that are not established therapies for subjects with renal disease or other conditions secondary to renal disease will be reviewed by the Principal Investigator and the Amgen Medical Monitor. Written documentation of the review and Amgen acknowledgment is required for subject participation. Paracetamol for analgesia will be allowed. Prior/Concurrent Clinical Study Experience • Currently receiving treatment in another investigational device or drug study, or less than 30 days or 5 half-lives (whichever is longer) since ending treatment on another investigational device or drug study(ies). Other investigational procedures while participating in this study are excluded. Diagnostic Assessments During Screening Subject has significant abnormalities on the most recent central laboratory test during the screening period prior to enrollment per the Investigator including but not limited to the following: a. Serum transaminase (alanine aminotransferase [ALT] or serum glutamic pyruvic transaminase [SGPT], aspartate aminotransferase [AST] or serum glutamic oxaloacetic transaminase [SGOT]) > 2.0 times the upper limit of normal (ULN). Corrected QT interval (QTc) > 500 ms, using Bazett's formula. QTc ≥ 450 to ≤ 500 ms, using Bazett's formula, unless written permission to enroll is provided by the investigator after consultation with a pediatric cardiologist. Subject has a clinically significant electrocardiogram (ECG) abnormality during screening that, in the opinion of the investigator, could pose a risk to subject safety or interfere with the study evaluation. Within the 60 days prior to enrollment • New onset or worsening of a pre-existing seizure disorder. Other Exclusions Subjects aged 28 days to 6 months of age who were born prematurely at < 36 weeks gestational age. Female subject is pregnant or breastfeeding or planning to become pregnant or breastfeed during treatment and for an additional 3 months after the last dose of etelcalcetide. (Females of childbearing potential should only be included in the study after a confirmed menstrual period and a negative highly sensitive serum pregnancy test within 7 days prior to the first dose of investigational product). Female subjects of childbearing potential unwilling to use 1 highly-effective or acceptable method of contraception during treatment and for an additional 3 months after the last dose of investigational product. Subject has known sensitivity to etelcalcetide or excipients to be administered during dosing. Subject likely to not be available to complete all protocol-required study visits or procedures, and/or to comply with all required study procedures (eg, to the best of the subject and investigator's knowledge). History or evidence of any other clinically significant disorder, condition, or disease (with the exception of those outlined above) that, in the opinion of the investigator or Amgen physician, if consulted, would pose a risk to subject safety or interfere with the study evaluation, procedures, or completion. Subject has previously entered this study

Ages Eligible for Study
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Minimum Age: 0 Years
Maximum Age: 18 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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Etelcalcetide<br>Randomized in a 3:1 ratio to receive etelcalcetide in addition to standard of care | Drug: Etelcalcetide<br>* Etelcalcetide has been shown to be safe and efficacious in treating adult CKD patients with SHPT by simultaneously controlling intact parathyroid hormone (iPTH), Ca, and phosphorus and has recently been approved for use in adult patients with SHPT treated with hemodialysis in both the United States and Europe<br>* Other names: Parsabiv;|
| Active Comparator: Control<br>Randomized in a 3:1 ratio to receive etelcalcetide in addition standard of care alone (control arm) | Drug: Etelcalcetide<br>* Etelcalcetide has been shown to be safe and efficacious in treating adult CKD patients with SHPT by simultaneously controlling intact parathyroid hormone (iPTH), Ca, and phosphorus and has recently been approved for use in adult patients with SHPT treated with hemodialysis in both the United States and Europe<br>* Other names: Parsabiv;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of participants with ≥ 30% reduction from baseline in intact parathyroid hormone (iPTH) level during the efficacy assessment phase (EAP) | Achievement of at least a 30% reduction from baseline in mean iPTH during the EAP (defined as weeks 20 through 27). | Baseline and Weeks 20-27 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum serum concentration (Cmax) of etelcalcetide | Cmax will be collected and reported for the etelcalcetide arm only. | 10-30 minutes post dose on Day 1 and 10-30 minutes post dose on Weeks 5, 9, 13, 17, and 21 | 
| Minimum serum concentration (Cmin) of etelcalcetide | Cmin will be collected and reported for the etelcalcetide arm only. | 10-30 minutes post dose on Day 1 and 10-30 minutes post dose on Weeks 5, 9, 13, 17, and 21 | 
| Incidence of adverse events | To characterize the safety of etelcalcetide treatment based on adverse events. Nature, frequency, severity, and relationship to treatment of all adverse events, including those of special interest reported during the study. | Day 1 to 30 days after last dose of etelcalcetide (up to approximately 30 weeks) | 
| Frequency of hypocalcemia | Occurrence of hypocalcemia at any point in time, assessed by serum chemistry. | Up to approximately 30 Weeks | 
| Number of participants with corrected serum calcium levels at any time during the study | Occurrence of corrected serum Ca levels <8.0 mg/dL (2.0 mmol/L) for subjects 2 to < 18 years of age and <8.6 mg/dL (2.15 mmol/L) for subjects 28 days to <2 years of age during the study. | Up to approximately 30 Weeks | 
| Number of participants with serum phosphorous levels below normal for age | Occurrence of serum phosphorous levels below the lower limit of normal for age. | Up to approximately 30 Weeks | 
| Number of participants with predialysis iPTH levels below normal | Occurrence of predialysis iPTH levels below the lower limit of normal for age. | Up to approximately 30 Weeks | 
| Change from baseline in systolic blood pressure | To characterize the safety of etelcalcetide treatment based on vital signs. | Week -2, Week -1, Day1, and Weeks 4, 8, 12, 16, 20, 24, and 27 | 
| Change from baseline in diastolic blood pressure | To characterize the safety of etelcalcetide treatment based on vital signs. | Week -2, Week -1, Day1, and Weeks 4, 8, 12, 16, 20, 24, and 27 | 
| Change from baseline in heart rate | To characterize the safety of etelcalcetide treatment based on vital signs. | Week -2, Week -1, Day1, and Weeks 4, 8, 12, 16, 20, 24, and 27 | 
| Change in Tanner Stage | Changes in tanner stage at scheduled visits. | Week -2 and Week 27 | 
| Change in height | Changes in height at scheduled visits. | Day 1 and Week 27 | 
| Change in weight | Changes in weight at scheduled visits. | Week -2, Day 1, and Week 27 | 
| Achievement of ≥ 30% reduction in iPTH from baseline on two consecutive visits | To characterize change in laboratory markers of CKD following etelcalcetide treatment. | Up to approximately 30 Weeks | 
| Mean change from baseline in predialysis iPTH | Mean change from baseline in predialysis iPTH during the EAP (defined as weeks 20 through 27). | Baseline and Weeks 20-27 | 
| Percentage change from baseline in predialysis iPTH | Percentage change from baseline in predialysis iPTH during the EAP (defined as weeks 20 through 27). | Baseline and Weeks 20-27 | 
| Percentage change from baseline in corrected total serum calcium | Percentage change from baseline in corrected total serum calcium during the EAP (defined as weeks 20 through 27). | Baseline and Weeks 20-27 | 
| Percentage change from baseline in corrected total serum phosphorous | Percentage change from baseline in corrected total serum phosphorous during the EAP (defined as weeks 20 through 27). | Baseline and Weeks 20-27 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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sHPT, CKD, pediatric, Secondary Hyperparathyroidism, Chronic Kidney disease