A Phase 3 Study of Etelcalcetide in Children With Secondary Hyperparathyroidism Receiving Hemodialysis

Study Overview
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Brief Summary
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Assess the efficacy, safety, pharmacokinetics (PK) and pharmacodynamics (PD) of etelcalcetide in the treatment of secondary hyperparathyroidism (SHPT) in pediatric subjects between ≥ 2 to < 18 years of age, with chronic kidney disease (CKD) on hemodialysis

Official Title
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Phase 3, Single-arm, Open-label, Multidose, Titration, Pharmacokinetic, Pharmacodynamic, and Safety Study of Etelcalcetide in Children and Adolescents ≥ 2 to < 18 Years of Age With Secondary Hyperparathyroidism and Chronic Kidney Disease Receiving Maintenance Hemodialysis

Conditions
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Secondary Hyperparathyroidism

Intervention / Treatment
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* Drug: Etelcalcetide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject's legally acceptable representative has provided informed consent when the subject is legally too young to provide informed consent and the subject has provided written assent based on local regulations and/or guidelines prior to any study-specific activities/procedures being initiated. Male or female subjects greater than or equal to 2 to less than 18 years of age at the time of enrollment. Targeted Dry weight greater than or equal to 7 kg at the time of screening Week -1. Diagnosed with chronic kidney disease (CKD) and secondary hyperparathyroidism (SHPT) undergoing hemodialysis/hemodiafiltration three times per week (TIW) at the time of screening greater than or equal to 1 month. Diagnosis of secondary hyperparathyroidism (SHPT) with the mean of the 2 consecutive central laboratory intact parathyroid hormone (iPTH) values greater than 300 pg/mL during screening, on separate days and within 2 weeks of enrollment obtained from the central laboratory during screening. Serum corrected calcium (cCa) value greater than or equal to 9.0 mg/dL obtained from the central laboratory during screening. Dialysate calcium (Ca) level greater than or equal to 2.5 mEq/L for at least 1 month prior to screening and throughout the duration of the study. Subject receiving active vitamin D sterols must have had no more than a maximum dose change of 50% within the 2 weeks prior to screening laboratory assessments, remain stable through enrollment, and be expected to maintain stable doses for the duration of the study, except for adjustments allowed per protocol. Subject receiving phosphate binders must have had no more than a maximum dose change of 50% within the 2 weeks prior to screening laboratory assessments, remain stable through enrollment, and be expected to maintain stable dose for the duration of the study, except for adjustments allowed per protocol. Subject receiving calcium (Ca) supplements must have had no more than a maximum dose change of 50% within the 2 weeks prior to screening laboratory assessments, remain stable through enrollment, and be expected to maintain stable dose for the duration of the study, except for adjustments allowed per protocol. Secondary hyperparathyroidism (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, history of symptomatic ventricular dysrhythmias Torsades de Pointes 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 enrollment. Other Medical Conditions: Current malignancy or history of other malignancy, except non-melanoma skin cancers within the last 5 years. Prior/Concomitant Therapy: Use of concomitant medications that may prolong the QTc (eg, ondansetron, albuterol, sotalol, amiodarone, erythromycin, or clarithromycin). Refer to CredibleMeds.org for guidance. Receipt of cinacalcet therapy within 30 days prior to screening and through enrollment. Receipt of etelcalcetide therapy within 6 months prior to screening and through enrollment. All herbal medicines (eg, St. John's wort), vitamins, and supplements consumed by the subject within the 30 days prior to enrollment, 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 enrollment 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 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]) greater than 1.5 times the upper limit of normal (ULN). Corrected QT interval greater than 500 ms, using Bazett's formula. Corrected QT interval greater than or equal to 450 to less than or equal 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 (eg, unstable arrhythmia) during screening that, in the opinion of the investigator, could pose a risk to subject safety or interfere with the study evaluation. Within the 3 Months Prior to Screening: New onset or worsening of a pre-existing seizure disorder. Subjects on anti-convulsant medication must be on a stable and therapeutic dose for 3 months prior to screening (if blood level monitoring is clinically available, then the subject must have a therapeutic blood level within 1 week of enrollment). Other Exclusions: 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 effective contraception during treatment and for an additional 3 months after the last dose of investigational product. Refer to Appendix 5 for additional contraceptive information. Female subjects of childbearing potential with a positive pregnancy test assessed at screening by a serum pregnancy test. 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 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) or unacceptable physical findings, 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 previously has entered this study or previously received treatment with etelcalcetide. Anemia, which in the opinion of the investigator makes it not advisable to undergo sequential blood draws. History of unstable chronic heart failure within the last 1 year prior to screening.

Ages Eligible for Study
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Minimum Age: 2 Years
Maximum Age: 17 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
Intervention Model: Single Group Assignment
Interventional Model Description: Subjects will remain on treatment for 26 weeks from day 1 or until the time of renal transplant or parathyroidectomy, whichever occurs first. Subjects will receive a starting dose of etelcalcetide 0.07 mg/kg or 5 mg, whichever is lower, 3 times a week (TIW) intravenously. The dose of etelcalcetide will be titrated every 4 weeks (weeks 5, 9, 13, and 17) based on intact parathyroid hormone (iPTH), calcium, and safety to a maximum dose of 0.21 mg/kg or 15 mg, whichever is lower. The lowest protocol specified dose (PSD) for this study is 0.035 mg/kg or 2.5 mg, whichever is lower.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Etelcalcetide<br>Patients will receive etelcalcetide in addition to standard of care | Drug: Etelcalcetide<br>* Etelcalcetide has been shown to be safe and efficacious in treating adult chronic kidney disease (CKD) patients with secondary hyperparathyroidism (SHPT) by simultaneously controlling intact parathyroid hormone (iPTH), calcium (Ca), and phosphorus and has recently been approved for use in adult patients with secondary hyperparathyroidism (SHPT) treated with hemodialysis in both the United States and Europe<br>* Other names: Parsabiv - brand name;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent change in intact parathyroid hormone (iPTH) from baseline during the efficacy assessment period (EAP) at weeks 20 to 26 | To evaluate the efficacy of etelcalcetide in reducing the intact parathyroid hormone (iPTH) level in children ages equal to or greater than 2 to less than 18 years with secondary hyperparathyroidism (SHPT) receiving maintenance hemodialysis | 20 to 26 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Achievement of a greater than 30% reduction from baseline in mean intact parathyroid hormone (iPTH) during the efficacy assessment period (EAP) | To evaluate the efficacy of etelcalcetide | 20 to 26 weeks | 
| Percent change from baseline in corrected total serum calcium (Ca) and serum phosphorus from baseline during the EAP | To characterize change in laboratory markers of chronic kidney disease | 20 to 26 weeks | 
| Proportion of subjects achieving corrected serum calcium (Ca) levels less than 8.0 mg/dL (2.0 mmol/L) at any time during the study | To characterize the safety of etelcalcetide treatment based on laboratory values | During the treatment period | 
| Proportion of subjects with hypocalcemia (corrected serum calcium levels less than 8.4 mg/dL) | To characterize the safety of etelcalcetide treatment based on laboratory values | During the treatment period | 
| Etelcalcetide plasma concentrations before and at the end of dialysis after single and multiple doses | Etelcalcetide plasma concentrations before and at the end of dialysis after single and multiple doses | During the treatment period | 
| Etelcalcetide PK parameter of maximum-observed concentration (Cmax) | Etelcalcetide plasma concentrations before and at the end of dialysis after single and multiple doses | During the treatment period | 
| Etelcalcetide pharmacokinetic (PK) parameter of plasma trough concentrations (Cmin) | To characterize the pharmacokinetic (PK) of etelcalcetide treatment after single and multiple doses | During the treatment period | 
| Subject incidence of all treatment-emergent 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 | During the treatment period | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Secondary hyperparathyroidism (sHPT), Chronic kidney disease (CKD), Paediatric