A Phase 1 Study to Evaluate PK, Safety and Tolerability of AMG 416

Study Overview
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Brief Summary
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This was a multiple-dose, double-blind, randomized, placebo-controlled study. Chinese subjects residing in Mainland China with chronic kidney disease (CKD) receiving hemodialysis were randomized in a 3:1 ratio to receive 5 mg intravenous (IV) of etelcalcetide or placebo 3 times a week (TIW) for approximately 4 weeks, with a subsequent follow up period of approximately 4 weeks. Doses were given at the end of each scheduled hemodialysis session on study days 1 through day 27 and subject participation was complete after day 55 end-of-study (EOS) procedures were performed. Doses were administered TIW for 4 weeks, for a total of 12 doses.

Official Title
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A Phase 1, Multiple Dose, Randomized, Double-blind, Placebo-controlled Study to Evaluate Pharmacokinetics, Safety and Tolerability of AMG 416 Administered Intravenously to Chinese Subjects With Chronic Kidney Disease on Hemodialysis

Conditions
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Secondary Hyperparathyroidism

Intervention / Treatment
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* Drug: Etelcalcetide
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject has provided informed consent prior to initiation of any study-specific activities/procedures Resident in Mainland China and of Chinese ancestry Male or female subject ≥ 18 and ≤ 70 years of age at the time of screening, with end stage renal disease receiving hemodialysis Subject must be receiving hemodialysis 3 times weekly for at least 3 months through a functioning permanent dialysis access prior to Day -2 and have adequate hemodialysis with a delivered Kt/V ≥ 1.2 or urea reduction ratio (URR) ≥ 65% within 4 weeks to screening. The subject's routine hemodialysis session must be of 3-4.5 hours in duration, inclusive Subject has stable dialysis prescription and this prescription is not anticipated to significantly change during the course of the study Exclusion Criteria: Corrected calcium (calculated) level is < 2.07 mmol/L (8.3 mg/dL), and/or intact PTH level is outside the range of 31.8 - 127.3 pmol/L (300 - 1200 pg/mL) Female subjects who are pregnant, lactating/breastfeeding, or who plan to conceive, or breastfeed while on study through 3 months after receiving the dose of study drug Female subject of reproductive potential not willing to use a(n) acceptable method(s) of effective birth control during treatment with AMG 416, and for an additional 3 months after the end of treatment with AMG 416. Female subjects who have had a hysterectomy, bilateral salpingectomy, bilateral oophorectomy, bilateral tubal ligation, or who are postmenopausal are not required to use contraception. Postmenopausal is defined as: Age > 55 years with cessation of menses for 12 months or more Age < 55 but no spontaneous menses for at least 2 years Age < 55 years and spontaneous menses within the past 1 years, but currently amenorrheic, AND with postmenopausal gonadrotropin levels (luteinizing hormone and follicle-stimulating hormone levels > 40 IU/L) or postmenopausal estradiol levels (<5.3 pmol/L or 5 ng/dL) or according to the definition of postmenopausal range for the laboratory involved Underwent a bilateral oophorectomy Females of reproductive potential with a positive pregnancy test, unless medical follow-up confirms the subject is not pregnant Previous administration of AMG 416 Subject has received cinacalcet within the 30 days prior to informed consent (treatment with cinacalcet is prohibited during the study) Subject has lost 500 mL or more of blood or plasma within 8 weeks of study drug administration or during the study period Anticipated or scheduled to have major surgical procedures during the study period such as kidney transplant or parathyroidectomy History of malignancy within 5 years before Day -2 (except non melanoma skin cancers, or cervical carcinoma in situ) Subject's 12-lead electrocardiogram (ECG) at screening suggests unstable arrhythmia or other cardiac abnormality that could place the subject at increased risk, based upon the Investigator's opinion Subject has current or history of cardiovascular conditions such as uncontrolled hypertension, symptomatic ventricular dysrhythmias, Torsades de Pointes, angina pectoris congestive heart failure (New York Heart Association Classification III or IV), myocardial infarction, coronary angioplasty, or coronary arterial bypass grafting within the past 6 months prior to screening

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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
Interventional Model Description: This is a multiple dose, double-blind, randomized, placebo-controlled clinical study conducted in Chinese subjects residing in Mainland China with chronic kidney disease receiving hemodialysis. The treatment duration will be approximately 4 weeks with a post treatment followup of 4 weeks. A dose will be given at each scheduled hemodialysis session (Dose administered three times a week for 4 weeks, for a total of 12 doses).
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Intravenous (IV) administration of placebo three times a week (TIW) for 4 weeks for a total of 12 doses. Participants were followed for an additional 4 weeks. | Drug: Placebo<br>* Placebo supplied to match active intervention.<br>|
| Experimental: Etelcalcetide<br>5 mg intravenous (IV) dose of etelcalcetide three times a week (TIW) for 4 weeks for a total of 12 doses. Participants were followed for an additional 4 weeks. | Drug: Etelcalcetide<br>* Etelcalcetide was supplied as a sterile, preservative-free, aqueous solution in a single-use 3 mL glass vial.<br>* Other names: AMG 416;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetic (PK) Parameter: Time to Maximum Drug Concentration (Tmax) of Plasma Etelcalcetide on Days 1 and 27 | Tmax is the time to maximum drug concentration of plasma etelcalcetide after dosing on Days 1 and 27. | Days 1 and 27; PK blood sampling predialysis, and at 10, 30, 60, 90 min postdose, as well as on Day 2 and 28 between 18 and 30 hours after study drug administration | 
| PK: Maximum Observed Drug Concentration (Cmax) of Plasma Etelcalcetide on Days 1 and 27 | Cmax was defined as the maximum observed plasma drug concentration measured between the time of drug administration to the beginning of the next dialysis session. | Days 1 and 27; PK blood sampling predialysis, and at 10, 30, 60, 90 min postdose, as well as on Day 2 and 28 between 18 and 30 hours after study drug administration | 
| Pharmacokinetic (PK) Parameter: Area Under the Curve From Time Zero to the Beginning of the Subsequent Hemodialysis Treatment (AUClast) of Plasma Etelcalcetide on Days 1 and 27 | AUClast was specifically defined in this study as the area under the concentration time curve measured from the time of drug administration to the beginning of the next dialysis session, following the first and last dose. | Days 1 and 27; PK blood sampling predialysis, and up to 44-50 hour postdose.at 10, 30, 60, 90 min postdose: Day 2 and 28 between 18 and 30 hours after study drug administration; Day 3 (predialysis) + Day 29 | 
| Pharmacokinetic (PK) Parameter: Accumulation Ratio Comparing Days 1 and 27 | Accumulation ratio, calculated as AUClast day 27/AUClast day 1. | Days 1 and 27; PK blood sampling predialysis, and up to 44-50 hour postdose.at 10, 30, 60, 90 min postdose: Day 2 and 28 between 18 and 30 hours after study drug administration; Day 3 (predialysis) + Day 29 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Participants With Treatment-Emergent Adverse Events (TEAEs) | The severity of each adverse event was assessed using the NCI-CTCAE Version 4.0 according to the following: Grade 1 - Mild: Asymptomatic or mild symptoms; intervention not indicated Grade 2 - Moderate: Minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental activities of daily living (ADL) Grade 3 - Severe: Medically significant but not life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care ADL Grade 4 - Life-threatening Grade 5 - Fatal. A serious AE is an AE that met one or more of the following criteria: Death Life-threatening Required inpatient hospitalization or prolongation of an existing hospitalization Resulted in persistent or significant disability/incapacity A congenital anomaly/birth defect Important medical events that required medical or surgical intervention to prevent one of the outcomes above. | Day 1 up to Day 55 (end of study) | 
| Participants With Treatment-Emergent Adverse Events (TEAEs) of Interest | Terms were coded with Medical Dictionary for Regulatory Activities (MedDRA) version 21.1. Narrow search criteria used for both standardized MedDRA queries (SMQ) and events of interest (EOI). One preferred term (PT) could match multiple EOIs. Infusion Reaction EOI counts included only those events which had onset day coinciding with study medication infusion and resolved on the same day or the day after onset. | Day 1 up to Day 55 (end of study) | 
| Participants With Clinically-Significant Changes in Electrocardiograms (ECGs) From Baseline to End of Study | Count of participants who exhibited a clinically significant change in the results of their 12-lead electrocardiograms (ECG) when comparing baseline to end of study ECGs. | Baseline is Day -2; End of Study is Day 55 | 
| Change From Baseline to End of Study in Weight | Change from baseline in weight measured at visit. | Day 1 up to Day 55 | 
| Change From Baseline to End of Study in Systolic and Diastolic Blood Pressures | Participants remained seated for at least 10 minutes prior to measurement of predialysis heart rate and blood pressure. | Baseline Day 1 prior to dialysis; End of Study is Day 55 | 
| Baseline and Change From Baseline to End of Study in Heart Rate | Participants remained seated for at least 10 minutes prior to measurement of predialysis heart rate and blood pressure. | Baseline Day 1 prior to dialysis; End of Study is Day 55 | 
| Change From Baseline to End of Study in Calcium | Calcium was tested at a central laboratory. | Baseline is Day 1 prior to dialysis; End of Study is Day 55 | 
| Change From Baseline to End of Study in Corrected Calcium (cCa) | Total serum calcium was corrected if the serum albumin was < 4 g/dL or 40 g/L, otherwise cCa equals total serum calcium. The correction formula was: Corrected calcium (mg/dL) = Total calcium (mg/dL) + (4 - albumin [g/dL]) * 0.8 | Baseline is the average of Day -2 and Day 1 prior to dialysis; End of Study is Day 55 | 
| Participants With Low Corrected Calcium (cCA) By Category | The lowest cCA value for each participant is reported. Total serum calcium was corrected if the serum albumin was < 4 g/dL or 40 g/L, otherwise cCa equals total serum calcium. The correction formula was: Corrected calcium (mg/dL) = Total calcium (mg/dL) + (4 - albumin [g/dL]) * 0.8 | Timeframes: Days 8, 15, 22, 27, 29, 34, 41, 55 | 
| Baseline and Change From Baseline to End of Study in Serum Albumin | Serum albumin was tested at a central laboratory. | Baseline is the average of Day -2 and Day 1 prior to dialysis; End of Study is Day 55 | 
| Change From Baseline to End of Study in Serum Phosphorus | Serum phosphorus was tested at a central laboratory. | Baseline is Day 1 prior to dialysis; End of Study is Day 55 | 
| Participants With Anti-etelcalcetide Antibody at Baseline and Postbaseline | Participants with positive titers for antibodies to etelcalcetide could be asked to return to the clinical research unit to provide additional serum samples. | Baseline: Day 1 prior to dialysis. Postbaseline: Days 29 and 55 prior to dialysis | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Secondary hyperparathyroidism, Chronic kidney disease CKD, Intact parathyroid hormone iPTH, Hemodialysis