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

Phase 1

Completed

Conditions: Secondary Hyperparathyroidism

Interventions: Drug: Placebo
Drug: Etelcalcetide

Registration Number: NCT03283098

Lead Sponsor: Amgen

Brief Summary: 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.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 33

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo	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.
Etelcalcetide	Etelcalcetide	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.

Primary Outcome Measures

Name	Time	Method
PK: Maximum Observed Drug Concentration (Cmax) of Plasma Etelcalcetide 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	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.
Pharmacokinetic (PK) Parameter: Accumulation Ratio Comparing Days 1 and 27	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	Accumulation ratio, calculated as AUClast day 27/AUClast day 1.
Pharmacokinetic (PK) Parameter: Time to Maximum Drug Concentration (Tmax) of Plasma Etelcalcetide 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	Tmax is the time to maximum drug concentration of plasma etelcalcetide after dosing on Days 1 and 27.
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	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	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.

Secondary Outcome Measures

Name	Time	Method
Change From Baseline to End of Study in Weight	Day 1 up to Day 55	Change from baseline in weight measured at visit.
Participants With Treatment-Emergent Adverse Events (TEAEs) of Interest	Day 1 up to Day 55 (end of study)	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.
Baseline and Change From Baseline to End of Study in Heart Rate	Baseline Day 1 prior to dialysis; End of Study is Day 55	Participants remained seated for at least 10 minutes prior to measurement of predialysis heart rate and blood pressure.
Change From Baseline to End of Study in Calcium	Baseline is Day 1 prior to dialysis; End of Study is Day 55	Calcium was tested at a central laboratory.
Participants With Treatment-Emergent Adverse Events (TEAEs)	Day 1 up to Day 55 (end of study)	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.
Participants With Clinically-Significant Changes in Electrocardiograms (ECGs) From Baseline to End of Study	Baseline is Day -2; End of Study is Day 55	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.
Change From Baseline to End of Study in Systolic and Diastolic Blood Pressures	Baseline Day 1 prior to dialysis; End of Study is Day 55	Participants remained seated for at least 10 minutes prior to measurement of predialysis heart rate and blood pressure.
Baseline and Change From Baseline to End of Study in Serum Albumin	Baseline is the average of Day -2 and Day 1 prior to dialysis; End of Study is Day 55	Serum albumin was tested at a central laboratory.
Change From Baseline to End of Study in Corrected Calcium (cCa)	Baseline is the average of Day -2 and Day 1 prior to dialysis; End of Study is Day 55	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
Participants With Anti-etelcalcetide Antibody at Baseline and Postbaseline	Baseline: Day 1 prior to dialysis. Postbaseline: Days 29 and 55 prior to dialysis	Participants with positive titers for antibodies to etelcalcetide could be asked to return to the clinical research unit to provide additional serum samples.
Participants With Low Corrected Calcium (cCA) By Category	Timeframes: Days 8, 15, 22, 27, 29, 34, 41, 55	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
Change From Baseline to End of Study in Serum Phosphorus	Baseline is Day 1 prior to dialysis; End of Study is Day 55	Serum phosphorus was tested at a central laboratory.