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

• Sponsor: Amgen (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03283098
• Collaborator: (none)
• Enrollment: 33
• Locations: 5
• Arms: 2
• Actual Duration (Months): 11.2
• Patients Per Site: 6.6
• Patients Per Site Per Month: 0.6

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Secondary Hyperparathyroidism	Drug: Etelcalcetide; Drug: Placebo	Phase 1

Study Design

• Study Type: Interventional
• Actual Enrollment: 33 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention 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).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 (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: Mar 1, 2018
• Actual Primary Completion Date: Feb 4, 2019
• Actual Study Completion Date: Feb 4, 2019

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: 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.	Drug: Placebo; Placebo supplied to match active intervention.
Experimental: 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.	Drug: Etelcalcetide; Etelcalcetide was supplied as a sterile, preservative-free, aqueous solution in a single-use 3 mL glass vial.; Other Names: AMG 416

Outcome Measures

Primary Outcome Measures

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.

2. 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.

3. 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.

4. 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.

Secondary Outcome Measures

1. 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.

2. 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.

3. 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.

4. Change From Baseline to End of Study in Weight [Day 1 up to Day 55]

   Change from baseline in weight measured at visit.

5. 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.

6. 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.

7. 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.

8. 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

9. 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

10. 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.

11. 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.

12. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 70 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	Beijing	Beijing	China	100044
2	Research Site	Nanjing	Jiangsu	China	210029
3	Research Site	Shanghai	Shanghai	China	200032
4	Research Site	Shanghai	Shanghai	China	200040
5	Research Site	Shanghai	Shanghai	China	200127

Sponsors and Collaborators

• Amgen

Investigators

• Study Director: MD, Amgen

Study Documents (Full-Text)

• Statistical Analysis Plan - Nov 26, 2018
• Study Protocol - May 25, 2018

More Information

Additional Information:

• AmgenTrials clinical trials website

Publications

None provided.

• Responsible Party: Amgen
• ClinicalTrials.gov Identifier: NCT03283098
• Other Study ID Numbers: 20140197
• First Posted: Sep 14, 2017
• Last Update Posted: Feb 10, 2020
• Last Verified: Jan 1, 2020

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: Yes
• Keywords provided by Amgen: Secondary hyperparathyroidism; Chronic kidney disease CKD; Intact parathyroid hormone iPTH; Hemodialysis
• Additional relevant MeSH terms: Hyperparathyroidism; Hyperparathyroidism, Secondary

Study Results

Participant Flow

Recruitment Details	This study was conducted at 5 centers in China.
Pre-assignment Detail	Of the 37 subjects screened, 33 participants were randomized in a 3:1 ratio to either etelcalcetide or placebo in a double-blind manner prior to the Day 1 activities.

Arm/Group Title	Placebo	Etelcalcetide
Arm/Group Description	Intravenous (IV) administration of placebo three times a week (TIW) administered at the end of dialysis for 4 weeks for a total of 12 doses (on Study Days 1, 3, 6, 8, 10, 13, 15, 17, 20, 22, 24, 27) . Participants were followed for an additional 4 weeks.	5 mg intravenous (IV) dose of etelcalcetide three times a week (TIW) administered at the end of dialysis for 4 weeks for a total of 12 doses (on Study Days 1, 3, 6, 8, 10, 13, 15, 17, 20, 22, 24, 27). Participants were followed for an additional 4 weeks.
Period Title: Overall Study
STARTED	8	25
COMPLETED	8	24
NOT COMPLETED	0	1

Baseline Characteristics

Arm/Group Title	Placebo	Etelcalcetide	Total
Arm/Group Description	Intravenous (IV) administration of placebo three times a week (TIW) administered at the end of dialysis for 4 weeks for a total of 12 doses (on Study Days 1, 3, 6, 8, 10, 13, 15, 17, 20, 22, 24, 27) . Participants were followed for an additional 4 weeks.	5 mg intravenous (IV) dose of etelcalcetide three times a week (TIW) administered at the end of dialysis for 4 weeks for a total of 12 doses (on Study Days 1, 3, 6, 8, 10, 13, 15, 17, 20, 22, 24, 27). Participants were followed for an additional 4 weeks.	Total of all reporting groups
Overall Participants	8	25	33
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	49.8 (12.5)	50.2 (11.4)	50.1 (11.5)
Sex: Female, Male (Count of Participants)
Female	3 37.5%	10 40%	13 39.4%
Male	5 62.5%	15 60%	20 60.6%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	8 100%	25 100%	33 100%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%
White	0 0%	0 0%	0 0%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Height (cm) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [cm]	167.54 (8.17)	164.48 (7.68)	165.22 (7.79)
Weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	65.74 (8.45)	67.71 (13.53)	67.24 (12.40)
Body Mass Index (BMI) (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	23.64 (3.03)	24.98 (4.03)	24.65 (3.81)
Systolic Blood Pressure (mmHg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mmHg]	139.25 (27.37)	141.24 (19.39)	140.76 (21.13)
Diastolic Blood Pressure (mmHg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mmHg]	80.38 (13.54)	81.68 (13.00)	81.36 (12.93)
Intact Parathyroid Hormone (iPTH) (pmol/L) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [pmol/L]	74.10 (35.08)	63.03 (20.10)	65.72 (24.40)
Corrected Calcium (mmol/L) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mmol/L]	2.57 (0.12)	2.46 (0.20)	2.49 (0.19)
Calcium (mmol/L) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mmol/L]	2.57 (0.14)	2.44 (0.22)	2.47 (0.21)
Phosphorus (mmol/L) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mmol/L]	2.17 (0.49)	2.11 (0.58)	2.13 (0.55)
Potassium (mmol/L) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mmol/L]	4.67 (0.48)	4.74 (0.80)	4.72 (0.73)

Outcome Measures

1. Primary Outcome

Title	Pharmacokinetic (PK) Parameter: Time to Maximum Drug Concentration (Tmax) of Plasma Etelcalcetide on Days 1 and 27
Description	Tmax is the time to maximum drug concentration of plasma etelcalcetide after dosing on Days 1 and 27.
Time Frame	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

Outcome Measure Data

Analysis Population Description

Pharmacokinetic Concentration Analysis Set: all participants who received at least 1 dose of etelcalcetide and had at least 1 pharmacokinetic sample collected.

Arm/Group Title	Placebo	Etelcalcetide
Arm/Group Description	Intravenous (IV) administration of placebo three times a week (TIW) administered at the end of dialysis for 4 weeks for a total of 12 doses (on Study Days 1, 3, 6, 8, 10, 13, 15, 17, 20, 22, 24, 27) . Participants were followed for an additional 4 weeks.	5 mg intravenous (IV) dose of etelcalcetide three times a week (TIW) administered at the end of dialysis for 4 weeks for a total of 12 doses (on Study Days 1, 3, 6, 8, 10, 13, 15, 17, 20, 22, 24, 27). Participants were followed for an additional 4 weeks.
Measure Participants	0	25
Day 1	0.22
Day 27	0.22

2. Primary Outcome

Title	PK: Maximum Observed Drug Concentration (Cmax) of Plasma Etelcalcetide on Days 1 and 27
Description	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.
Time Frame	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

Outcome Measure Data

Analysis Population Description

Pharmacokinetic concentration analysis set

Arm/Group Title	Placebo	Etelcalcetide
Arm/Group Description	Intravenous (IV) administration of placebo three times a week (TIW) administered at the end of dialysis for 4 weeks for a total of 12 doses (on Study Days 1, 3, 6, 8, 10, 13, 15, 17, 20, 22, 24, 27) . Participants were followed for an additional 4 weeks.	5 mg intravenous (IV) dose of etelcalcetide three times a week (TIW) administered at the end of dialysis for 4 weeks for a total of 12 doses (on Study Days 1, 3, 6, 8, 10, 13, 15, 17, 20, 22, 24, 27). Participants were followed for an additional 4 weeks.
Measure Participants	0	25
Day 1	216 (157)
Day 27	236 (53.7)

3. Primary Outcome

Title	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
Description	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.
Time Frame	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

Outcome Measure Data

Analysis Population Description

Pharmacokinetic concentration analysis set

Arm/Group Title	Placebo	Etelcalcetide
Arm/Group Description	Intravenous (IV) administration of placebo three times a week (TIW) administered at the end of dialysis for 4 weeks for a total of 12 doses (on Study Days 1, 3, 6, 8, 10, 13, 15, 17, 20, 22, 24, 27) . Participants were followed for an additional 4 weeks.	5 mg intravenous (IV) dose of etelcalcetide three times a week (TIW) administered at the end of dialysis for 4 weeks for a total of 12 doses (on Study Days 1, 3, 6, 8, 10, 13, 15, 17, 20, 22, 24, 27). Participants were followed for an additional 4 weeks.
Measure Participants	0	25
Day 1	1110 (311)
Day 27	3310 (893)

4. Primary Outcome

Title	Pharmacokinetic (PK) Parameter: Accumulation Ratio Comparing Days 1 and 27
Description	Accumulation ratio, calculated as AUClast day 27/AUClast day 1.
Time Frame	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

Outcome Measure Data

Analysis Population Description

Pharmacokinetic concentration analysis set

Arm/Group Title	Placebo	Etelcalcetide
Arm/Group Description	Intravenous (IV) administration of placebo three times a week (TIW) administered at the end of dialysis for 4 weeks for a total of 12 doses (on Study Days 1, 3, 6, 8, 10, 13, 15, 17, 20, 22, 24, 27) . Participants were followed for an additional 4 weeks.	5 mg intravenous (IV) dose of etelcalcetide three times a week (TIW) administered at the end of dialysis for 4 weeks for a total of 12 doses (on Study Days 1, 3, 6, 8, 10, 13, 15, 17, 20, 22, 24, 27). Participants were followed for an additional 4 weeks.
Measure Participants	0	25
Mean (Standard Deviation) [ratio]	3.02 (0.607)

5. Secondary Outcome

Title	Participants With Treatment-Emergent Adverse Events (TEAEs)
Description	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.
Time Frame	Day 1 up to Day 55 (end of study)

Outcome Measure Data

Analysis Population Description

Safety Analysis set containing all participants who received at least 1 dose of investigational product (IP)

Arm/Group Title	Placebo	Etelcalcetide
Arm/Group Description	Intravenous (IV) administration of placebo three times a week (TIW) administered at the end of dialysis for 4 weeks for a total of 12 doses (on Study Days 1, 3, 6, 8, 10, 13, 15, 17, 20, 22, 24, 27) . Participants were followed for an additional 4 weeks.	5 mg intravenous (IV) dose of etelcalcetide three times a week (TIW) administered at the end of dialysis for 4 weeks for a total of 12 doses (on Study Days 1, 3, 6, 8, 10, 13, 15, 17, 20, 22, 24, 27). Participants were followed for an additional 4 weeks.
Measure Participants	8	25
All TEAEs	7 87.5%	25 100%
TEAEs Grade >= 3	0 0%	5 20%
TEAEs Grade >= 4	0 0%	1 4%
Serious TEAEs	0 0%	3 12%
TEAEs leading to study treatment discontinuation	0 0%	0 0%
Fatal TEAEs	0 0%	0 0%
Treatment-related TEAEs	1 12.5%	18 72%
Treatment-related TEAEs Grade >= 3	0 0%	1 4%
Treatment-related TEAEs Grade >= 4	0 0%	0 0%
Treatment-related serious TEAEs	0 0%	1 4%
Trt-related TEAEs leading to study trt discon	0 0%	0 0%
Treatment-related Fatal TEAEs	0 0%	0 0%

6. Secondary Outcome

Title	Participants With Treatment-Emergent Adverse Events (TEAEs) of Interest
Description	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.
Time Frame	Day 1 up to Day 55 (end of study)

Outcome Measure Data

Analysis Population Description

Safety Analysis Set

Arm/Group Title	Placebo	Etelcalcetide
Arm/Group Description	Intravenous (IV) administration of placebo three times a week (TIW) administered at the end of dialysis for 4 weeks for a total of 12 doses (on Study Days 1, 3, 6, 8, 10, 13, 15, 17, 20, 22, 24, 27) . Participants were followed for an additional 4 weeks.	5 mg intravenous (IV) dose of etelcalcetide three times a week (TIW) administered at the end of dialysis for 4 weeks for a total of 12 doses (on Study Days 1, 3, 6, 8, 10, 13, 15, 17, 20, 22, 24, 27). Participants were followed for an additional 4 weeks.
Measure Participants	8	25
Adynamic bone (EOI)	0 0%	0 0%
Cardiac Failure (EOI)	0 0%	0 0%
Convulsions (SMQ)	0 0%	0 0%
Fractures (EOI)	0 0%	0 0%
Hypersensitivity (SMQ)	0 0%	5 20%
Dermatitis allergic (PT)	0 0%	2 8%
Rash (PT)	0 0%	2 8%
Dermatitis (PT)	0 0%	1 4%
Hypocalcemia (EOI)	0 0%	11 44%
Blood calcium decreased (PT)	0 0%	10 40%
Hypocalcaemia (PT)	0 0%	2 8%
Hypophosphatemia (EOI)	0 0%	0 0%
Infusion reaction (EOI)	0 0%	1 4%
Hypotension (PT)	0 0%	1 4%
Torsade de pointes-QT prolongation (SMQ)	0 0%	0 0%
Ventricular tachyarrhythmias (SMQ)	0 0%	0 0%

7. Secondary Outcome

Title	Participants With Clinically-Significant Changes in Electrocardiograms (ECGs) From Baseline to End of Study
Description	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.
Time Frame	Baseline is Day -2; End of Study is Day 55

Outcome Measure Data

Analysis Population Description

Safety Analysis set of participants with both a baseline and end of study ECG.

Arm/Group Title	Placebo	Etelcalcetide
Arm/Group Description	Intravenous (IV) administration of placebo three times a week (TIW) administered at the end of dialysis for 4 weeks for a total of 12 doses (on Study Days 1, 3, 6, 8, 10, 13, 15, 17, 20, 22, 24, 27) . Participants were followed for an additional 4 weeks.	5 mg intravenous (IV) dose of etelcalcetide three times a week (TIW) administered at the end of dialysis for 4 weeks for a total of 12 doses (on Study Days 1, 3, 6, 8, 10, 13, 15, 17, 20, 22, 24, 27). Participants were followed for an additional 4 weeks.
Measure Participants	8	24
Normal Baseline / Abnormal End of Study	0 0%	2 8%
Abnormal Baseline / Normal End of Study	0 0%	1 4%
No Change in Baseline to End of Study	8 100%	21 84%

8. Secondary Outcome

Title	Change From Baseline to End of Study in Weight
Description	Change from baseline in weight measured at visit.
Time Frame	Day 1 up to Day 55

Outcome Measure Data

Analysis Population Description

Safety Analysis set

Arm/Group Title	Placebo	Etelcalcetide
Arm/Group Description	Intravenous (IV) administration of placebo three times a week (TIW) administered at the end of dialysis for 4 weeks for a total of 12 doses (on Study Days 1, 3, 6, 8, 10, 13, 15, 17, 20, 22, 24, 27) . Participants were followed for an additional 4 weeks.	5 mg intravenous (IV) dose of etelcalcetide three times a week (TIW) administered at the end of dialysis for 4 weeks for a total of 12 doses (on Study Days 1, 3, 6, 8, 10, 13, 15, 17, 20, 22, 24, 27). Participants were followed for an additional 4 weeks.
Measure Participants	8	25
Mean (Standard Deviation) [kg]	1.32 (0.79)	0.76 (1.39)

9. Secondary Outcome

Title	Change From Baseline to End of Study in Systolic and Diastolic Blood Pressures
Description	Participants remained seated for at least 10 minutes prior to measurement of predialysis heart rate and blood pressure.
Time Frame	Baseline Day 1 prior to dialysis; End of Study is Day 55

Outcome Measure Data

Analysis Population Description

Safety Analysis set

Arm/Group Title	Placebo	Etelcalcetide
Arm/Group Description	Intravenous (IV) administration of placebo three times a week (TIW) administered at the end of dialysis for 4 weeks for a total of 12 doses (on Study Days 1, 3, 6, 8, 10, 13, 15, 17, 20, 22, 24, 27) . Participants were followed for an additional 4 weeks.	5 mg intravenous (IV) dose of etelcalcetide three times a week (TIW) administered at the end of dialysis for 4 weeks for a total of 12 doses (on Study Days 1, 3, 6, 8, 10, 13, 15, 17, 20, 22, 24, 27). Participants were followed for an additional 4 weeks.
Measure Participants	8	25
Systolic Blood Pressure	1.1 (15.5)	6.1 (18.6)
Diastolic Blood Pressure	4.4 (9.2)	1.5 (11.9)

10. Secondary Outcome

Title	Baseline and Change From Baseline to End of Study in Heart Rate
Description	Participants remained seated for at least 10 minutes prior to measurement of predialysis heart rate and blood pressure.
Time Frame	Baseline Day 1 prior to dialysis; End of Study is Day 55

Outcome Measure Data

Analysis Population Description

Safety Analysis set

Arm/Group Title	Placebo	Etelcalcetide
Arm/Group Description	Intravenous (IV) administration of placebo three times a week (TIW) administered at the end of dialysis for 4 weeks for a total of 12 doses (on Study Days 1, 3, 6, 8, 10, 13, 15, 17, 20, 22, 24, 27) . Participants were followed for an additional 4 weeks.	5 mg intravenous (IV) dose of etelcalcetide three times a week (TIW) administered at the end of dialysis for 4 weeks for a total of 12 doses (on Study Days 1, 3, 6, 8, 10, 13, 15, 17, 20, 22, 24, 27). Participants were followed for an additional 4 weeks.
Measure Participants	8	25
Baseline	79.5 (8.3)	82.8 (13.8)
Change from Baseline to End of Study	-2.9 (6.5)	-1.4 (8.9)

11. Secondary Outcome

Title	Change From Baseline to End of Study in Calcium
Description	Calcium was tested at a central laboratory.
Time Frame	Baseline is Day 1 prior to dialysis; End of Study is Day 55

Outcome Measure Data

Analysis Population Description

Safety Analysis set

Arm/Group Title	Placebo	Etelcalcetide
Arm/Group Description	Intravenous (IV) administration of placebo three times a week (TIW) administered at the end of dialysis for 4 weeks for a total of 12 doses (on Study Days 1, 3, 6, 8, 10, 13, 15, 17, 20, 22, 24, 27) . Participants were followed for an additional 4 weeks.	5 mg intravenous (IV) dose of etelcalcetide three times a week (TIW) administered at the end of dialysis for 4 weeks for a total of 12 doses (on Study Days 1, 3, 6, 8, 10, 13, 15, 17, 20, 22, 24, 27). Participants were followed for an additional 4 weeks.
Measure Participants	8	25
Mean (Standard Deviation) [mmol/L]	-0.10 (0.11)	-0.07 (0.12)

12. Secondary Outcome

Title	Change From Baseline to End of Study in Corrected Calcium (cCa)
Description	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
Time Frame	Baseline is the average of Day -2 and Day 1 prior to dialysis; End of Study is Day 55

Outcome Measure Data

Analysis Population Description

Safety Analysis set

Arm/Group Title	Placebo	Etelcalcetide
Arm/Group Description	Intravenous (IV) administration of placebo three times a week (TIW) administered at the end of dialysis for 4 weeks for a total of 12 doses (on Study Days 1, 3, 6, 8, 10, 13, 15, 17, 20, 22, 24, 27) . Participants were followed for an additional 4 weeks.	5 mg intravenous (IV) dose of etelcalcetide three times a week (TIW) administered at the end of dialysis for 4 weeks for a total of 12 doses (on Study Days 1, 3, 6, 8, 10, 13, 15, 17, 20, 22, 24, 27). Participants were followed for an additional 4 weeks.
Measure Participants	8	25
Mean (Standard Deviation) [mmol/L]	-0.08 (0.10)	-0.05 (0.10)

13. Secondary Outcome

Title	Participants With Low Corrected Calcium (cCA) By Category
Description	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
Time Frame	Timeframes: Days 8, 15, 22, 27, 29, 34, 41, 55

Outcome Measure Data

Analysis Population Description

Safety Analysis set

Arm/Group Title	Placebo	Etelcalcetide
Arm/Group Description	Intravenous (IV) administration of placebo three times a week (TIW) administered at the end of dialysis for 4 weeks for a total of 12 doses (on Study Days 1, 3, 6, 8, 10, 13, 15, 17, 20, 22, 24, 27) . Participants were followed for an additional 4 weeks.	5 mg intravenous (IV) dose of etelcalcetide three times a week (TIW) administered at the end of dialysis for 4 weeks for a total of 12 doses (on Study Days 1, 3, 6, 8, 10, 13, 15, 17, 20, 22, 24, 27). Participants were followed for an additional 4 weeks.
Measure Participants	8	25
Participants with cCA < 1.75 mmol/L	0 0%	0 0%
Participants with cCA 1.75 to < 1.87 mmol/L	0 0%	1 4%
Participants with cCA 1.87 to < 2.07 mmol/L	0 0%	12 48%

14. Secondary Outcome

Title	Baseline and Change From Baseline to End of Study in Serum Albumin
Description	Serum albumin was tested at a central laboratory.
Time Frame	Baseline is the average of Day -2 and Day 1 prior to dialysis; End of Study is Day 55

Outcome Measure Data

Analysis Population Description

Safety Analysis set

Arm/Group Title	Placebo	Etelcalcetide
Arm/Group Description	Intravenous (IV) administration of placebo three times a week (TIW) administered at the end of dialysis for 4 weeks for a total of 12 doses (on Study Days 1, 3, 6, 8, 10, 13, 15, 17, 20, 22, 24, 27) . Participants were followed for an additional 4 weeks.	5 mg intravenous (IV) dose of etelcalcetide three times a week (TIW) administered at the end of dialysis for 4 weeks for a total of 12 doses (on Study Days 1, 3, 6, 8, 10, 13, 15, 17, 20, 22, 24, 27). Participants were followed for an additional 4 weeks.
Measure Participants	8	25
Baseline	41.20 (2.37)	39.37 (2.79)
Change from Baseline to End of Study	-1.06 (1.81)	-0.59 (2.13)

15. Secondary Outcome

Title	Change From Baseline to End of Study in Serum Phosphorus
Description	Serum phosphorus was tested at a central laboratory.
Time Frame	Baseline is Day 1 prior to dialysis; End of Study is Day 55

Outcome Measure Data

Analysis Population Description

Safety Analysis set

Arm/Group Title	Placebo	Etelcalcetide
Arm/Group Description	Intravenous (IV) administration of placebo three times a week (TIW) administered at the end of dialysis for 4 weeks for a total of 12 doses (on Study Days 1, 3, 6, 8, 10, 13, 15, 17, 20, 22, 24, 27) . Participants were followed for an additional 4 weeks.	5 mg intravenous (IV) dose of etelcalcetide three times a week (TIW) administered at the end of dialysis for 4 weeks for a total of 12 doses (on Study Days 1, 3, 6, 8, 10, 13, 15, 17, 20, 22, 24, 27). Participants were followed for an additional 4 weeks.
Measure Participants	8	25
Mean (Standard Deviation) [mmol/L]	-0.03 (0.53)	-0.06 (0.56)

16. Secondary Outcome

Title	Participants With Anti-etelcalcetide Antibody at Baseline and Postbaseline
Description	Participants with positive titers for antibodies to etelcalcetide could be asked to return to the clinical research unit to provide additional serum samples.
Time Frame	Baseline: Day 1 prior to dialysis. Postbaseline: Days 29 and 55 prior to dialysis

Outcome Measure Data

Analysis Population Description

Safety Analysis set

Arm/Group Title	Placebo	Etelcalcetide
Arm/Group Description	Intravenous (IV) administration of placebo three times a week (TIW) administered at the end of dialysis for 4 weeks for a total of 12 doses (on Study Days 1, 3, 6, 8, 10, 13, 15, 17, 20, 22, 24, 27) . Participants were followed for an additional 4 weeks.	5 mg intravenous (IV) dose of etelcalcetide three times a week (TIW) administered at the end of dialysis for 4 weeks for a total of 12 doses (on Study Days 1, 3, 6, 8, 10, 13, 15, 17, 20, 22, 24, 27). Participants were followed for an additional 4 weeks.
Measure Participants	0	25
Binding antibody positive at or before baseline	1 12.5%
Positive postbaseline/negative baseline	0 0%
Transient, i.e. negative at last timepoint tested	0 0%

Adverse Events

Time Frame	Day 1 up to Day 55 (end of study)
Adverse Event Reporting Description	Treatment-emergent adverse events - any adverse events started on or after the first dose of investigational product (IP) up to the end of study date (Day 55).
Arm/Group Title	Placebo		Etelcalcetide
Arm/Group Description	Intravenous (IV) administration of placebo three times a week (TIW) administered at the end of dialysis for 4 weeks for a total of 12 doses (on Study Days 1, 3, 6, 8, 10, 13, 15, 17, 20, 22, 24, 27) . Participants were followed for an additional 4 weeks.		5 mg intravenous (IV) dose of etelcalcetide three times a week (TIW) administered at the end of dialysis for 4 weeks for a total of 12 doses (on Study Days 1, 3, 6, 8, 10, 13, 15, 17, 20, 22, 24, 27). Participants were followed for an additional 4 weeks.
All Cause Mortality
	Placebo		Etelcalcetide
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/8 (0%)		0/25 (0%)
Serious Adverse Events
	Placebo		Etelcalcetide
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/8 (0%)		3/25 (12%)
Infections and infestations
Pneumonia	0/8 (0%)		1/25 (4%)
Metabolism and nutrition disorders
Hypocalcaemia	0/8 (0%)		1/25 (4%)
Musculoskeletal and connective tissue disorders
Intervertebral disc protrusion	0/8 (0%)		1/25 (4%)
Other (Not Including Serious) Adverse Events
	Placebo		Etelcalcetide
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	7/8 (87.5%)		22/25 (88%)
Cardiac disorders
Arrhythmia	1/8 (12.5%)		0/25 (0%)
Atrioventricular block first degree	0/8 (0%)		2/25 (8%)
Eye disorders
Eye disorder	1/8 (12.5%)		0/25 (0%)
Gastrointestinal disorders
Constipation	1/8 (12.5%)		1/25 (4%)
Infections and infestations
Upper respiratory tract infection	0/8 (0%)		2/25 (8%)
Injury, poisoning and procedural complications
Contusion	1/8 (12.5%)		0/25 (0%)
Limb injury	1/8 (12.5%)		0/25 (0%)
Investigations
Blood alkaline phosphatase increased	1/8 (12.5%)		0/25 (0%)
Blood calcium decreased	0/8 (0%)		10/25 (40%)
Metabolism and nutrition disorders
Hyperphosphataemia	0/8 (0%)		2/25 (8%)
Hypertriglyceridaemia	1/8 (12.5%)		0/25 (0%)
Hypoalbuminaemia	2/8 (25%)		0/25 (0%)
Hypoproteinaemia	0/8 (0%)		2/25 (8%)
Musculoskeletal and connective tissue disorders
Muscle spasms	0/8 (0%)		4/25 (16%)
Pain in extremity	1/8 (12.5%)		0/25 (0%)
Nervous system disorders
Muscle spasticity	1/8 (12.5%)		0/25 (0%)
Somnolence	1/8 (12.5%)		1/25 (4%)
Respiratory, thoracic and mediastinal disorders
Oropharyngeal pain	1/8 (12.5%)		0/25 (0%)
Skin and subcutaneous tissue disorders
Dermatitis allergic	0/8 (0%)		2/25 (8%)
Pruritus	1/8 (12.5%)		4/25 (16%)
Rash	0/8 (0%)		2/25 (8%)
Vascular disorders
Blood pressure inadequately controlled	1/8 (12.5%)		0/25 (0%)
Hypertension	0/8 (0%)		2/25 (8%)
Hypotension	0/8 (0%)		4/25 (16%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The Clinical Trial Agreement generally does not restrict an investigator's discussion of trial results after completion. The Agreement permits Amgen a limited period of time to review material discussing trial results (typically up to 45 days and possible extension). Amgen may remove confidential information, but authors have final control and approval of publication content. For multicenter studies, the investigator agrees not to publish any results before the first multi-center publication.