Efficacy and Safety of Etelcalcetide (AMG 416) in the Treatment of Secondary Hyperparathyroidism (SHPT) in Patients With Chronic Kidney Disease on Hemodialysis

• Sponsor: Amgen (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01785849
• Collaborator: (none)
• Enrollment: 508
• Locations: 118
• Arms: 2
• Actual Duration (Months): 15
• Patients Per Site: 4.3
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

This study is designed to assess the efficacy and safety of etelcalcetide compared with placebo in the treatment of SHPT in patients with chronic kidney disease (CKD) receiving hemodialysis.

Condition or Disease	Intervention/Treatment	Phase
Hyperparathyroidism, Secondary	Drug: Etelcalcetide; Drug: Placebo	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 508 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-blind, Placebo-controlled, Phase 3 Study to Assess the Efficacy and Safety of AMG 416 in the Treatment of Secondary Hyperparathyroidism in Subjects With Chronic Kidney Disease on Hemodialysis
• Actual Study Start Date: Mar 12, 2013
• Actual Primary Completion Date: May 22, 2014
• Actual Study Completion Date: Jun 12, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Etelcalcetide Participants received etelcalcetide administered by intravenous bolus injection at the end of each hemodialysis session three times a week, for 26 weeks.	Drug: Etelcalcetide; Administered intravenously three times per week. The starting dose was 5 mg. The dose may have been increased at 4-week intervals by 2.5 mg or 5 mg on the basis of the predialysis parathyroid hormone and corrected calcium concentrations obtained in the prior week. The minimum dose was 2.5 mg and the maximum dose was 15 mg.; Other Names: AMG 416 KAI-4169
Placebo Comparator: Placebo Participants received placebo administered by intravenous bolus injection at the end of each hemodialysis session, three times per week (TIW) for 26 weeks.	Drug: Placebo; Administered intravenously (IV) three times per week.

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants With a > 30% Decrease From Baseline in Mean PTH During the Efficacy Assessment Phase [Baseline and the efficacy assessment phase (EAP; defined as Weeks 20 to 27, inclusive).]

   Participants who did not have any scheduled assessments during the EAP were considered non-responders.

Secondary Outcome Measures

1. Percentage of Participants With Mean Predialysis Parathyroid Hormone ≤ 300 pg/mL During the Efficacy Assessment Phase [Baseline and the efficacy assessment phase (Week 20 to Week 27)]

   Participants who had no scheduled assessments during the EAP were considered non-responders.

2. Percent Change From Baseline in Predialysis PTH During the Efficacy Assessment Phase [Baseline and the Efficacy Assessment Phase (Week 20 to Week 27)]

3. Percent Change From Baseline in Predialysis Corrected Calcium During the Efficacy Assessment Phase [Baseline and the efficacy assessment phase (Week 20 to Week 27)]

4. Percent Change From Baseline in Predialysis Corrected Calcium Phosphorus Product During the Efficacy Assessment Phase [Baseline and the efficacy assessment phase (Week 20 to Week 27)]

5. Percent Change From Baseline in Predialysis Phosphorus During the Efficacy Assessment Phase [Baseline and the efficacy assessment phase (Week 20 to Week 27)]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 100 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Subject understands the study procedures and agrees to participate in the study by giving written informed consent.

• Subject is 18 years of age or older.

• Subject must be receiving hemodialysis 3 times weekly for at least 3 months

• Subject agrees to not participate in another study of an investigational agent during the study.

• Other Inclusion Criteria may apply

Exclusion Criteria:

• Currently receiving treatment in another investigational device or drug study, or ended treatment on another investigational device or drug study(s) within 8 weeks prior to screening.

• Other investigational procedures while participating in this study are excluded.

• Anticipated or scheduled parathyroidectomy during the study period.

• Subject has received a parathyroidectomy within 3 months prior to dosing.

• Anticipated or scheduled kidney transplant during the study period.

• Subject has known sensitivity to any of the products or components to be administered during dosing.

• Subject has participated in a prior clinical trial of AMG 416 (also referred to as KAI-4169).

• Subject has received cinacalcet within the 4 weeks prior to screening labs (treatment with cinacalcet is prohibited during the study).

• Subject has an unstable medical condition based on medical history, physical examination, and routine laboratory tests, or is otherwise unstable in the judgment of the Investigator.

• Other Exclusion Criteria may apply

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	Birmingham	Alabama	United States	35211
2	Research Site	Pine Bluff	Arkansas	United States	71603
3	Research Site	Azusa	California	United States	91702
4	Research Site	Covina	California	United States	91723
5	Research Site	Lakewood	California	United States	90712
6	Research Site	Los Angeles	California	United States	90025
7	Research Site	Lynwood	California	United States	90262
8	Research Site	Northridge	California	United States	91324
9	Research Site	Ontario	California	United States	91762
10	Research Site	Panorama City	California	United States	91402
11	Research Site	Sacramento	California	United States	95825
12	Research Site	Whittier	California	United States	90603
13	Research Site	Pembroke Pines	Florida	United States	33028
14	Research Site	Meridian	Idaho	United States	83642
15	Research Site	Evanston	Illinois	United States	60201
16	Research Site	Springfield	Massachusetts	United States	01107
17	Research Site	Detroit	Michigan	United States	48236
18	Research Site	Kalamazoo	Michigan	United States	49007
19	Research Site	Pontiac	Michigan	United States	48341
20	Research Site	Southgate	Michigan	United States	48195
21	Research Site	Tupelo	Mississippi	United States	38801
22	Research Site	Kansas City	Missouri	United States	64111
23	Research Site	Reno	Nevada	United States	89511
24	Research Site	Amherst	New York	United States	14226
25	Research Site	Bronx	New York	United States	10461
26	Research Site	Brooklyn	New York	United States	11235
27	Research Site	Rosedale	New York	United States	11422
28	Research Site	Yonkers	New York	United States	10704
29	Research Site	Chapel Hill	North Carolina	United States	27599
30	Research Site	Durham	North Carolina	United States	27704
31	Research Site	Allentown	Pennsylvania	United States	18104
32	Research Site	Philadelphia	Pennsylvania	United States	19106
33	Research Site	Philadelphia	Pennsylvania	United States	19118
34	Research Site	Orangeburg	South Carolina	United States	29118
35	Research Site	Sumter	South Carolina	United States	29150
36	Research Site	Columbia	Tennessee	United States	38401
37	Research Site	Nashville	Tennessee	United States	37205
38	Research Site	Austin	Texas	United States	78758
39	Research Site	Fort Worth	Texas	United States	76105
40	Research Site	Fort Worth	Texas	United States	76164
41	Research Site	Grand Prairie	Texas	United States	75050
42	Research Site	Houston	Texas	United States	77030
43	Research Site	Mansfield	Texas	United States	76063
44	Research Site	San Antonio	Texas	United States	78205
45	Research Site	San Antonio	Texas	United States	78215
46	Research Site	San Antonio	Texas	United States	78229
47	Research Site	Tyler	Texas	United States	75701
48	Research Site	Fairfax	Virginia	United States	22033
49	Research Site	Mechanicsville	Virginia	United States	23116
50	Research Site	Norfolk	Virginia	United States	23502
51	Research Site	Bluefield	West Virginia	United States	24701
52	Research Site	Liverpool	New South Wales	Australia	2170
53	Research Site	St Leonards	New South Wales	Australia	2065
54	Research Site	Parkville	Victoria	Australia	3050
55	Research Site	Prahan	Victoria	Australia	3004
56	Research Site	Graz		Austria	8036
57	Research Site	Linz		Austria	4010
58	Research Site	Wien		Austria	1090
59	Research Site	Aalst		Belgium	9300
60	Research Site	Baudour		Belgium	7331
61	Research Site	Bruxelles		Belgium	1020
62	Research Site	Leuven		Belgium	3000
63	Research Site	Liège		Belgium	4000
64	Research Site	Brampton	Ontario	Canada	L6R 3J7
65	Research Site	Greenfield Park	Quebec	Canada	J4V 2H1
66	Research Site	Montreal	Quebec	Canada	H1T 2M4
67	Research Site	Quebec		Canada	G1R 2J6
68	Research Site	Hradec Kralove		Czechia	500 05
69	Research Site	Praha 4 - Nusle		Czechia	140 00
70	Research Site	Praha 6		Czechia	169 00
71	Research Site	Slavkov u Brna		Czechia	684 01
72	Research Site	Trinec		Czechia	739 61
73	Research Site	Nantes Cedex 01		France	44200
74	Research Site	Poitiers		France	86021
75	Research Site	Reims Cedex		France	51092
76	Research Site	Saint-Ouen		France	93400
77	Research Site	Salouel Cedex 1		France	80054
78	Research Site	Berlin		Germany	12053
79	Research Site	Dresden		Germany	01307
80	Research Site	Kiel		Germany	24105
81	Research Site	Villingen-Schwenningen		Germany	78052
82	Research Site	Baja		Hungary	6500
83	Research Site	Budapest		Hungary	1037
84	Research Site	Budapest		Hungary	1115
85	Research Site	Gyor		Hungary	9023
86	Research Site	Kaposvar		Hungary	7400
87	Research Site	Pecs		Hungary	7624
88	Research Site	Ashkelon		Israel	78278
89	Research Site	Nahariya		Israel	22100
90	Research Site	Tel Aviv		Israel	64239
91	Research Site	Milano		Italy	20122
92	Research Site	Napoli		Italy	80131
93	Research Site	Pavia		Italy	27100
94	Research Site	San Fermo Della Battaglia (CO)		Italy	22020
95	Research Site	Verona		Italy	37126
96	Research Site	Bialystok		Poland	15-540
97	Research Site	Warszawa		Poland	02-006
98	Research Site	Warszawa		Poland	02-097
99	Research Site	Warszawa		Poland	04-141
100	Research Site	Wroclaw		Poland	51-124
101	Research Site	Zamosc		Poland	87-100
102	Research Site	Saint Petersburg		Russian Federation	191104
103	Research Site	Saint Petersburg		Russian Federation	196247
104	Research Site	Saint Petersburg		Russian Federation	198510
105	Research Site	Saint-Petersburg		Russian Federation	195067
106	Research Site	Saint-Petersburg		Russian Federation	195257
107	Research Site	Santander	Cantabria	Spain	39008
108	Research Site	Barcelona	Cataluña	Spain	08003
109	Research Site	Barcelona	Cataluña	Spain	08025
110	Research Site	Madrid		Spain	28041
111	Research Site	Madrid		Spain	28046
112	Research Site	Cambridge		United Kingdom	CB2 2QQ
113	Research Site	Coventry		United Kingdom	CV2 2DX
114	Research Site	Glasgow		United Kingdom	G11 6NT
115	Research Site	London		United Kingdom	NW3 2QG
116	Research Site	Nottingham		United Kingdom	NG5 1PB
117	Research Site	Salford		United Kingdom	M6 8HD
118	Research Site	Sheffield		United Kingdom	S5 7AU

Sponsors and Collaborators

• Amgen

Investigators

• Study Director: MD, Amgen

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• AmgenTrials clinical trials website

Publications

• Block GA, Bushinsky DA, Cunningham J, Drueke TB, Ketteler M, Kewalramani R, Martin KJ, Mix TC, Moe SM, Patel UD, Silver J, Spiegel DM, Sterling L, Walsh L, Chertow GM. Effect of Etelcalcetide vs Placebo on Serum Parathyroid Hormone in Patients Receiving Hemodialysis With Secondary Hyperparathyroidism: Two Randomized Clinical Trials. JAMA. 2017 Jan 10;317(2):146-155. doi: 10.1001/jama.2016.19456.
• Block GA, Chertow GM, Sullivan JT, Deng H, Mather O, Tomlin H, Serenko M. An integrated analysis of safety and tolerability of etelcalcetide in patients receiving hemodialysis with secondary hyperparathyroidism. PLoS One. 2019 Mar 15;14(3):e0213774. doi: 10.1371/journal.pone.0213774. eCollection 2019.
• Chen P, Narayanan A, Wu B, Gisleskog PO, Gibbs JP, Chow AT, Melhem M. Population Pharmacokinetic and Pharmacodynamic Modeling of Etelcalcetide in Patients with Chronic Kidney Disease and Secondary Hyperparathyroidism Receiving Hemodialysis. Clin Pharmacokinet. 2018 Jan;57(1):71-85. doi: 10.1007/s40262-017-0550-4.
• Cunningham J, Block GA, Chertow GM, Cooper K, Evenepoel P, Iles J, Sun Y, Ureña-Torres P, Bushinsky DA. Etelcalcetide Is Effective at All Levels of Severity of Secondary Hyperparathyroidism in Hemodialysis Patients. Kidney Int Rep. 2019 Apr 16;4(7):987-994. doi: 10.1016/j.ekir.2019.04.010. eCollection 2019 Jul.
• Hain D, Tomlin H, Gibson C. Administration of Etelcalcetide for the Treatment of Secondary Hyperparathyroidism in Patients with CKD-MBD on Hemodialysis: A Nephrology Nursing Perspective. Nephrol Nurs J. 2019 May-Jun;46(3):315-290.
• Kroenke MA, Weeraratne DK, Deng H, Sloey B, Subramanian R, Wu B, Serenko M, Hock MB. Clinical immunogenicity of the d-amino acid peptide therapeutic etelcalcetide: Method development challenges and anti-drug antibody clinical impact assessments. J Immunol Methods. 2017 Jun;445:37-44. doi: 10.1016/j.jim.2017.03.005. Epub 2017 Mar 6.
• Stollenwerk B, Iannazzo S, Akehurst R, Adena M, Briggs A, Dehmel B, Parfrey P, Belozeroff V. A Decision-Analytic Model to Assess the Cost-Effectiveness of Etelcalcetide vs. Cinacalcet. Pharmacoeconomics. 2018 May;36(5):603-612. doi: 10.1007/s40273-017-0605-2.
• Stollenwerk B, Iannazzo S, Cooper K, Belozeroff V. Exploring the potential value of improved care for secondary hyperparathyroidism with a novel calcimimetic therapy. J Med Econ. 2017 Oct;20(10):1110-1115. doi: 10.1080/13696998.2017.1360309. Epub 2017 Aug 14.
• Wolf M, Block GA, Chertow GM, Cooper K, Fouqueray B, Moe SM, Sun Y, Tomlin H, Vervloet M, Oberbauer R. Effects of etelcalcetide on fibroblast growth factor 23 in patients with secondary hyperparathyroidism receiving hemodialysis. Clin Kidney J. 2019 Apr 26;13(1):75-84. doi: 10.1093/ckj/sfz034. eCollection 2020 Feb.

• Responsible Party: Amgen
• ClinicalTrials.gov Identifier: NCT01785849
• Other Study ID Numbers: 20120229; KAI-4169-006; 2012-002805-23
• First Posted: Feb 7, 2013
• Last Update Posted: Aug 26, 2019
• Last Verified: Aug 1, 2019

• Keywords provided by Amgen: Secondary Hyperparathyroidism (SHPT), chronic kidney disease (CKD), hemodialysis, parathyroid hormone (PTH), hypocalcemia, bone and mineral metabolism
• Additional relevant MeSH terms: Neoplasm Metastasis; Kidney Diseases; Renal Insufficiency, Chronic; Hyperparathyroidism; Hyperparathyroidism, Secondary

Study Results

Participant Flow

Recruitment Details	This study was conducted at 111 centers in the US, Canada, Europe, Israel, Russian Federation, and Australia. The first participant was enrolled on 12 March 2013 and the last participant enrolled on 08 November 2013.
Pre-assignment Detail	Eligible participants were randomized in a 1:1 ratio to etelcalcetide or placebo. Randomization was stratified by mean screening parathyroid hormone (PTH) (< 600 pg/mL, 600 to ≤ 1000 pg/mL, and > 1000 pg/mL), prior cinacalcet use and region (North America or non-North America).

Arm/Group Title	Placebo	Etelcalcetide
Arm/Group Description	Participants received placebo administered by intravenous bolus injection at the end of each hemodialysis session, three times per week (TIW) for 26 weeks.	Participants received etelcalcetide administered by intravenous bolus injection at the end of each hemodialysis session, TIW, for 26 weeks. The starting dose was 5 mg and may have been increased at weeks 5, 9, 13 and 17 to achieve a predialysis PTH ≤ 300 pg/mL.
Period Title: Overall Study
STARTED	254	254
Received Treatment	254	251
COMPLETED	193	220
NOT COMPLETED	61	34

Baseline Characteristics

Arm/Group Title	Placebo	Etelcalcetide	Total
Arm/Group Description	Participants received placebo administered by intravenous bolus injection at the end of each hemodialysis session, three times per week (TIW) for 26 weeks.	Participants received etelcalcetide administered by intravenous bolus injection at the end of each hemodialysis session, TIW, for 26 weeks. The starting dose was 5 mg and may have been increased at weeks 5, 9, 13 and 17 to achieve a predialysis PTH ≤ 300 pg/mL.	Total of all reporting groups
Overall Participants	254	254	508
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	57.1 (14.5)	58.4 (14.6)	57.7 (14.6)
Sex: Female, Male (Count of Participants)
Female	114 44.9%	103 40.6%	217 42.7%
Male	140 55.1%	151 59.4%	291 57.3%
Race (participants) [Number]
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	3 1.2%	5 2%	8 1.6%
Black (or African American)	69 27.2%	72 28.3%	141 27.8%
Native Hawaiian or Other Pacific Islander	2 0.8%	0 0%	2 0.4%
White	175 68.9%	173 68.1%	348 68.5%
Other	4 1.6%	4 1.6%	8 1.6%
Missing	1 0.4%	0 0%	1 0.2%
Stratification Factor: Mean Screening Serum Parathyroid Hormone (PTH) (participants) [Number]
< 600 pg/mL	84 33.1%	87 34.3%	171 33.7%
≥ 600 to ≤ 1000 pg/mL	114 44.9%	115 45.3%	229 45.1%
> 1000 pg/mL	56 22%	52 20.5%	108 21.3%
Stratification Factor: Cinacalcet Use Within 8 Weeks of Randomization (participants) [Number]
Yes	34 13.4%	33 13%	67 13.2%
No	220 86.6%	221 87%	441 86.8%
Stratification Factor: Region (participants) [Number]
North America	129 50.8%	132 52%	261 51.4%
Non-North America	125 49.2%	122 48%	247 48.6%
Parathyroid Hormone (PTH) (pg/mL) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [pg/mL]	819.7 (386.0)	848.7 (520.4)	834.2 (457.9)
Phosphorus (mg/dL) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mg/dL]	5.78 (1.60)	5.95 (1.59)	5.87 (1.59)
Corrected Calcium (mg/dL) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mg/dL]	9.61 (0.60)	9.65 (0.66)	9.63 (0.63)
Corrected Calcium Phosphorus Product (cCa x P) (mg²/dL²) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mg²/dL²]	55.54 (15.81)	57.37 (15.51)	56.46 (15.67)

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants With a > 30% Decrease From Baseline in Mean PTH During the Efficacy Assessment Phase
Description	Participants who did not have any scheduled assessments during the EAP were considered non-responders.
Time Frame	Baseline and the efficacy assessment phase (EAP; defined as Weeks 20 to 27, inclusive).

Outcome Measure Data

Analysis Population Description

The full analysis set, consisting of all randomized participants

Arm/Group Title	Placebo	Etelcalcetide
Arm/Group Description	Participants received placebo administered by intravenous bolus injection at the end of each hemodialysis session, three times per week (TIW) for 26 weeks.	Participants received etelcalcetide administered by intravenous bolus injection at the end of each hemodialysis session, TIW, for 26 weeks. The starting dose was 5 mg and may have been increased at weeks 5, 9, 13 and 17 to achieve a predialysis PTH ≤ 300 pg/mL.
Measure Participants	254	254
Number [percentage of participants]	8.3 3.3%	74.0 29.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Etelcalcetide
	Comments	A Cochran-Mantel-Haenszel test stratified by screening PTH category (< 600, ≥ 600 to ≤ 1000, and > 1000 pg/mL), recent cinacalcet use within 8 weeks before randomization (yes and no), and region (North America and non-North America) was used to compare the primary endpoint of proportion of participants with > 30% reduction from baseline in PTH during the EAP between etelcalcetide and placebo.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	32.46
	Confidence Interval	(2-Sided) 95%; 18.71 to 56.31
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Percentage of Participants With Mean Predialysis Parathyroid Hormone ≤ 300 pg/mL During the Efficacy Assessment Phase
Description	Participants who had no scheduled assessments during the EAP were considered non-responders.
Time Frame	Baseline and the efficacy assessment phase (Week 20 to Week 27)

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	Placebo	Etelcalcetide
Arm/Group Description	Participants received placebo administered by intravenous bolus injection at the end of each hemodialysis session, three times per week (TIW) for 26 weeks.	Participants received etelcalcetide administered by intravenous bolus injection at the end of each hemodialysis session, TIW, for 26 weeks. The starting dose was 5 mg and may have been increased at weeks 5, 9, 13 and 17 to achieve a predialysis PTH ≤ 300 pg/mL.
Measure Participants	254	254
Number [percentage of participants]	5.1 2%	49.6 19.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Etelcalcetide
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	Cochran-Mantel-Haenszel test stratified by screening PTH category, recent cinacalcet use within 8 weeks before randomization, and region.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	22.08
	Confidence Interval	(2-Sided) 95%; 11.47 to 42.48
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Percent Change From Baseline in Predialysis PTH During the Efficacy Assessment Phase
Time Frame	Baseline and the Efficacy Assessment Phase (Week 20 to Week 27)

Outcome Measure Data

Analysis Population Description

Full analysis set participants with observed data

Arm/Group Title	Placebo	Etelcalcetide
Arm/Group Description	Participants received placebo administered by intravenous bolus injection at the end of each hemodialysis session, three times per week (TIW) for 26 weeks.	Participants received etelcalcetide administered by intravenous bolus injection at the end of each hemodialysis session, TIW, for 26 weeks. The starting dose was 5 mg and may have been increased at weeks 5, 9, 13 and 17 to achieve a predialysis PTH ≤ 300 pg/mL.
Measure Participants	219	229
Mean (Standard Error) [percent change]	13.00 (2.81)	-55.11 (1.94)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Etelcalcetide
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Repeated Measures Mixed Effects Model
	Comments	Repeated measures mixed-effects model included treatment, stratification factors, visit, and treatment by visit interaction as covariates.
Method of Estimation	Estimation Parameter	Mean Difference
	Estimated Value	-71.11
	Confidence Interval	(2-Sided) 95%; -77.77 to -64.46
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.39
	Estimation Comments	Etelcalcetide - Placebo

4. Secondary Outcome

Title	Percent Change From Baseline in Predialysis Corrected Calcium During the Efficacy Assessment Phase
Time Frame	Baseline and the efficacy assessment phase (Week 20 to Week 27)

Outcome Measure Data

Analysis Population Description

Full analysis set participants with observed data

Arm/Group Title	Placebo	Etelcalcetide
Arm/Group Description	Participants received placebo administered by intravenous bolus injection at the end of each hemodialysis session, three times per week (TIW) for 26 weeks.	Participants received etelcalcetide administered by intravenous bolus injection at the end of each hemodialysis session, TIW, for 26 weeks. The starting dose was 5 mg and may have been increased at weeks 5, 9, 13 and 17 to achieve a predialysis PTH ≤ 300 pg/mL.
Measure Participants	219	229
Mean (Standard Error) [percent change]	1.18 (0.29)	-7.29 (0.53)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Etelcalcetide
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Repeated Measures Mixed Effects Model
	Comments	Repeated measures mixed-effects model included treatment, stratification factors, visit, and treatment by visit interaction as covariates.
Method of Estimation	Estimation Parameter	Mean Difference
	Estimated Value	-8.38
	Confidence Interval	(2-Sided) 95%; -9.52 to -7.23
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.58
	Estimation Comments	Etelcalcetide - Placebo

5. Secondary Outcome

Title	Percent Change From Baseline in Predialysis Corrected Calcium Phosphorus Product During the Efficacy Assessment Phase
Time Frame	Baseline and the efficacy assessment phase (Week 20 to Week 27)

Outcome Measure Data

Analysis Population Description

Full analysis set participants with observed data

Arm/Group Title	Placebo	Etelcalcetide
Arm/Group Description	Participants received placebo administered by intravenous bolus injection at the end of each hemodialysis session, three times per week (TIW) for 26 weeks.	Participants received etelcalcetide administered by intravenous bolus injection at the end of each hemodialysis session, TIW, for 26 weeks. The starting dose was 5 mg and may have been increased at weeks 5, 9, 13 and 17 to achieve a predialysis PTH ≤ 300 pg/mL.
Measure Participants	213	227
Mean (Standard Error) [percent change]	-0.19 (1.44)	-14.34 (2.06)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Etelcalcetide
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Repeated Measures Mixed Effects Model
	Comments	Repeated measures mixed-effects model included treatment, stratification factors, visit, and treatment by visit interaction as covariates.
Method of Estimation	Estimation Parameter	Mean Difference
	Estimated Value	-14.99
	Confidence Interval	(2-Sided) 95%; -19.73 to -10.25
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.41
	Estimation Comments	Etelcalcetide - Placebo

6. Secondary Outcome

Title	Percent Change From Baseline in Predialysis Phosphorus During the Efficacy Assessment Phase
Time Frame	Baseline and the efficacy assessment phase (Week 20 to Week 27)

Outcome Measure Data

Analysis Population Description

Full analysis set participants with observed data

Arm/Group Title	Placebo	Etelcalcetide
Arm/Group Description	Participants received placebo administered by intravenous bolus injection at the end of each hemodialysis session, three times per week (TIW) for 26 weeks.	Participants received etelcalcetide administered by intravenous bolus injection at the end of each hemodialysis session, TIW, for 26 weeks. The starting dose was 5 mg and may have been increased at weeks 5, 9, 13 and 17 to achieve a predialysis PTH ≤ 300 pg/mL.
Measure Participants	214	227
Mean (Standard Deviation) [percent change]	-1.31 (1.42)	-7.71 (2.16)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Etelcalcetide
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.003
	Comments
	Method	Repeated Measures Mixed Effects Model
	Comments	Repeated measures mixed-effects model included treatment, stratification factors, visit, and treatment by visit interaction as covariates.
Method of Estimation	Estimation Parameter	Mean Difference
	Estimated Value	-7.45
	Confidence Interval	(2-Sided) 95%; -12.31 to -2.59
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.47
	Estimation Comments	Etelcalcetide - Placebo

Adverse Events

Time Frame	From Day 1 until 30 days after the last dose; the treatment period was 26 weeks.
Adverse Event Reporting Description	Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.
Arm/Group Title	Placebo		Etelcalcetide
Arm/Group Description	Participants received placebo administered by intravenous bolus injection at the end of each hemodialysis session, three times per week (TIW) for 26 weeks.		Participants received etelcalcetide administered by intravenous bolus injection at the end of each hemodialysis session, TIW, for 26 weeks. The starting dose was 5 mg and may have been increased at weeks 5, 9, 13 and 17 to achieve a predialysis PTH ≤ 300 pg/mL.
All Cause Mortality
	Placebo		Etelcalcetide
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo		Etelcalcetide
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	78/254 (30.7%)		68/251 (27.1%)
Blood and lymphatic system disorders
Anaemia	4/254 (1.6%)		0/251 (0%)
Bone marrow failure	1/254 (0.4%)		0/251 (0%)
Nephrogenic anaemia	1/254 (0.4%)		0/251 (0%)
Cardiac disorders
Angina pectoris	1/254 (0.4%)		6/251 (2.4%)
Angina unstable	1/254 (0.4%)		0/251 (0%)
Aortic valve stenosis	0/254 (0%)		2/251 (0.8%)
Atrial fibrillation	4/254 (1.6%)		3/251 (1.2%)
Atrial flutter	1/254 (0.4%)		1/251 (0.4%)
Atrioventricular block first degree	1/254 (0.4%)		0/251 (0%)
Bradyarrhythmia	1/254 (0.4%)		0/251 (0%)
Cardiac arrest	1/254 (0.4%)		1/251 (0.4%)
Cardiac failure	1/254 (0.4%)		2/251 (0.8%)
Cardiac failure congestive	1/254 (0.4%)		3/251 (1.2%)
Cardiogenic shock	0/254 (0%)		1/251 (0.4%)
Cardiomyopathy	1/254 (0.4%)		0/251 (0%)
Coronary artery disease	2/254 (0.8%)		2/251 (0.8%)
Coronary artery occlusion	0/254 (0%)		1/251 (0.4%)
Myocardial infarction	1/254 (0.4%)		2/251 (0.8%)
Myocardial ischaemia	1/254 (0.4%)		1/251 (0.4%)
Supraventricular tachycardia	0/254 (0%)		1/251 (0.4%)
Ventricular fibrillation	1/254 (0.4%)		0/251 (0%)
Ventricular tachycardia	0/254 (0%)		1/251 (0.4%)
Congenital, familial and genetic disorders
Sickle cell anaemia with crisis	1/254 (0.4%)		0/251 (0%)
Eye disorders
Conjunctivitis allergic	1/254 (0.4%)		0/251 (0%)
Gastrointestinal disorders
Abdominal discomfort	0/254 (0%)		1/251 (0.4%)
Abdominal pain	2/254 (0.8%)		0/251 (0%)
Abdominal pain upper	1/254 (0.4%)		1/251 (0.4%)
Constipation	0/254 (0%)		1/251 (0.4%)
Diarrhoea	1/254 (0.4%)		0/251 (0%)
Gastric ulcer	0/254 (0%)		1/251 (0.4%)
Gastritis	1/254 (0.4%)		0/251 (0%)
Gastrointestinal haemorrhage	2/254 (0.8%)		0/251 (0%)
Gastrointestinal telangiectasia	1/254 (0.4%)		0/251 (0%)
Gastrooesophageal reflux disease	1/254 (0.4%)		0/251 (0%)
Haematochezia	1/254 (0.4%)		0/251 (0%)
Impaired gastric emptying	0/254 (0%)		1/251 (0.4%)
Large intestine polyp	0/254 (0%)		1/251 (0.4%)
Oesophageal ulcer haemorrhage	0/254 (0%)		1/251 (0.4%)
Pancreatitis	1/254 (0.4%)		1/251 (0.4%)
Small intestinal obstruction	1/254 (0.4%)		0/251 (0%)
Tooth impacted	1/254 (0.4%)		0/251 (0%)
Upper gastrointestinal haemorrhage	1/254 (0.4%)		0/251 (0%)
Vomiting	0/254 (0%)		1/251 (0.4%)
General disorders
Brain death	1/254 (0.4%)		0/251 (0%)
Chills	2/254 (0.8%)		0/251 (0%)
Death	0/254 (0%)		1/251 (0.4%)
Device issue	0/254 (0%)		1/251 (0.4%)
Impaired healing	1/254 (0.4%)		0/251 (0%)
Malaise	2/254 (0.8%)		0/251 (0%)
Medical device complication	0/254 (0%)		2/251 (0.8%)
Non-cardiac chest pain	2/254 (0.8%)		3/251 (1.2%)
Pyrexia	3/254 (1.2%)		0/251 (0%)
Thrombosis in device	1/254 (0.4%)		0/251 (0%)
Hepatobiliary disorders
Acute hepatic failure	0/254 (0%)		1/251 (0.4%)
Bile duct stone	1/254 (0.4%)		1/251 (0.4%)
Cholangitis	0/254 (0%)		1/251 (0.4%)
Cholecystitis	1/254 (0.4%)		1/251 (0.4%)
Cholelithiasis	1/254 (0.4%)		0/251 (0%)
Hyperbilirubinaemia	0/254 (0%)		1/251 (0.4%)
Ischaemic hepatitis	1/254 (0.4%)		0/251 (0%)
Immune system disorders
Kidney transplant rejection	1/254 (0.4%)		0/251 (0%)
Infections and infestations
Abdominal wall abscess	1/254 (0.4%)		0/251 (0%)
Abscess limb	1/254 (0.4%)		0/251 (0%)
Arteriovenous graft site infection	1/254 (0.4%)		0/251 (0%)
Arthritis bacterial	0/254 (0%)		1/251 (0.4%)
Bacteraemia	1/254 (0.4%)		0/251 (0%)
Bronchitis	0/254 (0%)		1/251 (0.4%)
Cellulitis	1/254 (0.4%)		1/251 (0.4%)
Clostridium difficile infection	1/254 (0.4%)		0/251 (0%)
Device related infection	0/254 (0%)		1/251 (0.4%)
Diabetic foot infection	1/254 (0.4%)		0/251 (0%)
Endocarditis bacterial	1/254 (0.4%)		0/251 (0%)
Gangrene	1/254 (0.4%)		1/251 (0.4%)
Gastroenteritis	0/254 (0%)		2/251 (0.8%)
H1N1 influenza	0/254 (0%)		1/251 (0.4%)
Lobar pneumonia	0/254 (0%)		1/251 (0.4%)
Osteomyelitis	1/254 (0.4%)		2/251 (0.8%)
Osteomyelitis acute	1/254 (0.4%)		0/251 (0%)
Pneumonia	4/254 (1.6%)		6/251 (2.4%)
Sepsis	3/254 (1.2%)		2/251 (0.8%)
Septic embolus	0/254 (0%)		1/251 (0.4%)
Septic shock	1/254 (0.4%)		1/251 (0.4%)
Staphylococcal sepsis	1/254 (0.4%)		0/251 (0%)
Subacute endocarditis	1/254 (0.4%)		0/251 (0%)
Upper respiratory tract infection	0/254 (0%)		1/251 (0.4%)
Urinary tract infection	2/254 (0.8%)		1/251 (0.4%)
Viral upper respiratory tract infection	0/254 (0%)		1/251 (0.4%)
Wound infection	0/254 (0%)		1/251 (0.4%)
Injury, poisoning and procedural complications
Ankle fracture	1/254 (0.4%)		0/251 (0%)
Arteriovenous fistula site complication	0/254 (0%)		2/251 (0.8%)
Arteriovenous fistula thrombosis	3/254 (1.2%)		0/251 (0%)
Clavicle fracture	1/254 (0.4%)		0/251 (0%)
Concussion	1/254 (0.4%)		0/251 (0%)
Femur fracture	2/254 (0.8%)		1/251 (0.4%)
Foot fracture	1/254 (0.4%)		0/251 (0%)
Graft haemorrhage	0/254 (0%)		1/251 (0.4%)
Hip fracture	0/254 (0%)		1/251 (0.4%)
Limb injury	1/254 (0.4%)		0/251 (0%)
Pelvic fracture	1/254 (0.4%)		0/251 (0%)
Peripheral artery restenosis	1/254 (0.4%)		0/251 (0%)
Perirenal haematoma	1/254 (0.4%)		0/251 (0%)
Postoperative respiratory distress	0/254 (0%)		1/251 (0.4%)
Rib fracture	1/254 (0.4%)		0/251 (0%)
Road traffic accident	0/254 (0%)		1/251 (0.4%)
Scapula fracture	0/254 (0%)		1/251 (0.4%)
Shunt thrombosis	0/254 (0%)		1/251 (0.4%)
Subdural haematoma	0/254 (0%)		1/251 (0.4%)
Vascular graft complication	0/254 (0%)		1/251 (0.4%)
Vascular graft thrombosis	1/254 (0.4%)		1/251 (0.4%)
Wound	1/254 (0.4%)		0/251 (0%)
Wound secretion	1/254 (0.4%)		0/251 (0%)
Investigations
Anticoagulation drug level above therapeutic	1/254 (0.4%)		0/251 (0%)
Metabolism and nutrition disorders
Diabetes mellitus inadequate control	0/254 (0%)		1/251 (0.4%)
Diabetic ketoacidosis	1/254 (0.4%)		0/251 (0%)
Fluid overload	5/254 (2%)		4/251 (1.6%)
Hyperglycaemia	1/254 (0.4%)		2/251 (0.8%)
Hyperkalaemia	1/254 (0.4%)		4/251 (1.6%)
Hypervolaemia	0/254 (0%)		1/251 (0.4%)
Hypoglycaemia	2/254 (0.8%)		2/251 (0.8%)
Metabolic acidosis	0/254 (0%)		1/251 (0.4%)
Musculoskeletal and connective tissue disorders
Arthritis	1/254 (0.4%)		0/251 (0%)
Back pain	1/254 (0.4%)		0/251 (0%)
Haemarthrosis	1/254 (0.4%)		0/251 (0%)
Lumbar spinal stenosis	1/254 (0.4%)		0/251 (0%)
Osteoarthritis	1/254 (0.4%)		0/251 (0%)
Spinal pain	1/254 (0.4%)		0/251 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Biliary cancer metastatic	0/254 (0%)		1/251 (0.4%)
Bone giant cell tumour benign	1/254 (0.4%)		0/251 (0%)
Lung neoplasm	0/254 (0%)		1/251 (0.4%)
Malignant melanoma	0/254 (0%)		1/251 (0.4%)
Nervous system disorders
Cerebrovascular accident	0/254 (0%)		1/251 (0.4%)
Convulsion	2/254 (0.8%)		1/251 (0.4%)
Haemorrhagic cerebral infarction	1/254 (0.4%)		0/251 (0%)
Hepatic encephalopathy	1/254 (0.4%)		0/251 (0%)
Hypoxic-ischaemic encephalopathy	1/254 (0.4%)		0/251 (0%)
Neuropathy peripheral	1/254 (0.4%)		0/251 (0%)
Syncope	0/254 (0%)		1/251 (0.4%)
Psychiatric disorders
Anxiety	0/254 (0%)		1/251 (0.4%)
Confusional state	1/254 (0.4%)		0/251 (0%)
Delirium	0/254 (0%)		1/251 (0.4%)
Mental status changes	0/254 (0%)		1/251 (0.4%)
Renal and urinary disorders
Urinary retention	0/254 (0%)		1/251 (0.4%)
Reproductive system and breast disorders
Ovarian cyst	2/254 (0.8%)		0/251 (0%)
Respiratory, thoracic and mediastinal disorders
Acute pulmonary oedema	1/254 (0.4%)		2/251 (0.8%)
Acute respiratory distress syndrome	0/254 (0%)		1/251 (0.4%)
Asthma	0/254 (0%)		1/251 (0.4%)
Chronic obstructive pulmonary disease	1/254 (0.4%)		1/251 (0.4%)
Dyspnoea	1/254 (0.4%)		2/251 (0.8%)
Dyspnoea exertional	1/254 (0.4%)		0/251 (0%)
Pleural effusion	1/254 (0.4%)		0/251 (0%)
Pulmonary oedema	1/254 (0.4%)		1/251 (0.4%)
Respiratory failure	1/254 (0.4%)		0/251 (0%)
Skin and subcutaneous tissue disorders
Diabetic foot	1/254 (0.4%)		0/251 (0%)
Skin ulcer	1/254 (0.4%)		1/251 (0.4%)
Vascular disorders
Accelerated hypertension	1/254 (0.4%)		0/251 (0%)
Aortic stenosis	0/254 (0%)		1/251 (0.4%)
Blood pressure fluctuation	1/254 (0.4%)		0/251 (0%)
Deep vein thrombosis	1/254 (0.4%)		0/251 (0%)
Granulomatosis with polyangiitis	0/254 (0%)		1/251 (0.4%)
Haematoma	1/254 (0.4%)		0/251 (0%)
Hypertension	2/254 (0.8%)		0/251 (0%)
Hypertensive emergency	0/254 (0%)		1/251 (0.4%)
Hypotension	1/254 (0.4%)		2/251 (0.8%)
Peripheral arterial occlusive disease	2/254 (0.8%)		1/251 (0.4%)
Peripheral artery stenosis	1/254 (0.4%)		0/251 (0%)
Peripheral vascular disorder	1/254 (0.4%)		1/251 (0.4%)
Shock	0/254 (0%)		1/251 (0.4%)
Shock haemorrhagic	0/254 (0%)		1/251 (0.4%)
Vascular rupture	1/254 (0.4%)		0/251 (0%)
Vascular stenosis	1/254 (0.4%)		0/251 (0%)
Venous stenosis	0/254 (0%)		1/251 (0.4%)
Other (Not Including Serious) Adverse Events
	Placebo		Etelcalcetide
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	110/254 (43.3%)		194/251 (77.3%)
Gastrointestinal disorders
Diarrhoea	17/254 (6.7%)		18/251 (7.2%)
Nausea	13/254 (5.1%)		31/251 (12.4%)
Vomiting	18/254 (7.1%)		25/251 (10%)
Infections and infestations
Nasopharyngitis	13/254 (5.1%)		11/251 (4.4%)
Injury, poisoning and procedural complications
Arteriovenous fistula site complication	14/254 (5.5%)		11/251 (4.4%)
Investigations
Blood calcium decreased	21/254 (8.3%)		153/251 (61%)
Metabolism and nutrition disorders
Hypocalcaemia	1/254 (0.4%)		18/251 (7.2%)
Musculoskeletal and connective tissue disorders
Muscle spasms	18/254 (7.1%)		30/251 (12%)
Pain in extremity	11/254 (4.3%)		17/251 (6.8%)
Nervous system disorders
Headache	20/254 (7.9%)		18/251 (7.2%)
Paraesthesia	3/254 (1.2%)		13/251 (5.2%)
Vascular disorders
Hypertension	16/254 (6.3%)		12/251 (4.8%)
Hypotension	10/254 (3.9%)		14/251 (5.6%)

Limitations/Caveats

[Not Specified]

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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.