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

• Sponsor: Amgen (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01788046
• Collaborator: (none)
• Enrollment: 515
• Locations: 106
• Arms: 2
• Actual Duration (Months): 13.9
• Patients Per Site: 4.9
• 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 (AMG 416) compared with placebo in the treatment of SHPT in CKD patients receiving hemodialysis.

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

Study Design

• Study Type: Interventional
• Actual Enrollment: 515 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: Apr 14, 2014
• Actual Study Completion Date: May 9, 2014

Arms and Interventions

Arm	Intervention/Treatment
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.
Experimental: Etelcalcetide Participants received etelcalcetide administered by intravenous bolus injection at the end of each hemodialysis session TIW for 26 weeks.	Drug: Etelcalcetide; Administered intravenously three times per week. The starting dose was 5 mg. The dose may have been increased at weeks 5, 9, 13, and 17 (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

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants With > 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 (cCa x P) 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 agrees to not participate in another study of an investigational agent during the study.

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

• 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

• 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.

• Subject has a history of any illness that, in the opinion of the Investigator, might confound the results of the study or pose additional risk to the subject.

• Other Exclusion Criteria may apply

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	Mobile	Alabama	United States	36608
2	Research Site	Azusa	California	United States	91702
3	Research Site	Beverly Hills	California	United States	90211
4	Research Site	Chula Vista	California	United States	91910
5	Research Site	Fairfield	California	United States	94534
6	Research Site	Glendale	California	United States	91205
7	Research Site	Los Angeles	California	United States	90022
8	Research Site	Northridge	California	United States	91324
9	Research Site	Norwalk	California	United States	90650
10	Research Site	Riverside	California	United States	92501
11	Research Site	Simi Valley	California	United States	93065
12	Research Site	Denver	Colorado	United States	80230
13	Research Site	Stamford	Connecticut	United States	06902
14	Research Site	Lauderdale Lakes	Florida	United States	33313
15	Research Site	Miami	Florida	United States	33173
16	Research Site	Ocala	Florida	United States	34471
17	Research Site	Augusta	Georgia	United States	30901
18	Research Site	Macon	Georgia	United States	31217
19	Research Site	Chicago	Illinois	United States	60616
20	Research Site	Gurnee	Illinois	United States	60031
21	Research Site	Merrillville	Indiana	United States	46410
22	Research Site	Wichita	Kansas	United States	67214-2998
23	Research Site	Shreveport	Louisiana	United States	71101
24	Research Site	Bethesda	Maryland	United States	20817
25	Research Site	Fort Washington	Maryland	United States	20744
26	Research Site	Detroit	Michigan	United States	48202
27	Research Site	Brookhaven	Mississippi	United States	39601
28	Research Site	Lincoln	Nebraska	United States	68510
29	Research Site	Las Vegas	Nevada	United States	89106
30	Research Site	Eatontown	New Jersey	United States	07724
31	Research Site	Brooklyn	New York	United States	11212
32	Research Site	Fresh Meadows	New York	United States	11365
33	Research Site	Great Neck	New York	United States	11021
34	Research Site	Charlotte	North Carolina	United States	28207
35	Research Site	New Bern	North Carolina	United States	28562
36	Research Site	Cincinnati	Ohio	United States	45206
37	Research Site	Columbia	South Carolina	United States	29203
38	Research Site	Chattanooga	Tennessee	United States	37408
39	Research Site	Knoxville	Tennessee	United States	37923
40	Research Site	Arlington	Texas	United States	76015
41	Research Site	Houston	Texas	United States	77054
42	Research Site	Lubbock	Texas	United States	79430
43	Research Site	Rutland	Vermont	United States	05701
44	Research Site	Alexandria	Virginia	United States	22304
45	Research Site	Morgantown	West Virginia	United States	26506-9165
46	Research Site	Westmead	New South Wales	Australia	2145
47	Research Site	Brisbane	Queensland	Australia	4102
48	Research Site	Adelaide	South Australia	Australia	5000
49	Research Site	Clayton	Victoria	Australia	3168
50	Research Site	Bonheiden		Belgium	2820
51	Research Site	Brussels		Belgium	1200
52	Research Site	Brussel		Belgium	1090
53	Research Site	Liege		Belgium	4000
54	Research Site	Roeselare		Belgium	8800
55	Research Site	Tournai		Belgium	7500
56	Research Site	Edmonton	Alberta	Canada	T6G 2B7
57	Research Site	New Westminister	British Columbia	Canada	V3L 0A6
58	Research Site	Halifax	Nova Scotia	Canada	B3H 1V7
59	Research Site	Toronto	Ontario	Canada	M5C 2T2
60	Research Site	Montreal	Quebec	Canada	H4J 1C5
61	Research Site	Novy Jicin		Czechia	741 01
62	Research Site	Plzen		Czechia	301 00
63	Research Site	Praha 4		Czechia	140 21
64	Research Site	Usti nad Orlici		Czechia	562 18
65	Research Site	Bordeaux Cedex		France	33075
66	Research Site	Caen		France	14000
67	Research Site	Grenoble		France	38000
68	Research Site	Marseille cedex 5		France	13385
69	Research Site	Marseille		France	13253
70	Research Site	Perpignan Cedex		France	66046
71	Research Site	Erfurt		Germany	99089
72	Research Site	Budapest		Hungary	1076
73	Research Site	Budapest		Hungary	1106
74	Research Site	Esztergom		Hungary	2500
75	Research Site	Kecskemet		Hungary	6000
76	Research Site	Miskolc		Hungary	3526
77	Research Site	Zalaegerszeg		Hungary	8900
78	Research Site	Jerusalem		Israel	91120
79	Research Site	Kfar-Saba		Israel	44281
80	Research Site	Tel Hashomer		Israel	52621
81	Research Site	Zerifin		Israel	70300
82	Research Site	Ancona		Italy	60131
83	Research Site	Lecco		Italy	23900
84	Research Site	Milano		Italy	20142
85	Research Site	Quartu Sant'Elena CA		Italy	09045
86	Research Site	Amsterdam		Netherlands	1081 HV
87	Research Site	Enschede		Netherlands	7511 JX
88	Research Site	Rotterdam		Netherlands	3079 DZ
89	Research Site	Venlo		Netherlands	5912 BL
90	Research Site	Gdansk		Poland	80-952
91	Research Site	Golub-Dobrzyn		Poland	87-400
92	Research Site	Krakow		Poland	31-501
93	Research Site	Lodz		Poland	90-153
94	Research Site	Rybnik		Poland	44-200
95	Research Site	Warszawa		Poland	04-749
96	Research Site	Moscow		Russian Federation	123183
97	Research Site	Saint Petersburg		Russian Federation	197110
98	Research Site	Yaroslavl		Russian Federation	150062
99	Research Site	Cordoba	Andalucía	Spain	14004
100	Research Site	Granada	Andalucía	Spain	18012
101	Research Site	Barcelona	Cataluña	Spain	08035
102	Research Site	Barcelona	Cataluña	Spain	08036
103	Research Site	Majadahonda	Madrid	Spain	28222
104	Research Site	Karlstad		Sweden	651 85
105	Research Site	Stockholm		Sweden	141 86
106	Research Site	Uppsala		Sweden	751 85

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: NCT01788046
• Other Study ID Numbers: 20120230; KAI-4169-007; 2012-002806-31
• First Posted: Feb 11, 2013
• Last Update Posted: Aug 20, 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 97 centers in the US, Canada, Europe, Israel, the Russian Federation, and Australia. The first participant was enrolled on 12 March 2013, and the last participant 07 October 2013.
Pre-assignment Detail	Eligible participants were randomized 1:1 to etelcalcetide or placebo. Randomization was stratified by 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.
Period Title: Overall Study
STARTED	260	255
Received Treatment	259	252
COMPLETED	204	218
NOT COMPLETED	56	37

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.	Total of all reporting groups
Overall Participants	260	255	515
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	59.0 (13.9)	58.4 (14.6)	58.7 (14.3)
Sex: Female, Male (Count of Participants)
Female	95 36.5%	93 36.5%	188 36.5%
Male	165 63.5%	162 63.5%	327 63.5%
Race/Ethnicity, Customized (participants) [Number]
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	6 2.3%	13 5.1%	19 3.7%
Black (or African American)	80 30.8%	64 25.1%	144 28%
Native Hawaiian or Other Pacific Islander	3 1.2%	7 2.7%	10 1.9%
White	169 65%	163 63.9%	332 64.5%
Other	2 0.8%	6 2.4%	8 1.6%
Missing	0 0%	2 0.8%	2 0.4%
Race/Ethnicity, Customized (participants) [Number]
Hispanic/Latino	33 12.7%	32 12.5%	65 12.6%
Not Hispanic/Latino	227 87.3%	221 86.7%	448 87%
Missing	0 0%	2 0.8%	2 0.4%
Stratification Factor: Screening Serum Parathroid Hormone (participants) [Number]
< 600 pg/mL	84 32.3%	84 32.9%	168 32.6%
≥ 600 to ≤ 1000 pg/mL	121 46.5%	118 46.3%	239 46.4%
> 1000 pg/mL	55 21.2%	53 20.8%	108 21%
Stratification Factor: Cinacalcet Use Within 8 Weeks of Randomization (participants) [Number]
Yes	33 12.7%	29 11.4%	62 12%
No	227 87.3%	226 88.6%	453 88%
Stratification Factor: Region (participants) [Number]
North America	150 57.7%	146 57.3%	296 57.5%
Non-North America	110 42.3%	109 42.7%	219 42.5%
Parathyroid Hormone (pg/mL) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [pg/mL]	851.7 (552.0)	845.0 (464.3)	848.4 (510.0)
Phosphorus (mg/dL) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mg/dL]	5.83 (1.45)	5.76 (1.60)	5.79 (1.53)
Corrected Calcium (cCa) (mg/dL) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mg/dL]	9.70 (0.69)	9.63 (0.65)	9.66 (0.67)
Corrected Calcium Phosphorus Product (cCa x P) (mg²/dL²) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mg²/dL²]	56.37 (14.50)	55.30 (15.27)	55.84 (14.88)

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants With > 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.
Measure Participants	260	255
Number [percentage of participants]	9.6 3.7%	75.3 29.5%

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 percentage 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	30.80
	Confidence Interval	(2-Sided) 95%; 18.18 to 52.17
	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.
Measure Participants	260	255
Number [percentage of participants]	4.6 1.8%	53.3 20.9%

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	Stratified by screening PTH category, prior cinacalcet use within 8 weeks prior to randomization, and region.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	33.92
	Confidence Interval	(2-Sided) 95%; 16.35 to 70.37
	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.
Measure Participants	237	227
Mean (Standard Error) [percent change]	13.72 (2.50)	-57.39 (1.91)

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	-71.34
	Confidence Interval	(2-Sided) 95%; -77.53 to -65.14
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.15
	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.
Measure Participants	237	227
Mean (Standard Error) [percent change]	0.58 (0.29)	-6.69 (0.55)

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	-7.20
	Confidence Interval	(2-Sided) 95%; -8.38 to -6.03
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.60
	Estimation Comments	Etelcalcetide - Placebo

5. Secondary Outcome

Title	Percent Change From Baseline in Predialysis Corrected Calcium Phosphorus Product (cCa x P) 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.
Measure Participants	234	223
Mean (Standard Error) [percent change]	-1.06 (1.42)	-15.84 (1.57)

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	-14.58
	Confidence Interval	(2-Sided) 95%; -18.65 to -10.51
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.07
	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.
Measure Participants	234	223
Mean (Standard Error) [percent change]	-1.60 (1.42)	-9.63 (1.61)

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	-8.04
	Confidence Interval	(2-Sided) 95%; -12.15 to -3.92
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.09
	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.
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	71/259 (27.4%)		62/252 (24.6%)
Blood and lymphatic system disorders
Anaemia	1/259 (0.4%)		1/252 (0.4%)
Bone marrow failure	1/259 (0.4%)		0/252 (0%)
Cardiac disorders
Acute myocardial infarction	3/259 (1.2%)		3/252 (1.2%)
Angina pectoris	2/259 (0.8%)		1/252 (0.4%)
Angina unstable	1/259 (0.4%)		1/252 (0.4%)
Arrhythmia	1/259 (0.4%)		0/252 (0%)
Arteriosclerosis coronary artery	1/259 (0.4%)		0/252 (0%)
Atrial fibrillation	1/259 (0.4%)		2/252 (0.8%)
Atrioventricular block complete	0/259 (0%)		1/252 (0.4%)
Bundle branch block right	1/259 (0.4%)		0/252 (0%)
Cardiac failure	0/259 (0%)		1/252 (0.4%)
Cardiac failure congestive	4/259 (1.5%)		2/252 (0.8%)
Coronary artery disease	0/259 (0%)		1/252 (0.4%)
Coronary artery stenosis	0/259 (0%)		1/252 (0.4%)
Left ventricular hypertrophy	1/259 (0.4%)		0/252 (0%)
Myocardial infarction	2/259 (0.8%)		2/252 (0.8%)
Supraventricular tachycardia	1/259 (0.4%)		0/252 (0%)
Tachycardia	1/259 (0.4%)		0/252 (0%)
Ventricular tachycardia	0/259 (0%)		1/252 (0.4%)
Ear and labyrinth disorders
Vertigo	1/259 (0.4%)		0/252 (0%)
Endocrine disorders
Primary hyperaldosteronism	1/259 (0.4%)		0/252 (0%)
Gastrointestinal disorders
Abdominal pain	2/259 (0.8%)		0/252 (0%)
Constipation	0/259 (0%)		1/252 (0.4%)
Diarrhoea	1/259 (0.4%)		1/252 (0.4%)
Duodenal ulcer	2/259 (0.8%)		0/252 (0%)
Faecaloma	0/259 (0%)		1/252 (0.4%)
Gastric antral vascular ectasia	0/259 (0%)		1/252 (0.4%)
Haematemesis	0/259 (0%)		1/252 (0.4%)
Lower gastrointestinal haemorrhage	0/259 (0%)		2/252 (0.8%)
Nausea	2/259 (0.8%)		0/252 (0%)
Oesophagitis	1/259 (0.4%)		0/252 (0%)
Pancreatitis	1/259 (0.4%)		0/252 (0%)
General disorders
Asthenia	2/259 (0.8%)		0/252 (0%)
Catheter site haematoma	0/259 (0%)		1/252 (0.4%)
Hernia obstructive	1/259 (0.4%)		0/252 (0%)
Medical device complication	1/259 (0.4%)		0/252 (0%)
Non-cardiac chest pain	2/259 (0.8%)		1/252 (0.4%)
Pyrexia	0/259 (0%)		3/252 (1.2%)
Sudden death	1/259 (0.4%)		1/252 (0.4%)
Surgical failure	0/259 (0%)		1/252 (0.4%)
Hepatobiliary disorders
Cholangitis	0/259 (0%)		1/252 (0.4%)
Cholecystitis	1/259 (0.4%)		0/252 (0%)
Cholecystitis acute	1/259 (0.4%)		0/252 (0%)
Cholelithiasis	1/259 (0.4%)		1/252 (0.4%)
Hepatitis acute	0/259 (0%)		1/252 (0.4%)
Infections and infestations
Abdominal abscess	1/259 (0.4%)		0/252 (0%)
Abscess limb	1/259 (0.4%)		0/252 (0%)
Appendicitis	1/259 (0.4%)		0/252 (0%)
Arteriovenous fistula site infection	0/259 (0%)		1/252 (0.4%)
Bacteraemia	0/259 (0%)		1/252 (0.4%)
Bacterial sepsis	1/259 (0.4%)		0/252 (0%)
Bronchitis	1/259 (0.4%)		1/252 (0.4%)
Burn infection	0/259 (0%)		1/252 (0.4%)
Cellulitis	1/259 (0.4%)		2/252 (0.8%)
Clostridium difficile colitis	1/259 (0.4%)		0/252 (0%)
Clostridium difficile sepsis	1/259 (0.4%)		0/252 (0%)
Device related sepsis	1/259 (0.4%)		0/252 (0%)
Diabetic foot infection	1/259 (0.4%)		0/252 (0%)
Diverticulitis	0/259 (0%)		1/252 (0.4%)
Gangrene	1/259 (0.4%)		1/252 (0.4%)
Gastroenteritis	3/259 (1.2%)		1/252 (0.4%)
Herpes zoster meningoencephalitis	0/259 (0%)		1/252 (0.4%)
Influenza	0/259 (0%)		1/252 (0.4%)
Intervertebral discitis	1/259 (0.4%)		0/252 (0%)
Meningitis aseptic	0/259 (0%)		1/252 (0.4%)
Metapneumovirus infection	1/259 (0.4%)		0/252 (0%)
Ophthalmic herpes zoster	0/259 (0%)		1/252 (0.4%)
Osteomyelitis	3/259 (1.2%)		0/252 (0%)
Periodontitis	1/259 (0.4%)		0/252 (0%)
Pneumonia	10/259 (3.9%)		4/252 (1.6%)
Postoperative abscess	1/259 (0.4%)		0/252 (0%)
Prostatic abscess	0/259 (0%)		1/252 (0.4%)
Respiratory tract infection	1/259 (0.4%)		0/252 (0%)
Sepsis	1/259 (0.4%)		2/252 (0.8%)
Sepsis syndrome	1/259 (0.4%)		0/252 (0%)
Skin graft infection	0/259 (0%)		1/252 (0.4%)
Staphylococcal bacteraemia	0/259 (0%)		1/252 (0.4%)
Staphylococcal sepsis	1/259 (0.4%)		1/252 (0.4%)
Upper respiratory tract infection	1/259 (0.4%)		0/252 (0%)
Urinary tract infection	2/259 (0.8%)		2/252 (0.8%)
Urinary tract infection bacterial	1/259 (0.4%)		0/252 (0%)
Urinary tract infection enterococcal	1/259 (0.4%)		0/252 (0%)
Urinary tract infection fungal	1/259 (0.4%)		0/252 (0%)
Viral infection	1/259 (0.4%)		0/252 (0%)
Viral myocarditis	0/259 (0%)		1/252 (0.4%)
Injury, poisoning and procedural complications
Arteriovenous fistula aneurysm	0/259 (0%)		1/252 (0.4%)
Arteriovenous fistula occlusion	1/259 (0.4%)		0/252 (0%)
Arteriovenous fistula site haematoma	1/259 (0.4%)		0/252 (0%)
Arteriovenous fistula site haemorrhage	1/259 (0.4%)		0/252 (0%)
Arteriovenous fistula thrombosis	2/259 (0.8%)		2/252 (0.8%)
Avulsion fracture	1/259 (0.4%)		0/252 (0%)
Burns second degree	1/259 (0.4%)		0/252 (0%)
Clavicle fracture	1/259 (0.4%)		0/252 (0%)
Complications of transplanted kidney	1/259 (0.4%)		0/252 (0%)
Face injury	0/259 (0%)		1/252 (0.4%)
Fall	0/259 (0%)		1/252 (0.4%)
Femur fracture	1/259 (0.4%)		1/252 (0.4%)
Graft complication	1/259 (0.4%)		0/252 (0%)
Hip fracture	1/259 (0.4%)		0/252 (0%)
Postoperative respiratory failure	0/259 (0%)		1/252 (0.4%)
Procedural hypotension	0/259 (0%)		1/252 (0.4%)
Procedural vomiting	0/259 (0%)		1/252 (0.4%)
Skin graft failure	0/259 (0%)		1/252 (0.4%)
Subdural haematoma	0/259 (0%)		1/252 (0.4%)
Tibia fracture	1/259 (0.4%)		2/252 (0.8%)
Toxicity to various agents	0/259 (0%)		1/252 (0.4%)
Vascular graft complication	1/259 (0.4%)		0/252 (0%)
Vascular graft thrombosis	4/259 (1.5%)		2/252 (0.8%)
Investigations
Electrocardiogram T wave inversion	1/259 (0.4%)		0/252 (0%)
Hepatic enzyme increased	0/259 (0%)		1/252 (0.4%)
Metabolism and nutrition disorders
Abnormal loss of weight	1/259 (0.4%)		0/252 (0%)
Fluid overload	2/259 (0.8%)		2/252 (0.8%)
Hypercalcaemia	1/259 (0.4%)		0/252 (0%)
Hyperglycaemia	0/259 (0%)		1/252 (0.4%)
Hyperkalaemia	1/259 (0.4%)		6/252 (2.4%)
Hypervolaemia	0/259 (0%)		1/252 (0.4%)
Hypoglycaemia	1/259 (0.4%)		1/252 (0.4%)
Hypokalaemia	1/259 (0.4%)		0/252 (0%)
Metabolic acidosis	0/259 (0%)		2/252 (0.8%)
Obesity	1/259 (0.4%)		1/252 (0.4%)
Musculoskeletal and connective tissue disorders
Arthralgia	1/259 (0.4%)		0/252 (0%)
Back pain	2/259 (0.8%)		0/252 (0%)
Muscle twitching	1/259 (0.4%)		0/252 (0%)
Musculoskeletal chest pain	1/259 (0.4%)		0/252 (0%)
Osteitis	1/259 (0.4%)		0/252 (0%)
Systemic lupus erythematosus	1/259 (0.4%)		0/252 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Oesophageal adenocarcinoma	1/259 (0.4%)		0/252 (0%)
Prostate cancer	1/259 (0.4%)		0/252 (0%)
Nervous system disorders
Balance disorder	1/259 (0.4%)		0/252 (0%)
Brain injury	0/259 (0%)		1/252 (0.4%)
Cerebrovascular accident	1/259 (0.4%)		1/252 (0.4%)
Convulsion	2/259 (0.8%)		1/252 (0.4%)
Dementia	1/259 (0.4%)		0/252 (0%)
Haemorrhagic stroke	1/259 (0.4%)		0/252 (0%)
Hyperglycaemic seizure	1/259 (0.4%)		0/252 (0%)
Syncope	1/259 (0.4%)		0/252 (0%)
Tremor	0/259 (0%)		1/252 (0.4%)
Unresponsive to stimuli	2/259 (0.8%)		0/252 (0%)
Uraemic encephalopathy	0/259 (0%)		1/252 (0.4%)
Psychiatric disorders
Anxiety disorder	1/259 (0.4%)		0/252 (0%)
Confusional state	0/259 (0%)		1/252 (0.4%)
Mental status changes	2/259 (0.8%)		2/252 (0.8%)
Renal and urinary disorders
Haematuria	0/259 (0%)		1/252 (0.4%)
Nephrolithiasis	0/259 (0%)		1/252 (0.4%)
Renal cyst haemorrhage	0/259 (0%)		1/252 (0.4%)
Renal failure chronic	1/259 (0.4%)		0/252 (0%)
Urethral stenosis	0/259 (0%)		1/252 (0.4%)
Urinary retention	0/259 (0%)		1/252 (0.4%)
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure	3/259 (1.2%)		0/252 (0%)
Chronic obstructive pulmonary disease	2/259 (0.8%)		2/252 (0.8%)
Dyspnoea	3/259 (1.2%)		2/252 (0.8%)
Hypoxia	0/259 (0%)		1/252 (0.4%)
Non-cardiogenic pulmonary oedema	0/259 (0%)		1/252 (0.4%)
Pleuritic pain	1/259 (0.4%)		0/252 (0%)
Pneumonitis	1/259 (0.4%)		0/252 (0%)
Pulmonary congestion	1/259 (0.4%)		0/252 (0%)
Pulmonary oedema	2/259 (0.8%)		2/252 (0.8%)
Respiratory distress	1/259 (0.4%)		2/252 (0.8%)
Respiratory failure	1/259 (0.4%)		1/252 (0.4%)
Skin and subcutaneous tissue disorders
Blister	1/259 (0.4%)		0/252 (0%)
Diabetic neuropathic ulcer	1/259 (0.4%)		0/252 (0%)
Diabetic ulcer	1/259 (0.4%)		0/252 (0%)
Palpable purpura	0/259 (0%)		1/252 (0.4%)
Skin ulcer	1/259 (0.4%)		1/252 (0.4%)
Surgical and medical procedures
Finger amputation	1/259 (0.4%)		0/252 (0%)
Vascular disorders
Accelerated hypertension	1/259 (0.4%)		0/252 (0%)
Hypertension	0/259 (0%)		1/252 (0.4%)
Hypertensive crisis	1/259 (0.4%)		0/252 (0%)
Hypotension	1/259 (0.4%)		0/252 (0%)
Malignant hypertension	0/259 (0%)		1/252 (0.4%)
Peripheral ischaemia	1/259 (0.4%)		0/252 (0%)
Poor peripheral circulation	1/259 (0.4%)		0/252 (0%)
Thrombophlebitis	1/259 (0.4%)		0/252 (0%)
Thrombosis	1/259 (0.4%)		0/252 (0%)
Venous stenosis	0/259 (0%)		1/252 (0.4%)
Other (Not Including Serious) Adverse Events
	Placebo		Etelcalcetide
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	132/259 (51%)		199/252 (79%)
Blood and lymphatic system disorders
Anaemia	13/259 (5%)		8/252 (3.2%)
Gastrointestinal disorders
Diarrhoea	25/259 (9.7%)		35/252 (13.9%)
Nausea	18/259 (6.9%)		23/252 (9.1%)
Vomiting	8/259 (3.1%)		19/252 (7.5%)
Infections and infestations
Upper respiratory tract infection	15/259 (5.8%)		13/252 (5.2%)
Injury, poisoning and procedural complications
Arteriovenous fistula site complication	12/259 (4.6%)		16/252 (6.3%)
Investigations
Blood calcium decreased	31/259 (12%)		168/252 (66.7%)
Metabolism and nutrition disorders
Hypocalcaemia	0/259 (0%)		17/252 (6.7%)
Musculoskeletal and connective tissue disorders
Arthralgia	15/259 (5.8%)		11/252 (4.4%)
Back pain	9/259 (3.5%)		14/252 (5.6%)
Muscle spasms	16/259 (6.2%)		28/252 (11.1%)
Nervous system disorders
Headache	11/259 (4.2%)		20/252 (7.9%)
Respiratory, thoracic and mediastinal disorders
Cough	15/259 (5.8%)		10/252 (4%)
Vascular disorders
Hypertension	12/259 (4.6%)		18/252 (7.1%)
Hypotension	15/259 (5.8%)		14/252 (5.6%)

Limitations/Caveats

[Not Specified]

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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.