Extension Study of Etelcalcetide in the Treatment of Secondary Hyperparathyroidism (SHPT) in Patients With Chronic Kidney Disease (CKD) on Hemodialysis

A Multicenter Single-arm Extension Study to Describe the Long-term Efficacy and Safety of AMG 416 in the Treatment of Secondary Hyperparathyroidism in Subjects With Chronic Kidney Disease on Hemodialysis

Status

Completed

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01785875

Enrollment

891

Registered

2013-02-07

Start date

2013-07-31

Completion date

2015-07-01

Last updated

2019-04-10

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Hyperparathyroidism, Secondary

Keywords

Secondary Hyperparathyroidism (SHPT), chronic kidney disease (CKD), hemodialysis, parathyroid hormone (PTH), hypocalcemia, bone and mineral metabolism

Brief summary

This study is designed to describe the long-term safety and efficacy of etelcalcetide (AMG 416) for the treatment of SHPT in adults with CKD on hemodialysis.

Interventions

DRUGEtelcalcetide

Administered by bolus injection into the venous line of the dialysis circuit at the end of hemodialysis treatment, and prior to or during rinse-back with each hemodialysis session (ie, 3 times per week).

Study design

Allocation

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to 100 Years

Healthy volunteers

Inclusion criteria

* Subject understands the study procedures and agrees to participate in the study by giving written informed consent. * Subject must complete the treatment and follow-up period, or have been discontinued for rising intact parathyroid hormone (iPTH), from an AMG 416 phase 3 parent study prior to the start of dosing in this study: 20120229 (NCT01785849), 20120230 (NCT01788046), or 20120359 (NCT01932970). * 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. * Currently receiving other investigational procedures while participating in this study. * Subject has known sensitivity to any of the products or components to be administered during dosing. * 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

Design outcomes

Primary

Measure	Time frame	Description
Number of Participants With Adverse Events (AEs)	From first dose until 30 days after last dose; the treatment period was 52 weeks.	Treatment-related adverse events are those the investigator indicated as having a reasonable possibility of having been caused by etelcalcetide. A serious adverse event is defined as an adverse event that meets at least 1 of the following serious criteria: • fatal • life threatening • requires in-patient hospitalization or prolongation of existing hospitalization • results in persistent or significant disability/incapacity • congenital anomaly/birth defect • other medically important serious event.
Number of Participants With Shift in Laboratory Values From Baseline Grade 0 or 1 to Post-baseline Grade 3 or 4	52 weeks	Laboratory toxicity grading was based on Common Terminology Criteria for Adverse Events (CTCAE) version 4.0, where Grade 0 represents values in the normal range and grade 4 represents values with life-threatening consequences and urgent intervention indicated.
Number of Participants Who Developed Anti-etelcalcetide Antibodies	Baseline, Week 12, Week 24, Week 36, Week 53, the 30-day follow-up visit	A validated dual flow-cell biosensor immunoassay was used to detect antibodies capable of binding etelcalcetide. The number of participants with a negative or no result at baseline and positive binding antibodies at any time post-baseline is reported.
Change From Baseline in Blood Pressure	Baseline and Weeks 24 and 48	Blood pressure (BP) values were taken post-hemodialysis assessments.

Secondary

Measure	Time frame	Description
Percent Change From Baseline in Mean PTH During the EAP	Baseline and the efficacy assessment phase	—
Percent Change From Baseline in Mean PTH During the EAP12	Baseline and the efficacy assessment phase at month 12 (weeks 46-53)	—
Percent Change From Baseline in Mean Corrected Calcium During the EAP	Baseline and the efficacy assessment phase	—
Percent Change From Baseline in Mean Corrected Calcium During the EAP12	Baseline and the efficacy assessment phase at month 12 (weeks 46-53)	—
Percentage of Participants With > 30% Reduction From Baseline in PTH During the Efficacy Assessment Phase	Baseline and the efficacy assessment phase, defined as the last 6 weeks prior to ending treatment for participants who completed a minimum of 8 weeks of treatment (weeks 46-52 for participants who completed 52 weeks of treatment)	The efficacy assessment phase (EAP) is defined as the last 6 weeks before ending treatment, which was only for participants who completed a minimum of 8 weeks of treatment with etelcalcetide. If multiple assessments were available during the EAP, values were averaged.
Percent Change From Baseline in Mean Corrected Calcium Phosphorus Product During the EAP12	Baseline and the efficacy assessment phase at month 12 (weeks 46-53)	—
Percent Change From Baseline in Mean Phosphorus During the EAP	Baseline and the efficacy assessment phase	—
Percent Change From Baseline in Mean Phosphorus During the EAP12	Baseline and the efficacy assessment phase at month 12 (weeks 46-53)	—
Percent Change From Baseline in Mean Corrected Calcium Phosphorus Product During the EAP	Baseline and the efficacy assessment phase	—
Percentage of Participants With > 30% Reduction From Baseline in PTH During the EAP12	Baseline and the efficacy assessment phase at month 12 (weeks 46-53)	The efficacy assessment phase at 12 months (EAP12) was defined as the period from week 46 to 53 (inclusive). If multiple assessments were available during the EAP12, values were averaged.
Percentage of Participants With PTH ≤ 300 pg/mL During the EAP	Baseline and the efficacy assessment phase	—
Percentage of Participants With PTH ≤ 300 pg/mL During the EAP12	Week 46 to 53	—

Countries

Australia, Austria, Belgium, Canada, Czechia, France, Germany, Hungary, Israel, Italy, Netherlands, Poland, Russia, Spain, Sweden, United Kingdom, United States

Participant flow

Recruitment details

This single-arm study was conducted at 205 centers in the US, Canada, Europe, Israel, Russian Federation and Australia. Participants were enrolled from 31 July 2013 to 9 June 2014. Participants who rolled over into another single-arm extension study 20130213 (NCT02102204) are reported as discontinuing the study due to protocol specified criteria.

Pre-assignment details

This extension study enrolled participants from 1 of 3 parent studies: 20120229 (NCT01785849), 20120230 (NCT01788046), or 20120359 (NCT01932970). In Studies 20120229 and 20120230, patients received either placebo or etelcalcetide 3 times a week (TIW) for up to 26 weeks; In Study 20120359, patients received 5 mg etelcalcetide TIW for 4 weeks.

Participants by arm

Arm	Count
Etelcalcetide All participants received etelcalcetide at a starting dose of 5 mg TIW for up to 52 weeks during the extension study. Etelcalcetide dose could be increased at weeks 5, 9, 17, 25, 33, 41, and 49 to a maximum dose of 15 mg to achieve predialysis serum parathyroid hormone levels ≤ 300 pg/mL.	891
Total	891

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002
Overall Study	Death	27	16	7
Overall Study	Lost to Follow-up	19	22	6
Overall Study	Missing	0	1	3
Overall Study	Protocol Specified Criteria	207	214	55
Overall Study	Sponsor Decision	0	2	0
Overall Study	Withdrawal by Subject	41	34	36

Baseline characteristics

Characteristic	Etelcalcetide
Age, Continuous	58.3 years STANDARD_DEVIATION 14.4
Age, Customized < 65 years	577 participants
Age, Customized ≥ 65 years	314 participants
Corrected Calcium	9.67 mg/dL STANDARD_DEVIATION 0.68
Corrected Calcium Phosphorus Product (cCa x P)	54.36 mg²/dL² STANDARD_DEVIATION 17.17
Ethnicity Hispanic/Latino	122 participants
Ethnicity Not Hispanic/Latino	769 participants
Parathyroid Hormone (PTH) Level > 1000 pg/mL	228 participants
Parathyroid Hormone (PTH) Level 600 - ≤ 1000 pg/mL	221 participants
Parathyroid Hormone (PTH) Level < 600 pg/mL	405 participants
Parathyroid Hormone (PTH) Level Missing	37 participants
Phosphorus	5.63 mg/dL STANDARD_DEVIATION 1.75
PTH Concentration	769.5 pg/mL STANDARD_DEVIATION 574.4
Race/Ethnicity, Customized American Indian or Alaska Native	1 participants
Race/Ethnicity, Customized Asian	29 participants
Race/Ethnicity, Customized Black (or African American)	270 participants
Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander	12 participants
Race/Ethnicity, Customized Other	12 participants
Race/Ethnicity, Customized White	567 participants
Sex: Female, Male Female	341 Participants
Sex: Female, Male Male	550 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk
deaths Total, all-cause mortality	— / —	— / —	— / —	— / —
other Total, other adverse events	289 / 383	249 / 384	75 / 123	613 / 890
serious Total, serious adverse events	161 / 383	142 / 384	53 / 123	356 / 890

Outcome results

Primary

Change From Baseline in Blood Pressure

Blood pressure (BP) values were taken post-hemodialysis assessments.

Time frame: Baseline and Weeks 24 and 48

Population: Participants who received at least 1 dose of etelcalcetide and with available data at each time point (indicated by n)

Arm	Measure	Group	Value (MEAN)	Dispersion
20120229 / 20120230 Placebo	Change From Baseline in Blood Pressure	Systolic BP Week 24 (n = 329, 342, 104, 775)	4.0 mmHg	Standard Error 1.5
20120229 / 20120230 Placebo	Change From Baseline in Blood Pressure	Systolic BP Week 48 (n = 305, 317, 74, 696)	3.5 mmHg	Standard Error 1.6
20120229 / 20120230 Placebo	Change From Baseline in Blood Pressure	Diastolic BP Week 24 (n = 329, 343, 104, 776)	2.2 mmHg	Standard Error 0.8
20120229 / 20120230 Placebo	Change From Baseline in Blood Pressure	Diastolic BP Week 48 (n = 305, 317, 74, 696)	1.1 mmHg	Standard Error 0.9
20120229 / 20120230 Etelcalcetide	Change From Baseline in Blood Pressure	Systolic BP Week 48 (n = 305, 317, 74, 696)	6.5 mmHg	Standard Error 1.5
20120229 / 20120230 Etelcalcetide	Change From Baseline in Blood Pressure	Diastolic BP Week 24 (n = 329, 343, 104, 776)	1.2 mmHg	Standard Error 0.9
20120229 / 20120230 Etelcalcetide	Change From Baseline in Blood Pressure	Diastolic BP Week 48 (n = 305, 317, 74, 696)	0.8 mmHg	Standard Error 0.9
20120229 / 20120230 Etelcalcetide	Change From Baseline in Blood Pressure	Systolic BP Week 24 (n = 329, 342, 104, 775)	4.5 mmHg	Standard Error 1.4
20120359 Etelcalcetide	Change From Baseline in Blood Pressure	Diastolic BP Week 24 (n = 329, 343, 104, 776)	-5.1 mmHg	Standard Error 1.5
20120359 Etelcalcetide	Change From Baseline in Blood Pressure	Systolic BP Week 48 (n = 305, 317, 74, 696)	-6.8 mmHg	Standard Error 3
20120359 Etelcalcetide	Change From Baseline in Blood Pressure	Diastolic BP Week 48 (n = 305, 317, 74, 696)	-2.6 mmHg	Standard Error 1.7
20120359 Etelcalcetide	Change From Baseline in Blood Pressure	Systolic BP Week 24 (n = 329, 342, 104, 775)	-5.5 mmHg	Standard Error 2.8
Etelcalcetide Total	Change From Baseline in Blood Pressure	Diastolic BP Week 48 (n = 305, 317, 74, 696)	0.6 mmHg	Standard Error 0.6
Etelcalcetide Total	Change From Baseline in Blood Pressure	Systolic BP Week 48 (n = 305, 317, 74, 696)	3.8 mmHg	Standard Error 1
Etelcalcetide Total	Change From Baseline in Blood Pressure	Systolic BP Week 24 (n = 329, 342, 104, 775)	2.9 mmHg	Standard Error 1
Etelcalcetide Total	Change From Baseline in Blood Pressure	Diastolic BP Week 24 (n = 329, 343, 104, 776)	0.8 mmHg	Standard Error 0.6

Primary

Number of Participants Who Developed Anti-etelcalcetide Antibodies

A validated dual flow-cell biosensor immunoassay was used to detect antibodies capable of binding etelcalcetide. The number of participants with a negative or no result at baseline and positive binding antibodies at any time post-baseline is reported.

Time frame: Baseline, Week 12, Week 24, Week 36, Week 53, the 30-day follow-up visit

Population: Participants who received at least 1 dose of etelcalcetide and with a post-baseline antibody result.

Arm	Measure	Value (NUMBER)
20120229 / 20120230 Placebo	Number of Participants Who Developed Anti-etelcalcetide Antibodies	10 participants
20120229 / 20120230 Etelcalcetide	Number of Participants Who Developed Anti-etelcalcetide Antibodies	15 participants
20120359 Etelcalcetide	Number of Participants Who Developed Anti-etelcalcetide Antibodies	2 participants
Etelcalcetide Total	Number of Participants Who Developed Anti-etelcalcetide Antibodies	27 participants

Primary

Number of Participants With Adverse Events (AEs)

Treatment-related adverse events are those the investigator indicated as having a reasonable possibility of having been caused by etelcalcetide. A serious adverse event is defined as an adverse event that meets at least 1 of the following serious criteria: • fatal • life threatening • requires in-patient hospitalization or prolongation of existing hospitalization • results in persistent or significant disability/incapacity • congenital anomaly/birth defect • other medically important serious event.

Time frame: From first dose until 30 days after last dose; the treatment period was 52 weeks.

Population: All participants who received at least 1 dose of etelcalcetide.

Arm	Measure	Group	Value (NUMBER)
20120229 / 20120230 Placebo	Number of Participants With Adverse Events (AEs)	Any adverse event	354 participants
20120229 / 20120230 Placebo	Number of Participants With Adverse Events (AEs)	Serious adverse events	161 participants
20120229 / 20120230 Placebo	Number of Participants With Adverse Events (AEs)	Treatment-related adverse events	215 participants
20120229 / 20120230 Placebo	Number of Participants With Adverse Events (AEs)	Treatment-related serious adverse events	6 participants
20120229 / 20120230 Placebo	Number of Participants With Adverse Events (AEs)	AEs leading to discontinuation of etelcalcetide	22 participants
20120229 / 20120230 Placebo	Number of Participants With Adverse Events (AEs)	Fatal adverse events	27 participants
20120229 / 20120230 Etelcalcetide	Number of Participants With Adverse Events (AEs)	Fatal adverse events	16 participants
20120229 / 20120230 Etelcalcetide	Number of Participants With Adverse Events (AEs)	Treatment-related serious adverse events	5 participants
20120229 / 20120230 Etelcalcetide	Number of Participants With Adverse Events (AEs)	Any adverse event	337 participants
20120229 / 20120230 Etelcalcetide	Number of Participants With Adverse Events (AEs)	Treatment-related adverse events	141 participants
20120229 / 20120230 Etelcalcetide	Number of Participants With Adverse Events (AEs)	Serious adverse events	142 participants
20120229 / 20120230 Etelcalcetide	Number of Participants With Adverse Events (AEs)	AEs leading to discontinuation of etelcalcetide	11 participants
20120359 Etelcalcetide	Number of Participants With Adverse Events (AEs)	Serious adverse events	53 participants
20120359 Etelcalcetide	Number of Participants With Adverse Events (AEs)	Treatment-related adverse events	36 participants
20120359 Etelcalcetide	Number of Participants With Adverse Events (AEs)	Treatment-related serious adverse events	2 participants
20120359 Etelcalcetide	Number of Participants With Adverse Events (AEs)	Fatal adverse events	8 participants
20120359 Etelcalcetide	Number of Participants With Adverse Events (AEs)	AEs leading to discontinuation of etelcalcetide	8 participants
20120359 Etelcalcetide	Number of Participants With Adverse Events (AEs)	Any adverse event	108 participants
Etelcalcetide Total	Number of Participants With Adverse Events (AEs)	AEs leading to discontinuation of etelcalcetide	41 participants
Etelcalcetide Total	Number of Participants With Adverse Events (AEs)	Fatal adverse events	51 participants
Etelcalcetide Total	Number of Participants With Adverse Events (AEs)	Serious adverse events	356 participants
Etelcalcetide Total	Number of Participants With Adverse Events (AEs)	Treatment-related serious adverse events	13 participants
Etelcalcetide Total	Number of Participants With Adverse Events (AEs)	Any adverse event	799 participants
Etelcalcetide Total	Number of Participants With Adverse Events (AEs)	Treatment-related adverse events	392 participants

Primary

Number of Participants With Shift in Laboratory Values From Baseline Grade 0 or 1 to Post-baseline Grade 3 or 4

Laboratory toxicity grading was based on Common Terminology Criteria for Adverse Events (CTCAE) version 4.0, where Grade 0 represents values in the normal range and grade 4 represents values with life-threatening consequences and urgent intervention indicated.

Time frame: 52 weeks

Population: All participants who received at least 1 dose of etelcalcetide.

Arm	Measure	Group	Value (NUMBER)
20120229 / 20120230 Placebo	Number of Participants With Shift in Laboratory Values From Baseline Grade 0 or 1 to Post-baseline Grade 3 or 4	Alanine aminotransferase increase	1 participants
20120229 / 20120230 Placebo	Number of Participants With Shift in Laboratory Values From Baseline Grade 0 or 1 to Post-baseline Grade 3 or 4	Albumin decrease	9 participants
20120229 / 20120230 Placebo	Number of Participants With Shift in Laboratory Values From Baseline Grade 0 or 1 to Post-baseline Grade 3 or 4	Alkaline phosphatase increase	2 participants
20120229 / 20120230 Placebo	Number of Participants With Shift in Laboratory Values From Baseline Grade 0 or 1 to Post-baseline Grade 3 or 4	Aspartate aminotransferase increase	3 participants
20120229 / 20120230 Placebo	Number of Participants With Shift in Laboratory Values From Baseline Grade 0 or 1 to Post-baseline Grade 3 or 4	Bilirubin increase	1 participants
20120229 / 20120230 Placebo	Number of Participants With Shift in Laboratory Values From Baseline Grade 0 or 1 to Post-baseline Grade 3 or 4	Calcium (corrected) decrease	51 participants
20120229 / 20120230 Placebo	Number of Participants With Shift in Laboratory Values From Baseline Grade 0 or 1 to Post-baseline Grade 3 or 4	Calcium (corrected) increase	8 participants
20120229 / 20120230 Placebo	Number of Participants With Shift in Laboratory Values From Baseline Grade 0 or 1 to Post-baseline Grade 3 or 4	Phosphorus decrease	77 participants
20120229 / 20120230 Placebo	Number of Participants With Shift in Laboratory Values From Baseline Grade 0 or 1 to Post-baseline Grade 3 or 4	Potassium decrease	9 participants
20120229 / 20120230 Placebo	Number of Participants With Shift in Laboratory Values From Baseline Grade 0 or 1 to Post-baseline Grade 3 or 4	Potassium increase	69 participants
20120229 / 20120230 Placebo	Number of Participants With Shift in Laboratory Values From Baseline Grade 0 or 1 to Post-baseline Grade 3 or 4	Hemoglobin decrease	4 participants
20120229 / 20120230 Placebo	Number of Participants With Shift in Laboratory Values From Baseline Grade 0 or 1 to Post-baseline Grade 3 or 4	Hemoglobin increase	1 participants

Secondary

Percentage of Participants With > 30% Reduction From Baseline in PTH During the EAP12

The efficacy assessment phase at 12 months (EAP12) was defined as the period from week 46 to 53 (inclusive). If multiple assessments were available during the EAP12, values were averaged.

Time frame: Baseline and the efficacy assessment phase at month 12 (weeks 46-53)

Population: Participants with pre-dialysis PTH assessment at baseline and during EAP12

Arm	Measure	Value (NUMBER)
20120229 / 20120230 Placebo	Percentage of Participants With > 30% Reduction From Baseline in PTH During the EAP12	82.5 percentage of participants
20120229 / 20120230 Etelcalcetide	Percentage of Participants With > 30% Reduction From Baseline in PTH During the EAP12	53.3 percentage of participants
20120359 Etelcalcetide	Percentage of Participants With > 30% Reduction From Baseline in PTH During the EAP12	63.5 percentage of participants
Etelcalcetide Total	Percentage of Participants With > 30% Reduction From Baseline in PTH During the EAP12	67.5 percentage of participants

Secondary

Percentage of Participants With > 30% Reduction From Baseline in PTH During the Efficacy Assessment Phase

The efficacy assessment phase (EAP) is defined as the last 6 weeks before ending treatment, which was only for participants who completed a minimum of 8 weeks of treatment with etelcalcetide. If multiple assessments were available during the EAP, values were averaged.

Time frame: Baseline and the efficacy assessment phase, defined as the last 6 weeks prior to ending treatment for participants who completed a minimum of 8 weeks of treatment (weeks 46-52 for participants who completed 52 weeks of treatment)

Population: Participants with pre-dialysis PTH assessment at baseline and during the EAP who completed a minimum of 8 weeks of treatment with etelcalcetide.

Arm	Measure	Value (NUMBER)
20120229 / 20120230 Placebo	Percentage of Participants With > 30% Reduction From Baseline in PTH During the Efficacy Assessment Phase	81.2 percentage of participants
20120229 / 20120230 Etelcalcetide	Percentage of Participants With > 30% Reduction From Baseline in PTH During the Efficacy Assessment Phase	54.5 percentage of participants
20120359 Etelcalcetide	Percentage of Participants With > 30% Reduction From Baseline in PTH During the Efficacy Assessment Phase	65.1 percentage of participants
Etelcalcetide Total	Percentage of Participants With > 30% Reduction From Baseline in PTH During the Efficacy Assessment Phase	67.7 percentage of participants

Secondary

Percentage of Participants With PTH ≤ 300 pg/mL During the EAP

Time frame: Baseline and the efficacy assessment phase

Population: Participants with predialysis PTH assessment during the EAP who completed a minimum of 8 weeks of treatment with etelcalcetide

Arm	Measure	Value (NUMBER)
20120229 / 20120230 Placebo	Percentage of Participants With PTH ≤ 300 pg/mL During the EAP	55.7 percentage of participants
20120229 / 20120230 Etelcalcetide	Percentage of Participants With PTH ≤ 300 pg/mL During the EAP	59.7 percentage of participants
20120359 Etelcalcetide	Percentage of Participants With PTH ≤ 300 pg/mL During the EAP	54.6 percentage of participants
Etelcalcetide Total	Percentage of Participants With PTH ≤ 300 pg/mL During the EAP	57.3 percentage of participants

Secondary

Percentage of Participants With PTH ≤ 300 pg/mL During the EAP12

Time frame: Week 46 to 53

Population: Participants with predialysis PTH assessment during the EAP12

Arm	Measure	Value (NUMBER)
20120229 / 20120230 Placebo	Percentage of Participants With PTH ≤ 300 pg/mL During the EAP12	54.8 percentage of participants
20120229 / 20120230 Etelcalcetide	Percentage of Participants With PTH ≤ 300 pg/mL During the EAP12	61.1 percentage of participants
20120359 Etelcalcetide	Percentage of Participants With PTH ≤ 300 pg/mL During the EAP12	42.7 percentage of participants
Etelcalcetide Total	Percentage of Participants With PTH ≤ 300 pg/mL During the EAP12	56.4 percentage of participants

Secondary