A Phase 1 interventional study of Etelcalcetide and Placebo in Secondary Hyperparathyroidism, sponsored by Amgen. Completed at 5 sites in China. Open to participants aged 18 Years to 70 Years. Per ClinicalTrials.gov, last updated 2020-02-10.
Sponsored by Amgen · Phase 1, Interventional, and Treatment
This was a multiple-dose, double-blind, randomized, placebo-controlled study. Chinese subjects residing in Mainland China with chronic kidney disease (CKD) receiving hemodialysis were randomized in a 3:1 ratio to receive 5 mg intravenous (IV) of etelcalcetide or placebo 3 times a week (TIW) for approximately 4 weeks, with a subsequent follow up period of approximately 4 weeks.
Doses were given at the end of each scheduled hemodialysis session on study days 1 through day 27 and subject participation was complete after day 55 end-of-study (EOS) procedures were performed. Doses were administered TIW for 4 weeks, for a total of 12 doses.
Exclusion Criteria:
Female subject of reproductive potential not willing to use a(n) acceptable method(s) of effective birth control during treatment with AMG 416, and for an additional 3 months after the end of treatment with AMG 416. Female subjects who have had a hysterectomy, bilateral salpingectomy, bilateral oophorectomy, bilateral tubal ligation, or who are postmenopausal are not required to use contraception. Postmenopausal is defined as:
Intravenous (IV) administration of placebo three times a week (TIW) for 4 weeks for a total of 12 doses. Participants were followed for an additional 4 weeks.
Drug: Placebo
5 mg intravenous (IV) dose of etelcalcetide three times a week (TIW) for 4 weeks for a total of 12 doses. Participants were followed for an additional 4 weeks.
Drug: Etelcalcetide
Etelcalcetide was supplied as a sterile, preservative-free, aqueous solution in a single-use 3 mL glass vial.
Also known as: AMG 416
Placebo supplied to match active intervention.
Pharmacokinetic (PK) Parameter: Time to Maximum Drug Concentration (Tmax) of Plasma Etelcalcetide on Days 1 and 27
Tmax is the time to maximum drug concentration of plasma etelcalcetide after dosing on Days 1 and 27.
Time frame: Days 1 and 27; PK blood sampling predialysis, and at 10, 30, 60, 90 min postdose, as well as on Day 2 and 28 between 18 and 30 hours after study drug administration
PK: Maximum Observed Drug Concentration (Cmax) of Plasma Etelcalcetide on Days 1 and 27
Cmax was defined as the maximum observed plasma drug concentration measured between the time of drug administration to the beginning of the next dialysis session.
Time frame: Days 1 and 27; PK blood sampling predialysis, and at 10, 30, 60, 90 min postdose, as well as on Day 2 and 28 between 18 and 30 hours after study drug administration
Pharmacokinetic (PK) Parameter: Area Under the Curve From Time Zero to the Beginning of the Subsequent Hemodialysis Treatment (AUClast) of Plasma Etelcalcetide on Days 1 and 27
AUClast was specifically defined in this study as the area under the concentration time curve measured from the time of drug administration to the beginning of the next dialysis session, following the first and last dose.
Time frame: Days 1 and 27; PK blood sampling predialysis, and up to 44-50 hour postdose.at 10, 30, 60, 90 min postdose: Day 2 and 28 between 18 and 30 hours after study drug administration; Day 3 (predialysis) + Day 29
Pharmacokinetic (PK) Parameter: Accumulation Ratio Comparing Days 1 and 27
Accumulation ratio, calculated as AUClast day 27/AUClast day 1.
Time frame: Days 1 and 27; PK blood sampling predialysis, and up to 44-50 hour postdose.at 10, 30, 60, 90 min postdose: Day 2 and 28 between 18 and 30 hours after study drug administration; Day 3 (predialysis) + Day 29
Participants With Treatment-Emergent Adverse Events (TEAEs)
The severity of each adverse event was assessed using the NCI-CTCAE Version 4.0 according to the following: * Grade 1 - Mild: Asymptomatic or mild symptoms; intervention not indicated * Grade 2 - Moderate: Minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental activities of daily living (ADL) * Grade 3 - Severe: Medically significant but not life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care ADL * Grade 4 - Life-threatening * Grade 5 - Fatal. A serious AE is an AE that met one or more of the following criteria: * Death * Life-threatening * Required inpatient hospitalization or prolongation of an existing hospitalization * Resulted in persistent or significant disability/incapacity * A congenital anomaly/birth defect * Important medical events that required medical or surgical intervention to prevent one of the outcomes above.
Time frame: Day 1 up to Day 55 (end of study)
Participants With Treatment-Emergent Adverse Events (TEAEs) of Interest
Terms were coded with Medical Dictionary for Regulatory Activities (MedDRA) version 21.1. Narrow search criteria used for both standardized MedDRA queries (SMQ) and events of interest (EOI). One preferred term (PT) could match multiple EOIs. Infusion Reaction EOI counts included only those events which had onset day coinciding with study medication infusion and resolved on the same day or the day after onset.
Time frame: Day 1 up to Day 55 (end of study)
Participants With Clinically-Significant Changes in Electrocardiograms (ECGs) From Baseline to End of Study
Count of participants who exhibited a clinically significant change in the results of their 12-lead electrocardiograms (ECG) when comparing baseline to end of study ECGs.
Time frame: Baseline is Day -2; End of Study is Day 55
Change From Baseline to End of Study in Weight
Change from baseline in weight measured at visit.
Time frame: Day 1 up to Day 55
Change From Baseline to End of Study in Systolic and Diastolic Blood Pressures
Participants remained seated for at least 10 minutes prior to measurement of predialysis heart rate and blood pressure.
Time frame: Baseline Day 1 prior to dialysis; End of Study is Day 55
Baseline and Change From Baseline to End of Study in Heart Rate
Participants remained seated for at least 10 minutes prior to measurement of predialysis heart rate and blood pressure.
Time frame: Baseline Day 1 prior to dialysis; End of Study is Day 55
Change From Baseline to End of Study in Calcium
Calcium was tested at a central laboratory.
Time frame: Baseline is Day 1 prior to dialysis; End of Study is Day 55
Change From Baseline to End of Study in Corrected Calcium (cCa)
Total serum calcium was corrected if the serum albumin was \< 4 g/dL or 40 g/L, otherwise cCa equals total serum calcium. The correction formula was: Corrected calcium (mg/dL) = Total calcium (mg/dL) + (4 - albumin \[g/dL\]) \* 0.8
Time frame: Baseline is the average of Day -2 and Day 1 prior to dialysis; End of Study is Day 55
Participants With Low Corrected Calcium (cCA) By Category
The lowest cCA value for each participant is reported. Total serum calcium was corrected if the serum albumin was \< 4 g/dL or 40 g/L, otherwise cCa equals total serum calcium. The correction formula was: Corrected calcium (mg/dL) = Total calcium (mg/dL) + (4 - albumin \[g/dL\]) \* 0.8
Time frame: Timeframes: Days 8, 15, 22, 27, 29, 34, 41, 55
Baseline and Change From Baseline to End of Study in Serum Albumin
Serum albumin was tested at a central laboratory.
Time frame: Baseline is the average of Day -2 and Day 1 prior to dialysis; End of Study is Day 55
Change From Baseline to End of Study in Serum Phosphorus
Serum phosphorus was tested at a central laboratory.
Time frame: Baseline is Day 1 prior to dialysis; End of Study is Day 55
Participants With Anti-etelcalcetide Antibody at Baseline and Postbaseline
Participants with positive titers for antibodies to etelcalcetide could be asked to return to the clinical research unit to provide additional serum samples.
Time frame: Baseline: Day 1 prior to dialysis. Postbaseline: Days 29 and 55 prior to dialysis
This study was conducted at 5 centers in China.
| Milestone | Placebo | Etelcalcetide |
|---|---|---|
| Started | 8 | 25 |
| Completed | 8 | 24 |
| Not completed | 0 | 1 |
| Withdrew: Withdrawal by subject | 0 | 1 |
Tmax is the time to maximum drug concentration of plasma etelcalcetide after dosing on Days 1 and 27.
| hour | Placebo | Etelcalcetide |
|---|---|---|
| Day 1 | — | 0.22 (0.17 to 0.27) |
| Day 27 | — | 0.22 (0.17 to 0.25) |
Cmax was defined as the maximum observed plasma drug concentration measured between the time of drug administration to the beginning of the next dialysis session.
| ng/mL | Placebo | Etelcalcetide |
|---|---|---|
| Day 1 | — | 216 ± 157 |
| Day 27 | — | 236 ± 53.7 |
AUClast was specifically defined in this study as the area under the concentration time curve measured from the time of drug administration to the beginning of the next dialysis session, following the first and last dose.
| hour*ng/mL | Placebo | Etelcalcetide |
|---|---|---|
| Day 1 | — | 1110 ± 311 |
| Day 27 | — | 3310 ± 893 |
Accumulation ratio, calculated as AUClast day 27/AUClast day 1.
| ratio | Placebo | Etelcalcetide |
|---|---|---|
| Pharmacokinetic (PK) Parameter: Accumulation Ratio Comparing Days 1 and 27 | — | 3.02 ± 0.607 |
The severity of each adverse event was assessed using the NCI-CTCAE Version 4.0 according to the following: * Grade 1 - Mild: Asymptomatic or mild symptoms; intervention not indicated * Grade 2 - Moderate: Minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental activities of daily living (ADL) * Grade 3 - Severe: Medically significant but not life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care ADL * Grade 4 - Life-threatening * Grade 5 - Fatal. A serious AE is an AE that met one or more of the following criteria: * Death * Life-threatening * Required inpatient hospitalization or prolongation of an existing hospitalization * Resulted in persistent or significant disability/incapacity * A congenital anomaly/birth defect * Important medical events that required medical or surgical intervention to prevent one of the outcomes above.
| Participants | Placebo | Etelcalcetide |
|---|---|---|
| All TEAEs | 7 | 25 |
| TEAEs Grade >= 3 | 0 | 5 |
| TEAEs Grade >= 4 | 0 | 1 |
| Serious TEAEs | 0 | 3 |
| TEAEs leading to study treatment discontinuation | 0 | 0 |
| Fatal TEAEs | 0 | 0 |
| Treatment-related TEAEs | 1 | 18 |
| Treatment-related TEAEs Grade >= 3 | 0 | 1 |
| Treatment-related TEAEs Grade >= 4 | 0 | 0 |
| Treatment-related serious TEAEs | 0 | 1 |
| Trt-related TEAEs leading to study trt discon | 0 | 0 |
| Treatment-related Fatal TEAEs | 0 | 0 |
Terms were coded with Medical Dictionary for Regulatory Activities (MedDRA) version 21.1. Narrow search criteria used for both standardized MedDRA queries (SMQ) and events of interest (EOI). One preferred term (PT) could match multiple EOIs. Infusion Reaction EOI counts included only those events which had onset day coinciding with study medication infusion and resolved on the same day or the day after onset.
| Participants | Placebo | Etelcalcetide |
|---|---|---|
| Adynamic bone (EOI) | 0 | 0 |
| Cardiac Failure (EOI) | 0 | 0 |
| Convulsions (SMQ) | 0 | 0 |
| Fractures (EOI) | 0 | 0 |
| Hypersensitivity (SMQ) | 0 | 5 |
| Dermatitis allergic (PT) | 0 | 2 |
| Rash (PT) | 0 | 2 |
| Dermatitis (PT) | 0 | 1 |
| Hypocalcemia (EOI) | 0 | 11 |
| Blood calcium decreased (PT) | 0 | 10 |
| Hypocalcaemia (PT) | 0 | 2 |
| Hypophosphatemia (EOI) | 0 | 0 |
| Infusion reaction (EOI) | 0 | 1 |
| Hypotension (PT) | 0 | 1 |
| Torsade de pointes-QT prolongation (SMQ) | 0 | 0 |
| Ventricular tachyarrhythmias (SMQ) | 0 | 0 |
Count of participants who exhibited a clinically significant change in the results of their 12-lead electrocardiograms (ECG) when comparing baseline to end of study ECGs.
| Participants | Placebo | Etelcalcetide |
|---|---|---|
| Normal Baseline / Abnormal End of Study | 0 | 2 |
| Abnormal Baseline / Normal End of Study | 0 | 1 |
| No Change in Baseline to End of Study | 8 | 21 |
Change from baseline in weight measured at visit.
| kg | Placebo | Etelcalcetide |
|---|---|---|
| Change From Baseline to End of Study in Weight | 1.32 ± 0.79 | 0.76 ± 1.39 |
Participants remained seated for at least 10 minutes prior to measurement of predialysis heart rate and blood pressure.
| mmHg | Placebo | Etelcalcetide |
|---|---|---|
| Systolic Blood Pressure | 1.1 ± 15.5 | 6.1 ± 18.6 |
| Diastolic Blood Pressure | 4.4 ± 9.2 | 1.5 ± 11.9 |
Participants remained seated for at least 10 minutes prior to measurement of predialysis heart rate and blood pressure.
| beats/minute | Placebo | Etelcalcetide |
|---|---|---|
| Baseline | 79.5 ± 8.3 | 82.8 ± 13.8 |
| Change from Baseline to End of Study | -2.9 ± 6.5 | -1.4 ± 8.9 |
Calcium was tested at a central laboratory.
| mmol/L | Placebo | Etelcalcetide |
|---|---|---|
| Change From Baseline to End of Study in Calcium | -0.10 ± 0.11 | -0.07 ± 0.12 |
Total serum calcium was corrected if the serum albumin was \< 4 g/dL or 40 g/L, otherwise cCa equals total serum calcium. The correction formula was: Corrected calcium (mg/dL) = Total calcium (mg/dL) + (4 - albumin \[g/dL\]) \* 0.8
| mmol/L | Placebo | Etelcalcetide |
|---|---|---|
| Change From Baseline to End of Study in Corrected Calcium (cCa) | -0.08 ± 0.10 | -0.05 ± 0.10 |
The lowest cCA value for each participant is reported. Total serum calcium was corrected if the serum albumin was \< 4 g/dL or 40 g/L, otherwise cCa equals total serum calcium. The correction formula was: Corrected calcium (mg/dL) = Total calcium (mg/dL) + (4 - albumin \[g/dL\]) \* 0.8
| Participants | Placebo | Etelcalcetide |
|---|---|---|
| Participants with cCA < 1.75 mmol/L | 0 | 0 |
| Participants with cCA 1.75 to < 1.87 mmol/L | 0 | 1 |
| Participants with cCA 1.87 to < 2.07 mmol/L | 0 | 12 |
Serum albumin was tested at a central laboratory.
| g/dL | Placebo | Etelcalcetide |
|---|---|---|
| Baseline | 41.20 ± 2.37 | 39.37 ± 2.79 |
| Change from Baseline to End of Study | -1.06 ± 1.81 | -0.59 ± 2.13 |
Serum phosphorus was tested at a central laboratory.
| mmol/L | Placebo | Etelcalcetide |
|---|---|---|
| Change From Baseline to End of Study in Serum Phosphorus | -0.03 ± 0.53 | -0.06 ± 0.56 |
Participants with positive titers for antibodies to etelcalcetide could be asked to return to the clinical research unit to provide additional serum samples.
| Participants | Placebo | Etelcalcetide |
|---|---|---|
| Binding antibody positive at or before baseline | — | 1 |
| Positive postbaseline/negative baseline | — | 0 |
| Transient, i.e. negative at last timepoint tested | — | 0 |
Collected over Day 1 up to Day 55 (end of study). Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Placebo | 0/8 (0%) | 0/8 (0%) | 7/8 (87.5%) |
| Etelcalcetide | 0/25 (0%) | 3/25 (12%) | 22/25 (88%) |
| Event | Placebo | Etelcalcetide |
|---|---|---|
| PneumoniaInfections and infestations | 0/8 | 1/25 |
| HypocalcaemiaMetabolism and nutrition disorders | 0/8 | 1/25 |
| Intervertebral disc protrusionMusculoskeletal and connective tissue disorders | 0/8 | 1/25 |
| Event | Placebo | Etelcalcetide |
|---|---|---|
| Blood calcium decreasedInvestigations | 0/8 | 10/25 |
| HypoalbuminaemiaMetabolism and nutrition disorders | 2/8 | 0/25 |
| Muscle spasmsMusculoskeletal and connective tissue disorders | 0/8 | 4/25 |
| PruritusSkin and subcutaneous tissue disorders | 1/8 | 4/25 |
| HypotensionVascular disorders | 0/8 | 4/25 |
| ArrhythmiaCardiac disorders | 1/8 | 0/25 |
| Eye disorderEye disorders | 1/8 | 0/25 |
| ConstipationGastrointestinal disorders | 1/8 | 1/25 |
| ContusionInjury, poisoning and procedural complications | 1/8 | 0/25 |
| Limb injuryInjury, poisoning and procedural complications | 1/8 | 0/25 |
Safety analysis set consisting of all participants who received at least 1 dose of investigational product.
| Age, Continuous(years) | Placebo | Etelcalcetide | Total |
|---|---|---|---|
| Mean | 49.8 ± 12.5 | 50.2 ± 11.4 | 50.1 ± 11.5 |
| Sex: Female, Male(Participants) | Placebo | Etelcalcetide | Total |
|---|---|---|---|
| Female | 3 | 10 | 13 |
| Male | 5 | 15 | 20 |
| Race (NIH/OMB)(Participants) | Placebo | Etelcalcetide | Total |
|---|---|---|---|
| American Indian or Alaska Native | 0 | 0 | 0 |
| Asian | 8 | 25 | 33 |
| Native Hawaiian or Other Pacific Islander | 0 | 0 | 0 |
| Black or African American | 0 | 0 | 0 |
| White | 0 | 0 | 0 |
| More than one race | 0 | 0 | 0 |
| Unknown or Not Reported | 0 | 0 | 0 |
| Height(cm) | Placebo | Etelcalcetide | Total |
|---|---|---|---|
| Mean | 167.54 ± 8.17 | 164.48 ± 7.68 | 165.22 ± 7.79 |
| Weight(kg) | Placebo | Etelcalcetide | Total |
|---|---|---|---|
| Mean | 65.74 ± 8.45 | 67.71 ± 13.53 | 67.24 ± 12.40 |
| Body Mass Index (BMI)(kg/m^2) | Placebo | Etelcalcetide | Total |
|---|---|---|---|
| Mean | 23.64 ± 3.03 | 24.98 ± 4.03 | 24.65 ± 3.81 |
| Systolic Blood Pressure(mmHg) | Placebo | Etelcalcetide | Total |
|---|---|---|---|
| Mean | 139.25 ± 27.37 | 141.24 ± 19.39 | 140.76 ± 21.13 |
| Diastolic Blood Pressure(mmHg) | Placebo | Etelcalcetide | Total |
|---|---|---|---|
| Mean | 80.38 ± 13.54 | 81.68 ± 13.00 | 81.36 ± 12.93 |
5 further baseline measures are reported on the registry.
Documents are hosted by the registry — open the source record to download them.
Plan to share: Yes — De-identified individual patient data for variables necessary to address the specific research question in an approved data sharing request.
Supporting information: Study protocol, Sap, Icf, Csr
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