Clinical trial NCT03960437
Conditions: Chronic Kidney Disease Mineral and Bone Disorder Renal Osteodystrophy Vascular Calcification Hyperparathyroidism; Secondary, Renal
Keywords: Kidney disease Bone disease Etelcalcetide Parsabiv
Sponsor: Thomas Nickolas, MD MS
Start date: 2018-09-06; Completion date: 2020-11-19
Enrollment: 22 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The proposed study will investigate the effects of etelcalcetide on the bone and blood-vessel health in patients with CKD-MBD. The investigators will test if etelcalcetide makes bone and blood-vessels healthier. The study hypotheses are that are that etelcalcetide keeps bones strong and lowers the risk of calcium deposits in blood vessels. In Aim 1, the investigators will test if 9-months of treatment with etelcalcetide improves bone strength in twenty ESKD patients with hyperparathyroidism (HPT) by bone biopsy. In Aim 2, the investigators will test if 9-months of treatment with etelcalcetide decreases serum propensity to calcify blood vessels. The potential significance of this study is to provide first-time data on the ability of etelcalcetide to protect bone and blood-vessel health in patients with ESKD.

Detailed description:
Chronic kidney disease - mineral and bone disease (CKD-MBD) is a disorder of bone and mineral metabolism in patients with CKD. When kidney function is poor, levels of vitamin D, phosphate and parathyroid hormone become abnormal and patients are at risk for bone disease and fractures (renal osteodystrophy) and the deposition of calcium in blood vessels and muscles. CKD-MBD increases the risk of fractures, heart attacks, strokes, and death. Treatment of CKD-MBD is focused on lowering levels of parathyroid hormone (PTH) by giving vitamin D and lowering levels of phosphorous by giving phosphate binders. In patients with end stage kidney disease (ESKD), target levels of PTH recommended by the Kidney Disease Improving Global Outcomes (KDIGO) guidelines are in the range of 2-9 times the upper limit of normal (ULN) for the PTH assay. In many cases, in patients with long-standing ESKD, the parathyroid gland may no longer respond to treatment with vitamin D and phosphate lowering. In these cases, treatment with a calcimimetic, a medicine that increases the sensitivity of the parathyroid gland to serum levels of calcium, can restore PTH levels to goal.

Arms: arm 1: Every study participant will receive etelcalcetide prescribed by their treating physician for the duration of the study.
Interventions: intervention 1: Etelcalcetide
Intervention descriptions: intervention 1: Administered intravenously at the end of each dialysis session. Dosing ranges from 5 mg to 15 mg set by the patient's physician.

Protocol documents:
Prot_SAP_000.pdf: 
Version Date: 1.3.2020 
The Effect of Etelcalcetide on Bone-tissue Properties and Calcification 
Propensity in End Stage Kidney Disease  
Principal Investigator: Thomas Nickolas, MD, MS
AAAR6244
NCT03960437
Protocol Version January 3, 2020


Version Date: 1.3.2020 
Title: The effect of etelcalcetide on bone-tissue properties and calcification propensity in end stage 
kidney disease 
Hypotheses: Our hypothesis is that etelcalcetide treatment improves bone tissue-properties and bone mineral 
density by reducing remodeling. We also hypothesize that etelcalcetide’s ability to lower serum calcium will 
decrease propensity of serum to calcify as determined by T50. 
Background and Study Objectives 
Chronic kidney disease – mineral and bone disease (CKD-MBD) is a systemic disorder of bone and mineral 
metabolism in patients with CKD. As kidney function declines, abnormal vitamin D metabolism and renal 
phosphate handling drive the development of hyperparathyroidism (HPT), hyperphosphatemia, renal 
osteodystrophy and soft tissue calcifications. Clinical outcomes associated with CKD-MBD include bone 
fractures, cardiovascular events and death. Treatment of CKD-MBD is centered around the suppression of 
parathyroid hormone (PTH) by supplementation with vitamin D (parent and active D) and correction of 
hyperphosphatemia. In patients with end stage kidney disease (ESKD), target levels of PTH recommended by 
the Kidney Disease Improving Global Outcomes (KDIGO) guidelines are in the range of 2-9 times the upper limit 
of normal (ULN) for the PTH assay1. However, in patients with long-standing ESKD, abnormalities may develop 
in the parathyroid gland that both diminish responsiveness to treatment and lead to failure to achieve PTH levels 
within the KDIGO target range. PTH levels greater than the target range increase the risks of bone loss, fractures, 
soft 
tissue 
calcification 
and 
cardiovascular events. In these cases, 
treatment 
with 
a 
calcimimetic, 
a 
pharmacologic agent that enhances 
sensitivity of the parathyroid glad to 
serum levels of calcium, can restore 
PTH levels to goal. Etelcalcetide is a 
Food and Drug Administration (FDA) 
approved calcimimetic for the treatment 
of secondary HPT in adult patients with 
CKD on hemodialysis2-4. The proposed 
prospective cohort study will investigate 
the effects of etelcalcetide on the bone 
and vascular calcification components of 
CKD-MBD. We will test if treatment with 
etelcalcetide improves bone properties 
on the tissue level, increases areal bone 
mineral density (BMD) by dual energy X-
ray absorptiometry (DXA), improves 
cortical 
and 
trabecular 
BMD 
and 
microarchitecture 
and 
mechanical 
competence 
by 
high 
resolution 
peripheral computed tomography (HR-
pQCT), 
and 
decreases 
serum 
propensity to calcify soft tissues. For all 
Aims, the enrollment scheme and study 
timeline are described in Figures 1 and 
2, respectively. 
Hypothesis 1. Etelcalcetide improves 
bone-tissue properties in patients 
with 
ESKD 
and 
severe 
hyperparathyroidism. 
Aim 1. To test if 6-months of treatment 
Figure 1. Study Procedures for All Aims 


Version Date: 1.3.2020 
with 
etelcalcetide 
improves 
bone 
hardness 
and 
mineralization 
using 
Ramen/nanoindentation 
and 
remodeling 
by 
histomorphometry 
using 
the 
quadruple label transiliac crest 
bone biopsy method in 20 ESKD 
patients with severe HPT.  
Table 1: Data Collection at each Study Visit 
Baseline 
3 Months 
9 Months 
Informed consent 
x 
Medical History 
x 
x 
Physical Exam 
x 
x 
Kt/V 
x 
x 
x 
Biomarkers of bone formation and 
resorption (BSAP, P1NP, CTX) 
x 
x 
x 
Figure 2. Study timeline. 


Version Date: 1.3.2020 
Procedures. 
This 
is 
a 
single-arm 
prospective cohort study to test the 
effects of 6-months of treatment with 
etelcalcetide on bone-tissue properties. 
We will obtain a single quadruple label 
bone biopsy to assess longitudinally the 
effects of 6-months of treatment with 
etelcalcetide on bone properties at the 
tissue level. We will enroll 20 adult patients with ESKD on hemodialysis who are scheduled to receive 
etelcalcetide for the treatment of HPT per standard of care. These 20 patients with ESKD will be treated with 
etelcalcetide to maintain levels of PTH between 300 and 400 pg/mL, which is at the mid-range of the KDIGO 
recommended range (2-9 times the ULN for the PTH assay1) for 6 months. Patients will be identified for inclusion 
based on clinical need for the treatment of severe HPT and high turnover bone disease and only patients whose 
treating physician plans to initiate etelcalcetide will be included. HPT will be defined by the KDIGO guidelines 
(PTH >9-times the ULN for the PTH assay1) and high turnover bone disease will be defined by a total alkaline 
phosphatase level ≥ upper tertile of the reference range for the assay. At study start, patients will undergo the 
initial double labeling procedure with tetracycline (TCN; 3-days of TCN followed by 12-days off TCN followed by 
3-days of TCN); during the labeling period etelcalcetide will not be administered (Figure 2). Patients will then 
undergo a 3-month etelcalcetide dose-titration phase to ensure that PTH levels are consistently maintained 
within target range (300-400 pg/mL), followed by a 6-month treatment (maintenance) phase. At the study 
endpoint (6-months of treatment), the final set of labels for transiliac crest bone biopsy will be given (3-days of 
demeclocycline followed by 12-days off demeclocycline followed by 3-days of demeclocycline) and bone biopsy 
will occur 5-days after the last dose of demeclocycline. During the final labeling period, the dose of etelcalcetide 
will continue to target the goal PTH level and the patient will continue to be managed as clinically indicated. The 
quadruple label approach permits longitudinal assessment of both dynamic indices of histomorphometry and 
bone-tissue level properties pre- and post-intervention, with the use of a single biopsy. The first label (TCN) is 
given prior to the initiation of etelcalcetide and the second label (demeclocycline) is given after 6-months of 
treatment (maintenance) with etelcalcetide. The fluorescence of tetracycline and demeclocycline differs, 
permitting differentiation of the labels under fluorescence microscopy and determination of dynamic indices of 
histomorphometry pre- and post-intervention. To assess bone tissue level effects of treatment, we will use a 
Raman/Nanoindentation system. This system allows the differentiation of tetracycline (pre-treatment) and 
demeclocycline (post-treatment) labels and permits precise measurement of localized bone tissue properties 
(e.g., mineral/matrix, collagen) and indentation properties (e.g., hardness) within these regions. Additionally, we 
will use 3-dimensional micro-CT (µCT) imaging (resolution 3 μm3) to obtain more complete structural indices 
from the bone biopsy specimens at the 6-month time point. Patients will have blood collected and stored at -
80ºC, at baseline (pre-treatment) and after 3- and 6-months of treatment (i.e., maintenance phase) (Table 1). 
Blood will be assayed for calcium, phosphorus, PTH, vitamin D metabolites, bone formation (bone specific 
alkaline phosphatase [BSAP], procollagen type-1 N-terminal propeptide [P1NP]) and resorption (C-Telopeptide 
[CTX]) markers, FGF-23 and sclerostin.  
Bone biopsy with quantitative histomorphometry and nanoindentation/Raman spectroscopy. After bone 
biopsy, the specimens will be transferred to Dr. Allen’s laboratory for tissue analysis (described below). 
µCT. 3D trabecular and cortical structure will be assessed on biopsies before embedding using a Skyscan 
1172 system (scanning resolution of 6 µm3). Outcome measurements will include both cortical parameters 
(porosity [%], mineralization [average value and variation] and thickness) and trabecular parameters (BV/TV, 
trabecular number, separation, thickness, and connectivity density) using manufacturer software and standard 
analytical protocols. At study initiation, we will perform short-term precision measurements on selected structural 
and mechanical properties. QC procedures are enforced by the in-house software system, and include weekly 
scanning of a QA/µCT phantom. The software system’s QA analysis monitors scanner performance and 
normalizes results for any fluctuations. QA data and specimen results can be exported to SAS or Excel. 
 Quantitative histomorphometry. Following CT scans, specimens will be embedded in methyl methacrylate 
using standard protocols. Sections will be cut with a rotary microtome and either left unstained or stained with 
McNeal tetracrome or tartrate resistant acid phosphatase for analysis. Histomorphometric indices will be defined 
in accordance with the American Society for Bone and Mineral Research5. The following histomorphometric 
indices will be measured or calculated: osteoid surface, area, and width; osteoclast surface, eroded surface, 
resorption depth, resorption period; cancellous wall width, mineral apposition rate, bone formation rate, adjusted 
PTH, Vitamin D metabolites, Serum 
calcium and phosphorus, FGF-23, 
Sclerostin, T50 
x 
x 
x 
Bone biopsy Labeling  
(for participants enrolled in Aim 1) 
x 
 
x 
Bone biopsy  
(for participants enrolled in Aim 1) 
 
 
x 
Imaging: DXA and HR-pQCT 
x 
 
x 
AGE Reader 
x 
 
x 


Version Date: 1.3.2020 
apposition rate, mineralization lag time, activation frequency. Note: architectural properties (BV/TV, porosity, etc) 
will not be collected, as these will be obtained from CT as above. 
Bone-tissue properties. We will use an integrated Raman/Nanoindentation system, which permits precise 
measurement of localized bone tissue properties (e.g., mineral/matrix, collagen) and indentation properties (e.g., 
hardness) within identical regions. Areas within the TCN and demeclocycline double label will be assessed for 
nanoindentation properties, and subsequently the same spatial location will be assessed for Raman-based 
measurements. Nanoindentation will occur using a Berkovich diamond indenter loading to a peak load of 10mN, 
a strain rate of 0.05 seconds and a holding period of 10 seconds. Oliver and Pharr methods will be used to 
determine the stiffness and hardness of the unloading curves. A total of 12-15 indentations will be performed 
within a given region. Following indentation, the same spatial regions will be assessed with Raman spectroscopy 
to determine the phosphate and matrix peaks after background and baseline shift correction. The ratio of 
phosphate:mineral will be calculated, along with other parameters (crystallinity and collagen crosslinking). 
 
 
Hypothesis 2. Etelcalcetide will improve bone density, microarchitecture, and biomechanical 
competence in patients with ESKD. 
Aim 2. To test if 6-months of treatment with etelcalcetide improves femoral neck areal BMD measured by DXA 
and failure load at the ultradistal radius measured by application of finite element analysis to HR-pQCT datasets. 
We will also quantify the effect of 6-months treatment with etelcalcetide on changes in areal BMD at the spine, 
total hip, and one-third and ultradistal radius measured by DXA, and cortical and trabecular volumetric BMD and 
microarchitecture, cortical porosity and tissue mineral density, and biomechanical competence at the ultradistal 
radius and tibia measured by HR-pQCT with application of finite element analysis. 
Procedures. We will enroll 35 patients (20 from Aim 1 and 15 de novo) into this prospective single-arm cohort 
study to test the hypothesis that 6 months of treatment (maintenance) with etelcalcetide will improve bone 
density, microarchitecture and mechanical competence measured by DXA and HR-pQCT with application of 
finite element analysis (FEA). Similar to Aim 1, eligibility for enrollment into Aim 2 will be based on a PTH level 
>9-times the ULN for the PTH assay (Figure 1), as well as their treating physician’s plan to initiate etelcalcetide 
per standard of care. However, the presence of high turnover bone disease based on total alkaline phosphatase 
will not be a criterion for enrollment into Aim 2. Furthermore, all patients enrolled in Aim 1 will be automatically 
enrolled into Aim 2 unless they choose to opt-out of Aim 2. As per Aim 1 (Figure 2), after enrollment, patients 
will undergo a 3-month dose titration phase to ensure that PTH levels are stability maintained within the target 
rage (300-400 pg/mL), followed by a 6-month treatment (maintenance) phase. All patients will have imaging 
(DXA and HR-pQCT) performed at baseline (prior to drug) and after 6-months of maintenance treatment.  
Imaging Methods for Measurement of Bone Mass, Microarchitecture, and Mechanical Competence 
 
DXA. areal BMD of spine (L1-4, AP), right proximal femur, forearm and whole body using Hologic QDR 4500 
(Hologic, Inc., Waltham, MA) in the array (fan beam) mode. Phantoms are scanned daily for QA. Short term, 
in vivo precision is 0.68%, 1.36%, and 0.70% for spine, FN, and radius respectively. 
 
HR-pQCT of the ultradistal radius and tibia. XtremeCT2 (Scanco Medical AG, Brüttisellen, Switzerland, 
voxel size 60µm). Methods and QC are described in our publications6, 7. Precision: cortical and volumetric 
trabecular BMD=0.9%±7.1% and 2.3±3.5%, respectively. HR-pQCT of the forearm will be performed at the 
non-dominant forearm. If dialysis access is located at the non-dominant forearm, we will use the dominant 
forearm for HR-pQCT imaging.  
Mechanical Analysis of Skeletal Imaging. Sanchita Agarwal MS will perform analyses of HR-pQCT datasets. 
HR-pQCT Finite Element Analysis (FEA). Ms. Agarwal will estimate mechanical competence (strength) from 
HR-pQCT images. Each image is converted to a µFE model by directly converting bone voxels to 8-node elastic 
brick elements. A uniaxial displacement equaling 1% of the bone segment height is applied perpendicularly to 
the distal surface of the radius or tibia while the proximal surface is imposed with zero displacement along the 
same direction. The total reaction force is calculated from the linear µFE analysis, and the axial stiffness is 
calculated as the reaction force divided by the imposed displacement. 
HR-pQCT Cortical Porosity. Ms. Agarwal will conduct analyses of cortical porosity using methods that have 
been described and validated in recent publications8.  
 
 
Hypothesis 3. Etelcalcetide decreases serum calcification propensity in patients with ESKD. 


Version Date: 1.3.2020 
Aim 3. To test if 6-months of treatment with etelcalcetide decreases serum propensity to calcify soft tissues. In 
a single-arm study of 35 patients with ESKD treated with 6-months of etelcalcetide, we will measure T50, 
calciotropic hormones, serum calcium and phosphorus, bone turnover markers, FGF-23 and Sclerostin pre-
treatment and 3- and 6-months after treatment.  
Procedures. We will enroll 35 patients (20 from Aim 1 and 15 de novo) into this prospective single-arm cohort 
study to test the hypothesis that 6 months of treatment (maintenance) with etelcalcetide will decrease the 
propensity to calcify soft tissues as measured by T50. Similar to Aim 1, eligibility for enrollment into Aim 3 will 
be based on a PTH level >9-times the ULN for the PTH assay (Figure 1), as well as their treating physician’s 
plan to initiate etelcalcetide per standard of care. However, the presence of high turnover bone disease based 
on total alkaline phosphatase will not be a criterion for enrollment into Aim 3. Furthermore, all patients enrolled 
in Aim 1 will be automatically enrolled into Aim 3 unless they choose to opt-out of Aim 3. Thus, we will use the 
biochemical data from the 20 enrollees participating in Aim 1 and enroll an additional 15 patients to be treated 
with etelcalcetide. As per Aim 1 (Figure 2), after enrollment, patients will undergo a 3-month dose titration phase 
to ensure that PTH levels are stability maintained within the target range (300-400 pg/mL), followed by a 6-month 
treatment (maintenance) phase. Patients will have blood collected and stored at -80ºC, at baseline (pre-
treatment) and after 3- and 6-months of treatment (i.e., maintenance phase). Blood will be assayed for T50, 
calcium, phosphorus, PTH, vitamin D metabolites, bone formation (BSAP, P1NP) and resorption (CTX) markers, 
FGF-23 and sclerostin. We will assess the effect of treatment on changes in levels of T50, a clinically relevant 
biomarker of calcification propensity9, 10. We will also determine relationships between changes in T50 and 
changes in phosphorus, calcium, bone turnover markers and calciotropic hormones. 
 
 
Exploratory. None 
 
 
Primary and Secondary Endpoints for Each Aim 
Aim 1  
1. Primary Endpoints: Hardness 
2. Secondary Endpoints: Bone formation rate, mineralization density 
 
Aim 2 
1. Primary Endpoints: Changes in: (a) femoral neck areal BMD by DXA and (b) radius failure load by HR-
pQCT 
2. Secondary Endpoints: Changes in: (a) spine, total hip, and one-third and ultradistal radius BMD by DXA 
and (b) radius and tibia cortical density, thickness, porosity and tissue mineral density, and trabecular 
density, thickness, number and spacing 
 
Aim 3  
1. Primary Endpoint: Change in T50 (percent and absolute) 
2. Secondary Endpoints: Changes in PTH, calciotropic hormones, FGF-23, Sclerostin, calcium and 
phosphorus 
 
 
Statistical methods (for analysis of primary and secondary endpoints or primary/interim analysis)  
For All Aims, distributions will be examined and Anderson-Darling tests of normality and Q-Q plots will be used 
to guide the application of transformations to normalize the values prior to inferential testing. (Data analyzed 
from transformations will be reported in raw units). Inferential tests will be adjusted for multiple comparisons 
within a measurement domain (BMD within DXA, cortical, trabecular and FEA within HRpQCT, and each of the 
four compartments within histomorphometry) using a resampling, step-down procedure to control the family-wise 
error rate. We favor this over a false-discovery rate approach given the limited number of hypotheses within each 
measurement domain and that the measurement domains are traditionally seen as free to vary independently of 
each other11, 12. 
 
For Aim 1. A two-tailed dependent T-test of the change in hardness measured by Ramen nano-indentation and 
mineralization measured by histomorphometry obtained primary dynamic and secondary structural bone quality 


Version Date: 1.3.2020 
outcome values from the pre-treatment baseline to the 6-month endpoint will be reported with an alpha-level of 
5% as the criterion for statistical significance. Outcome data missing, for whatever reason, will not be imputed.  
 
For Aim 2. A two-tailed dependent T-test of the change in femoral neck BMD by DXA and failure load measured 
at the distal radius by HR-pQCT from pre-treatment to the 6-month endpoint will be reported with an alpha-level 
of 5% as the criterion for statistical significance. Secondary endpoints include treatment differences in change 
in cortical density, thickness and porosity, trabecular density and thickness and spacing, and areal BMD at the 
forearm, spine, and total hip. Other predictors to be tested in multiple regression models of change from baseline 
include demographic characteristics collected in Aim 1 and PTH, calciotropic hormones, bone formation and 
resorption markers, sclerostin, and FGF-23 collected in Aim 3. A final multiple regression model will be based 
on predictors that are significant in multiple regression models including baseline bone measure. 
 
For Aim 3. A two-tailed dependent T-test of the change in primary calcification propensity (T50) and secondary 
biochemical indices (calciotropic hormones, FGF-23, sclerostin, calcium and phosphorus) from pre-treatment 
baseline to the 6-month endpoint will be reported with an alpha-level of 5% as the criterion for statistical 
significance. Secondary exploratory analyses will assess the within-subject temporal course of change in the 
biochemical outcome with linear mixed models for repeated measures with time as a fixed effect (0, 3 and 6 
months); the baseline value of the dependent variable entered as a continuous covariate; and a covariance 
structure determined by empirical testing performed prior to inferential testing. We will also assess whether the 
Aim 1 participants differ from the patients recruited de novo for Aim 3 with an independent T-test both of the two 
groups’ baseline values and of the two groups’ change in values from baseline to the 6-month endpoint. We will 
explore the covariances between changes in T50 and other biochemical markers of bone turnover and 
calciotropic hormones with simple and multiple regression with synchronized and lagged observations in time to 
determine whether leading, cotemporaneous or following patterns exist among these measures.  
 
 
Subject Recruitment and Selection 
Study site and number of patients eligible for enrollment. ESKD patients receiving hemodialysis at the 
Rogosin Institute, meeting enrollment criteria, and whose treating physicians intend to initiate treatment with 
etelcalcetide will be asked to participate in this study. Rogosin is the largest provider of hemodialysis in New 
York City and provides hemodialysis services to over 1300 patients. Approximately 25% of patients at Rogosin 
have PTH levels > 9-times the ULN for the PTH assay. Therefore, there are adequate numbers of patients at 
Rogosin who may be able and willing to participate in this prospective cohort study. 
 
Enrollment Criteria 
Inclusion criteria 
For All Aims: 
1. Patient has provided informed consent. 
2. Patient is 18 years of age or older. 
3. Patient must be receiving maintenance hemodialysis for at least 3 months, with adequate hemodialysis 
with a delivered Kt/V 1.2 or urea reduction ratio (URR) 65% within 4 weeks prior to screening laboratory 
assessments. 
4. Dialysate calcium concentration must be stable for at least 4 weeks prior to screening laboratory 
assessments. 
5. Patient must have severe HPT as defined by two laboratory screening pre-dialysis serum PTH values 
>9-times ULN for the PTH assay, measured on two consecutive monthly lab checks prior to entering the 
study. 
6. The patient has an uncontrolled PTH defined by KDIGO as a PTH greater than 9 times the upper limit of 
normal of the assay (720 pg/mL for Rogosin): 
AND one of the following: 
- The patient has never been on cinacalcet OR, 
- The patient received daily cinacalcet for less than 3 months and has been off cinacalcet for at 
least 3 months prior to enrollment OR , 


Version Date: 1.3.2020 
- The patient received daily cinacalcet for more than 3 months and has been off cinacalcet for at 
least 6 months prior to enrollment OR, 
- The patient received a modified dose of three times weekly cinacalcet and has been off 
cinacalcet for at least one month prior to enrollment. 
 
7. Scheduled to receive etelcalcetide for the treatment of HPT per standard of care. 
8. If receiving vitamin D sterols, patient must have had no more than a maximum dose change of 50% within 
the 4 weeks prior to screening laboratory assessments, remain stable through randomization, and be 
expected to maintain stable doses for the duration of the study, except for adjustments allowed per 
protocol*. 
9. Patient must have one screening pre-dialysis serum Ca laboratory value at least at the lower limit of 
normal for the assay measured within 4 weeks prior to entering the study. 
10. A patient receiving calcium supplements must have had no more than a maximum dose change of 50% 
within 2 weeks prior to screening laboratory assessments and remain stable throughout the study, except 
for adjustments allowed per protocol*. 
11. A patient receiving phosphate binders must have had no more than a maximum dose change of 50% 
within the 2 weeks prior to screening laboratory assessments, remain stable through, and be expected 
to maintain stable dose for the duration of the study, except for adjustments allowed per protocol*. 
12. The treating physician considers the etelcalcetide dose and timing points described in this protocol as 
acceptable/optimal for their patient. 
13. Female patients must be willing to use highly effective contraception during the study and for 3 months 
after the last dose of etelcalcetide (unless postmenopausal or surgically sterilized). 
 
For Aim 1: 
1. Total alkaline phosphatase ≥ the upper tertile of the reference range for the assay 
 
 
Exclusion criteria 
For All Aims: 
1. Currently receiving treatment in an investigational device or drug study, or less than 30 days since ending 
treatment on an investigational device or drug study(s). 
2. Currently receiving investigational procedures while participating in this study. 
3. Patient with controlled PTH as defined by KDIGO as a PTH of 2 to 9 times the upper limit of normal of 
the assay. 
4. Patients has received a bisphosphonate, denosumab or teriparatide during the 12 months prior to 
screening. 
5. Anticipated or scheduled parathyroidectomy during the study period. 
6. Patient has received a parathyroidectomy within 6 months prior to dosing. 
7. Scheduled kidney transplant during the study period or anticipated living donor evaluation within three 
months of recruitment  
8. Patient 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. 
9. Bilateral lower extremity amputations or non-ambulatory 
10. Metabolic bone diseases not related to the kidney (i.e., Pagets, Osteogenesis Imprefecta) 
11. Untreated hyperthyroidism or hypoparathyroidism 
12. Malignancy within the last 5 years (except non-melanoma skin cancers or cervical carcinoma in situ). 
13. Patient is pregnant or nursing. 
14. Patient likely to not be available to complete all protocol-required study visits or procedures, and/or to 
comply with all required study procedures to the best of the patient and Investigator’s knowledge. 
15. Weight >300 pounds 
 
For Aim 1: 
1. Allergy to tetracycline or demeclocycline. 
 
Early Study Cessation Clause 


Version Date: 1.3.2020 
For patients who may get a kidney transplant during the study: If patients have been on etelcalcetide for at least 
3 months, end of study procedures (bone biopsy, bone imaging, and labs) will be performed and patients will be 
included in the final analysis as long as patients come in within 4 weeks after transplant. 
 
 
* Administration and Dosing of Etelcalcetide and Management of Hypocalcemia and Over-suppression 
of PTH 
The protocol will allow for changes in the dose of etelcalcetide, vitamin D sterols, calcium supplements and 
phosphate binders based on the levels of serum PTH, calcium and phosphorus that are obtained on a monthly 
basis as part of the standard of care monthly lab set for patients on hemodialysis.  
1) Administration: by intravenous bolus injection into the venous line of the dialysis circuit at the end of 
hemodialysis treatment during rinse back or intravenously after rinse back. 
 
2) Initiation and dose adjustment of etelcalcetide 
a) Starting dose of etelcalcetide: 5.0 mg 
b) Maximum dose of etelcalcetide: 15.0 mg 
c) Dose adjustments: increase in 2.5-5.0 mg increments at weeks 4, 8, 12 during the titration phase and at 
the time of the monthly lab sets during the treatment phase based on PTH and calcium. 
 
3) Missed doses 
a) If a regularly scheduled hemodialysis treatment is missed, do not administer any missed doses. 
i) Resume etelcalcetide at the end of the next hemodialysis treatment at the prescribed dose.  
ii) If doses of etelcalcetide are missed for more than 2 weeks, re-initiate etelcalcetide at the 
recommended starting dose of 5 mg (or 2.5 mg if that was the patient’s last dose). 
 
4) Management of hypocalcemia 
a) Monitor corrected serum calcium one-week after starting or changing a dose of etelcalcetide 
b) Drop in corrected serum calcium WNL of the reference range 
i) no dose change 
c) Drop in serum calcium < LLN of the reference range but ≥ 7.5 mg/dL without symptoms of hypocalcemia 
i) increase calcium in dialysate to the next highest level and/or start calcium oral supplement and 
monitor as per HD unit safety protocol 
(1) If calcium has normalized and PTH remains within the target range: no dose change 
(2) If calcium has normalized but PTH has risen above the target range: increase dose by 2.5 mg 
and monitor PTH and calcium per HD unit safety policy 
(a) If calcium and PTH are at goal: no dose change 
(b) If calcium < LLN but ≥ 7.5 mg/d without symptoms: increase calcium in dialysate and/or start 
calcium oral supplement and monitor as per HD unit safety protocol 
(i) If calcium remains < LLN but ≥ 7.5 mg/d, changes in levels of active vitamin D sterols can 
be implemented 
1. Decreasing the dose of etelcalcetide can be implemented after the above steps have 
been undertaken. The dose should be lowered in 2.5 mg increments and monitoring 
of PTH and calcium should be obtained within a week of any changes. 
d) Drop in serum calcium < 7.5 mg/dL or below the reference range with symptoms of hypocalcemia 
i) Hold drug and monitor as per HD unit safety protocol 
(1) If repeat calcium level WNL: restart dose at 2.5-5.0 mg lower than the previous dose and monitor 
as per HD unit safety protocol 
(a) If repeat calcium level remains WNL and PTH at goal: no dose change 
(b) If repeat calcium level remains WNL and PTH above goal: increase dose by 2.5 mg and 
monitor per HD unit safety protocol 
(i) If calcium level < LLN but ≥ 7.5 mg/d without symptoms: follow algorithm 4c  
(ii) If calcium level < 7.5 mg/dL or below the reference range with symptoms of hypocalcemia: 
proceed as per 4di 
 
5) Management of excessive suppression of PTH below the KDIGO target (< 2x LLN) 


Version Date: 1.3.2020 
i) Measure PTH after 4 weeks from initiation or dose adjustment 
ii) Without hypocalcemia: decrease dose by 2.5-5.0 mg and monitor as per HD unit safety protocol 
iii) With hypocalcemia: as per (4) above  
 
 
Sample Size for Aim 1. N = 20 
Sample Size Justification for Aim 1. The proposed sample size of 20 participants provides 80% power and 
5% alpha for a two-tailed dependent T-test of the within-subject difference in the pre- and post-treatment 
hardness measured by Ramen/nanoindentation in the formation regions of 0.91-SDs. While we expect moderate 
variability in hardness between subjects, the within subject change due to treatment sought here is expected to 
be relatively similar across subjects given the established efficacy of etelcalcetide on other outcomes13. Behets 
et al14 reports patients with end stage renal disease show a baseline bone formation rate of 799 + 334 (mean + 
SD), a O.Pm/B.Pm(%) of 18.9 + 9.4 and a  E.Pm/B.Pm of 13.1 + 4.3 which assures a measurable region for the 
Ramen/nanoindentation assessment of hardness.  
 
Sample Size for Aim 2. N = 35 (20 from Aim 1 plus 15 additional patients) 
Sample Size Justification for Aim 2. The proposed sample size of 35 participants provides >80% power and 
5% alpha to detect a change in femoral neck BMD of 0.5% f and a 0.5 standard deviation change in radius failure 
load by HR-pQCT from pre-treatment to the 6-month endpoint. For femoral neck BMD by measured by DXA, 
Lien et al 15 reported that in 8 patients with CKD treated with cinacalcet for 6 months, areal BMD at the femoral 
neck increased 2.2 ± 1.1% (p < 0.05). For failure load outcomes, in a longitudinal study of 29 patients with ESKD 
who underwent kidney transplantation, we reported that failure load decreased by 3.5 ± 7.0% (p=0.0081) over 
12-months16; our larger sample size will permit detection of at least a 3.4% change in radius failure load due to 
suppression of PTH production by etelcalcetide. 
 
Sample Size for Aim 3: N = 35 (20 from Aim 1 plus 15 additional patients) 
Sample Size Justification for Aim 3: The proposed sample size of 35 participants provides >80% power and 
5% alpha two-tailed dependent T-test of the change in T50 from baseline to the 6-month endpoint. Based on 
Smith et al10, each standard deviation (SD) decrease in T50 was associated with a 39% increase in odds of all-
cause mortality. Assuming that the variability in T50 in patients on hemodialysis patients enrolled into this 
prospective cohort study are similar to those reported in Smith et al10, approximately 20 patients would be 
required to detect a 1-SD decrease in T50. Our sample size of 35 patients will permit the detection of a 0.7-
SDs decline in T50. We assume that a reduction of lesser magnitude is of unclear clinical significance


Version Date: 1.3.2020 
Protection of Human Subjects 
This study qualifies as clinical research and will be conducted in compliance with GCP and all regulatory 
requirements for the protection of human subjects. 
 
Informed Consent 
Informed consent will be obtained from all participants. The purpose of the study will be explained to patients 
prior to recruitment as part of the informed consent procedures, which is defined as “to evaluate the effects of 
etelcalcetide on bone quality and the tendency of your soft tissue to calcify”. The study methods, namely the 
assessment of physical exam and medical history; the evaluation by imaging modalities; the collection of blood; 
and bone biopsy will be described. The fact that the informed consent and the study protocol have been approved 
by the IRB will be emphasized. The potential risks and direct benefits to the patient will be explained. The 
potential benefit from this study to future patients will be explained. The fact that the patient has the option not 
to participate and will receive the same standard medical care regardless of participation will be emphasized. 
The rights of the patient, including the voluntary nature of participation and the right to withdraw the consent at 
any time, will be explained. We will also explain that this research does not affect the clinical management of the 
patient as determined by their nephrologist. In addition, patients will be informed that by enrolling they will have 
more intensive monitoring of bone health than they would if they do not participate. Thus, participating in this 
study should not put the subject at any risk for altering management deemed appropriate by the patient’s 
nephrologist. The methods in place for maintaining patient confidentiality will be explained. This will include 
registering all data under a subject specific alpha-numeric system, storing all records in password protected and 
encrypted files. A copy of the signed informed consent will be placed in the patient’s permanent medical record, 
a second copy of all consents will accompany the data to be kept in the PI’s office, and a third copy will be 
provided to the participant. 
 
Potential Risks 
All key personnel involved in the design or conduct of research involving human subjects will have received the 
required education on the protection of human research participants prior to funding of this project. 
 
The potential risks are related to hypocalcemia, loss of confidentiality, radiation exposure from DXA for 
measurement of bone density and HR-pQCT for measurement of volumetric density and microarchitectural 
parameters and the bone biopsy procedure. All blood will be obtained from the dialysis line to avoid venipuncture. 
 
Hypocalcemia. Etelcalcetide has been associated with a decrease in serum calcium. We will monitor for 
and minimize this risk as described in the main protocol. 
 
Loss of confidentiality. due to breaches in data security or deductive disclosure. To ensure that participants’ 
confidentiality is not compromised, we will minimize these risks through the procedures discussed below. 
 
Radiation. The total expected radiation dose for the entire study is approximately 8 mrem (80 µSv) for 2-
sets of DXA and HR-pQCT scans obtained at the baseline and 12-month visits. This compares to 2400 µSv 
natural background in a year, 8000 µSv for a standard chest CT, 450 µSv for a mammogram, and 60 µSv for 
a round-trip transcontinental plane flight. The total radiation exposure for the study will be below the maximal 
acceptable dose. 
a) CUMC DXA (2 sets of scans). Radiation exposure for DXA (spine, one hip, forearm) using the Hologic 
QDR4500 (fast scan) is 10.85 µSv (21.68 µSv for 2 sets of scans). 
b) HR-pQCT (one forearm and one leg; 3 sites each). 30 µSv (60 µSv for 2 sets of scans) 
 
Transiliac crest bone biopsy. The risks of the bone biopsy include those related to tetracycline and 
demeclocycline administered in advance of the biopsy to label sites of bone formation, the risks of conscious 
sedation, and the risks of the biopsy itself. Tetracycline-type agents may cause stomach upset and skin 
rashes when subjects taking them are exposed to sunlight. Subjects will be counseled to discontinue 
tetracycline/demeclocycline if gastrointestinal symptoms develop and to avoid sunlight exposure during the 
6 days they are taking the medication. Conscious sedation will be offered to subjects in order to minimize 
anxiety, provide pain relief, and diminish recall. Patients receiving conscious sedation may have brief, 
transient loss of protective reflexes. Either IV or PO sedation will be provided with a combination of a 
benzodiazepine (e.g, midazolam, valium) and a narcotic-based pain medication (e.g., fentanyl, oxycodone). 
Risks will be minimized by complying with all procedures as required by CUMC’s Policies and Procedures 
Manual. Specifically, all nurses and physicians involved in performing bone biopsies will have certification in 
Advanced Cardiac Life Support, the procedure will be conducted in the Biopsy Suite in the Division of 


Version Date: 1.3.2020 
Nephrology at CUMC, and vital signs (including O2 saturation) will be monitored at regular intervals during 
and after the procedure. An M.D. or Nurse-anesthetist will be present to administer the conscious sedation. 
Complications from the biopsy are very unusual. Occasionally there will be a bruise at the site or discomfort 
at the biopsy site that persists for a few days. 
 
Protection against risk  
The risks of DXA, HR-pQCT, bone biopsy and loss of confidentiality are described above. Provision for medical 
treatment, should it be required, will be included in the written informed consent; each subject will receive a copy. 
Confidentiality of patient data will be ensured. No patient will be identifiable in any publications resulting from 
this study. Patients are identified by code rather than name in the database. Access to the computer data bank 
is limited by password protection. 
 
Hypocalcemia. We have implemented a protocol to monitor and manage hypocalcemia. 
 
Radiation. DXA, and HR-pQCT have the risk of radiation exposure. The amount of radiation that participants 
will receive as a result of participation in the study will be discussed with each participant in detail as part of 
informed consent procedures. Females will undergo a urine pregnancy test prior to the DXA and HR-pQCT. 
Pregnant females will be excluded from the study at any time point in order to protect the unborn fetus. 
 
Bone biopsy. The risks of bone biopsy will be included in informed consent procedures. Furthermore, our 
use of a quadruple label method negates the need for 2 bone biopsy procedures. 
 
Confidentiality. Only investigators and the study research staff will have access to the data. All data are 
recorded with linkages to subject identities to be able to track changes over their longitudinal participation in 
the study. A data collection/tracking system developed for use in previous studies is used in this research, 
and will ensure confidentiality for all participants. All collected data will be identified by study identification 
numbers but not names. Only the study investigators will have access to a master list with the study 
identification numbers and names. The master list will be kept on a secure server on a research shared 
access network. All data containing PHI will be stored on password-protected encrypted CUMC computer or 
the secure research servers. Computers are password protected, encrypted and regularly backed-up to 
prevent data loss. Paper documents, such as consent forms, will be stored in locked cabinets in areas of 
restricted access. Only the research staff will have access to this information, unless written permission is 
received from the participant. The data collected as part of this study will be retained indefinitely. All data and 
records generated during this study will be kept confidential in accordance with Institutional policies and 
HIPAA on subject privacy, and the investigators and other site personnel will not use such data and records 
for any purpose other than conducting the study. 
 
Safety Reporting 
The Principal Investigator will be responsible for patient safety. As this is not a clinical trial, there is minimal 
potential for injury.  
 
Adverse events will be monitored throughout the study and reported to Amgen as follows: 
 
Suspected Unexpected Serious Adverse Reaction (SUSARs) will be submitted at the time of regulatory 
submission 
 
Pregnancy/Lactation Reports will be submitted within 10 calendar days of Sponsor awareness 
 
Applicable Annual Safety Reports will be submitted annually 
 
Other Aggregate Analyses (any report containing safety data generated during the course of the study) will 
be submitted at the time of ISS Sponsor submission to the IRB (or other body governing research conduct)  
 
The Final (End of Study) Report will be submitted to Amgen at the time of ISS Sponsor submission to the 
IRB (or other body governing research conduct), but not later than 1 calendar year of study completion 
 
Any unanticipated problem involving risks will be reported to the CUMC-IRB in accordance with their Reporting 
Policy effective January 24, 2008.  
 
Additionally, throughout the study, the Principal Investigator will review safety labs that are ordered per standard 
of care, and may provide recommendations to the treating physician based upon the drug dosing and 
management guidelines included in this protocol.  
 
 


Version Date: 1.3.2020 
References 
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10.1681/ASN.2012030240. PubMed PMID: 22956818; PMCID: PMC3458464. 
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Smith ER, Ford ML, Tomlinson LA, Bodenham E, McMahon LP, Farese S, Rajkumar C, Holt SG, Pasch
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Malluche HH, Porter DS, Monier-Faugere MC, Mawad H, Pienkowski D. Differences in bone quality in
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Behets GJ, Spasovski G, Sterling LR, Goodman WG, Spiegel DM, De Broe ME, D'Haese PC. Bone
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Lien YH, Silva AL, Whittman D. Effects of cinacalcet on bone mineral density in patients with secondary
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ICF_001.pdf: 
 
 
 
 
 
 
 
 
The Effect of Etelcalcetide on Bone-tissue Properties and 
Calcification Propensity in End Stage Kidney Disease 
PI: Thomas Nickolas, MD, MS 
AAAR6244 
NCT03960437   
ICF Version 18March2019 
 
 


Version Date: 3/18/19 
Page 1 of 11 
 
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