supplementary online content...patient has received amg 416 in a prior clinical trial of amg 416...

Supplementary Online Content

Block GA, Bushinsky DA, Cunningham J, et al. Effect of etelcalcetide vs placebo on serum parathyroid hormone in patients receiving hemodialysis with secondary hyperparathyroidism: two randomized clinical trials. JAMA. doi:10.1001/jama.2016.19456

eAppendix. Supplementary Methods eTable 1. Number of Randomized Patients by Country eTable 2. Summary of Dose Level of Study Medication eTable 3. Summary of Dialysate Calcium Concentration eTable 4. Change From Baseline Over Time in Bone-Specific Alkaline Phosphatase and Collagen Type I Cross-Linked C-Telopeptide eTable 5. Summary of Low Corrected Calcium During the Study eTable 6. Treatment Emergent Adverse Events (≥1% in Etelcalcetide Arm in at Least One Study) in Descending Order of Frequency eTable 7. Summary of Corrected QT Interval (Bazett and Fridericia) eFigure 1. Time to >30% Reduction From Baseline in PTH (Rolling Average of 3 PTH Values Were Used to Compare With Baseline) eFigure 2 A-B. Forest Plot for Difference in Proportion With >30% Decrease From Baseline in PTH Across Patient Subgroups eFigure 3 A-B. Use of Calcium Supplement or Calcium Containing Phosphate Binders Over Time eFigure 3 C-D. Use of Active Vitamin D Over Time eFigure 4. Mean PTH Value (pg/mL) (95% CI) by Study Week

This supplementary material has been provided by the authors to give readers additional information about their work.

© 2017 American Medical Association. All rights reserved.

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eAppendix. Supplementary Methods

Inclusion Criteria

Patient understands the study procedures and agrees to participate in the study by giving written

informed consent.

18 years of age or older.

Female patients who are post-menopausal (post-menopausal is defined as no menses for the

previous 1 year and over the age of 50 years), surgically sterilized, have a medical condition that

prevents pregnancy, remain abstinent, or are willing to use highly effective contraception during

the study and for 3 months after the last dose. Women of child-bearing potential must have a

negative serum pregnancy test within 2 weeks prior to the first dose of investigational product.

Patient receiving active vitamin D sterols 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.

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

randomization, and be expected to maintain stable dose for the duration of the study, except for

adjustments allowed per protocol.

Patient receiving calcium supplements must have had no more than a maximum dose change of

50% within the 2 weeks prior to screening laboratory assessments and remain stable through

randomization.



Patient must be receiving hemodialysis 3 times weekly for at least 3 months and have adequate

hemodialysis with a delivered Kt/V ≥ 1.2 or urea reduction ratio (URR) ≥ 65% within 4 weeks

prior to screening laboratory assessments.

Dialysis prescription dialysate calcium concentration must be ≥ 2.25 mEq/L and stable for at

least 4 weeks prior to screening laboratory assessments, remain stable through randomization

and remain ≥ 2.25 mEq/L for the duration of the study.

Patient must have 2 consecutive screening predialysis serum PTH labs drawn on separate days

within 2 weeks prior to randomization and the results of both must be > 400 pg/mL. Enrollment

of patients with mean screening iPTH > 1000 pg/mL will be limited to approximately 20% of

patients.

Patient must have 2 consecutive screening predialysis serum albumin-corrected calcium labs

drawn on separate days within 2 weeks prior to randomization and the results of both must be ≥

8.3 mg/dL.

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

Patient’s legally acceptable representative has provided informed consent when the patient has

any kind of condition that, in the opinion of the Investigator, may compromise the ability of the

patient to give written informed consent.

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.

Patient has received a parathyroidectomy within 3 months prior to dosing.



Anticipated or scheduled kidney transplant during the study period.

Patient has known sensitivity to any of the products or components to be administered during

dosing.

Patient has previously been randomized in this study.

Patient has received AMG 416 in a prior clinical trial of AMG 416 (also referred to as KAI-

4169).

Patient has received cinacalcet within the 4 weeks prior to screening labs (treatment with

cinacalcet is prohibited during the study).

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.

Patient 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 patient.

Patient history of malignancy within the last 5 years (except non-melanoma skin cancers, or

cervical carcinoma in situ).

Patient has a serious concurrent medical condition (e.g., malignancy) likely to result in death

during the next 12 months.

Patient is pregnant or nursing.

Patient has a history of symptomatic ventricular dysrhythmias or Torsades de Pointes.

Patient’s screening 12-lead electrocardiogram (ECG) suggests unstable arrhythmia or other

cardiac abnormality that could place the patient at increased risk, based upon the Investigator’s

opinion.

Patient has poorly controlled hypertension.



Patient has a history within the past 6 months of either angina pectoris with symptoms that occur

at rest or minimal activity, or congestive heart failure (New York Heart Association

Classification III or IV).

Patient has a history of myocardial infarction, coronary angioplasty, or coronary arterial bypass

grafting within the past 6 months prior to screening.

Patient is receiving treatment for a seizure disorder or has a history of a seizure within the last 12

months prior to screening.

Patient has had surgery (except minor surgery) within the last 8 weeks prior to screening.

Patient has clinically significant abnormalities on prestudy clinical examination or abnormalities

on the most recent central laboratory test during the screening period prior to randomization

according to the Investigator including but not limited to the following:

o Serum albumin ≤ 3.0 g/dL

o Serum magnesium < 1.5 mg/dL

o Serum transaminase (alanine transaminase [ALT] or serum glutamic pyruvic transaminase

[SGPT], aspartate aminotransferase [AST] or serum glutamic oxaloacetic transaminase

[SGOT]) > 2.5 times the upper limit of normal (ULN) at screening

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.

History or evidence of any other clinically significant disorder, condition or disease (with the

exception of those outlined above) that, in the opinion of the Investigator or Amgen physician, if

consulted, would pose a risk to patient safety or interfere with the study evaluation, procedures

or completion



eTable 1. Number of Randomized Patients by Country

Country

Trial A

(N = 508)

n (%)

Trial B

(N = 515)

n (%)

Australia 15 (3.0) 17 (3.3)

Austria 10 (2.0) 0 (0.0)

Belgium 23 (4.5) 20 (3.9)

Canada 11 (2.2) 13 (2.5)

Czech Republic 18 (3.5) 16 (3.1)

France 9 (1.8) 16 (3.1)

Germany 15 (3.0) 1 (0.2)

Hungary 27 (5.3) 25 (4.9)

Israel 6 (1.2) 9 (1.7)

Italy 19 (3.7) 9 (1.7)

Netherlands 0 (0.0) 12 (2.3)

Poland 23 (4.5) 35 (6.8)

Russian Federation 38 (7.5) 20 (3.9)

Spain 34 (6.7) 34 (6.6)

Sweden 0 (0.0) 5 (1.0)

United Kingdom 10 (2.0) 0 (0.0)

United States 250 (49.2) 283 (55.0)



eTable 2. Summary of Dose Level of Study Medication

Trial A Trial B

Dose (mg) per administration Etelcalcetide

(N = 251) Etelcalcetide

(N = 252) Week 1

n 249 251 Median (Q1, Q3) 5.0 (5.0, 5.0) 5.0 (5.0, 5.0)

Week 5

n 233 244 Median (Q1, Q3) 7.5 (5.0, 10.0) 7.5 (5.0, 10.0)

Week 9

n 230 239 Median (Q1, Q3) 7.5 (5.0, 10.0) 7.5 (5.0, 10.0)

Week 13

n 222 231 Median (Q1, Q3) 7.5 (5.0, 12.5) 7.5 (2.5, 12.5)

Week 17

n 227 227 Median (Q1, Q3) 7.5 (2.5, 12.5) 7.5 (2.5, 12.5)

Week 20

n 220 215 Median (Q1, Q3) 7.5 (2.5, 12.5) 7.5 (2.5, 10.0)

Week 23

n 218 213 Median (Q1, Q3) 7.5 (2.5, 10.0) 5.0 (2.5, 10.0)

Week 26

n 213 201 Median (Q1, Q3) 7.5 (2.5, 10.0) 5.0 (2.5, 10.0)

N: patients who received at least one dose of investigational product



eTable 3. Summary of Dialysate Calcium Concentration

Dialysate Calcium Concentration

Trial A Trial B Etelcalcetide (N = 251)

n (%)

Placebo (N = 254)

n (%)

Etelcalcetide (N = 252)

n (%)

Placebo (N = 259)

n (%) Baseline (mEq/L)

<2.5 13 (5.2) 18 (7.1) 24 (9.5) 28 (10.8)

2.5 179 (71.3) 180 (70.9) 142 (56.3) 159 (61.4)

>2.5 59 (23.5) 56 (22.0) 85 (33.7) 72 (27.8)

Missing 0 (0.0) 0 (0.0) 1 (0.4) 0 (0.0)

End of Study (mEq/L)

<2.5 10 (4.0) 19 (7.5) 16 (6.3) 27 (10.4)

2.5 148 (59.0) 177 (69.7) 106 (42.1) 157 (60.6)

>2.5 93 (37.0) 58 (22.8) 129 (51.2) 75 (29.0)

Missing 0 (0.0) 0 (0.0) 1 (0.4) 0 (0.0)




eTable 4. Change From Baseline Over Time in Bone-Specific Alkaline Phosphatase and Collagen Type I Cross-Linked C-Telopeptide

Trial A Trial B

Etelcalcetide

(N = 254) Placebo

(N = 254) Etelcalcetide

(N = 255) Placebo

(N = 260) Bone-Specific Alkaline Phosphatase

Change from Baseline to Week 12 (mcg/L) n 216 227 214 224 Median 0.85 0.06 0.31 1.26 Q1, Q3 -2.66, 5.56 -3.55, 4.69 -4.07, 6.92 -2.75, 6.12

Percent Change from Baseline to Week 12 (%) n 216 227 214 224 Median 4.66 0.38 2.61 5.96 Q1, Q3 -12.08, 24.85 -12.70, 20.86 -17.57, 26.36 -11.46, 25.40

Change from Baseline to Week 27 (mcg/L) n 210 186 201 194 Median -4.59 2.04 -5.01 3.05 Q1, Q3 -11.64, -0.41 -2.72, 9.42 -13.50, -0.16 -1.85, 9.00

Percent Change from Baseline to Week 27 (%) n 210 186 201 194 Median -23.01 9.45 -32.27 15.63 Q1, Q3 -43.15, -2.06 -12.11, 40.81 -47.26, -0.69 -9.68, 38.97

Collagen Type I Cross-linked C-telopeptide

Change from Baseline to Week 12 (ng/L) n 216 220 219 229 Median -685 40 -870 0 Q1, Q3 -1285, -165 -345, 530 -1540, -300 -460, 570

Percent Change from Baseline to Week 12 (%) n 216 220 219 229 Median -24.02 1.20 -31.71 0.00 Q1, Q3 -45.59, -5.93 -11.43, 21.02 -50.89, -11.28 -15.12, 20.85

Change from Baseline to Week 27 (ng/L)

n 206 182 195 184 Median -1075 -75 -1350 -80 Q1, Q3 -1780, -480 -600, 630 -1990, -660 -625, 565

Percent Change from Baseline to Week 27 (%) n 206 182 195 184 Median -39.30 -2.13 -50.33 -2.33 Q1, Q3 -58.43, -18.77 -20.00, 21.28 -63.30, -32.00 -21.51, 23.52



eTable 5. Summary of Low Corrected Calcium During the Study Trial A Trial B

Etelcalcetide

(N = 251)

n (%)

Placebo

(N = 254)

n (%)

Etelcalcetide

(N = 252)

n (%)

Placebo

(N = 259)

n (%)

Number of patients with at least one post-baseline cCa - N1 249 253 250 258

Number of patients with cCa < 7.0 mg/dL 16 (6.4) 7 (2.8) 22 (8.8) 9 (3.5)

Number of patients with cCa 7.0 - < 7.5 mg/dL 39 (15.7) 4 (1.6) 58 (23.2) 8 (3.1)

Number of patients with cCa 7.5 - < 8.3 mg/dL 132 (53.0) 33 (13.0) 125 (50.0) 38 (14.7)

N: patients who received at least one dose of investigational product. Percentages are based on N1.

Categories are mutually exclusive. The lowest corrected calcium value of each patient is used.



eTable 6. Treatment Emergent Adverse Events (≥1% in Etelcalcetide Arm in at Least One Study) in Descending Order of Frequency

Preferred Term


n (%)

Placebo (N = 254)

n (%)


n (%)

Placebo (N = 259)

n (%) Number of patients reporting 230 (91.6) 200 (78.7) 231 (91.7) 210 (81.1) treatment-emergent adverse events Blood calcium decreased 153 (61.0) 21 (8.3) 168 (66.7) 31 (12.0) Muscle spasms 30 (12.0) 18 (7.1) 28 (11.1) 16 (6.2) Diarrhoea 18 (7.2) 18 (7.1) 36 (14.3) 26 (10.0) Nausea 31 (12.4) 13 (5.1) 23 (9.1) 19 (7.3) Vomiting 26 (10.4) 18 (7.1) 19 (7.5) 8 (3.1) Headache 18 (7.2) 20 (7.9) 20 (7.9) 11 (4.2) Hypocalcaemia 18 (7.2) 1 (0.4) 17 (6.7) 0 (0.0) Hypertension 12 (4.8) 17 (6.7) 19 (7.5) 12 (4.6) Hypotension 16 (6.4) 10 (3.9) 14 (5.6) 16 (6.2) Arteriovenous fistula site complication 13 (5.2) 14 (5.5) 16 (6.3) 12 (4.6) Dyspnoea 11 (4.4) 8 (3.1) 13 (5.2) 12 (4.6) Pain in extremity 17 (6.8) 11 (4.3) 7 (2.8) 9 (3.5) Paraesthesia 13 (5.2) 3 (1.2) 11 (4.4) 0 (0.0) Back pain 8 (3.2) 8 (3.1) 14 (5.6) 11 (4.2) Cough 12 (4.8) 7 (2.8) 10 (4.0) 15 (5.8) Hyperkalaemia 10 (4.0) 6 (2.4) 12 (4.8) 5 (1.9) Arthralgia 10 (4.0) 10 (3.9) 11 (4.4) 16 (6.2) Upper respiratory tract infection 8 (3.2) 10 (3.9) 13 (5.2) 16 (6.2) Urinary tract infection 12 (4.8) 4 (1.6) 9 (3.6) 6 (2.3) Pyrexia 12 (4.8) 11 (4.3) 8 (3.2) 9 (3.5) Anaemia 10 (4.0) 8 (3.1) 9 (3.6) 14 (5.4) Dizziness 8 (3.2) 7 (2.8) 10 (4.0) 6 (2.3) Nasopharyngitis 10 (4.0) 13 (5.1) 7 (2.8) 10 (3.9) Constipation 7 (2.8) 9 (3.5) 9 (3.6) 7 (2.7) Fluid overload 9 (3.6) 7 (2.8) 7 (2.8) 4 (1.5) Fall 3 (1.2) 5 (2.0) 12 (4.8) 9 (3.5) Bronchitis 7 (2.8) 4 (1.6) 7 (2.8) 4 (1.5) Decreased appetite 8 (3.2) 4 (1.6) 6 (2.4) 4 (1.5) Oropharyngeal pain 8 (3.2) 4 (1.6) 6 (2.4) 6 (2.3) Procedural hypotension 7 (2.8) 12 (4.7) 7 (2.8) 6 (2.3) Abdominal pain 8 (3.2) 7 (2.8) 5 (2.0) 8 (3.1) Angina pectoris 11 (4.4) 2 (0.8) 2 (0.8) 3 (1.2) Asthenia 8 (3.2) 6 (2.4) 5 (2.0) 9 (3.5) Cellulitis 3 (1.2) 3 (1.2) 10 (4.0) 7 (2.7) Dyspepsia 10 (4.0) 5 (2.0) 3 (1.2) 2 (0.8) Abdominal pain upper 8 (3.2) 8 (3.1) 4 (1.6) 6 (2.3)



eTable 6. Treatment Emergent Adverse Events (≥1% in Etelcalcetide Arm in at Least One Study) in Descending Order of Frequency (continued)

Preferred Term


n (%)

Placebo (N = 254)

n (%)


n (%)

Placebo (N = 259)

n (%) Anxiety 9 (3.6) 4 (1.6) 3 (1.2) 3 (1.2) Hypoglycaemia 6 (2.4) 6 (2.4) 6 (2.4) 9 (3.5) Vascular graft thrombosis 4 (1.6) 5 (2.0) 8 (3.2) 5 (1.9) Atrial fibrillation 7 (2.8) 5 (2.0) 4 (1.6) 5 (1.9) Fatigue 7 (2.8) 4 (1.6) 4 (1.6) 3 (1.2) Pain 6 (2.4) 1 (0.4) 5 (2.0) 3 (1.2) Pneumonia 6 (2.4) 5 (2.0) 5 (2.0) 12 (4.6) Non-cardiac chest pain 8 (3.2) 5 (2.0) 2 (0.8) 3 (1.2) Oedema peripheral 2 (0.8) 2 (0.8) 8 (3.2) 6 (2.3) Pruritus 6 (2.4) 5 (2.0) 4 (1.6) 6 (2.3) Arteriovenous fistula thrombosis 4 (1.6) 6 (2.4) 5 (2.0) 4 (1.5) Hyperphosphataemia 6 (2.4) 5 (2.0) 3 (1.2) 4 (1.5) Hypoaesthesia 3 (1.2) 3 (1.2) 6 (2.4) 1 (0.4) Malaise 6 (2.4) 3 (1.2) 3 (1.2) 3 (1.2) Musculoskeletal pain 6 (2.4) 3 (1.2) 3 (1.2) 7 (2.7) Sinusitis 6 (2.4) 1 (0.4) 3 (1.2) 0 (0.0) Vascular graft complication 6 (2.4) 0 (0.0) 3 (1.2) 4 (1.5) Blood calcium increased 1 (0.4) 0 (0.0) 7 (2.8) 1 (0.4) Cardiac failure congestive 5 (2.0) 2 (0.8) 3 (1.2) 4 (1.5) Epistaxis 4 (1.6) 1 (0.4) 4 (1.6) 1 (0.4) Insomnia 4 (1.6) 6 (2.4) 4 (1.6) 8 (3.1) Myalgia 4 (1.6) 1 (0.4) 4 (1.6) 0 (0.0) Chest pain 3 (1.2) 1 (0.4) 4 (1.6) 6 (2.3) Chills 3 (1.2) 4 (1.6) 4 (1.6) 2 (0.8) Contusion 2 (0.8) 4 (1.6) 5 (2.0) 2 (0.8) Hypercalcaemia 5 (2.0) 1 (0.4) 2 (0.8) 8 (3.1) Hypophosphataemia 2 (0.8) 1 (0.4) 5 (2.0) 0 (0.0) Muscular weakness 4 (1.6) 2 (0.8) 3 (1.2) 2 (0.8) Vascular access complication 5 (2.0) 1 (0.4) 2 (0.8) 6 (2.3) Venous stenosis 4 (1.6) 0 (0.0) 3 (1.2) 3 (1.2) Wound 3 (1.2) 2 (0.8) 4 (1.6) 5 (1.9) Arteriovenous fistula site infection 2 (0.8) 0 (0.0) 4 (1.6) 2 (0.8) Blood parathyroid hormone decreased 0 (0.0) 1 (0.4) 6 (2.4) 3 (1.2) Bradycardia 3 (1.2) 4 (1.6) 3 (1.2) 1 (0.4) Hyperglycaemia 3 (1.2) 3 (1.2) 3 (1.2) 2 (0.8) Metabolic acidosis 3 (1.2) 0 (0.0) 3 (1.2) 2 (0.8) Neck pain 2 (0.8) 5 (2.0) 4 (1.6) 4 (1.5)




Preferred Term


n (%)

Placebo (N = 254)

n (%)


n (%)

Placebo (N = 259)

n (%) Tachycardia 2 (0.8) 2 (0.8) 4 (1.6) 8 (3.1) Toothache 3 (1.2) 3 (1.2) 3 (1.2) 1 (0.4) Abdominal discomfort 4 (1.6) 1 (0.4) 1 (0.4) 0 (0.0) Cataract 4 (1.6) 1 (0.4) 1 (0.4) 2 (0.8) Chronic obstructive pulmonary disease 3 (1.2) 2 (0.8) 2 (0.8) 2 (0.8) Depression 4 (1.6) 1 (0.4) 1 (0.4) 1 (0.4) Dysgeusia 3 (1.2) 2 (0.8) 2 (0.8) 1 (0.4) Gastroenteritis 2 (0.8) 0 (0.0) 3 (1.2) 4 (1.5) Gastrooesophageal reflux disease 4 (1.6) 1 (0.4) 1 (0.4) 2 (0.8) Haematuria 3 (1.2) 0 (0.0) 2 (0.8) 4 (1.5) Osteoarthritis 5 (2.0) 2 (0.8) 0 (0.0) 2 (0.8) Skin ulcer 3 (1.2) 2 (0.8) 2 (0.8) 3 (1.2) Supraventricular tachycardia 5 (2.0) 1 (0.4) 0 (0.0) 1 (0.4) Vertigo 3 (1.2) 2 (0.8) 2 (0.8) 6 (2.3) Arteriovenous fistula site haemorrhage 1 (0.4) 3 (1.2) 3 (1.2) 2 (0.8) Blood creatine phosphokinase increased 4 (1.6) 1 (0.4) 0 (0.0) 1 (0.4) Convulsion 1 (0.4) 2 (0.8) 3 (1.2) 2 (0.8) Coronary artery disease 3 (1.2) 2 (0.8) 1 (0.4) 1 (0.4) Device related infection 1 (0.4) 0 (0.0) 3 (1.2) 1 (0.4) Electrocardiogram QT prolonged 1 (0.4) 2 (0.8) 3 (1.2) 1 (0.4) Flank pain 3 (1.2) 0 (0.0) 1 (0.4) 1 (0.4) Haemorrhoids 1 (0.4) 1 (0.4) 3 (1.2) 0 (0.0) Limb injury 0 (0.0) 2 (0.8) 4 (1.6) 2 (0.8) Mental status changes 1 (0.4) 0 (0.0) 3 (1.2) 2 (0.8) Nasal congestion 3 (1.2) 0 (0.0) 1 (0.4) 1 (0.4) Neuropathy peripheral 1 (0.4) 2 (0.8) 3 (1.2) 1 (0.4) Osteomyelitis 3 (1.2) 1 (0.4) 1 (0.4) 3 (1.2) Procedural hypertension 3 (1.2) 0 (0.0) 1 (0.4) 0 (0.0) Pulmonary oedema 1 (0.4) 1 (0.4) 3 (1.2) 3 (1.2) Skin abrasion 1 (0.4) 3 (1.2) 3 (1.2) 1 (0.4) Thrombosis in device 3 (1.2) 2 (0.8) 1 (0.4) 2 (0.8) Abdominal distension 0 (0.0) 0 (0.0) 3 (1.2) 1 (0.4) Acute myocardial infarction 0 (0.0) 0 (0.0) 3 (1.2) 3 (1.2) Arteriovenous fistula site haematoma 3 (1.2) 1 (0.4) 0 (0.0) 2 (0.8) Chest discomfort 0 (0.0) 1 (0.4) 3 (1.2) 2 (0.8) Cholelithiasis 0 (0.0) 1 (0.4) 3 (1.2) 4 (1.5) Conjunctivitis 3 (1.2) 1 (0.4) 0 (0.0) 0 (0.0) Drug hypersensitivity 3 (1.2) 0 (0.0) 0 (0.0) 0 (0.0)




Preferred Term


n (%)

Placebo (N = 254)

n (%)


n (%)

Placebo (N = 259)

n (%) Feeling hot 0 (0.0) 1 (0.4) 3 (1.2) 4 (1.5) Hepatic enzyme increased 0 (0.0) 0 (0.0) 3 (1.2) 0 (0.0) Peripheral swelling 0 (0.0) 2 (0.8) 3 (1.2) 2 (0.8) Respiratory distress 0 (0.0) 0 (0.0) 3 (1.2) 1 (0.4) Seasonal allergy 0 (0.0) 0 (0.0) 3 (1.2) 0 (0.0)




eTable 7. Summary of Corrected QT Interval (Bazett and Fridericia)

Trial A Trial B

Corrected QT Interval

Etelcalcetide

(N = 251)

n (%)

Placebo

(N = 254)

n (%)

Etelcalcetide

(N = 252)

n (%)

Placebo

(N = 259)

n (%)

QTc Bazett (msec)

Baseline

≤ 450 149 (59.4) 163 (64.2) 152 (60.3) 159 (61.4)

> 450 to 480 59 (23.5) 67 (26.4) 67 (26.6) 65 (25.1)

> 480 to 500 17 (6.8) 9 (3.5) 17 (6.7) 14 (5.4)

> 500 8 (3.2) 6 (2.4) 5 (2.0) 8 (3.1)

Missing 18 (7.2) 9 (3.5) 11 (4.4) 13 (5.0)

Maximum post-baseline

≤ 450 84 (33.5) 126 (49.6) 79 (31.3) 124 (47.9)

> 450 to 480 78 (31.1) 88 (34.6) 103 (40.9) 82 (31.7)

> 480 to 500 38 (15.1) 18 (7.1) 36 (14.3) 24 (9.3)

> 500 25 (10.0) 11 (4.3) 22 (8.7) 17 (6.6)

Missing 26 (10.4) 11 (4.3) 12 (4.8) 12 (4.6)

Maximum increase from baseline

≤ 30 168 (66.9) 221 (87.0) 177 (70.2) 218 (84.2)

> 30 to 60 44 (17.5) 17 (6.7) 54 (21.4) 24 (9.3)

> 60 6 (2.4) 0 (0.0) 6 (2.4) 0 (0.0)

Missing 33 (13.1) 16 (6.3) 15 (6.0) 17 (6.6)



eTable 7. Summary of Corrected QT Interval (Bazett and Fridericia) (continued)

Trial A Trial B

Corrected QT Interval

Etelcalcetide

(N = 251)

n (%)

Placebo

(N = 254)

n (%)

Etelcalcetide

(N = 252)

n (%)

Placebo

(N = 259)

n (%)

QTc Fridericia (msec)

Baseline

≤ 450 179 (71.3) 210 (82.7) 198 (78.6) 199 (76.8)

> 450 to 480 46 (18.3) 25 (9.8) 36 (14.3) 31 (12.0)

> 480 to 500 6 (2.4) 6 (2.4) 7 (2.8) 14 (5.4)

> 500 2 (0.8) 4 (1.6) 0 (0.0) 2 (0.8)

Missing 18 (7.2) 9 (3.5) 11 (4.4) 13 (5.0)

Maximum post-baseline

≤ 450 124 (49.4) 177 (69.7) 134 (53.2) 172 (66.4)

> 450 to 480 72 (28.7) 49 (19.3) 72 (28.6) 53 (20.5)

> 480 to 500 15 (6.0) 13 (5.1) 23 (9.1) 15 (5.8)

> 500 14 (5.6) 4 (1.6) 11 (4.4) 7 (2.7)

Missing 26 (10.4) 11 (4.3) 12 (4.8) 12 (4.6)

Maximum increase from baseline

≤ 30 168 (66.9) 222 (87.4) 180 (71.4) 227 (87.6)

> 30 to 60 46 (18.3) 16 (6.3) 54 (21.4) 15 (5.8)

> 60 4 (1.6) 0 (0.0) 3 (1.2) 0 (0.0)

Missing 33 (13.1) 16 (6.3) 15 (6.0) 17 (6.6)




eFigure 1 A-B. Time to >30% Reduction From Baseline in PTH (Rolling Average of 3 PTH Values Were Used to Compare With Baseline)

Each marker indicates the study week when patient(s) achieved >30% reduction in PTH (calculated as rolling average of the 3 most recent PTH values) relative to baseline.

Number of patients at risk in each group was shown below the curves. All randomized patients were included.



eFigure 2 A-B. Forest Plot for Difference in Proportion With >30% Decrease From Baseline in PTH Across Patient Subgroups



eFigure 3 A-B. Use of Calcium Supplement or Calcium Containing Phosphate Binders Over Time

20

30

40

50

60

70

80

B 2 4 6 8 10 12 14 16 18 20 22 24 26

Prop

ortio

n of

Pat

ient

s (%

)

Study Week

Trial A Etelcalcetide

Placebo

Etelcalcetide n= 251 250 247 247 244 242 240 238 238 237 236 234 231 228 Placebo n= 254 254 252 252 252 251 250 246 242 241 238 222 220 214

20

30

40

50

60

70

80

B 2 4 6 8 10 12 14 16 18 20 22 24 26

Prop

ortio

n of

Pat

ient

s (%

)

Study Week

Trial B Etelcalcetide

Placebo




eFigure 3 C-D. Use of Active Vitamin D Over Time

55

60

65

70

75

80

85

B 2 4 6 8 10 12 14 16 18 20 22 24 26

Prop

ortio

n of

Pat

ient

s (%

)

Study Week


Placebo


55

60

65

70

75

80

85

B 2 4 6 8 10 12 14 16 18 20 22 24 26

Prop

ortio

n of

Pat

ient

s (%

)

Study Week


Placebo




eFigure 4 A-B. Mean PTH Value (pg/mL) (95% CI) by Study Week

200

400

600

800

1000

0 2 4 6 8 10 12 14 16 18 20 22 24 26

Mea

n PT

H (p

g/m

L)

Study Week


Placebo

Etelcalcetide n= 251 230 230 221 223 224 218 217 217 218 216 215 210 207 217 Placebo n= 254 244 242 235 230 229 229 222 216 205 198 191 183 182 191

Note: Week 27 was a post treatment visit.

27

200

400

600

800

1000

0 2 4 6 8 10 12 14 16 18 20 22 24 26

Mea

n PT

H (p

g/m

L)

Study Week


Placebo

Etelcalcetide n= 252 238 229 233 226 229 226 222 220 218 209 211 206 198 204 Placebo n= 259 246 246 245 241 237 227 235 224 222 218 211 200 186 201

Note: Week 27 was a post treatment visit.

27

27



supplementary online content...patient has received amg 416 in a prior clinical trial of amg 416...

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