Study to Evaluate the Safety and Tolerability of AMG 986 in Healthy Volunteers and Heart Failure Patients

• Sponsor: Amgen (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT03276728
• Collaborator: (none)
• Enrollment: 182
• Locations: 25
• Arms: 8
• Actual Duration (Months): 32.2
• Patients Per Site: 7.3
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

To evaluate the safety and tolerability of ascending single (Part A) and ascending multiple (Part B) doses of AMG 986 in healthy adults and of ascending multiple oral doses of AMG 986 in heart failure patients (Part C).

Condition or Disease	Intervention/Treatment	Phase
Heart Failure; Healthy Volunteer	Drug: AMG 986 IV; Drug: AMG 986 PO; Drug: Placebo PO; Drug: Placebo IV	Phase 1

Detailed Description

This study is a randomized, placebo-controlled, double-blind, single day ascending dose (SDAD) study (Part A), a multiple daily ascending dose (MDAD) study (Part B), in healthy adults, and a MDAD study (Part C) in heart failure patients. In Parts A and B of the study, healthy volunteers will receive AMG 986 by continuous IV infusion or by oral administration in a fasted state. IV Infusions will be divided into an initial loading dose (LD) for the first hour followed immediately by a maintenance dose (MD).

In Part C of the study, patients with heart failure and either reduced (HFrEF) or preserved (HFpEF) ejection fraction will receive MDAD of AMG 986 or matching placebo once daily by oral administration for 21 days.

Study Design

• Study Type: Interventional
• Actual Enrollment: 182 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Double-blind, placebo-controlledDouble-blind, placebo-controlled
• Masking: Double (Participant, Investigator)
• Masking Description: Double-blinded
• Primary Purpose: Treatment
• Official Title: A Phase I, Randomized, Double-Blind, Placebo-Controlled, Single and Multiple Ascending Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of AMG 986 in Healthy Subjects and Heart Failure Patients
• Actual Study Start Date: Aug 12, 2016
• Actual Primary Completion Date: Apr 18, 2019
• Actual Study Completion Date: Apr 18, 2019

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Part A: Placebo Healthy participants were administered placebo either intravenously (IV) or by mouth (PO) to match the 5 IV cohorts and 6 PO cohorts of AMG 986.	Drug: Placebo PO; Matching placebo tablets for oral administration; Drug: Placebo IV; Matching placebo solution for infusion
Experimental: Part A: AMG 986 Healthy participants were administered a single dose of AMG 986 either IV or PO. The 5 IV cohorts started at a 0.5 mg loading dose over one hour up to to the Cohort 5 IV dosage consisting of a 60 mg loading dose over 1 hour and a 360 mg maintenance dose lasting 23 hours. The 6 PO cohorts started at a single 5 mg dose up to the Cohort 6 PO dose of 650 mg.	Drug: AMG 986 IV; AMG 986 solution for infusion; Drug: AMG 986 PO; AMG 986 tablets for oral (PO) administration
Placebo Comparator: Part B: Placebo Healthy participants were administered placebo either IV for 4 consecutive days or PO for 7 days to match the 2 IV cohorts and 6 PO cohorts of AMG 986.	Drug: Placebo PO; Matching placebo tablets for oral administration; Drug: Placebo IV; Matching placebo solution for infusion
Experimental: Part B: AMG 986 Healthy participants were administered AMG 986 either IV or PO. IV cohort 1 was administered a loading dose of 6 mg over one hour followed by maintenance doses of 36 mg lasting 23 hours on Day 1 and 38 mg lasting 24 hours on Days 2-4. IV cohort 2 was administered a loading dose of 60 mg over one hour followed by maintenance doses of 360 mg lasting 23 hours on Day 1 and 376 mg lasting 24 hours on Days 2-4. The 6 PO cohorts started at 5 mg for 7 days up to Cohort 6 PO dose of 650 mg for 7 days.	Drug: AMG 986 IV; AMG 986 solution for infusion; Drug: AMG 986 PO; AMG 986 tablets for oral (PO) administration
Placebo Comparator: Part C: HFrEF Placebo Participants with heart failure with reduced ejection fraction (HFrEF) were administered a single PO placebo tablet daily from Days 1-21.	Drug: Placebo PO; Matching placebo tablets for oral administration
Placebo Comparator: Part C: HFpEF Placebo Participants with heart failure with preserved ejection fraction (HFpEF) were administered a single PO placebo tablet daily from Days 1-21.	Drug: Placebo PO; Matching placebo tablets for oral administration
Experimental: Part C: HFrEF AMG 986 Participants with heart failure with reduced ejection fraction (HFrEF) were administered a single PO AMG 986 tablet daily from Days 1-21 in ascending doses of 10 mg for Days 1-7, 30 mg for Days 8-14 and 100 mg for days 15-21.	Drug: AMG 986 PO; AMG 986 tablets for oral (PO) administration
Experimental: Part C: HFpEF AMG 986 Participants with heart failure with preserved ejection fraction (HFpEF) were administered a single PO AMG 986 tablet daily from Days 1-21 in ascending doses of 10 mg for Days 1-7, 30 mg for Days 8-14 and 100 mg for days 15-21.	Drug: AMG 986 PO; AMG 986 tablets for oral (PO) administration

Outcome Measures

Primary Outcome Measures

1. Participants With Treatment Emergent Adverse Events (TEAE) [Part A: Day 1 up to Day 31 Part B: Day 1 up to Day 37 Part C: Day 1 up to Day 51]

   An adverse event is defined as any untoward medical occurrence in a clinical trial subject. The event does not necessarily have a causal relationship with study treatment. Events categorized as TEAEs started on or after first dose of study drug and include up to 30 days after the last dose. 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.

Secondary Outcome Measures

1. Left Ventricular Ejection Fraction by Visit for Part C Heart Failure With Reduced Ejection Fraction (HFrEF) Cohort [Baseline (Day 1 predose), Day 8, Day 15, Day 21, Day 30]

   Heart failure (HF) refers to a clinical condition in which the cardiac output is insufficient to meet the metabolic needs of body organs and is marked by cardiac systolic and/or diastolic dysfunction. Heart failure with predominantly systolic dysfunction, which is identifiable as decreased contraction, is more aptly described as heart failure with reduced ejection fraction (HFrEF). Ejection fraction is a measurement, expressed as a percentage, of how much blood the left ventricle pumps out with each contraction and is measured by echocardiogram.

2. Stroke Volume (Method of Disks, Volumetric Assessment) by Visit for Part C Heart Failure With Reduced Ejection Fraction (HFrEF) Cohort [Baseline (Day 1 predose), Day 8, Day 15, Day 21, Day 30]

   Stroke volume is the amount of blood pumped by the left ventricle of the heart in one contraction reported by volumetric method of disks (MoD) assessment.

3. Stroke Volume (Left Ventricular Outflow Tract Using Doppler Assessment) by Visit for Part C Heart Failure With Reduced Ejection Fraction (HFrEF) Cohort [Baseline (Day 1 predose), Day 8, Day 15, Day 21, Day 30]

   Stroke volume is the amount of blood pumped by the left ventricle of the heart in one contraction as measured using left ventricular outflow tract (LVOT) Doppler assessment.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 85 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria

• Subject has provided informed consent prior to initiation of any study-specific activities/procedures.

• Male and female subjects ≥ 18 to ≤ 55 years old with no history or evidence of clinically relevant medical disorders as determined by the investigator and the Amgen physician (Parts A and B only)

• Body mass index (BMI) between 18 and 35 kg/m^2, inclusive, at screening.

• Physical examination including vital signs, clinical laboratory values, and electrocardiograms (ECGs) are clinically acceptable to the investigator. Abnormal findings for healthy volunteers and unexpected findings for heart failure patient subjects will be discussed with Amgen prior to study enrollment.

• Women must be of non-reproductive potential (ie, postmenopausal)

• Men must agree to practice an acceptable method of effective birth control while on study through 11 weeks after receiving the last dose of investigational product (AMG 986 or placebo). Acceptable methods of effective birth control include sexual abstinence; vasectomy and testing that shows there are no sperm in the semen; or a condom with spermicide (men) in combination with barrier methods (diaphragm, cervical cap or cervical sponge), hormonal birth control or IUS (women).

• Men must be willing to abstain from sperm donation while on study through 11 weeks after receiving the last dose of investigational product (AMG 986 or placebo).

• This inclusion criterion only applies to Parts B and C cohorts. Before inclusion in the study, subjects will undergo a screening echocardiogram to ensure that the following parameters can be accurately measured: left ventricular end-systolic and end-diastolic volumes, left atrial end-systolic and end-diastolic volumes, ejection fraction, fraction shortening, and end-systolic septal and posterior wall thickness.

For Part C

Additional Inclusion Criteria for HFrEF Patients:

• Subject must be of age 18 to 85 years, have a diagnosis of HF confirmed by medical records for ≥ 3 months, and be in stable condition for at least 4 weeks.

• Left ventricular ejection fraction (LVEF) ≤ 40% confirmed by echocardiogram, radionuclide ventriculography, cardiac magnetic resonance imaging, or contrast ventriculography within 12 months prior to randomization.

• New York Heart Association (NYHA) class II or III at screening

• Sinus rhythm

• N-terminal pro b-type natriuretic peptide (NT-proBNP) level ≥ 250 pg/ml

• Patients will be treated with stable, optimal pharmacological therapy for a minimum of 4 weeks prior to randomization. Treatment of HFrEF includes at least beta-blockers (carvedilol, metoprolol succinate or bisoprolol) and a RAAS inhibitor (ACEi, ARB or sacubitril/valsartan).

Additional Inclusion Criteria for HFpEF patients:

• Subject must be of age of 18 to 85 years, have a diagnosis of HF confirmed by medical records for ≥ 3 months, and be in stable condition for at least 4 weeks.

• LVEF ≥ 50% confirmed by echocardiogram, radionuclide ventriculography, cardiac magnetic resonance imaging, or contrast ventriculography within 12 months prior to randomization.

• LVEF never ≤ 40% in the past

• NYHA class II or III at screening

• Sinus rhythm

• NT-proBNP level ≥ 250 pg/ml

• Patients will be treated with stable, optimal pharmacological therapy for a minimum of 4 weeks prior to randomization. Treatment of HFpEF includes at least a daily dose of diuretics equivalent to furosemide 40 mg.

• For subjects in Parts A, B and C: Women must have negative results for both the screening (serum) and day -1 (serum or urine) pregnancy tests

Exclusion Criteria

• Currently receiving treatment in another investigational device or drug study, or less than 30 days or 5 half-lives (whichever is longer), since ending treatment on another investigational device or drug study(s) prior to receiving the first dose of investigational product (AMG 986 or placebo).

• Female subjects who are lactating/breastfeeding or who plan to breastfeed while on study through 11 weeks after receiving the last dose of investigational product (AMG 986 or placebo).

• Male subjects with partners who are pregnant or planning to become pregnant while the subject is on study through 11 weeks after receiving the last dose of investigational product (AMG 986 or placebo).

• Female subjects of reproductive potential.

• Subjects in Parts A and B of the study: estimated glomerular filtration rate (eGFR) within the screening period of less than 60 mL/min/1.73m^2 as calculated using the estimated Modification of Diet in Renal Disease (MDRD) formula.

• Current or prior malignancy within 5 years of randomization, with the exception of non-melanoma skin cancers, cervical or breast ductal carcinoma in situ, and adenocarcinoma of the prostate Stage I or IIa (defined as T1, T2a or T2b, N0, M0 with documented serum prostate-specific antigen (PSA) < 20 ng/mL and Gleason score ≤ 7) per the American Joint Committee on Cancer (AJCC) primary tumor, regional lymph nodes, and distant metastasis system.

• Positive results for human immunodeficiency virus (HIV), antibodies, hepatitis B surface antigen (HBsAg), or hepatitis C antibodies (HepCAb).

• Subject has known sensitivity to any of the products or components to be administered during dosing.

• Subject 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 subject 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 subject safety or interfere with the study evaluation, procedures or completion.

• Subject previously has entered this study or has been previously exposed to AMG 986.

• Concurrent or prior use of strong CYP3A4 inhibitors within 14 days of study Day 1, including (not limited to): macrolide antibiotics (eg, clarithromycin, telithromycin), antifungals (eg, itraconazole, voriconazole), antivirals (eg, ritonavir, saquinavir, indinavir, nelfinavir), nefazodone.

• Concurrent or prior ingestion of grapefruit or grapefruit products and other foods that are known to inhibit CYP3A4 within 7 days of study Day 1.

• Concurrent or prior use of strong CYP3A4 inducers within 28 days of study Day 1, Including (not limited to): phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital. Subjects should also not take St John's Wort.

• Concurrent or prior use of strong P-glycoprotein inhibitors within 28 days of study Day 1, including (not limited to): elacridar and valspodar.

• All herbal supplements, vitamins, and nutritional supplements taken within the last 30 days prior to dosing on Day 1 (and continued use, if appropriate), must be reviewed and approved by the PI and Amgen Medical Monitor.

• For subjects enrolled under Amendments 1-6, inclusive: QTc > 450 msec or history/evidence of long QT syndrome.

• Planned elective surgery within 30 days of study completion or before return of red blood cell parameters to normal values.

• Blood donation ≥ 500 mL within 60 days of Day 1.

• Systolic blood pressure > 150 mmHg or < 90 mmHg, or diastolic blood pressure > 95 mmHg or < 60 mmHg, assessed on 2 separate occasions prior to enrollment (Parts A and B only).

• Heart rate ≥ 100 beats per minute after 5 minutes of rest or an untreated symptomatic bradyarrhythmia within 1 month prior to enrollment.

• For Parts A and B: Troponin I at screening > upper limit of normal (ULN).

• In the opinion of the Investigator, a condition that compromises the ability of the subject to give written informed consent or to comply with study procedures.

• Unwilling or unable to abstain from nicotine or tobacco containing products (including but not limited to: snuff, chewing tobacco, cigars, cigarettes, pipes, or nicotine patches) throughout the screening period and for the duration of the study.

• Subjects who are unwilling or unable to limit alcohol consumption to 1 units/day (1 unit = 1 drink and 1 drink is equivalent to 12 ounces of regular beer, 8 to 9 ounces of malt liquor, 5 ounces of wine or 1.5 ounces of 80 proof distilled spirits).

• Subjects with a positive urine drug screen or alcohol breath test.

• Known history of drug or alcohol abuse.

• Concurrent use of phosphodiesterase 5 (PDE5) inhibitors including (not limited to) avanafil, sildenafil, tadalafil, vardenafil.

• Concurrent use of vasodilators by healthy subjects in Parts A and B that could in the opinion of the investigator potentially lead to a drop in blood pressure in combination with investigational product.

• Severe uncorrected valvular heart disease, or hypertrophic obstructive cardiomyopathy, active myocarditis, constrictive pericarditis, or clinically significant congenital heart disease.

• For subjects in Part C of the study: eGFR within the screening period of less than 30 mL/min/1.732m^2 as calculated using the MDRD formula.

• For subjects in Part C of the study: Systolic blood pressure > 160 mmHg or < 100 mmHg, or diastolic blood pressure > 110 mmHg or < 60 mmHg, assessed on 2 separate occasions prior to enrollment.

• For subjects in Part C of the study: troponin I > ULN if there is also evidence of an acute cardiovascular event.

• For subjects enrolled in Part C under Amendment 7: QTc > 500 msec or history/evidence of long QT syndrome.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	Anaheim	California	United States	92801
2	Research Site	Tustin	California	United States	92780
3	Research Site	Jacksonville	Florida	United States	32216
4	Research Site	Metairie	Louisiana	United States	70006
5	Research Site	Baltimore	Maryland	United States	21201
6	Research Site	Minneapolis	Minnesota	United States	55415
7	Research Site	Las Vegas	Nevada	United States	89148
8	Research Site	Durham	North Carolina	United States	27705
9	Research Site	Auchenflower	Queensland	Australia	4066
10	Research Site	Bundaberg	Queensland	Australia	4670
11	Research Site	Leabrook	South Australia	Australia	5068
12	Research Site	Berwick	Victoria	Australia	3806
13	Research Site	Bundoora	Victoria	Australia	3083
14	Research Site	Sherbrooke	Quebec	Canada	J1G 2E8
15	Research Site	Nantes Cedex 1		France	44093
16	Research Site	Paris		France	75015
17	Research Site	Rennes Cedex 9		France	35033
18	Research Site	Toulouse Cedex 9		France	31059
19	Research Site	Bad Neuheim		Germany	61231
20	Research Site	Berlin		Germany	13353
21	Research Site	Groningen		Netherlands	9713 GZ
22	Research Site	Christchurch		New Zealand	8011
23	Research Site	Jozefow		Poland	05-410
24	Research Site	Wroclaw		Poland	51-162
25	Research Site	Singapore		Singapore	169609

Sponsors and Collaborators

• Amgen

Investigators

• Study Director: MD, Amgen

Study Documents (Full-Text)

• Study Protocol - Jul 27, 2018
• Statistical Analysis Plan - Jun 17, 2019

More Information

Additional Information:

• AmgenTrials clinical trials website

Publications

None provided.

• Responsible Party: Amgen
• ClinicalTrials.gov Identifier: NCT03276728
• Other Study ID Numbers: 20150183; 2017-002940-34
• First Posted: Sep 8, 2017
• Last Update Posted: Aug 8, 2022
• Last Verified: Mar 1, 2022

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Amgen: Heart Failure; Cardiovascular Diseases; Heart Diseases; Ejection fraction; Heart Failure with reduced ejection fraction; Heart Failure with preserved ejection fraction
• Additional relevant MeSH terms: Heart Failure

Study Results

Participant Flow

Recruitment Details

Participants were enrolled at 13 study centers in 7 countries (Canada, France, New Zealand, Netherland, Poland, Singapore, United States). The study included Parts A, B (healthy volunteers) and C (participants with either heart failure with reduced ejection fraction [HFrEF] or heart failure with preserved ejection fraction [HFpEF]). Each part of the study consisted of ascending dose cohorts.

Pre-assignment Detail

Within each dose cohort participants were randomized to AMG 986 or placebo in a 3:1 ratio. At the conclusion of each cohort, safety and tolerability of AMG 986 was reviewed before advancing to the next dose cohort. The Statistical Analysis Plan for this study specified that AMG 986 and Placebo-treated participants in Part A and Part B would be combined to form pooled AMG 986 and placebo groups, respectively for each Part.

Arm/Group Title	Part A: Placebo Pooled	Part A: AMG 986 Pooled	Part B: Placebo Pooled	Part B: AMG 986 Pooled	Part C: HFrEF Placebo	Part C: HFpEF Placebo	Part C: HFrEF AMG 986	Part C: HFpEF AMG 986
Arm/Group Description	Healthy participants were administered placebo either intravenously (IV) or by mouth (PO) to match the 5 IV cohorts and 6 PO cohorts of AMG 986.	Healthy participants were administered a single dose of AMG 986 either IV or PO. The 5 IV cohorts started at a 0.5 mg loading dose over one hour up to the Cohort 5 IV dosage of a 60 mg loading dose over 1 hour and a 360 mg maintenance dose lasting 23 hours. The 6 PO cohorts started at a single 5 mg dose up to the Cohort 6 PO dose of 650 mg.	Healthy participants were administered placebo either IV for 4 consecutive days or PO for 7 days to match the 2 IV cohorts and 6 PO cohorts of AMG 986.	Healthy participants were administered AMG 986 either IV or PO. IV cohort 1 was administered a loading dose of 6 mg over one hour followed by maintenance doses of 36 mg lasting 23 hours on day 1 and 38 mg lasting 24 hours on days 2-4. IV cohort 2 was administered a loading dose of 60 mg lasting one hour followed by maintenance doses of 360 mg lasting 23 hours on day 1 and 376 mg lasting 24 hours on days 2-4. The 6 PO cohorts started at 5 mg for 7 days up to Cohort 6 PO dose of 650 mg for 7 days.	Participants with heart failure with reduced ejection fraction (HFrEF) were administered a single PO placebo tablet daily from days 1-21.	Participants with heart failure with preserved ejection fraction (HFpEF) were administered a single PO placebo tablet daily from days 1-21.	Participants with heart failure with reduced ejection fraction (HFrEF) were administered a single PO AMG 986 tablet daily from days 1-21 in ascending doses of 10 mg for days 1-7, 30 mg for days 8-14 and 100 mg for days 15-21.	Participants with heart failure with preserved ejection fraction (HFpEF) were administered a single PO AMG 986 tablet daily from days 1-21 in ascending doses of 10 mg for days 1-7, 30 mg for days 8-14 and 100 mg for days 15-21.
Period Title: Overall Study
STARTED	22	66	16	50	7	1	17	3
Treated Participants	22	66	16	50	7	1	16	3
COMPLETED	22	66	14	45	6	1	15	2
NOT COMPLETED	0	0	2	5	1	0	2	1

Baseline Characteristics

Arm/Group Title	Part A: Placebo Pooled	Part A: AMG 986 Pooled	Part B: Placebo Pooled	Part B: AMG 986 Pooled	Part C: HFrEF Placebo	Part C: HFpEF Placebo	Part C: HFrEF AMG 986	Part C: HFpEF AMG 986	Total
Arm/Group Description	Healthy participants were administered placebo either intravenously (IV) or by mouth (PO) to match the 5 IV cohorts and 6 PO cohorts of AMG 986.	Healthy participants were administered a single dose of AMG 986 either IV or PO. The 5 IV cohorts started at a 0.5 mg loading dose over one hour up to the Cohort 5 IV dosage of a 60 mg loading dose over 1 hour and a 360 mg maintenance dose lasting 23 hours. The 6 PO cohorts started at a single 5 mg dose up to the Cohort 6 PO dose of 650 mg.	Healthy participants were administered placebo either IV for 4 consecutive days or PO for 7 days to match the 2 IV cohorts and 6 PO cohorts of AMG 986.	Healthy participants were administered AMG 986 either IV or PO. IV cohort 1 was administered a loading dose of 6 mg over one hour followed by maintenance doses of 36 mg lasting 23 hours on day 1 and 38 mg lasting 24 hours on days 2-4. IV cohort 2 was administered a loading dose of 60 mg lasting one hour followed by maintenance doses of 360 mg lasting 23 hours on day 1 and 376 mg lasting 24 hours on days 2-4. The 6 PO cohorts started at 5 mg for 7 days up to Cohort 6 PO dose of 650 mg for 7 days.	Participants with heart failure with reduced ejection fraction (HFrEF) were administered a single PO placebo tablet daily from days 1-21.	Participants with heart failure with preserved ejection fraction (HFpEF) were administered a single PO placebo tablet daily from days 1-21.	Participants with heart failure with reduced ejection fraction (HFrEF) were administered a single PO AMG 986 tablet daily from days 1-21 in ascending doses of 10 mg for days 1-7, 30 mg for days 8-14 and 100 mg for days 15-21.	Participants with heart failure with preserved ejection fraction (HFpEF) were administered a single PO AMG 986 tablet daily from days 1-21 in ascending doses of 10 mg for days 1-7, 30 mg for days 8-14 and 100 mg for days 15-21.	Total of all reporting groups
Overall Participants	22	66	16	50	7	1	17	3	182
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	37.2 (9.4)	39.5 (9.8)	36.9 (10.0)	37.4 (9.8)	61.6 (10.1)	73.0	64.3 (7.8)	69.0 (1.0)	42.3 (13.4)
Age, Customized (Count of Participants)
18-64 years	22 100%	66 100%	16 100%	50 100%	4 57.1%	0 0%	11 64.7%	0 0%	169 92.9%
65-84 years	0 0%	0 0%	0 0%	0 0%	3 42.9%	1 100%	6 35.3%	3 100%	13 7.1%
85 years and over	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Sex: Female, Male (Count of Participants)
Female	0 0%	7 10.6%	0 0%	1 2%	3 42.9%	1 100%	3 17.6%	2 66.7%	17 9.3%
Male	22 100%	59 89.4%	16 100%	49 98%	4 57.1%	0 0%	14 82.4%	1 33.3%	165 90.7%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	6 27.3%	22 33.3%	1 6.3%	5 10%	1 14.3%	0 0%	0 0%	0 0%	35 19.2%
Not Hispanic or Latino	16 72.7%	44 66.7%	15 93.8%	45 90%	6 85.7%	1 100%	17 100%	2 66.7%	146 80.2%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	1 33.3%	1 0.5%
Race/Ethnicity, Customized (Count of Participants)
Asian	3 13.6%	6 9.1%	6 37.5%	11 22%	2 28.6%	0 0%	2 11.8%	0 0%	30 16.5%
Black	5 22.7%	16 24.2%	5 31.3%	17 34%	2 28.6%	0 0%	7 41.2%	2 66.7%	54 29.7%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	1 2%	0 0%	0 0%	0 0%	0 0%	1 0.5%
White	11 50%	35 53%	5 31.3%	18 36%	3 42.9%	1 100%	8 47.1%	0 0%	81 44.5%
Other	1 4.5%	8 12.1%	0 0%	3 6%	0 0%	0 0%	0 0%	1 33.3%	13 7.1%
Multiple	2 9.1%	1 1.5%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	3 1.6%

Outcome Measures

1. Primary Outcome

Title	Participants With Treatment Emergent Adverse Events (TEAE)
Description	An adverse event is defined as any untoward medical occurrence in a clinical trial subject. The event does not necessarily have a causal relationship with study treatment. Events categorized as TEAEs started on or after first dose of study drug and include up to 30 days after the last dose. 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	Part A: Day 1 up to Day 31 Part B: Day 1 up to Day 37 Part C: Day 1 up to Day 51

Outcome Measure Data

Analysis Population Description

All participants who received at least 1 dose of study drug

Arm/Group Title	Part A: Placebo Pooled	Part A: AMG 986 Pooled	Part B: Placebo Pooled	Part B: AMG 986 Pooled	Part C: HFrEF Placebo	Part C: HFpEF Placebo	Part C: HFrEF AMG 986	Part C: HFpEF AMG 986
Arm/Group Description	Healthy participants were administered placebo either intravenously (IV) or by mouth (PO) to match the 5 IV cohorts and 6 PO cohorts of AMG 986.	Healthy participants were administered a single dose of AMG 986 either IV or PO. The 5 IV cohorts started at a 0.5 mg loading dose over one hour up to the Cohort 5 IV dosage of a 60 mg loading dose over 1 hour and a 360 mg maintenance dose lasting 23 hours. The 6 PO cohorts started at a single 5 mg dose up to the Cohort 6 PO dose of 650 mg.	Healthy participants were administered placebo either IV for 4 consecutive days or PO for 7 days to match the 2 IV cohorts and 6 PO cohorts of AMG 986.	Healthy participants were administered AMG 986 either IV or PO. IV cohort 1 was administered a loading dose of 6 mg over one hour followed by maintenance doses of 36 mg lasting 23 hours on day 1 and 38 mg lasting 24 hours on days 2-4. IV cohort 2 was administered a loading dose of 60 mg lasting one hour followed by maintenance doses of 360 mg lasting 23 hours on day 1 and 376 mg lasting 24 hours on days 2-4. The 6 PO cohorts started at 5 mg for 7 days up to Cohort 6 PO dose of 650 mg for 7 days.	Participants with heart failure with reduced ejection fraction (HFrEF) were administered a single PO placebo tablet daily from days 1-21.	Participants with heart failure with preserved ejection fraction (HFpEF) were administered a single PO placebo tablet daily from days 1-21.	Participants with heart failure with reduced ejection fraction (HFrEF) were administered a single PO AMG 986 tablet daily from days 1-21 in ascending doses of 10 mg for days 1-7, 30 mg for days 8-14 and 100 mg for days 15-21.	Participants with heart failure with preserved ejection fraction (HFpEF) were administered a single PO AMG 986 tablet daily from days 1-21 in ascending doses of 10 mg for days 1-7, 30 mg for days 8-14 and 100 mg for days 15-21.
Measure Participants	22	66	16	50	7	1	16	3
All treatment-emergent adverse events (TEAEs)	3 13.6%	11 16.7%	2 12.5%	7 14%	2 28.6%	1 100%	6 35.3%	3 100%
Serious adverse events	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	1 33.3%
TEAEs leading to discontinuation of study drug	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	1 5.9%	2 66.7%
Fatal adverse events	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%

2. Secondary Outcome

Title	Left Ventricular Ejection Fraction by Visit for Part C Heart Failure With Reduced Ejection Fraction (HFrEF) Cohort
Description	Heart failure (HF) refers to a clinical condition in which the cardiac output is insufficient to meet the metabolic needs of body organs and is marked by cardiac systolic and/or diastolic dysfunction. Heart failure with predominantly systolic dysfunction, which is identifiable as decreased contraction, is more aptly described as heart failure with reduced ejection fraction (HFrEF). Ejection fraction is a measurement, expressed as a percentage, of how much blood the left ventricle pumps out with each contraction and is measured by echocardiogram.
Time Frame	Baseline (Day 1 predose), Day 8, Day 15, Day 21, Day 30

Outcome Measure Data

Analysis Population Description

Participants who received study drug with available LVEF at each time point

Arm/Group Title	Part C: HFrEF Placebo	Part C: HFrEF AMG 986
Arm/Group Description	Participants with heart failure with reduced ejection fraction (HFrEF) were administered a single PO placebo tablet daily from Days 1-21.	Participants with heart failure with reduced ejection fraction (HFrEF) were administered a single PO AMG 986 tablet daily from Days 1-21 in ascending doses of 10 mg for Days 1-7, 30 mg for Days 8-14 and 100 mg for days 15-21.
Measure Participants	7	16
Baseline	33.300 (8.420)	28.380 (6.483)
Day 8	34.900 (12.441)	32.553 (7.055)
Day 15	33.533 (9.194)	31.614 (7.154)
Day 21	33.550 (8.896)	31.436 (5.953)
Day 30	33.171 (8.140)	31.987 (7.036)

3. Secondary Outcome

Title	Stroke Volume (Method of Disks, Volumetric Assessment) by Visit for Part C Heart Failure With Reduced Ejection Fraction (HFrEF) Cohort
Description	Stroke volume is the amount of blood pumped by the left ventricle of the heart in one contraction reported by volumetric method of disks (MoD) assessment.
Time Frame	Baseline (Day 1 predose), Day 8, Day 15, Day 21, Day 30

Outcome Measure Data

Analysis Population Description

Participants who received study drug with available data at each time point

Arm/Group Title	Part C: HFrEF Placebo	Part C: HFrEF AMG 986
Arm/Group Description	Participants with heart failure with reduced ejection fraction (HFrEF) were administered a single PO placebo tablet daily from Days 1-21.	Participants with heart failure with reduced ejection fraction (HFrEF) were administered a single PO AMG 986 tablet daily from Days 1-21 in ascending doses of 10 mg for Days 1-7, 30 mg for Days 8-14 and 100 mg for days 15-21.
Measure Participants	7	16
Baseline	53.387 (16.995)	40.461 (14.193)
Day 8	55.185 (19.158)	46.130 (13.927)
Day 15	52.673 (19.514)	46.784 (14.348)
Day 21	54.113 (18.789)	44.014 (12.051)
Day 30	53.621 (19.258)	44.634 (13.491)

4. Secondary Outcome

Title	Stroke Volume (Left Ventricular Outflow Tract Using Doppler Assessment) by Visit for Part C Heart Failure With Reduced Ejection Fraction (HFrEF) Cohort
Description	Stroke volume is the amount of blood pumped by the left ventricle of the heart in one contraction as measured using left ventricular outflow tract (LVOT) Doppler assessment.
Time Frame	Baseline (Day 1 predose), Day 8, Day 15, Day 21, Day 30

Outcome Measure Data

Analysis Population Description

Participants who received study drug with available data at each time point

Arm/Group Title	Part C: HFrEF Placebo	Part C: HFrEF AMG 986
Arm/Group Description	Participants with heart failure with reduced ejection fraction (HFrEF) were administered a single PO placebo tablet daily from Days 1-21.	Participants with heart failure with reduced ejection fraction (HFrEF) were administered a single PO AMG 986 tablet daily from Days 1-21 in ascending doses of 10 mg for Days 1-7, 30 mg for Days 8-14 and 100 mg for days 15-21.
Measure Participants	7	16
Baseline	59.056 (18.120)	54.739 (14.523)
Day 8	52.657 (13.231)	53.512 (14.943)
Day 15	53.985 (21.580)	53.073 (14.747)
Day 21	55.805 (26.127)	53.858 (14.339)
Day 30	55.113 (20.900)	50.616 (14.212)

Adverse Events

Time Frame	Part A: Day 1 up to Day 31 Part B: Day 1 up to Day 37 Part C: Day 1 up to Day 51
Adverse Event Reporting Description	All-cause mortality is reported for all participants randomized in the study. Serious adverse events and other adverse events are reported for all participants who received at least one dose of study drug.
Arm/Group Title	Part A: Placebo Pooled		Part A: AMG 986 Pooled		Part B: Placebo Pooled		Part B: AMG 986 Pooled		Part C: HFrEF Placebo		Part C: HFpEF Placebo		Part C: HFrEF AMG 986		Part C: HFpEF AMG 986
Arm/Group Description	Healthy participants were administered placebo either intravenously (IV) or by mouth (PO) to match the 5 IV cohorts and 6 PO cohorts of AMG 986.		Healthy participants were administered a single dose of AMG 986 either IV or PO. The 5 IV cohorts started at a 0.5 mg loading dose over one hour up to the Cohort 5 IV dosage of a 60 mg loading dose over 1 hour and a 360 mg maintenance dose lasting 23 hours. The 6 PO cohorts started at a single 5 mg dose up to the Cohort 6 PO dose of 650 mg.		Healthy participants were administered placebo either IV for 4 consecutive days or PO for 7 days to match the 2 IV cohorts and 6 PO cohorts of AMG 986.		Healthy participants were administered AMG 986 either IV or PO. IV cohort 1 was administered a loading dose of 6 mg over one hour followed by maintenance doses of 36 mg lasting 23 hours on day 1 and 38 mg lasting 24 hours on days 2-4. IV cohort 2 was administered a loading dose of 60 mg lasting one hour followed by maintenance doses of 360 mg lasting 23 hours on day 1 and 376 mg lasting 24 hours on days 2-4. The 6 PO cohorts started at 5 mg for 7 days up to Cohort 6 PO dose of 650 mg for 7 days.		Participants with heart failure with reduced ejection fraction (HFrEF) were administered a single PO placebo tablet daily from days 1-21.		Participants with heart failure with preserved ejection fraction (HFpEF) were administered a single PO placebo tablet daily from days 1-21.		Participants with heart failure with reduced ejection fraction (HFrEF) were administered a single PO AMG 986 tablet daily from days 1-21 in ascending doses of 10 mg for days 1-7, 30 mg for days 8-14 and 100 mg for days 15-21.		Participants with heart failure with preserved ejection fraction (HFpEF) were administered a single PO AMG 986 tablet daily from days 1-21 in ascending doses of 10 mg for days 1-7, 30 mg for days 8-14 and 100 mg for days 15-21.
All Cause Mortality
	Part A: Placebo Pooled		Part A: AMG 986 Pooled		Part B: Placebo Pooled		Part B: AMG 986 Pooled		Part C: HFrEF Placebo		Part C: HFpEF Placebo		Part C: HFrEF AMG 986		Part C: HFpEF AMG 986
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/22 (0%)		0/66 (0%)		0/16 (0%)		0/50 (0%)		0/7 (0%)		0/1 (0%)		0/17 (0%)		0/3 (0%)
Serious Adverse Events
	Part A: Placebo Pooled		Part A: AMG 986 Pooled		Part B: Placebo Pooled		Part B: AMG 986 Pooled		Part C: HFrEF Placebo		Part C: HFpEF Placebo		Part C: HFrEF AMG 986		Part C: HFpEF AMG 986
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/22 (0%)		0/66 (0%)		0/16 (0%)		0/50 (0%)		0/7 (0%)		0/1 (0%)		0/16 (0%)		1/3 (33.3%)
Respiratory, thoracic and mediastinal disorders
Pleuritic pain	0/22 (0%)		0/66 (0%)		0/16 (0%)		0/50 (0%)		0/7 (0%)		0/1 (0%)		0/16 (0%)		1/3 (33.3%)
Other (Not Including Serious) Adverse Events
	Part A: Placebo Pooled		Part A: AMG 986 Pooled		Part B: Placebo Pooled		Part B: AMG 986 Pooled		Part C: HFrEF Placebo		Part C: HFpEF Placebo		Part C: HFrEF AMG 986		Part C: HFpEF AMG 986
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/22 (13.6%)		8/66 (12.1%)		2/16 (12.5%)		7/50 (14%)		2/7 (28.6%)		1/1 (100%)		6/16 (37.5%)		3/3 (100%)
Blood and lymphatic system disorders
Anaemia	0/22 (0%)		0/66 (0%)		0/16 (0%)		0/50 (0%)		0/7 (0%)		0/1 (0%)		1/16 (6.3%)		0/3 (0%)
Eye disorders
Swelling of eyelid	0/22 (0%)		0/66 (0%)		0/16 (0%)		0/50 (0%)		1/7 (14.3%)		0/1 (0%)		0/16 (0%)		0/3 (0%)
Gastrointestinal disorders
Abdominal pain upper	0/22 (0%)		0/66 (0%)		0/16 (0%)		1/50 (2%)		0/7 (0%)		0/1 (0%)		0/16 (0%)		0/3 (0%)
Constipation	0/22 (0%)		0/66 (0%)		0/16 (0%)		1/50 (2%)		0/7 (0%)		0/1 (0%)		0/16 (0%)		0/3 (0%)
Diarrhoea	0/22 (0%)		0/66 (0%)		0/16 (0%)		2/50 (4%)		0/7 (0%)		0/1 (0%)		0/16 (0%)		0/3 (0%)
Dyspepsia	0/22 (0%)		0/66 (0%)		1/16 (6.3%)		0/50 (0%)		0/7 (0%)		0/1 (0%)		0/16 (0%)		0/3 (0%)
Nausea	0/22 (0%)		1/66 (1.5%)		0/16 (0%)		1/50 (2%)		0/7 (0%)		0/1 (0%)		1/16 (6.3%)		1/3 (33.3%)
Oral mucosal eruption	0/22 (0%)		0/66 (0%)		0/16 (0%)		0/50 (0%)		0/7 (0%)		0/1 (0%)		0/16 (0%)		1/3 (33.3%)
Toothache	0/22 (0%)		2/66 (3%)		0/16 (0%)		0/50 (0%)		0/7 (0%)		0/1 (0%)		0/16 (0%)		0/3 (0%)
Vomiting	0/22 (0%)		0/66 (0%)		0/16 (0%)		3/50 (6%)		0/7 (0%)		0/1 (0%)		0/16 (0%)		0/3 (0%)
General disorders
Asthenia	0/22 (0%)		0/66 (0%)		0/16 (0%)		0/50 (0%)		0/7 (0%)		0/1 (0%)		0/16 (0%)		1/3 (33.3%)
Infections and infestations
Upper respiratory tract infection	0/22 (0%)		0/66 (0%)		1/16 (6.3%)		0/50 (0%)		0/7 (0%)		0/1 (0%)		0/16 (0%)		1/3 (33.3%)
Investigations
Alanine aminotransferase increased	0/22 (0%)		0/66 (0%)		0/16 (0%)		1/50 (2%)		0/7 (0%)		0/1 (0%)		0/16 (0%)		0/3 (0%)
Aspartate aminotransferase increased	0/22 (0%)		0/66 (0%)		0/16 (0%)		1/50 (2%)		0/7 (0%)		0/1 (0%)		0/16 (0%)		0/3 (0%)
Blood creatine phosphokinase increased	0/22 (0%)		0/66 (0%)		0/16 (0%)		1/50 (2%)		0/7 (0%)		0/1 (0%)		0/16 (0%)		0/3 (0%)
Platelet count decreased	0/22 (0%)		0/66 (0%)		0/16 (0%)		0/50 (0%)		0/7 (0%)		0/1 (0%)		1/16 (6.3%)		0/3 (0%)
White blood cell count decreased	0/22 (0%)		0/66 (0%)		0/16 (0%)		0/50 (0%)		0/7 (0%)		0/1 (0%)		1/16 (6.3%)		0/3 (0%)
Metabolism and nutrition disorders
Dehydration	0/22 (0%)		0/66 (0%)		0/16 (0%)		0/50 (0%)		1/7 (14.3%)		0/1 (0%)		0/16 (0%)		0/3 (0%)
Hypertriglyceridaemia	0/22 (0%)		0/66 (0%)		0/16 (0%)		0/50 (0%)		0/7 (0%)		0/1 (0%)		1/16 (6.3%)		0/3 (0%)
Hypoglycaemia	0/22 (0%)		0/66 (0%)		0/16 (0%)		0/50 (0%)		0/7 (0%)		0/1 (0%)		0/16 (0%)		1/3 (33.3%)
Hypokalaemia	0/22 (0%)		0/66 (0%)		0/16 (0%)		0/50 (0%)		0/7 (0%)		0/1 (0%)		0/16 (0%)		1/3 (33.3%)
Hypomagnesaemia	0/22 (0%)		0/66 (0%)		0/16 (0%)		0/50 (0%)		0/7 (0%)		0/1 (0%)		0/16 (0%)		1/3 (33.3%)
Musculoskeletal and connective tissue disorders
Arthralgia	0/22 (0%)		0/66 (0%)		0/16 (0%)		0/50 (0%)		0/7 (0%)		0/1 (0%)		1/16 (6.3%)		0/3 (0%)
Nervous system disorders
Dizziness	0/22 (0%)		0/66 (0%)		0/16 (0%)		0/50 (0%)		0/7 (0%)		1/1 (100%)		2/16 (12.5%)		1/3 (33.3%)
Headache	1/22 (4.5%)		6/66 (9.1%)		0/16 (0%)		1/50 (2%)		0/7 (0%)		0/1 (0%)		0/16 (0%)		0/3 (0%)
Psychiatric disorders
Social avoidant behaviour	0/22 (0%)		0/66 (0%)		0/16 (0%)		0/50 (0%)		0/7 (0%)		0/1 (0%)		1/16 (6.3%)		0/3 (0%)
Respiratory, thoracic and mediastinal disorders
Cough	1/22 (4.5%)		0/66 (0%)		0/16 (0%)		0/50 (0%)		0/7 (0%)		0/1 (0%)		0/16 (0%)		0/3 (0%)
Skin and subcutaneous tissue disorders
Pruritus	0/22 (0%)		0/66 (0%)		0/16 (0%)		1/50 (2%)		0/7 (0%)		0/1 (0%)		0/16 (0%)		0/3 (0%)
Rash	1/22 (4.5%)		0/66 (0%)		0/16 (0%)		0/50 (0%)		0/7 (0%)		0/1 (0%)		0/16 (0%)		0/3 (0%)
Skin irritation	0/22 (0%)		0/66 (0%)		0/16 (0%)		1/50 (2%)		0/7 (0%)		0/1 (0%)		0/16 (0%)		0/3 (0%)
Vascular disorders
Hypotension	0/22 (0%)		0/66 (0%)		0/16 (0%)		0/50 (0%)		0/7 (0%)		0/1 (0%)		0/16 (0%)		1/3 (33.3%)

Limitations/Caveats

This study was terminated early because the clinical development program was terminated. Therefore, no formal PK or pharmacodynamic analyses were conducted.

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The Clinical Trial Agreement generally does not restrict an investigator's discussion of trial results after completion. The Agreement permits Amgen a limited period of time to review material discussing trial results (typically up to 45 days and possible extension). Amgen may remove confidential information, but authors have final control and approval of publication content. For multicenter studies, the investigator agrees not to publish any results before the first multi-center publication.