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Trial details imported from ClinicalTrials.gov
For full trial details, please see the original record at
https://clinicaltrials.gov/ct2/show/NCT03276728
Registration number
NCT03276728
Ethics application status
Date submitted
17/08/2017
Date registered
8/09/2017
Date last updated
8/08/2022
Titles & IDs
Public title
Study to Evaluate the Safety and Tolerability of AMG 986 in Healthy Volunteers and Heart Failure Patients
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Scientific 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
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Secondary ID [1]
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2017-002940-34
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Secondary ID [2]
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20150183
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Universal Trial Number (UTN)
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Trial acronym
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
Heart Failure
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Healthy Volunteer
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Condition category
Condition code
Cardiovascular
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Coronary heart disease
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Cardiovascular
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Other cardiovascular diseases
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Intervention/exposure
Study type
Interventional
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Description of intervention(s) / exposure
Treatment: Drugs - AMG 986 IV
Treatment: Drugs - AMG 986 PO
Treatment: Drugs - Placebo PO
Treatment: Drugs - Placebo IV
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.
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.
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.
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.
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.
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.
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.
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.
Treatment: Drugs: AMG 986 IV
AMG 986 solution for infusion
Treatment: Drugs: AMG 986 PO
AMG 986 tablets for oral (PO) administration
Treatment: Drugs: Placebo PO
Matching placebo tablets for oral administration
Treatment: Drugs: Placebo IV
Matching placebo solution for infusion
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Intervention code [1]
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Treatment: Drugs
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Comparator / control treatment
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Control group
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Outcomes
Primary outcome [1]
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Participants With Treatment Emergent Adverse Events (TEAE)
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Assessment method [1]
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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.
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Timepoint [1]
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Part A: Day 1 up to Day 31 Part B: Day 1 up to Day 37 Part C: Day 1 up to Day 51
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Secondary outcome [1]
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Left Ventricular Ejection Fraction by Visit for Part C Heart Failure With Reduced Ejection Fraction (HFrEF) Cohort
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Assessment method [1]
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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.
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Timepoint [1]
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Baseline (Day 1 predose), Day 8, Day 15, Day 21, Day 30
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Secondary outcome [2]
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Stroke Volume (Method of Disks, Volumetric Assessment) by Visit for Part C Heart Failure With Reduced Ejection Fraction (HFrEF) Cohort
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Assessment method [2]
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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.
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Timepoint [2]
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Baseline (Day 1 predose), Day 8, Day 15, Day 21, Day 30
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Secondary outcome [3]
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Stroke Volume (Left Ventricular Outflow Tract Using Doppler Assessment) by Visit for Part C Heart Failure With Reduced Ejection Fraction (HFrEF) Cohort
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Assessment method [3]
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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.
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Timepoint [3]
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Baseline (Day 1 predose), Day 8, Day 15, Day 21, Day 30
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Eligibility
Key inclusion criteria
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
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Minimum age
18
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Maximum age
85
Years
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Sex
Both males and females
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Can healthy volunteers participate?
Yes
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Key exclusion criteria
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.
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Study design
Purpose of the study
Treatment
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Allocation to intervention
Randomised controlled trial
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Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
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Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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Masking / blinding
Blinded (masking used)
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Who is / are masked / blinded?
The people receiving the treatment/s
The people analysing the results/data
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Intervention assignment
Parallel
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Other design features
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Phase
Phase 1
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Type of endpoint/s
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Statistical methods / analysis
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Recruitment
Recruitment status
Terminated
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Data analysis
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Reason for early stopping/withdrawal
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Other reasons
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Date of first participant enrolment
Anticipated
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Actual
12/08/2016
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Date of last participant enrolment
Anticipated
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Actual
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Date of last data collection
Anticipated
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Actual
18/04/2019
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Sample size
Target
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Accrual to date
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Final
182
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Recruitment in Australia
Recruitment state(s)
QLD,SA,VIC
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Recruitment hospital [1]
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Research Site - Auchenflower
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Recruitment hospital [2]
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Research Site - Bundaberg
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Recruitment hospital [3]
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Research Site - Leabrook
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Recruitment hospital [4]
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Research Site - Berwick
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Recruitment hospital [5]
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Research Site - Bundoora
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Recruitment postcode(s) [1]
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4066 - Auchenflower
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Recruitment postcode(s) [2]
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4670 - Bundaberg
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Recruitment postcode(s) [3]
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5068 - Leabrook
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Recruitment postcode(s) [4]
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3806 - Berwick
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Recruitment postcode(s) [5]
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3083 - Bundoora
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Recruitment outside Australia
Country [1]
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United States of America
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State/province [1]
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California
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United States of America
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Florida
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United States of America
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Louisiana
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United States of America
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Maryland
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United States of America
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Minnesota
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United States of America
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Nevada
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United States of America
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North Carolina
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Country [8]
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Canada
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State/province [8]
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Quebec
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Country [9]
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France
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State/province [9]
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Nantes Cedex 1
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France
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Paris
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France
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Rennes Cedex 9
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France
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Toulouse Cedex 9
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Germany
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Bad Neuheim
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Germany
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Berlin
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Netherlands
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State/province [15]
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Groningen
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New Zealand
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State/province [16]
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Christchurch
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Poland
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Jozefow
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Poland
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Wroclaw
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Singapore
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Singapore
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Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
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Name
Amgen
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Address
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Country
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Ethics approval
Ethics application status
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Summary
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).
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Trial website
https://clinicaltrials.gov/ct2/show/NCT03276728
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Trial related presentations / publications
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Public notes
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Contacts
Principal investigator
Name
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MD
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Address
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Amgen
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Email
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Contact person for public queries
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Contact person for scientific queries
Summary Results
For IPD and results data, please see
https://clinicaltrials.gov/ct2/show/NCT03276728
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