Study to Evaluate the Safety and Tolerability of AMG 986 in Healthy Volunteers and Heart Failure Patients
Condition: Heart Failure; Healthy Volunteer
MeSH terms: Heart Failure
Intervention: AMG 986 IV; AMG 986 PO; Placebo PO; Placebo IV
Intervention description: AMG 986 solution for infusion; AMG 986 tablets for oral (PO) administration; Matching placebo tablets for oral administration; Matching placebo solution for infusion
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Double-blind, placebo-controlled
Masking: Double (Participant, Investigator)
Masking description: Double-blinded
Enrollment: 182.0
Sex: All
Minimum age: 18 Years
Maximum age: 85 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: Heart Failure; Cardiovascular Diseases; Heart Diseases; Ejection fraction; Heart Failure with reduced ejection fraction; Heart Failure with preserved ejection fraction

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).
    

Eligibility 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

        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.