Clinical trial NCT03276728: Study to Evaluate the Safety and Tolerability of AMG 986 in Healthy Volunteers and Heart Failure Patients
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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Heart Failure
Healthy Volunteer
Keywords: Heart Failure
Cardiovascular Diseases
Heart Diseases
Ejection fraction
Heart Failure with reduced ejection fraction
Heart Failure with preserved ejection fraction
Lead sponsor: Amgen
Sponsor class: INDUSTRY
First posted: 2017-09-08
Enrollment: 182
Sex: ALL
Minimum age (years): 18
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Double-blind, placebo-controlled
Primary purpose: TREATMENT

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).

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.

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.

Primary outcomes:
measure: Participants With Treatment Emergent Adverse Events (TEAE)
timeFrame: Part A: Day 1 up to Day 31 Part B: Day 1 up to Day 37 Part C: Day 1 up to Day 51
Secondary outcomes:
measure: Left Ventricular Ejection Fraction by Visit for Part C Heart Failure With Reduced Ejection Fraction (HFrEF) Cohort
timeFrame: Baseline (Day 1 predose), Day 8, Day 15, Day 21, Day 30
measure: Stroke Volume (Method of Disks, Volumetric Assessment) by Visit for Part C Heart Failure With Reduced Ejection Fraction (HFrEF) Cohort
timeFrame: Baseline (Day 1 predose), Day 8, Day 15, Day 21, Day 30
measure: Stroke Volume (Left Ventricular Outflow Tract Using Doppler Assessment) by Visit for Part C Heart Failure With Reduced Ejection Fraction (HFrEF) Cohort
timeFrame: Baseline (Day 1 predose), Day 8, Day 15, Day 21, Day 30
Other outcomes:
Locations:
city: Anaheim
country: United States
facility: Research Site
state: California
city: Tustin
country: United States
facility: Research Site
state: California
city: Jacksonville
country: United States
facility: Research Site
state: Florida
city: Metairie
country: United States
facility: Research Site
state: Louisiana
city: Baltimore
country: United States
facility: Research Site
state: Maryland
city: Minneapolis
country: United States
facility: Research Site
state: Minnesota
city: Las Vegas
country: United States
facility: Research Site
state: Nevada
city: Durham
country: United States
facility: Research Site
state: North Carolina
city: Auchenflower
country: Australia
facility: Research Site
state: Queensland
city: Bundaberg
country: Australia
facility: Research Site
state: Queensland
city: Leabrook
country: Australia
facility: Research Site
state: South Australia
city: Berwick
country: Australia
facility: Research Site
state: Victoria
city: Bundoora
country: Australia
facility: Research Site
state: Victoria
city: Sherbrooke
country: Canada
facility: Research Site
state: Quebec
city: Nantes Cedex 1
country: France
facility: Research Site
city: Paris
country: France
facility: Research Site
city: Rennes Cedex 9
country: France
facility: Research Site
city: Toulouse Cedex 9
country: France
facility: Research Site
city: Bad Neuheim
country: Germany
facility: Research Site
city: Berlin
country: Germany
facility: Research Site
city: Groningen
country: Netherlands
facility: Research Site
city: Christchurch
country: New Zealand
facility: Research Site
city: Jozefow
country: Poland
facility: Research Site
city: Wroclaw
country: Poland
facility: Research Site
city: Singapore
country: Singapore
facility: Research Site
Study officials:
affiliation: Amgen
name: MD
role: STUDY_DIRECTOR
References:
citation: Winkle P, Goldsmith S, Koren MJ, Lepage S, Hellawell J, Trivedi A, Tsirtsonis K, Abbasi SA, Kaufman A, Troughton R, Voors A, Hulot JS, Donal E, Kazemi N, Neutel J. A First-in-Human Study of AMG 986, a Novel Apelin Receptor Agonist, in Healthy Subjects and Heart Failure Patients. Cardiovasc Drugs Ther. 2023 Aug;37(4):743-755. doi: 10.1007/s10557-022-07328-w. Epub 2022 Apr 23.