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

NCT03276728 | Terminated Phase 1 Results FDA Drug

• 2 other identifiers: 201501832017-002940-34
• Study Type: interventional
• Target: 182
• Locations: 9 countries
• Sites: 25

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).

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

Outcome Measures

Primary Outcomes (1)

• Participants With Treatment Emergent Adverse Events (TEAE)

  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.

  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 (3)

• 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

• 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 (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

Study Arms (8)

Part A: Placebo

PLACEBO COMPARATOR

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; Drug: Placebo IV

Part A: AMG 986

EXPERIMENTAL

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; Drug: AMG 986 PO

Part B: Placebo

PLACEBO COMPARATOR

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; Drug: Placebo IV

Part B: AMG 986

EXPERIMENTAL

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; Drug: AMG 986 PO

Part C: HFrEF Placebo

PLACEBO COMPARATOR

Participants with heart failure with reduced ejection fraction (HFrEF) were administered a single PO placebo tablet daily from Days 1-21.

Drug: Placebo PO

Part C: HFpEF Placebo

PLACEBO COMPARATOR

Participants with heart failure with preserved ejection fraction (HFpEF) were administered a single PO placebo tablet daily from Days 1-21.

Drug: Placebo PO

Part C: HFrEF AMG 986

EXPERIMENTAL

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

Part C: HFpEF AMG 986

EXPERIMENTAL

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

Interventions

AMG 986 IV DRUG

AMG 986 solution for infusion

Part A: AMG 986; Part B: AMG 986

AMG 986 PO DRUG

AMG 986 tablets for oral (PO) administration

Part A: AMG 986; Part B: AMG 986; Part C: HFpEF AMG 986; Part C: HFrEF AMG 986

Placebo PO DRUG

Matching placebo tablets for oral administration

Part A: Placebo; Part B: Placebo; Part C: HFpEF Placebo; Part C: HFrEF Placebo

Placebo IV DRUG

Matching placebo solution for infusion

Part A: Placebo; Part B: Placebo

Eligibility Criteria

• Age: 18 Years - 85 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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).
• For Part C
• 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).
• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Amgen: lead

Study Sites (25)

Research Site

Anaheim, California, 92801, United States

Location

Research Site

Tustin, California, 92780, United States

Location

Research Site

Jacksonville, Florida, 32216, United States

Location

Research Site

Metairie, Louisiana, 70006, United States

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Research Site

Baltimore, Maryland, 21201, United States

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Minneapolis, Minnesota, 55415, United States

Location

Research Site

Las Vegas, Nevada, 89148, United States

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Research Site

Durham, North Carolina, 27705, United States

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Research Site

Auchenflower, Queensland, 4066, Australia

Location

Research Site

Bundaberg, Queensland, 4670, Australia

Location

Research Site

Leabrook, South Australia, 5068, Australia

Location

Research Site

Berwick, Victoria, 3806, Australia

Location

Research Site

Bundoora, Victoria, 3083, Australia

Location

Research Site

Sherbrooke, Quebec, J1G 2E8, Canada

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Research Site

Nantes, 44093, France

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Research Site

Paris, 75015, France

Location

Research Site

Rennes, 35033, France

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Research Site

Toulouse, 31059, France

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Research Site

Bad Neuheim, 61231, Germany

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Berlin, 13353, Germany

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Groningen, 9713 GZ, Netherlands

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Research Site

Christchurch, 8011, New Zealand

Location

Research Site

Józefów, 05-410, Poland

Location

Research Site

Wroclaw, 51-162, Poland

Location

Research Site

Singapore, 169609, Singapore

Location

Related Publications (1)

• 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.

  PMID: 35460392 DERIVED

Related Links

• AmgenTrials clinical trials website

MeSH Terms

Conditions

Heart Failure; Cardiovascular Diseases; Heart Diseases

Limitations and Caveats

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

Results Point of Contact

• Title: IHQ Medical Info-Clinical Trials
• Organization: Amgen (EUROPE) GmbH

MedInfoInternational@amgen.com

866-572-6436

Study Officials

• MD

  Amgen

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Masking Details: Double-blinded
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: Double-blind, placebo-controlled

Study Record Dates

• First Submitted: August 17, 2017
• First Posted: September 8, 2017
• Study Start: August 12, 2016
• Primary Completion: April 18, 2019
• Study Completion: April 18, 2019
• Last Updated: August 8, 2022
• Results First Posted: August 8, 2022

Record last verified: 2022-03

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• Time Frame: Data sharing requests relating to this study will be considered beginning 18 months after the study has ended and either 1) the product and indication (or other new use) have been granted marketing authorization in both the US and Europe or 2) clinical development for the product and/or indication discontinues and the data will not be submitted to regulatory authorities. There is no end date for eligibility to submit a data sharing request for this study.
• Access Criteria: Qualified researchers may submit a request containing the research objectives, the Amgen product(s) and Amgen study/studies in scope, endpoints/outcomes of interest, statistical analysis plan, data requirements, publication plan, and qualifications of the researcher(s). In general, Amgen does not grant external requests for individual patient data for the purpose of re-evaluating safety and efficacy issues already addressed in the product labelling. Requests are reviewed by a committee of internal advisors, and if not approved, may be further arbitrated by a Data Sharing Independent Review Panel. Upon approval, information necessary to address the research question will be provided under the terms of a data sharing agreement. This may include anonymized individual patient data and/or available supporting documents, containing fragments of analysis code where provided in analysis specifications. Further details are available at the link below.

Locations

NL (1); NZ (1); AU (5); DE (2); FR (4); CA (1); PL (2); US (8); SG (1)