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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT03276728




Registration number
NCT03276728
Ethics application status
Date submitted
17/08/2017
Date registered
8/09/2017

Titles & IDs
Public title
Study to Evaluate the Safety and Tolerability of AMG 986 in Healthy Volunteers and Heart Failure Patients
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
Secondary ID [1] 0 0
2017-002940-34
Secondary ID [2] 0 0
20150183
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Heart Failure 0 0
Healthy Volunteer 0 0
Condition category
Condition code
Cardiovascular 0 0 0 0
Coronary heart disease
Cardiovascular 0 0 0 0
Other cardiovascular diseases

Intervention/exposure
Study type
Interventional
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
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Participants With Treatment Emergent Adverse Events (TEAE)
Timepoint [1] 0 0
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 outcome [1] 0 0
Left Ventricular Ejection Fraction by Visit for Part C Heart Failure With Reduced Ejection Fraction (HFrEF) Cohort
Timepoint [1] 0 0
Baseline (Day 1 predose), Day 8, Day 15, Day 21, Day 30
Secondary outcome [2] 0 0
Stroke Volume (Method of Disks, Volumetric Assessment) by Visit for Part C Heart Failure With Reduced Ejection Fraction (HFrEF) Cohort
Timepoint [2] 0 0
Baseline (Day 1 predose), Day 8, Day 15, Day 21, Day 30
Secondary outcome [3] 0 0
Stroke Volume (Left Ventricular Outflow Tract Using Doppler Assessment) by Visit for Part C Heart Failure With Reduced Ejection Fraction (HFrEF) Cohort
Timepoint [3] 0 0
Baseline (Day 1 predose), Day 8, Day 15, Day 21, Day 30

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
Minimum age
18 Years
Maximum age
85 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
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.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s


The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 1
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Stopped early
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
12/08/2016
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
18/04/2019
Sample size
Target
Accrual to date
Final
182
Recruitment in Australia
Recruitment state(s)
QLD,SA,VIC
Recruitment hospital [1] 0 0
Research Site - Auchenflower
Recruitment hospital [2] 0 0
Research Site - Bundaberg
Recruitment hospital [3] 0 0
Research Site - Leabrook
Recruitment hospital [4] 0 0
Research Site - Berwick
Recruitment hospital [5] 0 0
Research Site - Bundoora
Recruitment postcode(s) [1] 0 0
4066 - Auchenflower
Recruitment postcode(s) [2] 0 0
4670 - Bundaberg
Recruitment postcode(s) [3] 0 0
5068 - Leabrook
Recruitment postcode(s) [4] 0 0
3806 - Berwick
Recruitment postcode(s) [5] 0 0
3083 - Bundoora
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
California
Country [2] 0 0
United States of America
State/province [2] 0 0
Florida
Country [3] 0 0
United States of America
State/province [3] 0 0
Louisiana
Country [4] 0 0
United States of America
State/province [4] 0 0
Maryland
Country [5] 0 0
United States of America
State/province [5] 0 0
Minnesota
Country [6] 0 0
United States of America
State/province [6] 0 0
Nevada
Country [7] 0 0
United States of America
State/province [7] 0 0
North Carolina
Country [8] 0 0
Canada
State/province [8] 0 0
Quebec
Country [9] 0 0
France
State/province [9] 0 0
Nantes Cedex 1
Country [10] 0 0
France
State/province [10] 0 0
Paris
Country [11] 0 0
France
State/province [11] 0 0
Rennes Cedex 9
Country [12] 0 0
France
State/province [12] 0 0
Toulouse Cedex 9
Country [13] 0 0
Germany
State/province [13] 0 0
Bad Neuheim
Country [14] 0 0
Germany
State/province [14] 0 0
Berlin
Country [15] 0 0
Netherlands
State/province [15] 0 0
Groningen
Country [16] 0 0
New Zealand
State/province [16] 0 0
Christchurch
Country [17] 0 0
Poland
State/province [17] 0 0
Jozefow
Country [18] 0 0
Poland
State/province [18] 0 0
Wroclaw
Country [19] 0 0
Singapore
State/province [19] 0 0
Singapore

Funding & Sponsors
Primary sponsor type
Commercial sector/industry
Name
Amgen
Address
Country

Ethics approval
Ethics application status

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
MD
Address 0 0
Amgen
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
De-identified individual patient data for variables necessary to address the specific research question in an approved data sharing request

Supporting document/s available: Study protocol, Statistical analysis plan (SAP), Informed consent form (ICF), Clinical study report (CSR)
When will data be available (start and end dates)?
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.
Available to whom?
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.
Available for what types of analyses?
How or where can data be obtained?
IPD available at link: https://www.amgen.com/datasharing


What supporting documents are/will be available?




Results publications and other study-related documents

No documents have been uploaded by study researchers.


Results are available at https://clinicaltrials.gov/study/NCT03276728