To evaluate the safety and tolerability of ascending multiple PO doses of AMG 986 in heart failure patients (Part C).* To characterize AMG 986 pharmacokinetics (PK) after IV infusion and oral administrationin heart failure patients.* To characterize…
ID
Source
Brief title
Condition
- Heart failures
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Subject incidence of treatment-emergent adverse events.
* Subject incidence of clinically significant changes in physical examinations,
vital signs,
laboratory safety tests, and electrocardiograms (ECGs).
Secondary outcome
AMG 986 PK parameters including, but not limited to, maximum observed
concentration
(Cmax), the time of maximum observed concentration (tmax), area under the
concentration-time curve (AUC), and oral bioavailability.
* Changes over time from baseline in echocardiographic parameters of left
ventricular
systolic and diastolic functions (left ventricular ejection fraction, fraction
shortening, stroke
volume, wall thickening, end-systolic and end-diastolic volumes and indexes,
septal and
lateral e*, E/A ratio, E/e* ratio, E wave deceleration time, left atrial volume
index) in
heart failure patients, as well as changes in ventriculo-arterial coupling and
global strain in heart failure patients
Background summary
AMG 986 is a novel apelin receptor (APJ) small molecule agonist that binds and
activates APJ receptor to improve cardiac function by increasing cardiac
contraction and
relaxation, by improving cardiac reserve, and by decreasing systemic vascular
resistance without a significant impact on heart rate and myocardial oxygen
consumption. AMG 986 is being developed as a potential treatment for heart
failure
Study objective
To evaluate the safety and tolerability of ascending multiple PO doses of AMG
986 in heart failure patients (Part C).
* To characterize AMG 986 pharmacokinetics (PK) after IV infusion and oral
administration
in heart failure patients.
* To characterize the pharmacodynamic (PD) effects of AMG 986 in heart failure
patients.
Study design
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 subjects, 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
IP by once daily oral administration for 21 days.
All available safety and laboratory data will be reviewed in an unblinded
fashion by the members
of the Dose Level Review Meeting (DLRM) prior to the first dose administration
of IP at the higher
dose level. For study Part A, PK assessments will be part of each DLRM. For
study Parts B and
C, vital signs, and all available PK and PD data will also be reviewed at the
DLRM. All cohorts in
Part B will enroll sequentially after review of safety data at the previous
dose level. Both cohorts
in Part C (HFrEF cohort and HFpEF cohort) will enroll concurrently after
completion of study Part
B.
Based on emerging safety and tolerability data and upon assessment by the
Principal Investigator
(PI), Medical Monitor and Global Safety Officer (DLRM members), cohorts may be
removed or
additional cohorts may be added. Subject numbers within each cohort may also be
increased or
decreased based on the decision from the DLRM. Doses to be administered within
each cohort
may be higher or lower than the last. Dosing of any subject shall not exceed
the highest planned
IV and PO cohorts.
Please Note that the Netherlands will only participate in Part C of the
protocol.
Intervention
Blood sampling, Echocardigram, ECG
Study burden and risks
Potential risks associated with IP in this study are outlined in Section 2 of
the protocol and in the informed consent. Bloodsampling will be the most
invasive assessment done in this study.There are risks associated with the
procedures which are outlined in section 7 of the protocol and the informed
consent.
Minervum 7061 Minervum 7061
4800DH Breda 4800DH Breda
NL
Minervum 7061 Minervum 7061
4800DH Breda 4800DH Breda
NL
Listed location countries
Age
Inclusion criteria
Criteria for HFrEF- Patients between the ages of 18 and 85 years with stable NYHA class
II or III chronic HF in sinus rhythm on optimal therapy and a left ventricular ejection
fraction of < 40% and NT-proBNP level of > 250 pg/mL.
* Criteria for HFpEF- Patients between the ages of 18 and 85 years with stable NYHA
class II or III chronic HF, in sinus rhythm on optimal standard of care therapy with a left
ventricular ejection fraction of > 50% and NT-proBNP level of > 250 pg/mL.
Exclusion criteria
*Heart rate * 100 beats per minute after 5 minutes of rest or an untreated symptomatic bradyarrhythmia within 1 month prior to enrollment.
*Severe uncorrected valvular heart disease, or hypertrophic obstructive
cardiomyopathy, active myocarditis, constrictive pericarditis, or clinically
significant congenital heart disease.
*Estimated glomerular filtration rate (eGFR)
within the screening period of less than 30 mL/min/1.732m2 as calculated using
the Modification of Diet in Renal Disease (MDRD) formula.
*For subjects in Part C of the study: Systolic blood pressure > 160 mm Hg or <
100 mm Hg, or diastolic blood pressure > 110 mm Hg or < 60 mm Hg, 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.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2017-002940-34-NL |
| ClinicalTrials.gov | NCT03276728 |
| CCMO | NL63274.100.17 |