The purpose of this study is to evaluate the effectiveness of the BMS-986259 study drug on blood pressure events in stable participants diagnosed with heart failure admitted to the hospital with Acute Decompensated Heart Failure (ADHF).
ID
Source
Brief title
Condition
- Heart failures
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary objective of the study is to establish the safety and tolerability
of BMS-986259 study drug when initiated in hospital in-patients, who are
medically stable after an admission for Acute Decompensated Heart Failure.
The outcome will be measured by the incidence of clinically relevant
hypotension. This is defined as:
- Supine Systolic Blood Pressure less than 85mmHg (confirmed by repeat
measurement within 30 minutes) regardless of symptoms
OR
- Supine Systolic Blood Pressure less than 90mmHg (confirmed by repeat
measurement within 30 minutes) AND symptoms of Hypotension.
Secondary outcome
*The secondary objective of this study is to evaluate serum PK parameters in
participants with Heart Failure. This outcome will be measured by trough PK
sampling on day 5 including: serum PK parameters Cmax, Tmax, Area Under the
Curve (AUC) and C24.
Additional objectives will be:
*To explore the potential diuretic effects of BMS-986259 study drug. This will
be assessed by measuring the change from baseline in natriuresis after IV loop
diuretic administration. The total and daily dose of loop diuretics
administered during the study will be collected.
*To explore biomarkers related to the mechanism of action of BMS-986259 and
related physiolocigal changes which cause Heart Failure. These may include but
are not limited to Troponin, NT-proBNP, ST2, eGFR, cystatin C, aldosterone,
urine creatinine, urine electrolytes, collagen markers such as ProC6. This will
be explored by measuring the change from baseline in these biomarker levels, in
blood and urine.
*To evaluate the presence of Anti-Drug Antibodies(ADA) and Neutralising
Antibodies(nAb). These antibodies may effect movement of BMS-986259 (relaxin)
through the body or cancel-out the therapeutic effects of the study treatment.
These will be measured through blood sample collection.
*To evaluate blood pressure changes during daytime and night time. This will be
measured and compared between the two arms (treatment vs placebo) using a 48
hours Ambulatory Blood pressure monitor device. The device will measure mean
ambulatory Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP), in
addition to daytime and night time mean SBP and DBP.
*To explore patient reported outcomes. These will be measured using the Kansas
City Cardiomyopathy Questionnaire (KCCQ) score from baseline (Day 1 of
treatment), at the end of treatment (Day 14) and follow-up (Day 30).
Background summary
CV019-010 is a multicentre, phase 2A, double-blinded study involving adult
patients recently admitted to hospital with Acute Decompensated Heart Failure
(ADHF). The study will evaluate the effect of BMS-986259 study drug on blood
pressure events in stable patients diagnosed with heart failure. The study will
be placebo-controlled. Patients are considered for participation if already
medically stabilised and before discharge from the hospital. 72 patients will
take part in the study globally, approximately 4 of these will be from the
Netherlands.
The global burden of heart failure (HF) is substantial. There is an estimated
global prevalence of 26 million. In the United States, an estimated 6.5 million
people suffer from Heart Failure. This number is projected to increase by
approximately 46% by the year 2030. In the recent European data, 12-month
all-cause mortality rate for hospitalised and stable ambulatory HF patients
were 17% and 7%, respectively and hospitalisation rates were 44% and 32%,
respectively.
Current treatment guidelines categorise HF patients based on ejection fraction
(EF):
1.)Heart failure with reduced ejection fraction (HFrEF) with an EF less than or
equal to 40%. 2.) Heart failure with a mid-range ejection fraction (HFmrEF)
with an EF between 41% to 49% 3.) Heart failure with preserved ejection
fraction (HFpEF) with an EF greater than or equal to 50%.
The causes of Heart Failure pathophysiology are highly complex and diverse.
Although current standard of care treatment (beta-blockers, angiotensin
converting enzyme inhibitors and other renin angiotensin-aldosterone system
(RAAS) inhibitors, as well as mineral corticoid receptor antagonists) have led
to a decrease in mortality rates in Heart Failure patients with reduced
ejection fraction (HFrEF), unmet medical need remains high. The overall benefit
of these treatments is often limited by co-morbidities and undesired effects
such as kidney disease, hyperkalemia, and high blood pressure. For Heart
Failure patients with preserved ejection fraction (HFpEF), no therapy has yet
been proven in a placebo-controlled clinical trial to reduce mortality rates.
Human relaxin (H2-relaxin) is a peptide hormone believed to be, at least in
part, responsible for the many physiological adaptations that occur during
human pregnancy. These changes include an increase in global arterial
compliance and a decrease in total systemic vascular resistance (SVR). Renal
blood flow (RBF) and glomerular filtration rate (GFR) are increased by up to
80% and 50% respectively.
In previous clinical studies a short-acting recombinant form of H2-relaxin
(serelaxin), administered in the form of an IV was demonstrated to have
vasodilatory properties and to enhance both RBF and estimated GFR in patients
with HF. In a large phase 3 clinical study, serelaxin when administered as a
short-term 48 hour continuous IV infusion, failed to improve long-term clinical
outcomes in patients with ADHF, compared with placebo. Although this failure
represents a setback for the advancement of novel therapeutics to treat HF,
learnings from the multitude of serelaxin clinical trials, indicate that
chronic administration of a therapeutic with H2-relaxin-like activity (ie,
beyond 48 hours) could potentially benefit HF patients. In a separate
double-blind and placebo-controlled study in which serelaxin was given to
chronic HF patients as a continuous 48-hour IV infusion, statistically
significant increases in eGFR were observed for serelaxin when compared to
placebo. Hemodynamic effects of serelaxin were also studied in a double-blind,
placebo-controlled trial in patients hospitalised for ADHF. When serelaxin was
given as a 20-hour IV infusion, hemodynamic effects were detected early (within
30 minutes), and were characterised by statistically significant reductions in
pulmonary capillary wedge pressure (PCWP) and pulmonary arterial pressure
(PAP), with a concomitant decrease in SVR. Serelaxin administration also
improved renal function and decreased circulating levels of N-terminal
pro-brain natriuretic peptide (NT-proBNP), a biomarker of cardiac stress.
As short term IV injections cannot be expected to exhibit lasting effects,
there has been a need to develop a formulation of the peptide hormone that
allows for chronic administration. BMS-986259, is a recombinant form of H2-
relaxin that contains a covalently attached fatty acid chain which binds to
circulating albumin, to extend its half-life. It has a pharmacokinetic (PK)
profile that supports once daily dosing and exhibits H2-relaxin-like activity.
This has been tested in vitro-cell based assays, as well as in vivo. These
activity data, together with the preclinical PK and toxicology data, indicate
that BMS-986259 can be safely administered subcutaneously. Preliminary data
from an ongoing first in human (FIH) study also support safe subcutaneous use
up to 14 days.
Study objective
The purpose of this study is to evaluate the effectiveness of the BMS-986259
study drug on blood pressure events in stable participants diagnosed with heart
failure admitted to the hospital with Acute Decompensated Heart Failure (ADHF).
Study design
DESIGN
This is a randomised, double-blind, placebo-controlled phase 2a study to
Evaluate the Safety and Tolerability of BMS-986259 study drug in stabilised
patients hospitalised for Acute Decompensated Heart Failure (ADHF). The study
is divided into a screening period, study treatment period and a follow-up
period.
The screening period may last anywhere from 24 hours and up to 8 days from the
time of presentation to the emergency room. Time of presentation is defined as
the time of the first dose of IV diuretic in the hospital.
After signing the consent form and completing the screening tests to determine
eligibility, patients eligible for the study will be randomised to one of the
following treatment arms in a 1:1 ratio:
Arm A
BMS-986259 (3mg or 1mg down-titrated as a 1ml sub-cutaneous injection)
administered daily for 14 days
Arm B
BMS-986259 placebo (subcutaneous injection) administered daily for 14 days
Patients will be randomised at least 24 hours and no later than 8 days after
presentation to the hospital. Patients will only begin treatment at least 12
hours after the last dose change of IV loop diuretics. In addition at least 24
hours must have passed since the last dose of positive inotropes and at least
12 hours since the last dose of IV vasodilators.
Randomisation will be done by an automated sorting process through IVRS (a
telephone based computer system). This ensures that both the treatment arm and
the placebo arm are equally balanced with subject numbers for comparison at
time of analysis, while maintaining the integrity of the randomisation itself.
There is no data available on the risk of clinically significant hypotension
with relaxin administered to medically stabilised patients admitted for ADHF,
especially in patients with systolic blood pressure (SBP) less than 125 mmHg.
For this reason a sentinel group of patients will be treated initially. These
patients must have a SBP greater than or equal to 115 mmHg and less than 130
mmHg to qualify. They will be randomized 1:1 to receive 3 mg subcutaneous
Relaxin or placebo daily. After approximately 8 participants have completed the
treatment period, a Safety Review Committee will review the safety data from
this sentinel group. The main group will consist of patients with a SBP greater
than or equal to 100mg. The number of patients with SBP greater than 125 mmHg
will be capped at 48 patients.
Approximately 72 participants will be randomised to have at least 60 patients
complete the study by the last patient last visit date, assuming a potentially
high dropout rate due to the long treatment period.
VISITS AND ASSESSMENTS
Patients will receive treatment in hospital after the first treatment dose for
a minimum of 5 days. If patients are discharged from the hospital before the
end of the study treatment they will complete study visits at an outpatient
clinic or at home, where they will receive the remainder of the study
treatment. A home nurse or healthcare provider will carry out daily study
visits at home.
Exploratory blood samples (study drug blood levels and biomarkers [taken to
measure substances in the blood such as cells, DNA, RNA and other markers])
will be collected from all patients at certain visits throughout the study.
Study drug blood levels will be measured to assess plasma concentration at
various points. Biomarkers will be collected to further explore biological
activities and the mechanism of action of BMS-986259.
Vital signs and blood pressure monitoring will be performed daily throughout
the treatment period as per the protocol, to monitor patient safety and measure
the effect on the study drug on blood pressure events. If the patient is
discharged before the end of the treatment period, the home nurse or healthcare
provider will be responsible to measure pre-dose blood pressure, administer
study treatment and to collect pharmacokinetic, immunogenicity and biomarker
blood samples. A home nurse will install an Ambulatory Blood Pressure
Monitoring device on day 6 and day 12. The device will collect blood pressure
monitoring data over a 48 hour period.
Patients will visit the hospital on day 8 and day 14 of the treatment period,
for ambulatory visits. During these visits patients will undergo a physical
examination, ECG and body weight assessment, in addition to routine blood and
urine tests, vital sign measurements and study drug administration.
Patients will be asked to complete a questionnaire about how they feel and any
symptoms they are having on Day 1, Day 14 and Day 30. This is called the Kansas
City Cardiomyopathy Questionnaire (KCCQ).
Treatment will be discontinued if the subject withdraws consent, if their
condition gets worse, if it is no longer safe for the subject to continue in
the trial or if the sponsor decides to discontinue development of the study
medication for any reason.
The follow-up visit will take place 30 days (+/-2 days) after the first
treatment dose. During this visit patients will undergo an ECG, blood and urine
tests and they will be asked to complete the KCCQ. In the event that patients
develop any Anti-Drug Antibodies, they will return to the hospital 3 months
later for an additional follow-up visit.
SAFETY MONITORING COMMITTEE
To assure an ongoing favourable risks/benefit assessment for participants
enrolled into this study, an internal Safety Review Committee will assess blood
pressure data after completion of the Sentinel Group. The committee may request
access to unblinded treatment codes for individual participants. The Committee
will consist of senior clinical development individuals not directly involved
in the study conduct and overseeing, including (but not limited to) senior
Worldwide Patients Safety representative, a statistician, and a senior
clinician.
Intervention
Patients will undergo screening tests and assessments to determine eligibility.
Those eligible to participate in the study will be randomised to the treatment
arm or the placebo-controlled arm in a 1:1 ratio:
Arm A (Treatment arm)
BMS-986259 (3mg or 1mg down-titrated as a 1ml sub-cutaneous injection)
administered daily for 14 days
Arm B (Control arm)
BMS-986259 placebo (subcutaneous injection) administered daily for 14 days
Patients in both arms will undergo the same on treatment study evaluation
procedures: blood and urine collection for checking safety, pharmacokinetics,
immunogenicity and biomarkers, vital signs monitoring, ambulatory blood
pressure assessments and ECG. Patients will be asked to complete the KCCQ
questionnaire which will measure quality of life and disease symptoms.
After patients complete the treatment period, they will return to the hospital
on Day 30 (+/- 2 days) for the follow-up visit.
Study burden and risks
Only patients currently hospitalised for acute decompensated heart failure will
be considered for the study. The average length of stay for patients with this
condition is 5 days. Patients may be considered and screened for the study
anywhere from 24 hours and up to 8 days after presentation to the emergency
room. During the screening period patients will be asked questions about their
medical history, including smoking history and alcohol consumption, ethnic
origin and medication use. If a patient provides consent and is eligible for
the study, they will be expected to remain in hospital as an in-patient for up
to a minimum of 5 days from the start of study treatment. The entire treatment
duration is 14 days.
Patients may be discharged from hospital from day 6 of the treatment period, to
continue the 14 day treatment at home with the assistance of the home nurse. If
patients are discharged before the end of the 14 day treatment period they will
be provided with the remaining supply of the study medication to store in
refrigerated conditions, at home. Patients must allow nurses or healthcare
professionals to administer the study medication daily, via subcutaneous
injection, at their home. Patients must also give their consent for home nurses
to complete the study assessments. Timings of these visits will be based on the
protocol schedule but will be mutually agreed with both the study research
staff and the patient to avoid patient and/or staff attending at unsocial
hours, and to minimise any inconvenience to the patient. Patients will be
reimbursed for reasonable travel expenses incurred for attending study visits.
As part of the study patients will be expected to attend hospital visits on day
8 and day 14, where they will undergo a physical examination, body weight
assessment, ECG and blood and urine test for safety assessments. Blood samples
will also be collected for research purposes. Patients will be asked to
complete a questionnaire about their quality of life (Kansas City
Cardiomyopathy Questionnaire (KCCQ)).
The number of procedures carried out during this study would typically be
considered over and above standard of care. The procedures are carried out by
trained medical professionals and every effort will be made to minimise any
risks or discomfort to the patient.
Patients will be required to wear an Ambulatory Blood Pressure Monitoring
device on day 6 and day 12. The device will be installed and removed by a home
nurse or a member of the study research team. The device will collect
ambulatory systolic and diastolic blood pressure monitoring data to compare
blood pressure changes between the group of patients receiving the study drug
and the group receiving the placebo.
The study drug may cause side effects. BMS-986259 will be administered to
patients with Heart Failure for the first time in this study. However
BMS-986259 administration was generally safe and well-tolerated when
administered to normal health volunteers, in an ongoing phase 1 study. To
ensure an ongoing favourable risk/benefit assessment for participants enrolled
onto the study, an independent Safety Review Committee will be established to
provide oversight of safety and efficacy considerations. Sites and study
investigators will receive training on the adiminstration of BMS-986259 and
adverse event manafement strategies.
BMS-986259 could provide clinical benefit and improvements in the outcomes for
patients with acute heart failure. However, with all experimental drugs and
clinical trials, there are known and unknown risks. Study medication and
procedure related risks are outlined in the patient information sheet in detail
to ensure the patients are fully informed before agreeing to take part in the
study.
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Orteliuslaan 1000
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Age
Inclusion criteria
* Patients currently hospitalized for ADHF, regardless of Left Ventricular
Ejection Fraction (LVEF) 24 hours or greater since presentation to the
Emergency Room defined as the time of the first dose of IV diuretic
administered at the hospital, maximum of 8 days since presentation to ER and
before hospital discharge.
* Acute Decompensated Heart Failure is the main reason for admission and there
is no other potential cause for congestive symptoms leading to index
hospitalization (eg, concurrent pneumonia, acute COPD exacerbation)
* Dyspnea at rest or with minimal exertion upon presentation to ER, plus signs
and symptoms of fluid overload that require IV therapy with loop diuretics
* NT-proBNP greater than or equal to 1400 pg/mL OR BNP greater than or equal to
350 pg/mL upon presentation to the hospital; NT-proBNP greater than or equal
to 2000 pg/mL OR BNP greater than or equal to 500 pg/mL if Atrial Fibrillation
(AFib) present at presentation. For participants on Entresto, NT-proBNP should
be used.
* Patients must be hemodynamically stable, as assessed by the investigator, and
as defined by the following criteria:
- * 12 hours since the last dose change of IV loop diuretics (ie,
participants may still be on IV loop diuretics at randomization, as long as
dose is stable for 12 hours or greater).
- * 24 hours since last dose of positive inotropes.
- * 12 hours since the last dose of IV vasodilators.
- Absence of symptoms of hypotension (eg, dizziness, lightheadedness,
etc),
- Supine Systolic Blood Pressure (SBP) must remain within the following
range*, on at least 2 routine consecutive measurements, over the 12 hours
before randomization:
1.) Sentinel Group: SBP greater than or equal to 115 mmHg
2.) Main Group: SBP greater than or equal to 100 mmHg
* Males and Females at least 18 years of age
* Males who are sexually active with Woman of Child-Bearing Potential (WOCBP)
must agree to follow instructions for method(s) of contraception defined in the
protocol, during the study and for at least 6 days after the last dose of the
study treatment
* Female Participants:
- Are eligible to participate if they are not pregnant or breast
feeding and if they are not a WOCBP
- Women must have documented proof that they are not of childbearing
potential
Exclusion criteria
* At randomisation Systolic Blood Pressure (SBP) less than 100 mmHg or greater
than 145 mmHg
* At randomisation Heart Rate (HR) greater than 120 bpm
* Acute cardiovascular condition other than HF decompensation either
contributing to hospitalisation or making the participant unstable, such as
acute MI/acute coronary syndrome, myocarditis, or arrhythmia with the exception
of atrial fibrillation if HR within criteria limit.
* Cardiogenic shock (defined as SBP below 90 mmHg, signs of end-organ
hypoperfusion plus need for intubation, mechanical circulatory support and
other life-sustaining emergency measures) at presentation to Emergency Room or
at any time before randomisation.
* History of heart or any other solid organ transplant or currently on the
transplant list.
* Recipient of ventricular assist devices.
* Use of any cardiac extracorporeal devices, within 12 weeks of study
randomisation. Cardiac Resynchronization Therapy Defibrillator (CRTD) and
pacemakers / Implantable Cardioverter-Defibrillator (ICDs) are allowed, if
implanted at least 4 weeks before randomization and no discharge within 4 weeks
prior to randomisation.
* Participants with contraindications to vasodilator therapy such as
restrictive or obstructive cardiomyopathy, severe mitral or aortic stenosis.
* Women cannot be pregnant or breastfeeding.
* Any major surgery within 12 weeks of study randomization.
* Suspected acute pulmonary disease such as pneumonia, exacerbation of asthma
or COPD or severe chronic, pulmonary disease (eg. severe COPD , pulmonary
fibrosis, patients with hypercapnia or requiring home oxygen or chronic
systemic steroids).
* Hereditary or idiopathic pulmonary hypertension.
* History of stroke, or transient ischemic attack (TIA) within the 30 days
prior to screening (according to the participants' records) or during screening.
* Acute coronary event within 30 days prior to screening or during screening
(myocardial infarction, acute coronary syndrome, or unstable angina; according
to the participants' records).
* Terminal non-cardiovascular disease such as cancer with a life expectancy for
less than 6 months.
* Severe liver disease such as cirrhosis with evidence of portal hypertension,
or acute viral hepatitis.
* Participant is on dialysis or history of chronic or intermittent dialysis or
ultrafiltration.
* Need for mechanical ventilation any time before screening or non-invasive
ventilation (CPAP, BiPAP) less than 2 hrs prior to screening.
* Inability to comply with restrictions and prohibited treatments as listed in
the protocol.
* Exposure to any investigational drug or placebo, including serelaxin; within
30 days of initial study drug administration or 4 months prior to the first
dose of investigational product, in case of exposure to long-acting biological
investigational drug.
* Persistent electrolytes abnormalities not corrected before randomization
- (1) A sodium concentration less than 130 or greater than 145 mEq/l
- (2) A potassium concentration less than 3.1 or greater than 5.5 mEq/l
* Haemoglobin less than 9 g/dL, which is defined as severe anaemia.
* eGFR less than 30 ml/min./1.73 m2.
* Liver abnormalities including total bilirubin greater than 2 mg/dL (greater
than 34.2 micromol/L) or significant elevation of liver enzymes (AST, ALT
greater than 3 x ULN).
* Positive blood screen for hepatitis C antibody, hepatitis B surface antigen,
or human immunodeficiency virus (HIV)-1 and -2 antibodies.
* History of any significant drug allergy or drug-related serious AE (SAE)
(such as anaphylaxis or hepatotoxicity).
* History of ADAs to relaxin (eg, while in a serelaxin development program).
* History of adverse reactions to aminoglycosides.
* Prisoners or participants who are involuntarily incarcerated.
* Employees of CRO or BMS and their first-line relatives
* Legal incapacity or limited legal capacity
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 | EUCTR2019-004186-40-NL |
| ClinicalTrials.gov | NCT04318093 |
| CCMO | NL73330.042.20 |