The purpose of this research study is to compare 1 dose (15 ng/kg/minute) of Ularitide with a placebo-substance, to see whether Ularitide is safe and effective for the treatment of acute decompensated heart failure.
ID
Source
Brief title
Condition
- Heart failures
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary Efficacy Endpoint 1:
Improvement in a hierarchical clinical composite comprised of elements
associated with: patient global assessment using a 7-point scale of symptomatic
improvement, lack of improvement, or worsening; persistent or worsening heart
failure (HF) requiring an intervention (initiation or intensification of IV
therapy, circulatory or ventilatory mechanical support, surgical intervention,
ultrafiltration, hemofiltration or dialysis); and all-cause mortality.
Assessment of the clinical composite will be performed at 6 hour (h), 24 h and
48 h after start of IV ularitide infusion.
Patients will be classified as *improved* if the patients are moderately or
markedly improved at all 3 time points (at 6 h, 24 h and 48 h) and do not
fulfill criteria for *worse* during the first 48 hours following the start of
the study drug infusion. Patients will be classified as *worse* if (during the
48 h) they die; experience worsening HF requiring a prespecified intervention
at any time during the first 48 h; or experienced moderate or marked worsening
of their global assessment at any of the 3 time points (at 6 h, 24 h or 48 h).
Co-primary efficacy endpoint 2: evaluates freedom from cardiovascular mortality
following randomization for the entire duration of the trial.
Primary Safety Endpoints:
All-cause mortality and cardiovascular rehospitalization at 30 days after start
of study drug infusion.
Secondary outcome
Secondary Endpoints:
•Length of stay of index hospitalization in hours after start of study drug
infusion up to 30 days.
•Length of stay in intensive care (intensive care unit [ICU] or critical care
unit [CCU]) during the first 120 h following the start of the study
drug infusion.
•Number of events of persistent or worsening HF requiring an intervention from
the start of the study drug infusion to 120 h.
•Proportion of patients with persistent or worsening HF and requiring an
intervention from the start of study drug infusion to 120 h.
•Reduction in rehospitalization for heart failure within 30 days after initial
hospital discharge.
•Change of N-terminal pro-brain natriuretic peptide (NT-pro BNP) at 48 h of
treatment compared to baseline.
•Time to completion of last dose of any IV drugs that can be used for the
treatment of HF (e.g., diuretics, vasodilators, or positive inotropic
agents) for the first 120 h following the start of the drug infusion.
•Change in serum creatinine from baseline through 72 h.
•Combined all-cause mortality and cardiovascular rehospitalization at Day 180
after start of study drug infusion, including patients still hospitalized at
Day 30.
Background summary
This is a Prospective, randomized, placebo-controlled, double-blind,
multinational, multi-center, Phase III study to evaluate the effect of a
continuous intravenous (IV) ularitide infusion on the clinical status of
patients (males and females between 18 and 85 years old) with ADHF. Ularitide
is an investigational (experimental) drug that has not been yet approved by
regulatory agencies in any country. It is a chemically synthesized form of
urodilatin, a human renal natriuretic peptide that is produced in the kidneys
and found primarily in urine and in very low concentrations in blood plasma.
Study objective
The purpose of this research study is to compare 1 dose (15 ng/kg/minute) of
Ularitide with a placebo-substance, to see whether Ularitide is safe and
effective for the treatment of acute decompensated heart failure.
Study design
Patients with ADHF who meet all inclusion and exclusion criteria will be
randomized on a 1:1 basis to continuous IV infusion of either ularitide 15
ng/kg BW/min or matching placebo for 48 h. In addition, patients may receive
all appropriate therapy that may include vasodilatory, inotropic, and diuretic
support as clinically indicated. However, use of nesiritide, levosimendan,
milrinone, or any other phosphodiesterase inhibitor is not allowed during the
first 72 h following the start of the infusion.
All timepoints refer to the start of the study drug infusion at the timepoint
called *0 hours* (t0). Efficacy endpoints will be assessed at 6 h, 24 h and 48
h from the start of infusion.
Safety parameters will be assessed during hospitalization and adverse events
(AEs) and serious adverse events (SAEs) will be evaluated until Day 30 after
the start of therapy.
All patients will be assessed through phone call follow-ups at Day 60, Day 90,
Day 180 and every 90 days after start of the study treatment for the occurrence
of cardiovascular rehospitalization and all-cause mortality.
Intervention
- Ularitide for injection. Ularitide, a natriuretic peptide, is lyophilized
with mannitol (2.5 mg ularitide with 20 mg mannitol) in labeled 10 mL vials.
- Matching placebo, i.e., 20 mg mannitol in vials that are identical to the
ularitide vials to maintain blinding.
- In addition, patients may receive all appropriate therapy that may include
vasodilatory, inotropic, and diuretic support as clinically indicated. However,
use of nesiritide, levosimendan, milrinone, or any other phosphodiesterase
inhibitor is not allowed during the first 72 h following the start of the
infusion.
- Pregnancy test at screening visit in potential childbearing females
- Routine evaluations like physical examination, check of vital signs (blood
pressure, heart rate, body temperature), electrocardio¬grams (recordings of
heart*s electrical activity), chest x-ray, and blood samples for routine
laboratory testing will be done.
- During this study approximately 120 mL of blood will be drawn. Information
like race, sex, height, weight, medical history and medications subjects are
taking will be collected.
- Subject may give permission to give a blood sample to investigate biomarkers
substances in their blood. This is optional and subject can participate in the
rest of the study, even if they do not want to give a blood sample for
biomarker research.
- Study assessments will be performed at time points 0 hour (h), 6h, 24h, 48h,
60h, 72h and 120h after start of the study treatment. Several follow up
telephone calls (Day 60, Day 90, Day 180 and every 90 days after start of the
study treatment until the end of trial) are planned.
Study burden and risks
Benefit:
Study investigations and monitoring could provide additional information that
might improve subjects healthcare. In two previous clinical trials, Ularitide
significantly reduced some clinical effects of ADHF (significantly reduced
PCWP; significanlty improvement in dyspnea; a dose-dependent increase in the
mean cGMP plasma concentration).
Burden and risks:
Whenever a catheter is placed in a vein, there is a risk of bruising,
discomfort, bleeding or infection. Needle punctures of a vein for blood draws
may cause bleeding, bruising, discomfort, infections and/or pain at the needle
site; subject may experience feeling of light-headedness or dizziness.
Intravenous infusions may result in leakage of fluid into the surrounding
tissues and formation of blood clots. Skin irritation can occur during an ECG
from the electrodes or gel that is used. During chest x-ray, you will be
exposed to a small dose of radiation.
Treatment with Ularitide may lead to the occurrence of unwanted symptoms (*side
effects*) like hypotension (low blood pressure), confusion, restlessness,
dyspnea, dizziness, sweating increased, weakness, headache and increased or
decreased heart rate, nausea, loss of consciousness, and paleness of skin.
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Cardiorentis, Steinhauserstr. 74
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Listed location countries
Age
Inclusion criteria
1) Males and females aged 18 to 85 years.
2) Unplanned hospitalization or emergency department visit for ADHF. Acute HF is defined as including all of the following:
a) Dyspnea at rest in a recumbent sitting position (30 to 45 degrees), which has worsened within the past week.
b) Radiological evidence of HF on a chest X-ray (if an appropriate chest computerized tomography scan is done; the X-ray need not be performed).
c) Brain natriuretic peptide (BNP) >500 pg/mL or NT-pro BNP >2000 pg/mL.
3) Ability to start infusion of the study drug within 12 h after initial clinical assessment performed by a physician at the emergency room/hospital.
4) Ability to reliably carry out self-assessment of symptoms.
5) Systolic blood pressure (SBP) >=116 mmHg and <=180 mmHg.
6) Persisting dyspnea at rest despite standard background therapy for ADHF (as determined by the Investigator) which must include IV furosemide (or equivalent diuretic) at >=40 mg (or its equivalent) at any time after start of emergency services (ambulance, emergency department, or hospital). At the time of randomization, the patient must still be symptomatic. In addition, the patient should not have received an IV bolus of a diuretic for at least 2 h prior to randomization, and the infusion rates of ongoing IV infusions of medication to treat HF must not have been increased or decreased for at least 2 h prior to randomization.
7) Ability to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use protected health information (in accordance with national and local privacy regulations).
Exclusion criteria
1) Known active myocarditis, obstructive hypertrophic cardiomyopathy, congenital heart disease, restrictive cardiomyopathy, constrictive pericarditis, uncorrected clinically significant primary valvular disease.
2) Treatment with dobutamine at a dose >5 µg/kg/min or use of drugs for support of BP at the time of randomization.
3) Treatment with levosimendan, milrinone, or any other phosphodiesterase inhibitor within 7 days before randomization.
4) Treatment with nesiritide within 30 days before randomization.
5) Creatinine clearance <25 mL/min/1.73m² (as measured by the MDRD formula) at the time of screening.
6) Planned coronary revascularization procedure (percutaneous coronary intervention or coronary artery bypass grafting) within 5 days of randomization.
7) Clinical diagnosis of acute coronary syndrome meeting any 2 of the following 3 criteria:
a) Prolonged chest pain at rest, or an accelerated pattern of angina;
b) ECG changes indicative of ischemia or myocardial injury, defined as: a new ST elevation at the J point of two anatomically contiguous leads with the cut-off points: >= 0.2 mV in men >=40 years (> 0.25 mV in men < 40 years) or >= 0.15 mV in women in leads V2-V3 and/or >= 0.1 mV in other leads; or ST depression and T wave changes. New horizontal or down-sloping ST depression >= 0.05 mV in two contiguous leads; and/or new T inversion >= 0.3 mV in two contiguous leads;
c) Serum troponin >3 times upper limit of normal.
8) Clinically suspected acute mechanical cause of ADHF (e.g., papillary muscular rupture). The diagnosis need not be confirmed by imaging or cardiac catheterization.
9) Anemia (hemoglobin <9 g/dL or a hematocrit <25%).
10) Known vasculitis, active infective endocarditis, or suspected infections including pneumonia, acute hepatitis, systemic inflammatory response syndrome, or sepsis.
11) Body temperature >=38°C just prior to randomization.
12) Acute or chronic respiratory disorder (e.g., severe chronic obstructive pulmonary disease) or primary pulmonary hypertension sufficient to cause dyspnea at rest, which may interfere with the ability to interpret dyspnea assessments or hemodynamic measurements.
13) Terminal illness other than congestive heart failure with expected survival <180 days.
14) Any previous exposure to ularitide.
15) Known allergy to natriuretic peptides.
16) Participation in an investigational clinical drug trial within 30 days prior to randomization.
17) Current drug abuse or chronic alcoholism sufficient to impair participation and compliance to study protocol.
18)Women who are breast-feeding.
19)Women of child-bearing potential (i.e. pre-menopausal women) without documentation of a negative urine/blood pregnancy assay within 12 h prior to randomization.
20) Any condition that, in the Investigator's opinion, makes the patient unsuitable for study participation.
21) Legal incapacity or limited legal capacity.
22) Patients requiring mechanical circulatory support.
23) Patients with severe hepatic impairment.
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 | EUCTR2010-024249-59-NL |
| ClinicalTrials.gov | NCT01661634 |
| CCMO | NL41635.008.12 |