An Exploratory Study of Nesiritide in Participants With Acute Heart Failure

Heart Failure, Congestive Clinical Trial

Official title:

An Exploratory Study of JNS004 (Nesiritide) in Patients With Acute Heart Failure (J2)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00490724
• Other study ID #: CR013903
• Secondary ID: JNS004-JPN-02
• Status: Completed
• Phase: Phase 2
• First received: June 21, 2007
• Last updated: December 31, 2013
• Start date: March 2007
• Est. completion date: July 2008

Study information

• Verified date: December 2013
• Source: Janssen Pharmaceutical K.K.
• Contact: n/a
• Is FDA regulated: No
• Health authority: Japan: Pharmaceuticals and Medical Devices Agency
• Study type: Interventional

Clinical Trial Summary

The purpose of this exploratory study is to assess the efficacy and safety of nesiritide in participants with acute (a quick and severe form of illness in its early stage) heart failure (when the heart inadequately pumps blood through the body) including acute exacerbation of chronic (lasting a long time) heart failure, administered intravenous (into a vein) bolus (a large amount) followed by intravenous infusion (a fluid or a medicine delivered into a vein by way of a needle).

Description:

This is an open-label (a medical research study in which participants and researchers are told which treatments the participants are receiving, "unblinded"), multi-center (when more than 1 hospital or medical school team work on a medical research study), randomized (study medication assigned by chance), stepwise, bolus plus intravenous infusion, fixed-flexible (arbitrary dose titration [slow increase in drug dosage, guided by participant's responses]) study. The study consists of 3 periods: Observation period (from the time of obtaining consent to the start of study treatment), Treatment period, and Follow-up period (from 24 hours after the initiation of study treatment [discontinuation] to 30 days after the initiation of study treatment). The participants will be randomly assigned to 1 of the following 3 treatment groups: 2+0.005 group, 1+0.01 group and 2+0.01 group. The treatment period consists of treatment with bolus injection (over 1 minute) followed by intravenous infusion (over 24 hours: Period 1 [fixed-dose period] of 3 hours and Period 2 [flexible-dose period] of 21 hours).The study will be conducted stepwise and hence, initially participants will be randomly assigned to 1 of the following 2 groups: 1+0.01 group and 2+0.005 group. Participants will receive nesiritide at an initial dose of 0.005 or 0.01 microgram per kilogram per minute (mcg/kg/min), and the dose escalation of 0.005 mcg/kg/min per dose will be conducted every 3 hours up to maximum of 0.03 mcg/kg/min in Period 2. Safety data of at least 5 participants will be assessed for each group, and after confirming the safety of 2 groups, the participants will be assigned to third group of nesiritide 2 microgram per kilogram (mcg/kg) +0.01 mcg/kg/min. Then participants will be followed up to a maximum of 30 days after the initiation of study treatment, in follow-up period. Participants will primarily be evaluated for the effect of nesiritide on hemodynamic parameters such as pulmonary capillary wedge pressure (PCWP), or if it is unmeasurable then it will be complemented with pulmonary arterial diastolic pressure (PADP). Participants' safety will also be monitored throughout the study.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 67
• Est. completion date: July 2008
• Est. primary completion date: June 2008
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 20 Years and older

Eligibility

Inclusion Criteria:

• Participants with acute heart failure (including acute exacerbation of chronic heart failure) requiring hospitalization whose placement of right-heart catheter (flexible, tube-like tool used to take fluids out or put fluids into the body) is judged to be possible and useful for treatment

• Participants with findings of pulmonary (having to do with the lungs) congestion on a chest X-ray (an image of a site produced on photographic film by X-rays passing through the site) film taken within 12 hours before starting the treatment

• Participants with 2 systolic blood pressure (SBP: refers to blood pressure [pressure of the blood on the arteries and other blood vessel] when the heart beats while pumping blood) values greater than or equal to 100 millimeters of mercury (mmHg) measured at an interval of at least 15 minutes in the hemodynamic (related to blood flow) assessment in observation period

• In a hemodynamic assessment in observation period, participants with 2 pulmonary capillary wedge pressure (PCWP [if it is not available, pulmonary arterial diastolic pressure {PADP}]) values greater than or equal to 18 mmHg measured at an interval of at least 15 minutes and the second measurement value is within positive 20 percent (%) and negative 20% compared with the first 1

Exclusion Criteria:

• Participants with severe (very serious, life threatening) hepatic (to do with liver) impairment or renal (to do with kidney) impairment, cancer (abnormal tissue that grows and spreads in the body until it kills), or malignant (cancerous) tumor (a mass in a specific area)

• Participants who are or may be pregnant or breast-feeding

• Participants receiving non-invasive (puncture, opening or cutting of the skin) positive pressure ventilation (NIPPV) or scheduled to receive this during the study period

• Participants who received treatment with another investigational product within 4 weeks before the initiation of investigational treatment or who were enrolled in a clinical study of nesiritide in the past

• Participants who received prohibited concomitant medications within 3 hours before the initiation of investigational treatment or those who are receiving such a medication

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Heart Failure
• Heart Failure, Congestive

Intervention

Drug:
• Nesiritide (1+0.01)
Intravenous bolus treatment will be administered over 1 minute (min) at a dose of 1 microgram per kilogram (mcg/kg) followed by 24 hour intravenous infusion which is comprised of Period 1 (fixed-dose) with dose of 0.01 mcg/kg/min and Period 2 (flexible-dose) where dosage will be increased by 0.005 mcg/kg/min every 3 hours. Total dosage to be administered will be 15.4 to 35.2 mcg/kg.
• Nesiritide (2+0.005)
Intravenous bolus treatment will be administered over 1 minute (min) at a dose of 2 microgram per kilogram (mcg/kg) followed by 24 hour intravenous infusion which is comprised of Period 1 (fixed-dose) with dose of 0.005 mcg/kg/min and Period 2 (flexible-dose) where dosage will be increased by 0.005 mcg/kg/min every 3 hours. Total dosage to be administered will be 9.2 to 31.7 mcg/kg.
• Nesritide (2+0.01)
Intravenous bolus treatment will be administered over 1 minute (min) at a dose of 2 microgram per kilogram (mcg/kg) followed by 24 hour intravenous infusion which is comprised of Period 1 (Fixed-dose) with dose of 0.01 mcg/kg/min and Period 2 (Flexible-dose) where dosage will be increased by 0.005 mcg/kg/min every 3 hours. Total dosage to be administered will be 16.4 to 36.2 mcg/kg.

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Janssen Pharmaceutical K.K.

Country where clinical trial is conducted

Japan, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change From Baseline in Pulmonary Capillary Wedge Pressure (PCWP or Pulmonary Arterial Diastolic Pressure[PADP]) at 3 Hours	Change in PCWP was unmeasurable, therefore it was complemented with PADP. PCWP was measured by pulmonary artery catheterization and provided an indirect measure of left atrial pressure.	Baseline and 3 Hours	No
Secondary	Change From Baseline in Mean Right Atrial Pressure (MRAP) at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 12, 15 and 24 Hour	The MRAP was a measured hemodynamic parameter. MRAP was measured using a Swan-Ganz catheter.	Baseline, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 12, 15 and 24 Hour	No
Secondary	Change From Baseline in Pulmonary Arterial Systolic Pressure (PASP) at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 9, 12, 15 and 24 Hour	The PASP was a measured hemodynamic parameters. PASP was assessed by Swan-Ganz catheter.	Baseline, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 9, 12, 15 and 24 Hour	No
Secondary	Change From Baseline in Pulmonary Arterial Diastolic Pressure (PADP) at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 9, 12, 15 and 24 Hour	The PADP was a measured hemodynamic parameter. Normal range of PADP is 8 to 15 millimeters of mercury (mmHg). PADP was assessed by Swan-Ganz catheter.	Baseline, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 9, 12, 15 and 24 Hour	No
Secondary	Change From Baseline in Mean Pulmonary Arterial Pressure (MPAP) at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 9, 12, 15 and 24 Hour	The MPAP was a measured hemodynamic parameter. MPAP was measured using a Swan-Ganz catheter.	Baseline, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 9, 12, 15 and 24 Hour	No
Secondary	Change From Baseline in Pulmonary Capillary Wedge Pressure (PCWP) at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 9, 12, 15 and 24 Hour	The PCWP was a measured hemodynamic parameter. It was the blood pressure, recorded after wedging a catheter in a small pulmonary artery; believed to reflect the pressure in the pulmonary capillaries. It was measured by pulmonary artery catheterization and provided an indirect measure of left atrial pressure.	Baseline, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 9, 12, 15 and 24 Hour	No
Secondary	Change From Baseline in Cardiac Output (CO) at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 9, 12, 15 and 24 Hour	The CO was a measured cardiopulmonary hemodynamic parameter. It is the volume of blood expelled by the ventricles of the heart with each beat. It was calculated as the product of stroke volume (output of either ventricle per heartbeat) and the number of beats per minute. Cardiac output is commonly measured by the thermodilution technique.	Baseline, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 9, 12, 15 and 24 Hour	No
Secondary	Change From Baseline in Mean Blood Pressure (MBP) at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 9, 12, 15, 18, 21 and 24 Hour	The MBP was a calculated hemodynamic parameter and the calculation was done on the basis of the measured hemodynamic parameters. MBP was calculated as sum of diastolic blood pressure (DBP) and (0.33*[SBP-DBP])	Baseline, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 9, 12, 15, 18, 21 and 24 Hour	No
Secondary	Change From Baseline in Cardiac Index (CI) at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 9, 12, 15 and 24 Hour	The CI was a calculated hemodynamic parameter and the calculation was done on the basis of the measured hemodynamic parameters. CI was calculated by dividing CO and body surface area.	Baseline, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 9, 12, 15 and 24 Hour	No
Secondary	Change From Baseline in Stroke Volume (SV) at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 9, 12, 15 and 24 Hour	The SV was a calculated hemodynamic parameter and the calculation was done on the basis of the measured hemodynamic parameters. Stroke volume is the volume of blood ejected from a ventricle at each beat of the heart, equal to the difference between the end-diastolic volume and the end-systolic volume. SV was calculated by dividing CO and heart rate (HR).	Baseline, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 9, 12, 15 and 24 Hour	No
Secondary	Change From Baseline in Stroke Volume Index (SVI) at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 9, 12, 15 and 24 Hour	The SVI was a calculated hemodynamic parameter and the calculation was done on the basis of the measured hemodynamic parameters. Stroke volume is the volume of blood ejected from a ventricle at each beat of the heart, equal to the difference between the end-diastolic volume and the end-systolic volume. The stroke volume index is a method of relating the stroke volume to the size of the person by dividing the stroke volume by the body surface area (BSA).	Baseline, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 9, 12, 15 and 24 Hour	No
Secondary	Change From Baseline in Systemic Vascular Resistance (SVR) at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 9, 12 and 24 Hour	The SVR was a calculated hemodynamic parameter and the calculation was done on the basis of the measured hemodynamic parameters. SVR was calculated by dividing (80*[MBP-MRAP]) and CO.	Baseline, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 9, 12 and 24 Hour	No
Secondary	Change From Baseline in Pulmonary Vascular Resistance (PVR) at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 9, 12, 15 and 24 Hour	The PVR (force that opposes the flow of blood through a vascular bed) was a calculated hemodynamic parameter and the calculation was done on the basis of the measured hemodynamic parameters. PVR was calculated by dividing (80*[MPAP-PCWP]) and CO.	Baseline, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 9, 12, 15 and 24 Hour	No
Secondary	Number of Participants With Dyspnea Symptoms Assessed by Borg Scale Score	Assessment of Dyspnea (difficult or labored breathing) was done using Borg scale. It is a 10-point scale where following scores stands for severity of dyspnea: 0=no breathlessness at all; 0.5=very very slight (just noticeable); 1=very slight; 2=slight; 3=moderate; 4=somewhat severe; 5=severe; 7=very severe breathlessness; 9=very very severe (almost maximum) and 10=maximum.	Baseline, 1 h and 24 h	No
Secondary	Number of Participants With Dyspnea Symptoms Assessed by Likert Scale Score	Assessment of Dyspnea was done using Likert scale. It is a 7-point scale where following scores stands for severity of dyspnea: 1=markedly better; 2=moderately better; 3=minimally better; 4=no change; 5=minimally worse; 6=moderately worse and 7= markedly worse	3, 6 and 24 hour	No
Secondary	Number of Participants With Orthopnea	Assessment of dyspnea was done by measuring percentage of participants showing presence or absence of orthopnea (it is the sensation of breathlessness in the recumbent position, relieved by sitting or standing) symptoms	Baseline, 1 and 24 hour	No
Secondary	Number of Participants With Oxygen Therapy	Assessment of dyspnea was done by measuring number of participants showing presence or absence of oxygen therapy.	Baseline,1 and 24 hour	No
Secondary	Assessment of Dyspnea Using Percutaneous Arterial Oxygen Saturation (SpO2)	Assessment of dyspnea was done by measuring SpO2 via pulse oximetry, by making the participant lye quietly in the post anesthesia care unit (PACU) and breathing room air (RA)	Baseline, 1, 2, 3, 6, 9, 12, 15 and 24 hour	No
Secondary	Assessment of Dyspnea Using Respiratory Rate	Assessment of dyspnea was done by measuring respiratory rate which is the number of times an organism breathes with the lungs (respiration) per unit time, usually per minute	Baseline, 1, 2, 3, 6, 9, 15 and 24 hour	No
Secondary	Urinary Volume	The urinary volume was measured because nesiritide has a diuretic effect. Measurement of hour urine was done in the observation period and treatment period. 1-hour urine before treatment initiation was measured in the observation period. In the treatment period, 1-hour urine for period 1 and 3-hour urine for period 2 was measured. Urinary volume was recorded for participants without urethral catheterization having spontaneous micturition when needed.	Baseline, 3 and 24 hour	No