The Effects of Nitric Oxide for Inhalation During Left Ventricular Assists Device (LVAD) Implantation

• Sponsor: Mallinckrodt (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00060840
• Collaborator: (none)
• Enrollment: 150
• Locations: 11
• Arms: 2
• Duration (Months): 60
• Patients Per Site: 13.6
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

The purpose of this study is to assess the utility of nitric oxide for inhalation during left ventricular assist device (LVAD) implantation following cardiopulmonary bypass (CPB). This is to be assessed by the number of patients in each treatment group meeting failure criteria within 24 hours on study drug, as defined by two or more of the following:

• Left ventricular flow rate index (LVFRI) ≤ 2.0 L/min/m^2

• Administration of ≥ 20 inotropic equivalents (IE)

• 10 µg/kg/min dopamine, dobutamine, enoximone or amrinone is equivalent to 10 IE

• 0.1 µg/kg/min epinephrine or norepinephrine is equivalent to 10 IE

• 1 µg/kg/min milrinone is equivalent to 15 IE

• 0.1 U/min vasopressin is equivalent to 10 IE

• Mean arterial pressure (MAP) ≤ 55 mmHg

• Central venous pressure (CVP) ≥ 16 mmHg

• Percent mixed venous oxygen saturation (SvO2) ≤ 55%

Or at least one of the following criteria:

• Failure to wean from cardiopulmonary bypass at least once due to hemodynamic failure. Re-initiation of cardiopulmonary bypass to correct bleeding or other technical issues will not be considere 'failure to wean'

• Death

Condition or Disease	Intervention/Treatment	Phase
Congestive Heart Failure	Drug: Nitric Oxide; Drug: Nitrogen	Phase 2

Detailed Description

40 ppm of either nitric oxide for inhalation or N2 (placebo) will be continuously administered to the patient starting at least 5 minutes prior to initiating the first weaning attempt from CPB and continue until the patient is either extubated, has reached failure criteria, or has been treated with study drug for 48 hours following discontinuation of CPB, whichever come first.

All patients will be monitored peri-operatively with a pulmonary arterial line, central venous line, and systemic arterial line. Baseline data collection by a designated clinical staff member will begin following induction of anesthesia and prior to skin incision. Following a successful wean from cardiopulmonary bypass, post-op data will be collected within 1 hour following end time of surgery. Data will then be collected at 6, 12, 18, 24, and 48 hours from post-op or until extubation, in which case weaning from study drug will begin.

Open label investigational nitric oxide for inhalation may be administered once a patient meets a minimum of two of the failure criteria or fails to wean at least once due to hemodynamic failure from cardiopulmonary bypass.

Study Design

• Study Type: Interventional
• Actual Enrollment: 150 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: The Effects of Nitric Oxide for Inhalation During Left Ventricular Assist Device (LVAD) Implantation
• Study Start Date: Jul 1, 2003
• Actual Primary Completion Date: Jun 1, 2008
• Actual Study Completion Date: Jul 1, 2008

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Inhaled Nitric Oxide Inhaled Nitric Oxide (iNO) at 40 parts per million (ppm)	Drug: Nitric Oxide; 40 ppm of Nitric Oxide continuously administered for 48 hours; Other Names: INOmax
Placebo Comparator: Nitrogen Nitrogen (N2) administered at 40 ppm.	Drug: Nitrogen; Nitrogen (N2) administered at 40 ppm for 48 hours

Outcome Measures

Primary Outcome Measures

1. The Number of Subjects With Left Ventricular Failure During Left Ventricular Assistance Device (LVAD) Placement After Cardio Pulmonary Bypass, as Determined by Failure Criteria, After Administration of Nitric Oxide. [28 days]

   Failure criteria used to measure outcome includes: Left ventricular flow rate index (LVFRI) ≤ 2.0 L/min/m^2 Administration of ≥ 20 inotropic equivalents (IE) Mean arterial pressure (MAP) ≤ 55 mm Hg Central venous pressure (CVP) ≥ 16 mm Hg Percentage of mixed venous oxygen saturation (SvO2) of ≤ 55% OR failure to wean from cardio pulmonary bypass (CPB) at least once due to hemodynamic failure or death.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion criteria:

• Scheduled to undergo their first LVAD implantation, (or at least 6 months after explanation of a previous LVAD).

• Has a pulmonary vascular resistance of at least 2.5 Wood units (200 dynes/sec.) in the 30 days prior to LVAD placement.

• Greater than 18 years of age.

• Signed IRB approved informed consent.

Exclusion criteria:

• Patients with congestive heart failure due to giant cell myocarditis or restrictive cardiomyopathy.

• Elective Biventricular Assist Device (BiVAD) surgery, or current support with a temporary BiVad.

• LVAD procedure expected to be done without cardiopulmonary bypass.

• Pregnancy (a negative pregnancy test must be documented prior to enrollment).

• Received nitric oxide by inhalation therapy within the past 24 hours.

• Investigational drugs that are expected to change systemic or pulmonary vascular resistance are not allowed.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Newark Beth Isreal Medical Center	Newark	New Jersey	United States	07112
2	Duke University Medical Center	Durham	North Carolina	United States	27710
3	University of Cincinnati	Cincinnati	Ohio	United States	45219
4	Cleveland Clinic Foundation	Cleveland	Ohio	United States	44195
5	Allegheny General Hospital	Pittsburgh	Pennsylvania	United States	15212
6	Baylor University Medical Center	Dallas	Texas	United States	75226
7	University of Texas/St. Paul Medical Center	Dallas	Texas	United States	75390
8	Texas Heart Institute	Houston	Texas	United States	20345
9	Herz-und Diabeteszentrum Nordrhein-Westfalen	Gergstrab	Bad Oeynhausen	Germany	32545
10	Deutsches Herfzzentrum Berlin	Augustenburger Platz	Berlin	Germany	13353
11	Harefield Hospital	Harefield	Middlesex	United Kingdom	UB96JH

Sponsors and Collaborators

• Mallinckrodt

Investigators

• Study Director: James Baldassarre, MD, Mallinckrodt

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Mallinckrodt
• ClinicalTrials.gov Identifier: NCT00060840
• Other Study ID Numbers: INOT 41
• First Posted: May 15, 2003
• Last Update Posted: Aug 22, 2016
• Last Verified: Jul 1, 2016

• Keywords provided by Mallinckrodt: Left Ventricular Assist Device Implantation; Progressive Left Ventricular Failure
• Additional relevant MeSH terms: Heart Failure; Nitric Oxide

Study Results

Participant Flow

Recruitment Details	There were 8 study medical centers that participated and enrolled subjects; 6 centers in the United States and 2 centers in Germany. There were 150 subjects enrolled in the study.

Arm/Group Title	Inhaled Nitric Oxide	Nitrogen
Arm/Group Description	Inhaled Nitric Oxide (iNO) administered through the INOvent delivery system to subjects at 40 parts per million (ppm) for up to 48 hours	Nitrogen (N2) administered through the INOvent delivery system to subjects at 40 ppm for up to 48 hours.
Period Title: Overall Study
STARTED	73	77
COMPLETED	69	68
NOT COMPLETED	4	9

Baseline Characteristics

Arm/Group Title	Inhaled Nitric Oxide	Nitrogen	Total
Arm/Group Description	Inhaled Nitric Oxide (iNO) administered through the INOvent delivery system to subjects at 40 parts per million (ppm) for up to 48 hours	Nitrogen (N2) administered through the INOvent delivery system to subjects at 40 ppm for up to 48 hours.	Total of all reporting groups
Overall Participants	73	77	150
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	73 100%	77 100%	150 100%
>=65 years	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	57.6 (9.75)	54.0 (11.95)	55.8 (11.04)
Sex: Female, Male (Count of Participants)
Female	9 12.3%	12 15.6%	21 14%
Male	64 87.7%	65 84.4%	129 86%
Region of Enrollment (participants) [Number]
United States	38 52.1%	42 54.5%	80 53.3%
Germany	35 47.9%	35 45.5%	70 46.7%

Outcome Measures

1. Primary Outcome

Title	The Number of Subjects With Left Ventricular Failure During Left Ventricular Assistance Device (LVAD) Placement After Cardio Pulmonary Bypass, as Determined by Failure Criteria, After Administration of Nitric Oxide.
Description	Failure criteria used to measure outcome includes: Left ventricular flow rate index (LVFRI) ≤ 2.0 L/min/m^2 Administration of ≥ 20 inotropic equivalents (IE) Mean arterial pressure (MAP) ≤ 55 mm Hg Central venous pressure (CVP) ≥ 16 mm Hg Percentage of mixed venous oxygen saturation (SvO2) of ≤ 55% OR failure to wean from cardio pulmonary bypass (CPB) at least once due to hemodynamic failure or death.
Time Frame	28 days

Outcome Measure Data

Analysis Population Description

The analysis was determined for intent-to-treat population.

Arm/Group Title	Inhaled Nitric Oxide	Nitrogen
Arm/Group Description	Inhaled Nitric Oxide (iNO) administered through the INOvent delivery system to subjects at 40 parts per million (ppm) for up to 48 hours	Nitrogen (N2) administered through the INOvent delivery system to subjects at 40 ppm for up to 48 hours.
Measure Participants	73	77
Number [Participants]	7 9.6%	12 15.6%

Adverse Events

Arm/Group Title	Inhaled Nitric Oxide		Nitrogen
Arm/Group Description	Inhaled Nitric Oxide (iNO) administered through the INOvent delivery system to subjects at 40 parts per million (ppm) for up to 48 hours		Nitrogen (N2) administered through the INOvent delivery system to subjects at 40 ppm for up to 48 hours.
All Cause Mortality
	Inhaled Nitric Oxide		Nitrogen
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Inhaled Nitric Oxide		Nitrogen
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	7/73 (9.6%)		11/77 (14.3%)
Blood and lymphatic system disorders
Thrombocytopenia	0/73 (0%)	0	1/77 (1.3%)	1
Cardiac disorders
Right Ventricular Failure	3/73 (4.1%)	3	3/77 (3.9%)	3
Injury, poisoning and procedural complications
Postprocedural hemorrhage	2/73 (2.7%)	2	3/77 (3.9%)	3
Haemothorax	0/73 (0%)	0	1/77 (1.3%)	1
Procedural Complication	1/73 (1.4%)	1	0/77 (0%)	0
Vascular disorders
Hemorrhage	1/73 (1.4%)	1	3/77 (3.9%)	3
Other (Not Including Serious) Adverse Events
	Inhaled Nitric Oxide		Nitrogen
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	14/73 (19.2%)		6/77 (7.8%)
Blood and lymphatic system disorders
Haemorrhagic Anaemia	0/73 (0%)	0	1/77 (1.3%)	1
Anaemia	1/73 (1.4%)	1	0/77 (0%)	0
Coagulopathy	1/73 (1.4%)	1	0/77 (0%)	0
Cardiac disorders
Atrial Fibrillation	1/73 (1.4%)	1	0/77 (0%)	0
Right Ventricular Dysfunction	0/73 (0%)	0	1/77 (1.3%)	1
Supraventricular Tachycardia	1/73 (1.4%)	1	0/77 (0%)	0
Ventricular Tachycardia	0/73 (0%)	0	1/77 (1.3%)	1
General disorders
Hypothermia	1/73 (1.4%)	1	0/77 (0%)	0
Pyrexia	1/73 (1.4%)	1	0/77 (0%)	0
Injury, poisoning and procedural complications
Pharyngeal Injury	0/73 (0%)	0	1/77 (1.3%)	1
Investigations
Central Venous Pressure Decreased	1/73 (1.4%)	1	0/77 (0%)	0
Alanine Aminotransferase Increased	1/73 (1.4%)	1	0/77 (0%)	0
Aspartate Aminotransferase Abnormal	1/73 (1.4%)	1	0/77 (0%)	0
Metabolism and nutrition disorders
Hyperglycaemia	1/73 (1.4%)	1	0/77 (0%)	0
Hypocalcaemia	1/73 (1.4%)	1	0/77 (0%)	0
Nervous system disorders
Cerebrovascular Accident	0/73 (0%)	0	1/77 (1.3%)	1
Renal and urinary disorders
Renal Failure Acute	1/73 (1.4%)	1	0/77 (0%)	0
Respiratory, thoracic and mediastinal disorders
Respiratory Disorder	0/73 (0%)	0	1/77 (1.3%)	1
Vascular disorders
Hypotension	1/73 (1.4%)	1	0/77 (0%)	0
Haemodynamic Instability	1/73 (1.4%)	1	0/77 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.