Trial Outcomes & Findings for The Effects of Intravenous Heme Arginate on Heme Oxygenase-1 Expression (HO-1) and Oxidative Stress in the Human Heart (NCT NCT02314780)

NCT ID: NCT02314780

Last Updated: 2021-02-15

Results Overview

The right atrial appendage was clamped and cut for cannulation before cardiopulmonary bypass. The tissue samples were snap-frozen in the operating theater after sampling.

• Recruitment status: COMPLETED
• Study phase: PHASE2
• Target enrollment: 31 participants
• Primary outcome timeframe: intraoperative
• Results posted on: 2021-02-15

Participant Flow

Patients who were scheduled for elective surgical aortic valve replacement were assessed for eligibility after hospitalization at the Medical University of Vienna.

A total of 31 patients signed the informed consent to participate in the study. Of them, 27 patients were assigned to a group and 4 patients (3 patients for organizational reasons and 1 patient for other reasons) were excluded from the study prior to assignment to a group.

Participant milestones

Measure	Heme Arginate (High Dose) 24 hours prior to the planned surgical aortic valve replacement, heme arginate at a dose of 3 mg/kg diluted to 110ml with 0.9% sodium chloride was administered at a single intravenous infusion using an infusion pump.	Heme Arginate (Low Dose) 24 hours prior to the planned surgical aortic valve replacement, heme arginate at a dose of 1 mg/kg diluted to 110ml with 0.9% sodium chloride was administered at a single intravenous infusion using an infusion pump.	Placebo 24 hours prior to the planned surgical aortic valve replacement, subjects received a single intravenous infusion of an equivalent volume of 0.9% sodium chloride solution.
Overall Study STARTED	9	10	8
Overall Study COMPLETED	9	7	8
Overall Study NOT COMPLETED	0	3	0

Reasons for withdrawal

Measure	Heme Arginate (High Dose) 24 hours prior to the planned surgical aortic valve replacement, heme arginate at a dose of 3 mg/kg diluted to 110ml with 0.9% sodium chloride was administered at a single intravenous infusion using an infusion pump.	Heme Arginate (Low Dose) 24 hours prior to the planned surgical aortic valve replacement, heme arginate at a dose of 1 mg/kg diluted to 110ml with 0.9% sodium chloride was administered at a single intravenous infusion using an infusion pump.	Placebo 24 hours prior to the planned surgical aortic valve replacement, subjects received a single intravenous infusion of an equivalent volume of 0.9% sodium chloride solution.
Overall Study organizational reasons	0	2	0
Overall Study Adverse Event	0	1	0

Baseline Characteristics

Race and Ethnicity were not collected from any participant.

Baseline characteristics by cohort

Measure	Heme Arginate (High Dose) n=9 Participants 24 hours prior to the planned surgical aortic valve replacement, heme arginate at a dose of 3 mg/kg diluted to 110ml with 0.9% sodium chloride was administered at a single intravenous infusion using an infusion pump.	Heme Arginate (Low Dose) n=10 Participants 24 hours prior to the planned surgical aortic valve replacement, heme arginate at a dose of 1 mg/kg diluted to 110ml with 0.9% sodium chloride was administered at a single intravenous infusion using an infusion pump.	Placebo n=8 Participants 24 hours prior to the planned surgical aortic valve replacement, subjects received a single intravenous infusion of an equivalent volume of 0.9% sodium chloride solution.	Total n=27 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=9 Participants	0 Participants n=10 Participants	0 Participants n=8 Participants	0 Participants n=27 Participants
Age, Categorical Between 18 and 65 years	2 Participants n=9 Participants	1 Participants n=10 Participants	3 Participants n=8 Participants	6 Participants n=27 Participants
Age, Categorical >=65 years	7 Participants n=9 Participants	9 Participants n=10 Participants	5 Participants n=8 Participants	21 Participants n=27 Participants
Sex: Female, Male Female	6 Participants n=9 Participants	5 Participants n=10 Participants	5 Participants n=8 Participants	16 Participants n=27 Participants
Sex: Female, Male Male	3 Participants n=9 Participants	5 Participants n=10 Participants	3 Participants n=8 Participants	11 Participants n=27 Participants
Race and Ethnicity Not Collected	—	—	—	0 Participants Race and Ethnicity were not collected from any participant.
Region of Enrollment Austria	9 participants n=9 Participants	10 participants n=10 Participants	8 participants n=8 Participants	27 participants n=27 Participants

PRIMARY outcome

Timeframe: intraoperative

The right atrial appendage was clamped and cut for cannulation before cardiopulmonary bypass. The tissue samples were snap-frozen in the operating theater after sampling.

Outcome measures

Measure	Heme Arginate (High Dose) n=9 Participants 24 hours prior to the planned surgical aortic valve replacement, heme arginate at a dose of 3 mg/kg diluted to 110ml with 0.9% sodium chloride was administered at a single intravenous infusion using an infusion pump.	Heme Arginate (Low Dose) n=7 Participants 24 hours prior to the planned surgical aortic valve replacement, heme arginate at a dose of 1 mg/kg diluted to 110ml with 0.9% sodium chloride was administered at a single intravenous infusion using an infusion pump.	Placebo n=8 Participants 24 hours prior to the planned surgical aortic valve replacement, subjects received a single intravenous infusion of an equivalent volume of 0.9% sodium chloride solution.
Heme Oxygenase-1 (HO-1) Messenger Ribonucleic Acid (mRNA) Levels (Atrial Tissue)	392.7 arbitrary units Standard Deviation 195.7	229.8 arbitrary units Standard Deviation 173.1	10.8 arbitrary units Standard Deviation 8.8

PRIMARY outcome

Timeframe: intraoperative

A small biopsy was taken from the right ventricular free wall directly before aortic cross-clamping. The tissue samples were snap-frozen in the operating theater after sampling.

Outcome measures

Measure	Heme Arginate (High Dose) n=9 Participants 24 hours prior to the planned surgical aortic valve replacement, heme arginate at a dose of 3 mg/kg diluted to 110ml with 0.9% sodium chloride was administered at a single intravenous infusion using an infusion pump.	Heme Arginate (Low Dose) n=7 Participants 24 hours prior to the planned surgical aortic valve replacement, heme arginate at a dose of 1 mg/kg diluted to 110ml with 0.9% sodium chloride was administered at a single intravenous infusion using an infusion pump.	Placebo n=8 Participants 24 hours prior to the planned surgical aortic valve replacement, subjects received a single intravenous infusion of an equivalent volume of 0.9% sodium chloride solution.
Myocardial HO-1 mRNA Levels (Ventricular Tissue Before Aortic Cross-clamping)	203.6 arbitrary units Standard Deviation 148.7	88.6 arbitrary units Standard Deviation 49.1	7.9 arbitrary units Standard Deviation 5.0

PRIMARY outcome

Timeframe: intraoperative

A small biopsy was taken from the right ventricular free wall after aortic clamp release before weaning from cardiopulmonary bypass. The tissue samples were snap-frozen in the operating theater after sampling.

Outcome measures

Measure	Heme Arginate (High Dose) n=9 Participants 24 hours prior to the planned surgical aortic valve replacement, heme arginate at a dose of 3 mg/kg diluted to 110ml with 0.9% sodium chloride was administered at a single intravenous infusion using an infusion pump.	Heme Arginate (Low Dose) n=7 Participants 24 hours prior to the planned surgical aortic valve replacement, heme arginate at a dose of 1 mg/kg diluted to 110ml with 0.9% sodium chloride was administered at a single intravenous infusion using an infusion pump.	Placebo n=8 Participants 24 hours prior to the planned surgical aortic valve replacement, subjects received a single intravenous infusion of an equivalent volume of 0.9% sodium chloride solution.
Myocardial HO-1 mRNA Levels (Ventricular Tissue After Aortic Cross-clamping)	219.4 arbitrary units Standard Deviation 162.8	108.1 arbitrary units Standard Deviation 73.2	8.3 arbitrary units Standard Deviation 5.4

PRIMARY outcome

Timeframe: intraoperative

The right atrial appendage was clamped and cut for cannulation before cardiopulmonary bypass.The tissue samples were snap-frozen. Western blot analysis was performed. The amount of HO-1 protein (quantified as pixels under the curve) was evaluated.

Outcome measures

Measure	Heme Arginate (High Dose) n=9 Participants 24 hours prior to the planned surgical aortic valve replacement, heme arginate at a dose of 3 mg/kg diluted to 110ml with 0.9% sodium chloride was administered at a single intravenous infusion using an infusion pump.	Heme Arginate (Low Dose) n=7 Participants 24 hours prior to the planned surgical aortic valve replacement, heme arginate at a dose of 1 mg/kg diluted to 110ml with 0.9% sodium chloride was administered at a single intravenous infusion using an infusion pump.	Placebo n=8 Participants 24 hours prior to the planned surgical aortic valve replacement, subjects received a single intravenous infusion of an equivalent volume of 0.9% sodium chloride solution.
Myocardial HO-1 Protein Concentrations (Atrial Tissue)	29022 pixels under the curve Standard Deviation 8583	28585 pixels under the curve Standard Deviation 10692	8401 pixels under the curve Standard Deviation 3889

PRIMARY outcome

Timeframe: intraoperative

A small biopsy was taken from the right ventricular free wall directly before aortic cross-clamping. The tissue samples were snap-frozen. Western blot analysis was performed. The amount of HO-1 protein (quantified as pixels under the curve) was evaluated.

Outcome measures

Measure	Heme Arginate (High Dose) n=9 Participants 24 hours prior to the planned surgical aortic valve replacement, heme arginate at a dose of 3 mg/kg diluted to 110ml with 0.9% sodium chloride was administered at a single intravenous infusion using an infusion pump.	Heme Arginate (Low Dose) n=7 Participants 24 hours prior to the planned surgical aortic valve replacement, heme arginate at a dose of 1 mg/kg diluted to 110ml with 0.9% sodium chloride was administered at a single intravenous infusion using an infusion pump.	Placebo n=8 Participants 24 hours prior to the planned surgical aortic valve replacement, subjects received a single intravenous infusion of an equivalent volume of 0.9% sodium chloride solution.
Myocardial HO-1 Protein Concentrations (Ventricular Tissue Before Aortic Cross-clamping)	13752 pixels under the curve Standard Deviation 8069	10534 pixels under the curve Standard Deviation 4686	6842 pixels under the curve Standard Deviation 4343

PRIMARY outcome

Timeframe: intraoperative

A small biopsy was taken from the right ventricular free wall after aortic clamp release before weaning from cardiopulmonary bypass. The tissue samples were snap-frozen in the operating theater after sampling. Western blot analysis was performed. The amount of HO-1 protein (quantified as pixels under the curve) was evaluated.

Outcome measures

Measure	Heme Arginate (High Dose) n=9 Participants 24 hours prior to the planned surgical aortic valve replacement, heme arginate at a dose of 3 mg/kg diluted to 110ml with 0.9% sodium chloride was administered at a single intravenous infusion using an infusion pump.	Heme Arginate (Low Dose) n=7 Participants 24 hours prior to the planned surgical aortic valve replacement, heme arginate at a dose of 1 mg/kg diluted to 110ml with 0.9% sodium chloride was administered at a single intravenous infusion using an infusion pump.	Placebo n=8 Participants 24 hours prior to the planned surgical aortic valve replacement, subjects received a single intravenous infusion of an equivalent volume of 0.9% sodium chloride solution.
Myocardial HO-1 Protein Concentrations (Ventricular Tissue After Aortic Cross-clamping)	17062 pixels under the curve Standard Deviation 18164	11277 pixels under the curve Standard Deviation 3918	12037 pixels under the curve Standard Deviation 10962

Adverse Events

Heme Arginate (High Dose)

Serious events: 2 serious events

Other events: 1 other events

Deaths: 0 deaths

Heme Arginate (Low Dose)

Serious events: 0 serious events

Other events: 5 other events

Deaths: 0 deaths

Placebo

Serious events: 1 serious events

Other events: 4 other events

Deaths: 0 deaths

Serious adverse events

Measure	Heme Arginate (High Dose) n=9 participants at risk 24 hours prior to the planned surgical aortic valve replacement, heme arginate at a dose of 3 mg/kg diluted to 110ml with 0.9% sodium chloride was administered at a single intravenous infusion using an infusion pump.	Heme Arginate (Low Dose) n=10 participants at risk 24 hours prior to the planned surgical aortic valve replacement, heme arginate at a dose of 1 mg/kg diluted to 110ml with 0.9% sodium chloride was administered at a single intravenous infusion using an infusion pump.	Placebo n=8 participants at risk 24 hours prior to the planned surgical aortic valve replacement, subjects received a single intravenous infusion of an equivalent volume of 0.9% sodium chloride solution.
Injury, poisoning and procedural complications Post procedural haemorrhage	0.00% 0/9 • Adverse events occuring within 96 hours after the administration of heme arginate/sodium chloride solution were reported.	0.00% 0/10 • Adverse events occuring within 96 hours after the administration of heme arginate/sodium chloride solution were reported.	12.5% 1/8 • Number of events 1 • Adverse events occuring within 96 hours after the administration of heme arginate/sodium chloride solution were reported.
Injury, poisoning and procedural complications Coronary artery compression	11.1% 1/9 • Number of events 1 • Adverse events occuring within 96 hours after the administration of heme arginate/sodium chloride solution were reported.	0.00% 0/10 • Adverse events occuring within 96 hours after the administration of heme arginate/sodium chloride solution were reported.	0.00% 0/8 • Adverse events occuring within 96 hours after the administration of heme arginate/sodium chloride solution were reported.
Cardiac disorders Atrioventricular block complete	11.1% 1/9 • Number of events 1 • Adverse events occuring within 96 hours after the administration of heme arginate/sodium chloride solution were reported.	0.00% 0/10 • Adverse events occuring within 96 hours after the administration of heme arginate/sodium chloride solution were reported.	0.00% 0/8 • Adverse events occuring within 96 hours after the administration of heme arginate/sodium chloride solution were reported.

Other adverse events

Measure	Heme Arginate (High Dose) n=9 participants at risk 24 hours prior to the planned surgical aortic valve replacement, heme arginate at a dose of 3 mg/kg diluted to 110ml with 0.9% sodium chloride was administered at a single intravenous infusion using an infusion pump.	Heme Arginate (Low Dose) n=10 participants at risk 24 hours prior to the planned surgical aortic valve replacement, heme arginate at a dose of 1 mg/kg diluted to 110ml with 0.9% sodium chloride was administered at a single intravenous infusion using an infusion pump.	Placebo n=8 participants at risk 24 hours prior to the planned surgical aortic valve replacement, subjects received a single intravenous infusion of an equivalent volume of 0.9% sodium chloride solution.
Injury, poisoning and procedural complications Procedural pneumothorax	0.00% 0/9 • Adverse events occuring within 96 hours after the administration of heme arginate/sodium chloride solution were reported.	10.0% 1/10 • Number of events 1 • Adverse events occuring within 96 hours after the administration of heme arginate/sodium chloride solution were reported.	0.00% 0/8 • Adverse events occuring within 96 hours after the administration of heme arginate/sodium chloride solution were reported.
Investigations Blood culture positive	0.00% 0/9 • Adverse events occuring within 96 hours after the administration of heme arginate/sodium chloride solution were reported.	0.00% 0/10 • Adverse events occuring within 96 hours after the administration of heme arginate/sodium chloride solution were reported.	12.5% 1/8 • Number of events 1 • Adverse events occuring within 96 hours after the administration of heme arginate/sodium chloride solution were reported.
Cardiac disorders Atrial fibrillation	11.1% 1/9 • Number of events 1 • Adverse events occuring within 96 hours after the administration of heme arginate/sodium chloride solution were reported.	30.0% 3/10 • Number of events 3 • Adverse events occuring within 96 hours after the administration of heme arginate/sodium chloride solution were reported.	37.5% 3/8 • Number of events 3 • Adverse events occuring within 96 hours after the administration of heme arginate/sodium chloride solution were reported.
Blood and lymphatic system disorders Heparin-induced thrombocytopenia	0.00% 0/9 • Adverse events occuring within 96 hours after the administration of heme arginate/sodium chloride solution were reported.	10.0% 1/10 • Number of events 1 • Adverse events occuring within 96 hours after the administration of heme arginate/sodium chloride solution were reported.	0.00% 0/8 • Adverse events occuring within 96 hours after the administration of heme arginate/sodium chloride solution were reported.
Psychiatric disorders Acute stress disorder	0.00% 0/9 • Adverse events occuring within 96 hours after the administration of heme arginate/sodium chloride solution were reported.	10.0% 1/10 • Number of events 1 • Adverse events occuring within 96 hours after the administration of heme arginate/sodium chloride solution were reported.	0.00% 0/8 • Adverse events occuring within 96 hours after the administration of heme arginate/sodium chloride solution were reported.

Additional Information

Dr. Martin Andreas

Medical University of Vienna

Phone: + 43 1 40400

Email: martin.andreas@meduniwien.ac.at

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place