A Study to Evaluate the Efficacy, Safety and Tolerability of PDNO Infusion in Patients With Pulmonary Hypertension After Cardiopulmonary Bypass Surgery

• PDNO (Drug), also known as Nitrosooxypropanol: PDNO consists of propylene glycol (1,2-propanediol, PD) chemically combined with NO (to be donated). The drug substance is formulated as an inherent mixture of 4 structure analogues. The mixture consists of an equilibrium of the 2 regioisomers 1-(nitrosooxy) propan-2-ol and 2-(nitrosooxy) propan-1-ol. In addition, each regioisomer is a racemic mixture.
• Sodium chloride (placebo) (Drug), also known as NaCl: Placebo (NaCl, commercially available dilution solution for parenteral use, 9 mg/mL)

Primary outcomes

• Mean change in pulmonary vascular resistance (PVR) [From baseline (mean of -15 minutes and 0 minutes) to time point 15, 30, 45, 60, and 75 minutes with PDNO, respectively; and 85 and 95 minutes with placebo.]: PVR, will be derived as the mean pulmonary artery pressure (MPAP) - pulmonary capillary wedge pressure (PCWP) divided by cardiac output (CO), (PVR=(MPAP-PCWP)/CO), as measured with a pulmonary artery catheter (PAC) including thermodilution-determined cardiac output. Assessments will be done at the following timepoints: T0 (-15 minutes) and T1 (0 minutes) with placebo; T2 (15 minutes), T3 (30 minutes), T4 (45 minutes), T5 (60 minutes), and T6 (75 minutes) with 3, 10, 30, 45, 60 nmol/kg/min with PDNO, respectively; and T7 (85 minutes) and T8 (95 minutes) with placebo.

Secondary outcomes

• Mean change in the pulmonary vascular resistance/systemic vascular resistance ratio (PVR/SVR ratio) [From baseline (mean of -15 minutes and 0 minutes) to time point 15, 30, 45, 60, and 75 minutes with PDNO, respectively; and 85 and 95 minutes with placebo.]: PVR, will be derived as the mean pulmonary artery pressure (MPAP) - pulmonary capillary wedge pressure (PCWP) divided by cardiac output (CO), (PVR=(MPAP-PCWP)/CO), as measured with a pulmonary artery catheter (PAC) including thermodilution-determined cardiac output. SVR is determined from mean pulmonary artery pressure - central venous pressure divided by cardiac output (CO), (SVR=(MABP-CVP)/CO). Assessments will be done at the following timepoints: T0 (-15 minutes) and T1 (0 minutes) with placebo; T2 (15 minutes), T3 (30 minutes), T4 (45 minutes), T5 (60 minutes), and T6 (75 minutes) with 3, 10, 30, 45, 60 nmol/kg/min with PDNO, respectively; and T7 (85 minutes) and T8 (95 minutes) with placebo.
• Mean change in fractional area change (FAC) [From baseline (mean of -15 minutes and 0 minutes) to time point 15, 30, 45, 60, and 75 minutes with PDNO, respectively; and 85 and 95 minutes with placebo.]: Assessments will be done at the following timepoints: T0 (-15 minutes) and T1 (0 minutes) with placebo; T2 (15 minutes), T3 (30 minutes), T4 (45 minutes), T5 (60 minutes), and T6 (75 minutes) with 3, 10, 30, 45, 60 nmol/kg/min with PDNO, respectively; and T7 (85 minutes) and T8 (95 minutes) with placebo.
• Mean change in tricuspidannular plane systolic excursion (TAPSE) [From baseline (mean of -15 minutes and 0 minutes) to time point 15, 30, 45, 60, and 75 minutes with PDNO, respectively; and 85 and 95 minutes with placebo.]: Assessments will be done at the following timepoints: T0 (-15 minutes) and T1 (0 minutes) with placebo; T2 (15 minutes), T3 (30 minutes), T4 (45 minutes), T5 (60 minutes), and T6 (75 minutes) with 3, 10, 30, 45, 60 nmol/kg/min with PDNO, respectively; and T7 (85 minutes) and T8 (95 minutes) with placebo.
• Mean change in right ventricular (RV) free wall strain [From baseline (mean of -15 minutes and 0 minutes) to time point 15, 30, 45, 60, and 75 minutes with PDNO, respectively; and 85 and 95 minutes with placebo.]: Assessments will be done at the following timepoints: T0 (-15 minutes) and T1 (0 minutes) with placebo; T2 (15 minutes), T3 (30 minutes), T4 (45 minutes), T5 (60 minutes), and T6 (75 minutes) with 3, 10, 30, 45, 60 nmol/kg/min with PDNO, respectively; and T7 (85 minutes) and T8 (95 minutes) with placebo.
• Safety and tolerability of PDNO in patients undergoing Cardiopulmonary Bypass (CPB) surgery [Until study end (i.e., end of Day 1 [95 minutes]). All AEs (including SAEs) will be collected from the initiation of any study specific procedure, starting when postoperative preparatory preparations are performed on Day 1 and until the end of the study.]: Measured by incidence of: treatment-emergent adverse events (AEs), treatment-emergent serious AEs (SAEs), treatment-emergent AEs of special interest (AESI), treatment-emergent changes in vital signs (blood pressure, pulse, oxygen saturation, respiratory frequency, body temperature), treatment-emergent electrocardiogram (ECG) abnormalities, and treatment-emergent laboratory abnormalities.
• Exposure parameters for 1,2-propanediol (PD): estimated area under the curve from time 0 to time t (AUC0-t) [Assessments at time points T0 (-15 minutes; placebo), T6 (75 minutes; PDNO), and T8 (95 minutes; placebo).]: To assess the exposure of PD.
• Exposure parameters for 1,2-propanediol (PD): estimated area under the curve from time 0 to infinity (AUC0-inf) [Assessments at time points T0 (-15 minutes; placebo), T6 (75 minutes; PDNO), and T8 (95 minutes; placebo).]: To assess the exposure of PD.
• Exposure parameters for 1,2-propanediol (PD): maximum plasma concentration (Cmax) [Assessments at time points T0 (-15 minutes; placebo), T6 (75 minutes; PDNO), and T8 (95 minutes; placebo).]: To assess the exposure of PD.
• Exposure parameters for 1,2-propanediol (PD): estimated elimination half life (t½) [Assessments at time points T0 (-15 minutes; placebo), T6 (75 minutes; PDNO), and T8 (95 minutes; placebo).]: To assess the exposure of PD.

Other outcomes

• Assess the levels of the following biomarkers: nitrite and nitrate in plasma (µM) [Change from baseline T0 (-15 minutes; placebo) to time point T6 (75 minutes; PDNO).]: Explore potential biomarkers.
• Assess the levels of the following biomarkers: 1,2-propanediol (PD) metabolites in serum [Change from baseline T0 (-15 minutes; placebo) to time point T6 (75 minutes; PDNO).]: Explore PD metabolites.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* Ability to understand and willing to sign an informed consent form (ICF)
* Male and female patients, age ≥ 18 years
* Planned to undergo elective cardiopulmonary bypass (CPB) for coronary artery bypass grafting (CABG), aortic valve repair (AVR) or mitral valve repair (MVR) with or without CABG
* Diagnosed with echocardiographic signs of pulmonary artery systolic pressure (PASP) >50 mmHg , as estimated by doppler defined echocardiography using a modified Bernoulli equation: PASP ≈ 4 (tricuspid regurgitant jet velocity)\^2 + central venous pressure (CVP)

Exclusion Criteria:

* History of chronic pulmonary hypertension (PH) (WHO group 1, 3, 4 or 5), not group 2 due to left heart disease
* Patients with contraindications for pulmonary artery catheter (PAC)
* History of severe chronic obstructive pulmonary disease
* Left heart failure with ejection fraction (EF) <35%
* Non-ST elevation myocardial infarction (non-STEMI) or ST elevation myocardial infarction (STEMI) within 1 months prior to informed consent
* Stroke (cerebrovascular lesion \[CVL\]), transient ischemic attack (TIA), AV block III within 3 months prior to informed consent or QTcF >450ms at the time of screening
* High inotropic requirement (no more than one inotrope treatment and the vasopressor norepinephrine at time of screening/postoperative evaluation)
* (Increased) mediastinal bleeding >100 mL/hour in mediastinal drainage at postoperative evaluation
* Mechanical circulatory assistance (intra aortic balloon pump \[IABP\] or right/left-ventricular assist device \[R/L VAD\])
* Echocardiographic evidence of significant tricuspid insufficiency
* Body Mass Index (BMI) >40 kg/m\^2
* Estimated glomerular filtration rate (eGFR) < 30 mL/min preoperative value
* Methemoglobin >3%
* Indication of liver disease, defined by serum levels of either alanine aminotransferase (ALT), aspartate aminotransferase (AST) or alkaline phosphatase (ALP) above 3 x upper limit of normal (ULN) (preoperative value)
* Preoperative haemoglobin <10 g/dL, postoperative: Hb < 9 g/dL
* Thrombocytopenia (platelet count <100,000/mm\^3), preoperative value
* Prothrombin time International ratio (INR) > 1.3, preoperative value
* Pregnant or lactating women, or with a positive pregnancy test at screening (for fertile women only)
* Ongoing daily treatment the last 3 days with non-steroidal anti-inflammatory drugs (NSAIDs, excluding low dose, i.e. 75 mg, acetylsalicylic acid), new oral anticoagulants (NOACs), warfarin, heparin, clopidogrel (last 5 days). Low molecular weight heparin (LMWH) is not an exclusion criterion. Any use of PDE5 inhibitors (sildenafil, tadalafil, vardenafil and avanafil) within 48 hours prior to the administration of PDNO.
* Known active malignancy within the past 3 years except for localized prostate cancer, cervical carcinoma in situ, breast cancer in situ, or nonmelanoma skin cancer that has been definitively treated
* History of allergy/hypersensitivity to PD or ongoing allergy/hypersensitivity or history of hypersensitivity to drugs with a similar chemical structure or class to PDNO
* History of any other clinically significant disease or disorder
* Participation in any interventional clinical study or has been treated with any investigational research products within 30 days or 5 half-lives, whichever is longer, prior to the initiation of screening

• Cecilia Kemi, PhD, Study director, Attgeno AB