Pulmonary Hypertension
Conditions
Keywords
Acute pulmonary hypertension
Brief summary
This is an open-label, multicenter study evaluating the dose, effect, safety and tolerability of intravenous PDNO infusion given to patients undergoing cardiopulmonary bypass (CPB) surgery with post-operative acute pulmonary hypertension (aPH).
Interventions
DRUGPDNO
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.
Placebo (NaCl, commercially available dilution solution for parenteral use, 9 mg/mL)
Sponsors
Aurevia
Attgeno AB
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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): 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. |
| 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. |
Other
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
Sweden
Contacts
Primary ContactChristofer Adding, MD/PhD
Outcome results
None listed