An Open-Label, Multicenter Study To Evaluate the Dose, Efficacy, Safety and Tolerability of PDNO (Nitrosooxypropanol) Infusion in Patients With Pulmonary Hypertension After Cardiopulmonary Bypass (CPB) Surgery for Coronary Artery Bypass Grafting (CABG) or Mitral or Aortic Valve Repair or Replacement With or Without CABG
Overview
- Phase
- Phase 2
- Intervention
- PDNO
- Conditions
- Pulmonary Hypertension
- Sponsor
- Attgeno AB
- Enrollment
- 12
- Locations
- 2
- Primary Endpoint
- Mean change in pulmonary vascular resistance (PVR)
- Status
- Recruiting
- Last Updated
- 2 years ago
Overview
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).
Investigators
Eligibility Criteria
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
Arms & Interventions
Treatment with PDNO (placebo during baseline and washout observation periods before & after PDNO)
PDNO will be administered as an incremental intravenous infusion of respectively 15 minutes with the planned dosage: 3, 10, 30, 45 and 60 nmol/kg/min. If no effect on MPAP/PVR is seen at 60 nmol/kg/min in the first patients treated, further dose escalation up to 120 nmol/kg/min is possible, if recommended by the Internal Safety Review Committe (iSRC) following careful review of collected safety data. The iSRC will in any case review all collected data after 4, 8 and 12 patients (if applicable also after 16 and 20 patients). PDNO is administered together with a carrier buffer (NaHCO3-) flow into a central venous catheter. Placebo (NaCl, commercially available dilution solution for parenteral use, 9 mg/mL) will be administered during the baseline and washout observation periods before and after start of IMP infusion.
Intervention: PDNO
Treatment with PDNO (placebo during baseline and washout observation periods before & after PDNO)
PDNO will be administered as an incremental intravenous infusion of respectively 15 minutes with the planned dosage: 3, 10, 30, 45 and 60 nmol/kg/min. If no effect on MPAP/PVR is seen at 60 nmol/kg/min in the first patients treated, further dose escalation up to 120 nmol/kg/min is possible, if recommended by the Internal Safety Review Committe (iSRC) following careful review of collected safety data. The iSRC will in any case review all collected data after 4, 8 and 12 patients (if applicable also after 16 and 20 patients). PDNO is administered together with a carrier buffer (NaHCO3-) flow into a central venous catheter. Placebo (NaCl, commercially available dilution solution for parenteral use, 9 mg/mL) will be administered during the baseline and washout observation periods before and after start of IMP infusion.
Intervention: Sodium chloride (placebo)
Outcomes
Primary Outcomes
Mean change in pulmonary vascular resistance (PVR)
Time Frame: 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 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.)
- 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.)
- 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.)
- 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).)
- 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.)
- 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.)
- 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).)
- 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).)
- 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).)