Clinical trial NCT05699486: A Study to Evaluate the Efficacy, Safety and Tolerability of PDNO Infusion in Patients With Pulmonary Hypertension After Cardiopulmonary Bypass Surgery
Official title: 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Pulmonary Hypertension
Keywords: Acute pulmonary hypertension
Lead sponsor: Attgeno AB
Sponsor class: INDUSTRY
Collaborators: name: Aurevia
First posted: 2023-01-26
Enrollment: 12
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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).


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
* 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

Primary outcomes:
measure: Mean change in pulmonary vascular resistance (PVR)
timeFrame: 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.
Secondary outcomes:
measure: Mean change in the pulmonary vascular resistance/systemic vascular resistance ratio (PVR/SVR ratio)
timeFrame: 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.
measure: Mean change in fractional area change (FAC)
timeFrame: 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.
measure: Mean change in tricuspidannular plane systolic excursion (TAPSE)
timeFrame: 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.
measure: Mean change in right ventricular (RV) free wall strain
timeFrame: 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.
measure: Safety and tolerability of PDNO in patients undergoing Cardiopulmonary Bypass (CPB) surgery
timeFrame: 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.
measure: Exposure parameters for 1,2-propanediol (PD): estimated area under the curve from time 0 to time t (AUC0-t)
timeFrame: Assessments at time points T0 (-15 minutes; placebo), T6 (75 minutes; PDNO), and T8 (95 minutes; placebo).
measure: Exposure parameters for 1,2-propanediol (PD): estimated area under the curve from time 0 to infinity (AUC0-inf)
timeFrame: Assessments at time points T0 (-15 minutes; placebo), T6 (75 minutes; PDNO), and T8 (95 minutes; placebo).
measure: Exposure parameters for 1,2-propanediol (PD): maximum plasma concentration (Cmax)
timeFrame: Assessments at time points T0 (-15 minutes; placebo), T6 (75 minutes; PDNO), and T8 (95 minutes; placebo).
measure: Exposure parameters for 1,2-propanediol (PD): estimated elimination half life (t½)
timeFrame: Assessments at time points T0 (-15 minutes; placebo), T6 (75 minutes; PDNO), and T8 (95 minutes; placebo).
Other outcomes:
measure: Assess the levels of the following biomarkers: nitrite and nitrate in plasma (µM)
timeFrame: Change from baseline T0 (-15 minutes; placebo) to time point T6 (75 minutes; PDNO).
measure: Assess the levels of the following biomarkers: 1,2-propanediol (PD) metabolites in serum
timeFrame: Change from baseline T0 (-15 minutes; placebo) to time point T6 (75 minutes; PDNO).
Locations:
city: Gothenburg
country: Sweden
facility: Sahlgrenska University Hospital, Anaesthesiology and Intensive Care
city: Örebro
country: Sweden
facility: Örebro University Hospital, Vascular and Thoracic Department (Kärl-Thoraxkliniken)
Study officials:
affiliation: Attgeno AB
name: Cecilia Kemi, PhD
role: STUDY_DIRECTOR
References: