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

NCT ID: NCT05699486

Last Updated: 2023-08-01

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: PHASE2
• Total Enrollment: 12 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2022-10-23
• Study Completion Date: 2023-12-31

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).

Conditions

Pulmonary Hypertension

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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.

Group Type: EXPERIMENTAL

PDNO

Intervention Type: DRUG

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)

Intervention Type: DRUG

Placebo (NaCl, commercially available dilution solution for parenteral use, 9 mg/mL)

Interventions

PDNO

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.

Intervention Type: DRUG

Sodium chloride (placebo)

Placebo (NaCl, commercially available dilution solution for parenteral use, 9 mg/mL)

Intervention Type: DRUG

Other Intervention Names

Nitrosooxypropanol; NaCl

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Aurevia

INDUSTRY

Sponsor Role: collaborator

Attgeno AB

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Cecilia Kemi, PhD

Role: STUDY_DIRECTOR

Attgeno AB

Locations

Sahlgrenska University Hospital, Anaesthesiology and Intensive Care

Gothenburg, , Sweden

Site Status: RECRUITING

Örebro University Hospital, Vascular and Thoracic Department (Kärl-Thoraxkliniken)

Örebro, , Sweden

Site Status: RECRUITING

Countries

Sweden

Central Contacts

Christofer Adding, MD/PhD

Role: CONTACT

christofer.adding@attgeno.com

+46 (0) 70 788 67 66

Facility Contacts

Sven-Erik Ricksten, MD

Role: primary

Jenny Seilitz, MD

Role: primary

Other Identifiers

2021-005032-30

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

2021-PDNO-003

Identifier Type: -

Identifier Source: org_study_id