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

NCT05699486 | Unknown Phase 2 DMC

• 2 other identifiers: 2021-PDNO-0032021-005032-30
• Study Type: interventional
• Target: 12
• Locations: 1 country
• Sites: 2

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

Keywords

Acute pulmonary hypertension

Outcome Measures

Primary Outcomes (1)

• Mean change in pulmonary vascular resistance (PVR)

  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.

  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 (9)

• 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.

• 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.

• 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.

Other Outcomes (2)

• 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).

• 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).

Study Arms (1)

Treatment with PDNO (placebo during baseline and washout observation periods before & after PDNO)

EXPERIMENTAL

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.

Drug: PDNO; Drug: Sodium chloride (placebo)

Interventions

PDNO 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.

Also known as: Nitrosooxypropanol

Treatment with PDNO (placebo during baseline and washout observation periods before & after PDNO)

Sodium chloride (placebo) DRUG

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

Also known as: NaCl

Treatment with PDNO (placebo during baseline and washout observation periods before & after PDNO)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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)

You may not qualify if:

• 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

Sponsors & Collaborators

• Attgeno AB: lead
• Aurevia: collaborator

Study Sites (2)

Sahlgrenska University Hospital, Anaesthesiology and Intensive Care

Gothenburg, SE-413 45, Sweden

RECRUITING

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

Örebro, SE-701 85, Sweden

RECRUITING

MeSH Terms

Conditions

Hypertension, Pulmonary

Interventions

1-(nitrosooxy)propan-2-ol and 2-(nitrosooxy)propan-1-ol drug combination; Sodium Chloride

Condition Hierarchy (Ancestors)

Lung Diseases; Respiratory Tract Diseases; Hypertension; Vascular Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Chlorides; Hydrochloric Acid; Chlorine Compounds; Inorganic Chemicals; Sodium Compounds

Study Officials

• Cecilia Kemi, PhD

  Attgeno AB

  STUDY DIRECTOR

Central Study Contacts

Christofer Adding, MD/PhD

CONTACT

+46 (0) 70 788 67 66; christofer.adding@attgeno.com

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 19, 2022
• First Posted: January 26, 2023
• Study Start: October 23, 2022
• Primary Completion: December 31, 2023
• Study Completion: December 31, 2023
• Last Updated: August 1, 2023

Record last verified: 2023-07

Data Sharing

• IPD Sharing: Will not share

Locations

SE (2)