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

Primary Purpose

Pulmonary Hypertension

Status
Recruiting
Phase
Phase 2
Locations
Sweden
Study Type
Interventional
Intervention
PDNO
Sodium chloride (placebo)
Sponsored by
Attgeno AB
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Pulmonary Hypertension focused on measuring Acute pulmonary hypertension

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Sahlgrenska University Hospital, Anaesthesiology and Intensive CareRecruiting
  • Örebro University Hospital, Vascular and Thoracic Department (Kärl-Thoraxkliniken)Recruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

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

Arm Description

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.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

Mean change in the pulmonary vascular resistance/systemic vascular resistance ratio (PVR/SVR ratio)
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)
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)
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
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
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): estimated area under the curve from time 0 to time t (AUC0-t)
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)
To assess the exposure of PD.
Exposure parameters for 1,2-propanediol (PD): maximum plasma concentration (Cmax)
To assess the exposure of PD.
Exposure parameters for 1,2-propanediol (PD): estimated elimination half life (t½)
To assess the exposure of PD.

Full Information

First Posted
December 19, 2022
Last Updated
July 31, 2023
Sponsor
Attgeno AB
Collaborators
Scandinavian CRO AB
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1. Study Identification

Unique Protocol Identification Number
NCT05699486
Brief Title
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

2. Study Status

Record Verification Date
July 2023
Overall Recruitment Status
Recruiting
Study Start Date
October 23, 2022 (Actual)
Primary Completion Date
December 31, 2023 (Anticipated)
Study Completion Date
December 31, 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Attgeno AB
Collaborators
Scandinavian CRO AB

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

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).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Pulmonary Hypertension
Keywords
Acute pulmonary hypertension

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
12 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Treatment with PDNO (placebo during baseline and washout observation periods before & after PDNO)
Arm Type
Experimental
Arm Description
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 Type
Drug
Intervention Name(s)
PDNO
Other Intervention Name(s)
Nitrosooxypropanol
Intervention Description
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
Intervention Name(s)
Sodium chloride (placebo)
Other Intervention Name(s)
NaCl
Intervention Description
Placebo (NaCl, commercially available dilution solution for parenteral use, 9 mg/mL)
Primary Outcome Measure Information:
Title
Mean change in pulmonary vascular resistance (PVR)
Description
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.
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.
Secondary Outcome Measure Information:
Title
Mean change in the pulmonary vascular resistance/systemic vascular resistance ratio (PVR/SVR ratio)
Description
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.
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.
Title
Mean change in fractional area change (FAC)
Description
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.
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.
Title
Mean change in tricuspidannular plane systolic excursion (TAPSE)
Description
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.
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.
Title
Mean change in right ventricular (RV) free wall strain
Description
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.
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.
Title
Safety and tolerability of PDNO in patients undergoing Cardiopulmonary Bypass (CPB) surgery
Description
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.
Time Frame
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.
Title
Exposure parameters for 1,2-propanediol (PD): estimated area under the curve from time 0 to time t (AUC0-t)
Description
To assess the exposure of PD.
Time Frame
Assessments at time points T0 (-15 minutes; placebo), T6 (75 minutes; PDNO), and T8 (95 minutes; placebo).
Title
Exposure parameters for 1,2-propanediol (PD): estimated area under the curve from time 0 to infinity (AUC0-inf)
Description
To assess the exposure of PD.
Time Frame
Assessments at time points T0 (-15 minutes; placebo), T6 (75 minutes; PDNO), and T8 (95 minutes; placebo).
Title
Exposure parameters for 1,2-propanediol (PD): maximum plasma concentration (Cmax)
Description
To assess the exposure of PD.
Time Frame
Assessments at time points T0 (-15 minutes; placebo), T6 (75 minutes; PDNO), and T8 (95 minutes; placebo).
Title
Exposure parameters for 1,2-propanediol (PD): estimated elimination half life (t½)
Description
To assess the exposure of PD.
Time Frame
Assessments at time points T0 (-15 minutes; placebo), T6 (75 minutes; PDNO), and T8 (95 minutes; placebo).
Other Pre-specified Outcome Measures:
Title
Assess the levels of the following biomarkers: nitrite and nitrate in plasma (µM)
Description
Explore potential biomarkers.
Time Frame
Change from baseline T0 (-15 minutes; placebo) to time point T6 (75 minutes; PDNO).
Title
Assess the levels of the following biomarkers: 1,2-propanediol (PD) metabolites in serum
Description
Explore PD metabolites.
Time Frame
Change from baseline T0 (-15 minutes; placebo) to time point T6 (75 minutes; PDNO).

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Christofer Adding, MD/PhD
Phone
+46 (0) 70 788 67 66
Email
christofer.adding@attgeno.com
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Cecilia Kemi, PhD
Organizational Affiliation
Attgeno AB
Official's Role
Study Director
Facility Information:
Facility Name
Sahlgrenska University Hospital, Anaesthesiology and Intensive Care
City
Gothenburg
ZIP/Postal Code
SE-413 45
Country
Sweden
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Sven-Erik Ricksten, MD
Facility Name
Örebro University Hospital, Vascular and Thoracic Department (Kärl-Thoraxkliniken)
City
Örebro
ZIP/Postal Code
SE-701 85
Country
Sweden
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Jenny Seilitz, MD

12. IPD Sharing Statement

Plan to Share IPD
No

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

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