A Study to Evaluate the Efficacy, Safety and Tolerability of PDNO Infusion in COVID-19 Patients With Acute Pulmonary Hypertension

Study Overview
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Brief Summary
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This is an open-label, multicentre study evaluating the effect, safety and tolerability of the two regioisomers 1-(nitrosooxy)propan-2-ol and 2-(nitrosooxy)propan-1-ol (PDNO) infusion given to COVID-19 patients with acute pulmonary hypertension (aPH) and/or acute cor pulmonale (ACP).

Official Title
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An Open-Label, Multicenter Study to Evaluate the Efficacy, Safety and Tolerability of PDNO (Nitrosooxypropanol) Infusion in COVID-19 Patients With Acute Pulmonary Hypertension

Conditions
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Pulmonary Hypertension, COVID-19

Intervention / Treatment
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* Drug: Sodium chloride (placebo)
* Drug: PDNO


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Ability to understand and willing to sign an ICF Male and female patients at least 18 years of age Diagnosed with COVID-19 at admission to the ICU Diagnosed with echocardiographic signs of pulmonary artery systolic pressure (PASP) > 40 mmHg Exclusion Criteria: History of chronic pulmonary hypertension (PH), as judged by the Investigator at screening Known New York Heart Association (NYHA) Functional Class III or IV symptoms Left heart failure with ejection fraction (EF) < 35% Acute coronary syndrome Body Mass Index (BMI) > 45 kg/m^2 Estimated glomerular filtration rate (eGFR) < 30 mL/min MetHb > 3% PCO2 > 7 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) at screening Haemoglobin < 80 g/dL Thrombocytopenia (platelet count < 80000/mm^3) Prothrombin time International ratio (INR) > 1.4 Pregnancy, or a positive pregnancy test Ongoing daily treatment the last 3 days with non-steroidal anti-inflammatory drugs Known active malignancy within the past 3 years 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: Observational period with placebo treatment, followed by treatment with PDNO.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment with PDNO<br>Placebo treatment administered during the 120-minute observation period, followed by PDNO infusion. PDNO administered as an i.v. infusion of 5-15 minutes, respectively, for the increased planned dose titration steps: 3, 10 and thereafter steps of max 10 nmol/kg/min until the target effect on the mean pulmonary arterial pressure/pulmonary vascular resistance (MPAP/PVR) or a maximal dose of 120 nmol/kg/min is reached. After 4 patients have been treated, the internal safety review committee (iSRC) will decide if the start dose will be increased. The new start dose could be in the interval 1 to 5 nmol/kg/min. | Drug: Sodium chloride (placebo)<br>* Placebo (NaCl, commercially available dilution solution for parenteral use, 9 mg/mL)<br>* Other names: NaCl;Drug: PDNO<br>* 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.<br>* Other names: Nitrosooxypropanol;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in MPAP and calculated PVR measured with PAC, at target dose after up-titration and 10 minutes after steady state. | Mean pulmonary arterial pressure (MPAP) and pulmonary vascular resistance (PVR), as measured with a pulmonary artery catheter (PAC). | During 24 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and tolerability of PDNO in patients with COVID-19, as measured by incidence of treatment-emergent AEs, SAEs, and AESI. | Treatment-emergent adverse events (AEs) Treatment-emergent serious AEs (SAEs) Treatment-emergent AEs of special interest (AESI) | Through study completion (i.e., Day 30) | 
| Safety and tolerability of PDNO in patients with COVID-19, as measured by incidence of treatment-emergent changes in vital signs, ECG abnormalities, and laboratory abnormalities. | Treatment-emergent changes in vital signs (blood pressure, pulse, oxygen saturation, respiratory frequency, body temperature) Treatment-emergent electrocardiogram (ECG) abnormalities Treatment-emergent laboratory abnormalities | From baseline until Day 7 | 
| Number of participants with the following clinical outcome (dead, intubated at the intensive care unit [ICU], non-intubated at the ICU, discharged from ICU to other hospital care or discharged to home). |  | At Days 7, 14, 21, and 30. | 
| Time to obtain first negative upper respiratory tract sample in the SARS-CoV-2-rt-PCR assay |  | From Day 1 to Day 14 | 
| Change in troponin I/T and BNP/NT-proBNP |  | From end of PDNO infusion to Day 7. | 
| Change in the ratio PVR/SVR | Pulmonary vascular resistance (PVR) and systemic vascular resistance (SVR) will be calculated from the obtained values according to the following formulas: PVR= (mean pulmonary arterial pressure [MPAP] - pulmonary capillary wedge pressure [PCWP])/cardiac output (CO) SVR= (mean arterial pressure [MAP] - central venous pressure [CVP])/CO Ratio of PVR to SVR = PVR/SVR | During 24 hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Acute Pulmonary Hypertension