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

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

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).

Study Overview

• Status: Withdrawn
• Conditions: COVID-19; Pulmonary Hypertension
• Intervention / Treatment: Drug: Sodium chloride (placebo); Drug: PDNO

Detailed Description

This is an open-label, multicentre study to evaluate the efficacy, safety and tolerability of the two regio isomers 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). PDNO is developed to be used as part of peri- and post-operative pulmonary hypåertension (PH) treatment in adults in conjunction to heart surgery, to selectively decrease pulmonary arterial pressure and improve Right ventricular (RV) function and oxygenation. Current treatment options for aPH in patients with COVID-19 are limited. In addition to the hemodynamic effects, it is believed to be beneficial to use an iv-administered lung-selective Nitrogen Oxide (NO) donor that will more effectively reach affected areas in the lung and give maximal NO-exposure to the endothelium. The potential antiviral effects of NO, by inhibition of receptor binding and inhibition of earlystage virus replication, are also part of the rational to evaluate the benefits of using of PDNO in COVID-19 patients.

• Study Type: Interventional
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Christofer Adding, MD/PhD; Phone Number: +46 (0) 70 788 67 66; Email: christofer.adding@attgeno.com

Study Locations

• Sweden
  • Danderyd, Sweden, 182 88
    • Danderyd Hospital
  • Örebro, Sweden, 701 85
    • Orebro University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Treatment with PDNO; 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); Placebo (NaCl, commercially available dilution solution for parenteral use, 9 mg/mL); Other Names: NaCl; Drug: 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.; Other Names: Nitrosooxypropanol

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Time Frame
Levels of SARS-CoV-2 virus in plasma and sputum/tracheal secretion	From Day 1 to Day 2
Collection of plasma for future analysis of biomarkers such as nitrite and nitrate in plasma (µM)	From Day 1 to Day 7

Collaborators and Investigators

• Sponsor: Attgeno AB
• Collaborators: Vinnova
• Investigators: Study Director: Cecilia Kemi, PhD, Attgeno AB

Study record dates

Study Major Dates

• Study Start (Actual): May 7, 2021
• Primary Completion (Actual): April 30, 2023
• Study Completion (Actual): April 30, 2023

Study Registration Dates

• First Submitted: February 15, 2021
• First Submitted That Met QC Criteria: May 12, 2021
• First Posted (Actual): May 13, 2021

Study Record Updates

• Last Update Posted (Actual): August 1, 2023
• Last Update Submitted That Met QC Criteria: July 31, 2023
• Last Verified: July 1, 2023

More Information

Terms related to this study

• Keywords: Acute Pulmonary Hypertension
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; COVID-19; Hypertension; Hypertension, Pulmonary
• Other Study ID Numbers: 2020-PDNO-002

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No