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

Primary Purpose

Pulmonary Hypertension, COVID-19

Status
Withdrawn
Phase
Phase 1
Locations
Sweden
Study Type
Interventional
Intervention
Sodium chloride (placebo)
PDNO
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:

  1. Ability to understand and willing to sign an ICF.
  2. Male and female patients, age at least 18 years.
  3. Diagnosed with COVID-19 at admission to the ICU.
  4. Diagnosed with echocardiographic signs of pulmonary artery systolic pressure (PASP) >40 mmHg.

Exclusion Criteria:

  1. History of chronic PH, as judged by the Investigator at screening
  2. Known New York Heart Association (NYHA) Functional Class III or IV symptoms
  3. Left heart failure with ejection fraction (EF) < 35 %
  4. Acute coronary syndrome
  5. Body Mass Index (BMI) > 40 kg/m2
  6. Estimated glomerular filtration rate (eGFR) < 30 mL/min
  7. MetHb >3%
  8. PCO2 > 7
  9. 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
  10. Haemoglobin <80 g/dL
  11. Thrombocytopenia (platelet count <80000/mm3)
  12. Prothrombin time International ratio (INR) > 1.4
  13. Pregnancy, or a positive pregnancy test
  14. Ongoing daily treatment the last 3 days with non-steroidal anti-inflammatory drugs
  15. Known active malignancy within the past 3 years
  16. 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.
  17. History of any other clinically significant disease or disorder
  18. Participation in any interventional clinical study

Sites / Locations

  • Danderyd Hospital
  • Örebro University Hospital

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treatment with PDNO

Arm Description

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.

Outcomes

Primary Outcome Measures

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).

Secondary Outcome Measures

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)
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
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).
Time to obtain first negative upper respiratory tract sample in the SARS-CoV-2-rt-PCR assay
Change in troponin I/T and BNP/NT-proBNP
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

Full Information

First Posted
February 15, 2021
Last Updated
July 31, 2023
Sponsor
Attgeno AB
Collaborators
Vinnova
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1. Study Identification

Unique Protocol Identification Number
NCT04885491
Brief Title
A Study to Evaluate the Efficacy, Safety and Tolerability of PDNO Infusion in COVID-19 Patients With Acute Pulmonary Hypertension
Official Title
An Open-Label, Multicenter Study to Evaluate the Efficacy, Safety and Tolerability of PDNO (Nitrosooxypropanol) Infusion in COVID-19 Patients With Acute Pulmonary Hypertension
Study Type
Interventional

2. Study Status

Record Verification Date
July 2023
Overall Recruitment Status
Withdrawn
Why Stopped
Since the availability of vaccines, a drastic drop in number of patients with increased PAP was observed and when the WHO re-categorized the COVID-19 pandemic from PHEIC to an "established and ongoing health issue" the study was withdrawn.
Study Start Date
May 7, 2021 (Actual)
Primary Completion Date
April 30, 2023 (Actual)
Study Completion Date
April 30, 2023 (Actual)

3. Sponsor/Collaborators

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

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, 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).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Pulmonary Hypertension, COVID-19
Keywords
Acute Pulmonary Hypertension

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Model Description
Observational period with placebo treatment, followed by treatment with PDNO.
Masking
None (Open Label)
Allocation
N/A
Enrollment
0 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Treatment with PDNO
Arm Type
Experimental
Arm Description
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.
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)
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.
Primary Outcome Measure Information:
Title
Change in MPAP and calculated PVR measured with PAC, at target dose after up-titration and 10 minutes after steady state.
Description
Mean pulmonary arterial pressure (MPAP) and pulmonary vascular resistance (PVR), as measured with a pulmonary artery catheter (PAC).
Time Frame
During 24 hours
Secondary Outcome Measure Information:
Title
Safety and tolerability of PDNO in patients with COVID-19, as measured by incidence of treatment-emergent AEs, SAEs, and AESI.
Description
Treatment-emergent adverse events (AEs) Treatment-emergent serious AEs (SAEs) Treatment-emergent AEs of special interest (AESI)
Time Frame
Through study completion (i.e., Day 30)
Title
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.
Description
Treatment-emergent changes in vital signs (blood pressure, pulse, oxygen saturation, respiratory frequency, body temperature) Treatment-emergent electrocardiogram (ECG) abnormalities Treatment-emergent laboratory abnormalities
Time Frame
From baseline until Day 7
Title
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).
Time Frame
At Days 7, 14, 21, and 30.
Title
Time to obtain first negative upper respiratory tract sample in the SARS-CoV-2-rt-PCR assay
Time Frame
From Day 1 to Day 14
Title
Change in troponin I/T and BNP/NT-proBNP
Time Frame
From end of PDNO infusion to Day 7.
Title
Change in the ratio PVR/SVR
Description
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
Time Frame
During 24 hours
Other Pre-specified Outcome Measures:
Title
Levels of SARS-CoV-2 virus in plasma and sputum/tracheal secretion
Time Frame
From Day 1 to Day 2
Title
Collection of plasma for future analysis of biomarkers such as nitrite and nitrate in plasma (µM)
Time Frame
From Day 1 to Day 7

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 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
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
Danderyd Hospital
City
Danderyd
ZIP/Postal Code
182 88
Country
Sweden
Facility Name
Örebro University Hospital
City
Örebro
ZIP/Postal Code
701 85
Country
Sweden

12. IPD Sharing Statement

Plan to Share IPD
No

Learn more about this trial

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

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