E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Acute pulmonary hypertension during COVID-19 infection |
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E.1.1.1 | Medical condition in easily understood language |
Acute high blood pressure in the pulmonary circulation during COVID-19 infection |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | HLT |
E.1.2 | Classification code | 10037401 |
E.1.2 | Term | Pulmonary hypertensions |
E.1.2 | System Organ Class | 100000004855 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To evaluate the efficacy of PDNO on pulmonary vascular resistance (PVR) and mean pulmonary artery pressure (MPAP), as measured with a pulmonary artery catheter (PAC), in patients with Covid 19 and pulmonary hypertension (PH). |
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E.2.2 | Secondary objectives of the trial |
- To evaluate the safety and tolerability of PDNO in patients with COVID-19. - To evaluate general clinical outcome. - To decide the time to non-SARS-CoV-2 infection. - To evaluate the change in troponin I/T and BNP/NT-proBNP after 3 hours of PDNO dosing in patients with Covid-19 and PH. - To evaluate the efficacy of PDNO on the pulmonary resistance. Exploratory Objectives: - To explore potential biomarkers. - To assess presence of SARS-CoV-2 virus.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Ability to understand and willing to sign an informed consent form after information at the pre-screening visit. 2. Male and female patients, age at least 18 years on the date of the informed consent at the time of the pre-screening visit. 3. Diagnosed with COVID-19 at admission to the ICU and, at the ICU, sedated and intubated. 4. Diagnosed with echocardiographic signs of pulmonary artery systolic pressure (PASP) >40 mmHg, as estimated by doppler defined echocardiography using a modified Bernoulli equation: PASP ≈ 4 (tricuspid regurgitant jet velocity)2 + CVP. After insertion of the PAC, a MPAP ≥20 mmHg will allow continued participation and start of PDNO infusion. If MPAP is <20 mm Hg, the patient is considered a screen failure and may be replaced. |
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E.4 | Principal 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 (pre-Covid 19) at screening.* 3. Left heart failure with ejection fraction (EF) < 35 % at screening 4. Acute coronary syndrome (non ST elevation myocardial infarction [non-STEMI], ST elevation myocardial infarction [STEMI], unstable angina pectoris [AP]), myocardial infarction, stroke, transient ischemic attack (TIA), AV block III within 3 months prior to informed consent or QTcF >450ms at the time of screening.* 5. Body Mass Index (BMI) > 45 kg/m2 at screening* 6. Estimated glomerular filtration rate (eGFR) < 30 mL/min at screening 7. Any cardiac dysfunction (malignant arrhythmia, acute myocarditis, valve dysfunction or tamponade) which, in the opinion of the investigator, may put the patient at increased risk because of participation in the study 8. The need of norepinephrine infusion of > 0.25 µg/kg/min, or the use of two vasopressors at screening to keep the patient hemodynamically stable 9. MetHb >3% at screening 10. PCO2 > 7 at screening 11. 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 12. Haemoglobin <80 g/dL at screening 13. Thrombocytopenia (platelet count <80000/mm3) at screening 14. Prothrombin time International ratio (INR) > 1.4 at screening 15. Pregnancy, or a positive pregnancy test at screening (for fertile women only) 16. 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. 17. 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.* 18. 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.* 19. History of any other clinically significant disease or disorder which, in the opinion of the investigator, may either put the patient at increased risk because of participation in the study, or influence the results or the ability to participate in the study.* 20. 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.*
*evaluated at pre-screening
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E.5 End points |
E.5.1 | Primary end point(s) |
Change in MPAP and calculated PVR measured with pulmonary arterial catheterization, at target dose after up-titration and 10 minutes after steady state. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
At target dose after up-titration and 10 minutes after steady state (according to study flow chart) |
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E.5.2 | Secondary end point(s) |
- Adverse events (AEs) until end of study - Serious AEs (SAEs) until end of study - Changes in vital signs (systemic blood pressure, pulse, oxygen saturation, respiratory frequency, body temperature) until 7 days after completion of the iv infusion - Electrocardiogram (ECG) abnormalities until 7 days after completion of the iv infusion - Laboratory abnormalities until 7 days after completion of the iv infusion - 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. - Change in troponin I/T and BNP/NT-proBNP at the end of IMP infusion and 7 days after end of IMP infusion. - Change in the ratio PVR / systemic vascular resistance (SVR)
Exploratory endpoints: - Collection of plasma for future analysis of biomarkers such as nitrite and nitrate in plasma and, if possible, cGMP. - SARS-CoV-2 levels in plasma |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
According to study flow chart. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | Yes |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | Yes |
E.7.1.3.1 | Other trial type description |
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E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 3 |
E.8.9.1 | In the Member State concerned days | |