A Study of Micro Dose Ambrisentan in Hospitalized Patients With Respiratory Insufficiency Due to COVID-19

Study Overview
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Brief Summary
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Patients with COVID-19 frequently develop lower respiratory complications. Difficulty breathing and a low concentration of oxygen in the blood are of concern in patients with COVID-19, as they indicate that the lungs may be significantly affected. In some patients, respiratory symptoms may progress to the point where oxygen support is needed (i.e. use of an oxygen prongs, mask or ventilator). The exact mechanism of why patients with COVID-19 develop low concentrations of oxygen in blood is not fully understood. Some data suggest that the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the virus causing Coronavirus Disease 2019 (COVID-19), can affect the body's blood vessels directly and extensively. In the lung, blood vessels participate in the absorption of oxygen. Endothelin is a potent hormone produced by human blood vessels. When increased, endothelin can result in the narrowing of blood vessels in the lung and decrease the volume of blood flowing through the lungs. This decrease in in blood flow through the lungs may be one of many factors affecting normal lung function. Ambrisentan can block the effects of endothelin in the body, and this could theoretically improve blood flow through the lungs. This study will evaluate whether ambrisentan, by blocking the effects of the hormone endothelin in the lungs, improves the breathing capacity of patients with COVID-19, increases the concentration of oxygen in the blood and prevents the progression to respiratory failure and death. Ambrisentan is a drug that is currently used to treat patients with pulmonary hypertension, a disease where blood flow through the lungs is decreased. Subjects participating in this study are those patients hospitalised with severe respiratory symptoms related to COVID-19, and are considered to be at high-risk of developing respiratory complications. Ambrisentan will be administered in the hospital, and will be continued at home for up to 28 days. In this study, ambrisentan will be administered at much lower doses that those used in patients with pulmonary hypertension.

Detailed Description
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This is a randomized, double-blind, placebo-controlled, multi-centre trial to evaluate the safety and efficacy of ambrisentan for the treatment of severe COVID-19. The population consists of hospitalized subjects who have a confirmed SARS-CoV-2 (a coronavirus (CoV) ) infection, are at high-risk of progression to respiratory failure or death and have low oxygen saturation and/or require oxygen supplementation at the time of admission. Pregnant or lactating women will not be allowed to participate in this study given the teratogenic potential of ambrisentan. Subjects requiring mechanical ventilation or intubation at the time of enrolment are considered to have respiratory failure and will not be allowed into the study, as one primary objective of the study is to evaluate the effect of ambrisentan in preventing respiratory failure. Enrolled subjects will be randomly assigned to the treatment arm or control arm at a 1:1 ratio. In the treatment arm, subjects will receive ambrisentan on top of the standard-of-care. In the control arm, subjects will receive the administration vehicle only (i.e., placebo) and on top of the standard of care. The study medication (ambrisentan or placebo) will be administered for up to 28 days. In the event that the subject is discharged between Day 4 and Day 28, the subject will continue the study treatment at home until completion of the 28-day study medication regimen. Investigators, the Sponsor and the subject will be blinded to the treatment assignment. A Drug Safety Monitoring Board will be monitoring the safety of the study.

Official Title
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A Randomised, Double-blind, Placebo-controlled Trial to Evaluate the Efficacy and Safety of Ambrisentan in Patients With Severe COVID-19

Conditions
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Covid19, Hypoxemia

Intervention / Treatment
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* Drug: Ambrisentan
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject (or legally authorized representative) provides informed consent (written or oral) prior to initiation of any study procedures. Male or non-pregnant, non-lactating female. Women of child-bearing potential must have a confirmed negative serum pregnancy test at the time of screening and must use a highly effective contraceptive method throughout the study (such as implants, injectables, hormonal contraceptives and condom, double barrier contraception [i.e., condom + diaphragm/spermicidal gel or foam]) and until one month after completing treatment with the study medication. In the case of hormonal contraception, women should have been on a stable regimen for a minimum of three months before study enrolment. Women not of child-bearing potential include post-menopausal females (defined as having a history of amenorrhea for at least one year) or a documented status as being surgically sterile (hysterectomy, bilateral oophorectomy, tubal ligation/salpingectomy). Men must use an effective contraception method (i.e., condom + diaphragm/spermicidal gel or foam, or vasectomy), and should not donate semen during the study. Men are considered to be fertile from the time of puberty, except for those men with permanent sterility secondary to bilateral orchiectomy. At least 18 years of age and not older than 85 years of age at time of enrolment Confirmed SARS-CoV-2 infection defined as: Positive Real-Time Polymerase Chain Reaction (RT-PCR) result in sample collected in the 10 days prior to randomisation, OR positive antigenic test result in sample collected in the 10 days prior to randomisation. Radiological confirmation of pneumonia. Subject receiving low-flow oxzgen supplementation of at least 2 L/min and not more than 15 L/min. Subject (or legally authorized representative) understands and agrees to comply with planned study procedures. Subject (or legally authorized representative) agrees to not participate in any other clinical trial, including clinical trials for the treatment or prevention of COVID-19 or SARS-CoV-2 through Day 30. Exclusion Criteria: Subject at a high risk of death, according to investigator's opinion, in the 3 months following enrollment from other causes than Acute Respiratory Distress Syndrome (e.g., severe neurological damage or cancer patients in terminal stages of the disease). Subject currently being treated with an endothelin receptor antagonist. Subject currently being treated with another pulmonary vasodilator. Anticipated need for high-flow oxygen supplementation, non-invasive mechanical ventilation, endotracheal intubation or tracheostomy at the time of screening. History of mechanical ventilation (invasive or non-invasive) in the last 7 days. Documented history of end-stage liver disease, cirrhosis or idiopathic pulmonary fibrosis (IPF) with or without pulmonary arterial hypertension. Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT) > 3-times the upper limit of normal (ULN). Anticipated discharge from the hospital or transfer to another hospital which is not a study site within 96 hours. Participation in another interventional clinical trial in the 15 days prior to enrollment. Known hypersensitivity to ambrisentan or propylene glycol.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ambrisentan<br>Ambrisentan, 125µg twice a day for up to 28 days | Drug: Ambrisentan<br>* Endothelin receptor antagonist<br>* Other names: N-003 (ambrisentan solution);|
| Placebo Comparator: Placebo<br>Placebo | Drug: Placebo<br>* Placebo<br>* Other names: Propylene glycol;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of subjects alive and not having developed respiratory failure from randomization to Day 14 | The number of patients that are alive and have not developed respiratory failure by day 30 after entering the study will be compared between the experimental and placebo arms | 30 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of subjects alive and free of respiratory failure at Day 14 and Day 30 | The number of patients that are alive and have not developed respiratory failure on day 14 will will be compared between the experimental and placebo arms | 14 days and 30 days | 
| Proportion of subjects alive and not requiring oxygen supplementation or higher respiratory support at Day 14. | The number of patients not requiring supplemental oxygen, or any other type of respiratory support at day 14 will be compared between the experimental and placebo arms | 14 days | 
| Time to hospital discharge (up to Day 30) | The time in days required for subjects to be discharged from the first hospitalisation will be estimated and compared between the experimental and placebo groups | 30 days | 
| Proportion of subjects admitted to the Intensive Care Unit or High-Dependency Unit (up to Day 30) | The number of patients who qualified for admission or where admitted to an intensive care or a high-dependency unit at any time during the first 30 days after entering the study will be estimated and compared between the experimental and placebo groups | 30 days | 
| Time until weaning from oxygen therapy (up to Day 30) | The time in days subjects required to breathe independently and without oxygen support will be estimated and compared for the experimental and placebo groups | 30 days | 
| Time until weaning from respiratory support other than low-flow oxygen supplementation for subjects having developed respiratory failure (up to Day 30) | The time in days subjects required to breathe independently with or without supplemental oxygen will be estimated and compared for the experimental and placebo groups | 30 days | 
| Change in SpO2/FiO2 from baseline to the time-weighted average obtained on Day 3 | The difference in blood oxygen saturation (SpO2) corrected by the inspired fraction of oxygen (FiO2) between baseline and the time-adjusted average calculated for day 3 will be compared between the experimental and placebo arms | 3 days | 
| Change in SpO2/FiO2 from baseline to the time-weighted average obtained on Day 1 | The difference in blood oxygen saturation corrected by the inspired fraction of oxygen between baseline and the time-adjusted average calculated for day 1 will be compared between the experimental and placebo arms | 1 day | 
| Change in SpO2/FiO2 from baseline to the time-weighted average obtained on Day 2 | The difference in blood oxygen saturation corrected by the inspired fraction of oxygen between baseline and the time-adjusted average calculated for day 2 will be compared between the experimental and placebo arms | 2 days | 
| Proportion of subjects experiencing at least one event of venous thrombosis (specifically deep venous thrombosis or pulmonary embolism) (up to Day 30). | The number of patients who developed thrombosis or pulmonary embolism during the first 30 days after entering the study will be estimated and compared between the experimental and placebo groups | 30 days | 
| Proportion of subjects by clinical status reported on a 11-point ordinal scale at Day 14 and Day 30 | The number of patients classified according to an 11-pont scale on their clinical status at day 14 and day 30 will be calculated and compared between the experimental and placebo groups. The 11-point scale is as follows: Uninfected (0 points), Ambulatory and Asymptomatic (1 point), Symptomatic and independent (2 points), Symptomatic requiring assistance (3 points), Hospitalized with no oxygen therapy (4 points), Hospitalized with oxygen by mask or nasal prongs (5 points), Hospitalized with oxygen by non-invasive ventilation or high flow (6 points), Intubation and mechanical ventilation, PaO2/FiO2 ≥ 150 or SpO2/FiO2 ≥ 200 (7 points), Mechanical ventilation, PaO2/FiO2 <150 (SpO2/FiO2 < 200) or vasopressors (8 points), Mechanical ventilation, PaO2/FiO2 < 150 (SpO2/FiO2 < 200) and vasopressors, dialysis or Extracorporeal Membrane Oxygenation (ECMO) (9 points), Dead (10 points). | 14 days and 30 days | 
| Time to death due to any cause (up to Day 30) | For those subjects dying in the first 30 days after study entry, the time from study entry to death will be estimated and compared between the experimental and placebo groups | 30 days | 
| All-cause mortality at Day 30 | The number of patients dying during the study observation period independent of the cause of death will be calculated and compared between the experimental and placebo groups. | 30 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Covid19, Hypoxemia, Endothelin, Endothelin receptor antagonist, Ambrisentan, Micro-dose, Acute Respiratory Distress Syndrome (ARDS), Mechanical ventilation, Pulmonary vasodilator, Hypoxic respiratory failure, Respiratory Failure