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

NCT04771000 | Terminated Phase 2 DMC

• 1 other identifier: N-003-CRD008
• Study Type: interventional
• Target: 88
• Locations: 2 countries
• Sites: 13

Brief Summary

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.

Conditions

Covid19; Hypoxemia

Keywords

Covid19; Hypoxemia; Endothelin; Endothelin receptor antagonist; Ambrisentan; Micro-dose; Acute Respiratory Distress Syndrome (ARDS); Mechanical ventilation; Pulmonary vasodilator; Hypoxic respiratory failure; Respiratory Failure

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (13)

• Proportion of subjects alive and free of respiratory failure at Day 14 and Day 30

  14 days and 30 days

• Proportion of subjects alive and not requiring oxygen supplementation or higher respiratory support at Day 14.

  14 days

• Time to hospital discharge (up to Day 30)

  30 days

• Proportion of subjects admitted to the Intensive Care Unit or High-Dependency Unit (up to Day 30)

  30 days

• Time until weaning from oxygen therapy (up to Day 30)

  30 days

Other Outcomes (1)

• Change in SpO2/FiO2 from baseline to the time-weighted average obtained on Day 14

  14 days

Study Arms (2)

Ambrisentan

EXPERIMENTAL

Ambrisentan, 125µg twice a day for up to 28 days

Drug: Ambrisentan

Placebo

PLACEBO COMPARATOR

Placebo

Drug: Placebo

Interventions

Ambrisentan DRUG

Endothelin receptor antagonist

Also known as: N-003 (ambrisentan solution)

Ambrisentan

Placebo DRUG

Placebo

Also known as: Propylene glycol

Placebo

Eligibility Criteria

• Age: 18 Years - 85 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Noorik Biopharmaceuticals AG: lead

Study Sites (13)

General Hopital Zadar

Zadar, 23000, Croatia

Location

University Hospital for Infectious Diseases Fran Mihaljevic

Zagreb, 10000, Croatia

Location

Hospital Universitario Virgen de las Nieves

Granada, Comunidad de Andalucia, 18014, Spain

Location

Hospital Universitario San Cecilio

Granada, Comunidad de Andalucia, 18016, Spain

Location

Hospital Universitario de Jaén

Jaén, Comunidad de Andalucía, 23007, Spain

Location

Hospital Universitario de Galdakao-Usansolo

Galdakao, Comunidad de Bizkaia, 48960, Spain

Location

Complejo Hospitalario de Navarra

Pamplona, Comunidad de Navarra, 31008, Spain

Location

Hospital Rey Juan Carlos

Móstoles, Madrid, 28933, Spain

Location

Hospital Universitario de Cabueñes

Gijón, Principality of Asturias, 33394, Spain

Location

Hospital Universitario Infanta Leonor

Madrid, 28031, Spain

Location

University Hospital 12 de Octubre

Madrid, 28041, Spain

Location

Hospital Universitario La Paz

Madrid, 28046, Spain

Location

Hospital de Emergencias Enfermera Isabel Zendal

Madrid, 28055, Spain

Location

Related Publications (16)

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• Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, Xiang J, Wang Y, Song B, Gu X, Guan L, Wei Y, Li H, Wu X, Xu J, Tu S, Zhang Y, Chen H, Cao B. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020 Mar 28;395(10229):1054-1062. doi: 10.1016/S0140-6736(20)30566-3. Epub 2020 Mar 11.

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• Ackermann M, Verleden SE, Kuehnel M, Haverich A, Welte T, Laenger F, Vanstapel A, Werlein C, Stark H, Tzankov A, Li WW, Li VW, Mentzer SJ, Jonigk D. Pulmonary Vascular Endothelialitis, Thrombosis, and Angiogenesis in Covid-19. N Engl J Med. 2020 Jul 9;383(2):120-128. doi: 10.1056/NEJMoa2015432. Epub 2020 May 21.

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MeSH Terms

Conditions

COVID-19; Hypoxia; Respiratory Distress Syndrome; Respiratory Insufficiency

Interventions

ambrisentan; Propylene Glycol

Condition Hierarchy (Ancestors)

Pneumonia, Viral; Pneumonia; Respiratory Tract Infections; Infections; Virus Diseases; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Lung Diseases; Respiratory Tract Diseases; Signs and Symptoms, Respiratory; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Respiration Disorders

Intervention Hierarchy (Ancestors)

Propylene Glycols; Glycols; Alcohols; Organic Chemicals

Study Officials

• Rok Civljak, MD

  University Hospital for Infectious Diseases Fran Mihaljevic

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 24, 2021
• First Posted: February 25, 2021
• Study Start: February 8, 2021
• Primary Completion: February 27, 2023
• Study Completion: February 27, 2023
• Last Updated: March 21, 2023

Record last verified: 2023-03

Locations

CR (2); ES (11)