Telmisartan in Respiratory Failure Due to COVID-19

Study Overview
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Brief Summary
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Rationale: The renin-angiotensin-aldosterone system (RAAS) dysregulation may play a central role in the pathophysiology of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection associated acute lung injury (ALI) / acute respiratory distress syndrome (ARDS). In the RAAS, Angiotensin I (Ang I) is converted to angiotensin II (Ang II) by angiotensin converting enzyme (ACE). Ang II mediates vasoconstrictive, pro-inflammatory and pro-oxidative effects through agonism at Ang II type 1 receptor (AT1R). ACE2 converts Ang II to angiotensin 1-7 (Ang1-7), which finally binds to Mas receptor (MasR) and mediates many beneficial actions, including vasodilation and anti-inflammatory, anti-oxidant and antiapoptotic effects. ACE2, a homologue of ACE, is an integral cell membrane protein with a catalytic domain on the extracellular surface exposed to vasoactive peptides. SARS-CoV-2 penetrates the cell through ACE2, and the increase of this receptor (due to the use of ACE inhibitors or angiotensin receptor blockers [ARBs]) may facilitate SARS-CoV-2 infection, which might increase the risk of developing severe and fatal SARS-CoV-2 infection. However, through upregulation of ACE2, ACE inhibitors/ARBs can exert anti-inflammatory and antioxidative effects, which may be beneficial in preventing ALI and ARDS. Objective: To evaluate the effectiveness and safety of telmisartan in respiratory failure due to COVID-19. Study design: This is an open label, phase 2 clinical trial. Study population: Adult hospitalized SARS-CoV-2-infected patients (n=60). Intervention: The active-treatment arm will receive telmisartan 40 mg daily and the control arm will receive standard care. Treatment duration will be 14 days or up to hospital discharge <14 days or occurrence of the primary endpoint if <14 days. Main study endpoint: The primary study endpoint is the occurrence within 14 days of randomization of either: 1) Mechanical ventilation or 2) Death.

Official Title
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Effectiveness and Safety of Telmisartan in Acute Respiratory Failure Due to COVID-19

Conditions
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COVID-19, Respiratory Insufficiency, Telmisartan, Respiratory Distress Syndrome, Adult

Intervention / Treatment
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* Drug: Telmisartan


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age greater than or equal to 18 years of age. Admitted to the Hospital Regional de Alta Especialidad de Zumpango. Confirmed SARS-CoV-2 infection with either: positive laboratory test for SARS-CoV-2; or positive CT thorax diagnostic for SARS-CoV-2 infection according to the prevailing criteria. Hypoxic respiratory failure: SpO2 ≤94% on room OR tachypnea (respiratory rate ≥22 breaths/min). Randomization: Within 24 hours of confirmed in-hospital SARS-CoV-2 infection diagnosis OR within 24 hours of hospital admission in case of pre-hospital confirmed SARS-CoV-2 infection. In case there is a lack of laboratory tests for SARS-CoV-2 in a potentially eligible patient, a positive laboratory test for SARS-CoV-2 will be no longer required. In that case, the potentially eligible patient needs to meet the prevailing criteria for the diagnosis of SARS-CoV-2 infection, such as typical abnormalities on pulmonary CT in the setting of high clinical suspicion of SARS-CoV-2 infection. Exclusion Criteria: Admitted to ICU prior to randomization. Currently taking an an angiotensin converting enzyme inhibitor (ACEi) or Angiotensin receptor blocker (ARB). Use of other investigational drugs at the time of enrollment Prior reaction or intolerance to an ARB; or severe intolerance to an ACEi, defined as angio-oedema requiring medical intervention. Systolic blood pressure < 105 mmHg or diastolic blood pressure <65mmHg. Potassium greater than 5.5 mEq/L within 4 weeks of study enrollment. Estimated Glomerular Filtration Rate (eGFR) of < 30ml/min/1.73 m2 within 4 weeks of study initiation. A known history of renal artery stenosis. AST and/or ALT > 3 times the upper limit of normal within 4 weeks of study enrollment. Severe liver dysfunction (Child-Pugh score C), biliary cirrhosis or cholestasis. Severe volume depletion or severe acute kidney injury. Inability to obtain informed consent. Pregnancy or breastfeeding.

Ages Eligible for Study
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Minimum Age: 18 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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Telmisartan<br>Patients in this group will receive telmisartan 40 mg daily plus standard care. | Drug: Telmisartan<br>* Patients in this group will receive telmisartan 40 mg daily plus standard care.<br>|
| No Intervention: Control<br>Patients in this group will receive standard care. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Death | Death is defined as all-cause mortality | Within 30 days | 
| Mechanical ventilation | Occurrence of mechanical ventilation | Within 14 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Occurrence of acute kidney injury | Defined as a 50% decline in estimated glomerular filtration rate relative to baseline, or decrease of >30 ml/min/1.73m2 and to a value below 60 ml/min/1.73m2 | Within 14 days | 
| Incidence of hypotension | Incidence of episodes of blood pressure less than 90 mm Hg systolic or 60 mm Hg diastolic | Within 14 days | 
| Incidence of hypotension requiring vasopressors | Outcome reported as the number of participants in each arm requiring the use of vasopressors for hypotension | Within 14 days | 
| Incidence of Sepsis | Outcome reported as the number of participants in each arm who experience sepsis, defined as the presence of at least 2 of the following clinical criteria together (qSOFA score): respiratory rate of 22/min or greater, altered mentation, or systolic blood pressure of 100 mm Hg or less | Within 14 days | 
| Hospital length of stay | Hospital length of stay (days) | Within 14 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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COVID-19, telmisartan, respiratory failure, respiratory distress syndrome, adult