Clinical trial NCT04510662: Telmisartan in Respiratory Failure Due to COVID-19
Official title: Effectiveness and Safety of Telmisartan in Acute Respiratory Failure Due to COVID-19
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: COVID-19
Respiratory Insufficiency
Telmisartan
Respiratory Distress Syndrome, Adult
Keywords: COVID-19
telmisartan
respiratory failure
respiratory distress syndrome, adult
Lead sponsor: Hospital Regional de Alta Especialidad de Zumpango
Sponsor class: OTHER_GOV
Collaborators: name: National Polytechnic Institute, Mexico
First posted: 2020-08-12
Enrollment: 66
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: 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.

Primary outcomes:
measure: Death
timeFrame: Within 30 days
measure: Mechanical ventilation
timeFrame: Within 14 days
Secondary outcomes:
measure: Occurrence of acute kidney injury
timeFrame: Within 14 days
measure: Incidence of hypotension
timeFrame: Within 14 days
measure: Incidence of hypotension requiring vasopressors
timeFrame: Within 14 days
measure: Incidence of Sepsis
timeFrame: Within 14 days
measure: Hospital length of stay
timeFrame: Within 14 days
Other outcomes:
Locations:
city: Zumpango
country: Mexico
facility: Hospital Regional de Alta Especialidad de Zumpango
state: Estado De Mexico
Study officials:
affiliation: Hospital Regional de Alta Especialidad de Zumpango
name: Abraham Edgar Gracia-Ramos, MD MSc
role: PRINCIPAL_INVESTIGATOR
References:
citation: Rothlin RP, Vetulli HM, Duarte M, Pelorosso FG. Telmisartan as tentative angiotensin receptor blocker therapeutic for COVID-19. Drug Dev Res. 2020 Nov;81(7):768-770. doi: 10.1002/ddr.21679. Epub 2020 May 1.
citation: Sanchis-Gomar F, Lavie CJ, Perez-Quilis C, Henry BM, Lippi G. Angiotensin-Converting Enzyme 2 and Antihypertensives (Angiotensin Receptor Blockers and Angiotensin-Converting Enzyme Inhibitors) in Coronavirus Disease 2019. Mayo Clin Proc. 2020 Jun;95(6):1222-1230. doi: 10.1016/j.mayocp.2020.03.026. Epub 2020 Apr 4.
citation: Patel AB, Verma A. COVID-19 and Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers: What Is the Evidence? JAMA. 2020 May 12;323(18):1769-1770. doi: 10.1001/jama.2020.4812. No abstract available.
citation: Bavishi C, Maddox TM, Messerli FH. Coronavirus Disease 2019 (COVID-19) Infection and Renin Angiotensin System Blockers. JAMA Cardiol. 2020 Jul 1;5(7):745-747. doi: 10.1001/jamacardio.2020.1282. No abstract available.
citation: Vaduganathan M, Vardeny O, Michel T, McMurray JJV, Pfeffer MA, Solomon SD. Renin-Angiotensin-Aldosterone System Inhibitors in Patients with Covid-19. N Engl J Med. 2020 Apr 23;382(17):1653-1659. doi: 10.1056/NEJMsr2005760. Epub 2020 Mar 30. No abstract available.