Effects of acutely altering the renin-angiotensin system in patients with COVID-19

INTERVENTION: Trade Name: All ACE‐inhibitors marketed in Denmark ATC codes: C09AA03, C09AA01, C09AA02, C09AA04, C09AA10, C09AA05 A total of 81 possibilities Pharmaceutical Form: Tablet Trade Name: Viacoram Pharmaceutical Form: Tablet Trade Name: All ACE‐inhibitors combined with a thiazide diuretic marketed in Denmark ATC codes: C09BA02, C09BA04, C09BA03, C09BA05 A total of 18 possibilities Pharmaceutical Form: Tablet Trade Name: All angiontensin‐II receptor antagonists marketed in Denmark ATC codes: C09CA01, C09CA04, C09CA06, C09CA03, C09CA07, C09CA08 A total of 91 possibilities Pharmaceutical Form: Tablet Trade Name: All angiontensin‐II receptor antagonists combined with a thiazide diuretic marketed in Denmark ATC codes: C09DA01, C09DA06, C09DA04, C09DA07, C09DA08, C09DA03 A total of 65 possibilities Pharmaceutical Form: Tablet Trade Name: Amlodipin/valsartan "Stada" or Exforge Pharmaceutical Form: Tablet Trade Name: All angiontensin‐II receptor antagonists combined with a thiazide diuretic and a calcium receptor antagonist marketed in Denmark A total of 4 possibilities Pharmaceutical Form: Tablet Trade Name: Entresto Pharmaceutical Form: Tablet CONDITION: Coronavirus disease 2019 (COVID‐19) ; MedDRA version: 20.0 Level: LLT Classification code 10005747 Term: Blood pressure high System Organ Class: 100000004866 ; MedDRA version: 23.0 Level: PT Classification code 10051905 Term: Coronavirus infection System Organ Class: 10021881 ‐ Infections and infestations Therapeutic area: Diseases [C] ‐ Virus Diseases [C02] PRIMARY OUTCOME: Main Objective: This randomised clinical trial will investigate continued or discontinued treatment with angiotensin‐converting enzyme inhibitors or angiotensin‐II receptor antagonists in hospitalised patients with COVID‐19. Primary end point(s): The primary endpoint is days alive and out of hospital within 14 days after recruitment. Secondary Objective: Not applicable Timepoint(s) of evaluation of this end point: Daily evaluation during hospital admission INCLUSION CRITERIA: 1. Verified COVID‐19 2. Hospital admitted 3. Daily administration of RAS‐inhibiting therapy 4. Age 18 years and above 5. Informed consent Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18‐64 years) yes F.1.2.1 Number of subjects for this age range 60 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 155 SECONDARY OUTCOME: Secondary end point(s): The key‐secondary endpoint is the occurrence of worsening of COVID‐19 as assessed by (whichever comes first):; 1. Severe respiratory insufficiency; defined by the occurrence of one of the following:; a. PaO2/FiO2 ratio =40 kPa (300 mm Hg); PaO2 = partial pressure of arterial oxygen; FiO2 = percentage of inspired oxygen; b. Commencement of Non‐invasive Ventilation (NIV) ; c. Commencement of continuous CPAP (continuous positive airway pressure) treatment; d. Commencement of high flow oxygen therapy (HFOT); defined as an oxygen flow >16 l/min ; 2. Referral to treatment in an intensive care unit ; 3. Death; ; Other secondary endpoints include occurrence and time to occurrence of each of the components of the primary composite endpoint, kidney function (as assessed by plasma creatinin and eGFR), duration of index hospitalisation, 30 days‐mortality, number of days alive during the intervention period, discharge beyond 30 days and number of readmissions after 30 days. To support the clinical findings of the endpoints, blood samples will be analysed for ACE, ACE2, aldosteron, angiotensin‐II and renin by a collaborating laboratory within the Capital Region of Denmark. ; Timepoint(s) of evaluation of this end point: Daily / after 30 days; Blood samples: After end of trial