Effects of RAS Inhibitors (ARB, ACEi, DRI) in People With Hypertension 1-2 Stages on the Course of COVID-19 (BIRCOV Trial: ARB, ACEI, DRi Effects on COVID-19)
Conditions: Hypertension, COVID-19
Sponsor: Medical Practice Prof D. Ivanov

Unique Protocol ID: COVID20 
Brief Title: 
ARB, ACEi, DRi Effects on COVID-19 Course Disease (BIRCOV)   
Official Title: Effects of RAS Inhibitors (ARB, ACEi, DRI) in People with Hypertension 1-2 
Stages on the Course of COVID-19 (BIRCOV Trial: ARB, ACEI, DRi Effects on COVID-19) 
 
registered in ClinicalTrials.gov (NCT04364984).  
The study begun on April 1 2020, primary completion was achieved on July 24, 2021, and 
final results were available on August 1, 2021 [9]. 
 
Document date 27.01.2022 
January 27, 2022: Document updated for additional results 
December 01, 2021:  Document updated for Delayed Results. 
April 16, 2020:  Modified Outcome Measure Description definition to describe when the 
Description is required. 
March 20, 2020: Clarified that Document Upload Information (Study Protocol, Statistical 
Analysis Plan, Informed Consent Form) should be the version reviewed by a human subjects 
protection review board (if applicable) and must include a cover page. 
June 23, 2020:  Minor editorial changes. 
October 31, 2020:  subanalysis for CKD. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
Background  
Current international guidelines suggest continuing the usage of antihypertensive drugs, in 
particular inhibitors of renin-angiotensin-aldosterone system, in people with hypertension who 
become ill with COVID-19 [1] with no differences between 5 classes of anti-hypertensive agents 
[2]. 
It is well-known that the SARS-CoV-2 uses an ACE2 receptor and furin to enter the cell [3-5]. So if 
ACE2 levels are higher or lower in some hypertensive subjects, then the severity of disease and 
blood pressure (BP) level might be different [6]. It is natural to assume that SARS-CoV-2 can affect 
the state of the iRAS. 
Although most studies do not point out a negative effect of the virus on blood pressure levels, there 
is information about the different effects of different RAS inhibitors. Mandeep R et al (2020) found 
some differences between ACEi (Angiotensin-converting enzyme inhibitors) and ARB 
(Angiotensin receptor blockers) [7]. Probably, there also could be a difference for DRi (Direct renin 
inhibitor) [8]. 
In this regard, in March 2020, we initiated a study which was aimed to pinpoint possible clinical 
and laboratory differences in people with hypertension who received iRAS and suffered coronavirus 
infection. 
 
Study protocol. POEM (Patient-Oriented Evidence that Matters) [10] intervention was performed 
as an open prospective randomized two medical centers trial in subjects suffering with COVID-19 
who have been receiving iRAS, either ACEi, ARB or DRi as basic antihypertensive therapy.  
120 people with stage 1-2 hypertension and COVID-19 have been screened, 108 was enrolled the 
trial which has been formed 2 clinical arms: clinical arm, consists of 108 people, and kidney arm, 
consists of 85 people with chronic kidney disease. 
Study Population: patients with proved COVID-19 and preliminary stage 1-2 hypertension 
receiving iRAS at the onset of COVID-19 had been inspected for 24 weeks.  
Details about the collection method: documents and records. 
Sampling Method: Non-Probability Sample. Minimum Age:18 Years, Maximum Age: 90 Years,  
Sex: All   
Inclusion Criteria: Hypertension, stage 1-2  
Exclusion Criteria: Hypertension, stage 3, HF (NYHA) 3-4 
COVID-19 was confirmed by a PCR test, the disease follow-up was divided into 2 periods: up to 12 
weeks and up to 24 weeks.  
Primary Outcome Measure: BP was known one week before COVID-19 and was tested during the 
disease onset on weeks 2, 4, 12, 24. Secondary Outcome Measures: number of patients with fever 
(above 37.2C) up to 3 weeks after COVID-19 onset, number of patients with cough (Time Frame: 
12 weeks), number of patients with throat pain (Time Frame: 2 weeks), number of patients with 
diarrhoea (Time Frame: 2 weeks) and number of patients who needed hospital admission and 
intensive care unit (Time Frame: 24 weeks). 

Informed Consent Form - optional under 42 CFR Part 11, all patients gave their oral consent to 
submit personal data. 
BIRCOV trial included sub analysis of CKD patients - kidney arm, with primary endpoint: BP and 
eGFR measures and secondary endpoint: albuminuria grade (picture 1). 
Picture 1. BIRCOV trial  
 
 
Hydration status was elevated according to Ivanova MD et al [11]. Risk of progression to kidney 
failure requiring dialysis or transplantation (using the Kidney Failure Risk Equation) [13] have been 
calculated for all patients of kidney arm on 2, 4, 12 and 24 weeks from COVID-19 onset. 
The protocol was approved by a human subjects protection review board. 
Outcome Measures 
A table of data for each primary and secondary outcome measure by arm (that is, initial assignment 
of participants to arms or groups) or comparison group (that is, analysis groups), including the 
result(s) of scientifically appropriate statistical analyses that were performed on the outcome 
measure data. 
Outcome Measure Type  
Primary 
Definition: Blood pressure.  
 
Outcome Measure Description  
Definition: mm Hg 
2 characters: systolic and dyastolic. 
Outcome Measure Time Frame through study completion, on 2, 4, 12, 24 week after COVID-19 
onset 
BIRCOV trial
Clinical arm, n=108
fever, cough, 
thoat pain, 
diarrhoea
hospitalization 
or ICU
Kidney 
arm, n=85
eGFR, 
albuminuria

 
Arm/Group Information  
 
Arm/Group Title: 3 groups: patients who were taken ARB (1), ACEi (2) or DRI (3). 
Definition: Blood pressure, in mm Hg, 2 characters: systolic and diastolic blood pressure 
Analysis Population Information 
Overall Number of Participants Analyzed is 108, for each outcome measure and each arm/group are 
32 (group 1), 34 (group 2) and 31 patient (group 3). 
 
Type of Units Analyzed: sex, age, level of blood pressure 
 Count of Participants: Number 
Count of Units of blood pressure: median 
Measure of Dispersion/Precision  
Standard Error 
95% Confidence Interval 
 
Number of Units Analyzed: absolute number of patients 
Statistical Analyses [*] 
Definition: Results of scientifically appropriate tests of statistical significance of the primary and 
secondary outcome measures. Such analyses include: pre-specified in the protocol and statistical 
analysis plan. 
Statistical Analysis Overview 
Definition: Summary description of the analysis performed. 
Comparison Group Selection: 3 mentioned groups 
Type of Statistical Test  
Superiority 
Statistical Test of Hypothesis  
Definition: Procedure used for statistical analysis of outcome measure data and the calculated p-
value. 
P-Value  
Definition: Calculated p-value given the null-hypothesis 
Method  
Definition: The statistical test used to calculate the p-value, if a P-Value is ANOVA 
Method of Estimation  

Definition: Procedure used to estimate effect of intervention. Estimation Parameter is Cox 
Proportional Hazard 
Parameter Dispersion Type is Standard Deviation 
 
 
 
 
 BIRCOV trial (ARB, ACEI, DRi in COVID-19) registered in ClinicalTrials.gov 
(NCT04364984) Diagram of Statistical Analysis Plan 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
References 
Assessed for eligibility (n=120  ) 
Excluded  (n=12) 
   Not meeting inclusion criteria (n=9) 
   Declined to participate (n=2) 
   Other reasons (n=1) 
Analysed  (n=108) 
 Excluded from analysis (give reasons) (n=0) 
Lost to follow-up (give reasons) (n=4), dead 
Discontinued intervention (give reasons) (n=0) 
Allocated to intervention (n=108) divided in 3 
groups ACEi - 42 (39%), ARB - 35 (32%) or 
DRi – 31 (29%) 
 Received allocated intervention (n=108) 

Lost to follow-up (give reasons) (n=2), dead 
Discontinued intervention (give reasons) (n=0) 
Among them Subanalysis Kidney arm 
Allocated to intervention (n=85) 
 Received allocated intervention (n=85) 
Analysed  (n=85) 
 Excluded from analysis (give reasons) (n=0) 
Allocation 
Analysis 
Follow-Up 
Randomized (n=108) 
Enrollment 

1. 
www.era-edta.org/en/covid-19-news-and-information/#toggle-id-8  
2. 
Renin–Angiotensin–Aldosterone System Inhibitors and Risk of Covid-19. Harmony R. 
Reynolds, M.D., Samrachana Adhikari, Ph.D., Claudia Pulgarin, M.A., M.S., Andrea B. Troxel, 
Sc.D., Eduardo Iturrate, M.D., M.S.W., Stephen B. Johnson, Ph.D., Anaïs Hausvater, M.D., 
Jonathan D. Newman, M.D., M.P.H., Jeffrey S. Berger, M.D., Sripal Bangalore, M.D., Stuart D. 
Katz, M.D., Glenn I. Fishman, M.D., et al. The NEJM May 1, 2020 DOI: 
10.1056/NEJMoa2008975 
3. 
Lei Y, Zhang J, Schiavon CR, He M, Chen L, Shen H, Zhang Y, Yin Q et al SARS-CoV-2 
Spike Protein Impairs Endothelial Function via Downregulation of ACE 2 Circulation Research. 
2021;128:1323–1326 doi.org/10.1161/CIRCRESAHA.121.318902  
4. 
Denisa Bojkova KK, Koch B, Widera M, Krause D, Ciesek S, Cinatl J, Münch C. SARS-
CoV-2 infected host cell proteomics reveal potential therapy targets. Nature (2020) DOI: 
10.21203/rs.3.rs-17218/v1 
5. 
Davidson, A.D., Williamson, M.K., Lewis, S. et al. Characterisation of the transcriptome 
and proteome of SARS-CoV-2 reveals a cell passage induced in-frame deletion of the furin-like 
cleavage site from the spike glycoprotein. Genome Med 12, 68 (2020) DOI: 10.1186/s13073-020-
00763-0 
6. 
http://www.nephjc.com/news/covidace2 
7. 
Сardiovascular Disease, Drug Therapy, and Mortality in Covid-19 Mandeep R. Mehra, 
M.D., Sapan S. Desai, M.D., Ph.D., SreyRam Kuy, M.D., M.H.S., Timothy D. Henry, M.D., and 
Amit N. Patel, M.D. The NEJM May 1, 2020 DOI: 10.1056/NEJMoa2007621 
8. 
Mourad, J., Levy, B.I. Interaction between RAS inhibitors and ACE2 in the context of 
COVID-19. Nat Rev Cardiol (2020). https://doi.org/10.1038/s41569-020-0368-x 
9.
 
https://clinicaltrials.gov/ct2/show/NCT04364984?term=NCT04364984&cntry=UA&draw=2
&rank=1 
10. https://wilkes.libguides.com/c.php?g=191942&p=1266516  
11.  Ivanova, M.D., Gozhenko, A.I., Crestanello, T., Ivanov, D.D. Early Coaching to Increase 
Water Intake in CKD. Annals of nutrition & metabolism, 2020, 76, pp. 69–70 DOI: 
10.1159/000515276 
12. https://www.gigacalculator.com/calculators/  
13. https://qxmd.com/calculate/calculator_308/kidney-failure-risk-equation-4-variable