Clinical trial NCT04508985: The McGill RAAS-COVID-19 Trial
Official title: Management of Renin-Angiotensin-Aldosterone System Blockade in Patients Admitted in Hospital With Confirmed Coronavirus Disease (COVID-19) Infection: The McGill RAAS-COVID-19 Randomized Controlled Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: COVID-19
Cardiovascular Diseases
Keywords: Renin
Angiotensin
Aldosterone
coronavirus
Cardiovascular Diseases
COVID-19
Lead sponsor: McGill University Health Centre/Research Institute of the McGill University Health Centre
Sponsor class: OTHER
Collaborators: name: Jewish General Hospital (Montreal, Quebec, Canada)
name: Montreal General Hospital (Montreal, Quebec, Canada)
name: Université de Lorraine, Centre d'Investigation Clinique- Plurithématique Inserm
First posted: 2020-08-11
Enrollment: 46
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: Open-label, randomized, study of approximately 40 adults. The following groups of participants will be considered: i) within 48 hours of diagnosis of COVID-19; ii) who have received a diagnosis of COVID-19 from another facility and are within 48 hours of transfer to a study recruitment site (Royal Victoria Hospital, Montreal General Hospital, and Jewish General Hospital \[all in Montreal, Quebec, Canada\])). Participants will be randomized 1:1 to an upfront temporary discontinuation) of RAAS inhibition for the duration of the hospitalization (and to consider re-initiate on discharge) versus a strategy continuation of RAAS inhibition.
Primary purpose: TREATMENT

Brief summary: Coronavirus disease (COVID-19) related pneumonia significantly impact patients with underlying cardiovascular (CV) conditions. Animal studies suggest that drugs commonly used to treated CV diseases may increase the ability of COVID-19 to infect cells. The RAAS-COVID-19 trial aims to assess whether temporarily holding these CV drugs in patients who are admitted with COVID-19, versus continuing them, in patients admitted with COVID-19 can impact short term outcomes.

Detailed description: Open-label, pragmatic, randomized, study of approximately 40 adults. The following groups of participants will be considered: i) within 48 hours of diagnosis of COVID-19; ii) who have received a diagnosis of COVID-19 from another facility and are within 48 hours of transfer to a study recruitment site (Royal Victoria Hospital, Montreal General Hospital, and Jewish General Hospital \[all in Montreal, Quebec, Canada\]). Participants will be randomized 1:1 to an upfront temporary discontinuation) of RAAS inhibition for the duration of the hospitalization (and to consider re-initiate after day 7 of admission or on discharge) versus a strategy continuation of RAAS inhibition. Re-initiation of held RAAS inhibition will be based on treating team's clinical judgement. The RAAS-COVID-19 RCT will evaluate whether an upfront strategy of temporary discontinuation of RAAS inhibition compared to the continuation of RAAS inhibition among patients admitted with established COVID-19 infection and on chronic RAAS inhibition therapy impacts short term clinical outcomes and biomarkers.

Eligibility criteria: Inclusion Criteria:

* Age ≥ 18 years old.
* Hospitalization with a Covid-19 infection
* Chronically treated with RAAS blockers (ACE inhibitors or ARBs on the last prescription prior to admission with a treatment duration ≥ 1 month
* Diagnosis of COVID-19 confirmed by the presence of SARS-CoV-2 on any biological sample
* Participants are within 48 hours of diagnosis of COVID-19 or have received a diagnosis of COVID-19 from another facility and are within 48 hours of transfer to a study recruitment site

Exclusion Criteria:

* Shock requiring vasoactive agents.
* Requiring invasive mechanical ventilation.
* History of malignant hypertension
* Use of five or more antihypertensive drugs.
* History of heart failure with reduced ejection fraction
* History of hospitalization for acute heart failure in past 3 months
* History of hospitalization for hemorrhagic stroke in the past 3 months.
* History of CKD with an eGFR \<45 ml/min/1.73m2
* History of COPD GOLD III/IV
* History of end-stage dementia
* History of active liver cirrhosis
* RAAS blockers therapy previously stopped \> 48h.
* Anticipated discharge in less than 24 hours.
* History of current active cancer receiving chemotherapy
* Inability to obtain informed consent.

Primary outcomes:
measure: Global rank score
timeFrame: Baseline - day 7
Secondary outcomes:
Other outcomes:
Locations:
city: Montreal
country: Canada
facility: Muhc-Rimuhc
state: Quebec
Study officials:
affiliation: McGill University Health Centre/Research Institute of the McGill University Health Centre
name: Abhinav Sharma, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Brown PM, Ezekowitz JA. Composite End Points in Clinical Trials of Heart Failure Therapy: How Do We Measure the Effect Size? Circ Heart Fail. 2017 Jan;10(1):e003222. doi: 10.1161/CIRCHEARTFAILURE.116.003222.
citation: Kuhn JH, Li W, Choe H, Farzan M. Angiotensin-converting enzyme 2: a functional receptor for SARS coronavirus. Cell Mol Life Sci. 2004 Nov;61(21):2738-43. doi: 10.1007/s00018-004-4242-5.
citation: Ferrario CM, Jessup J, Chappell MC, Averill DB, Brosnihan KB, Tallant EA, Diz DI, Gallagher PE. Effect of angiotensin-converting enzyme inhibition and angiotensin II receptor blockers on cardiac angiotensin-converting enzyme 2. Circulation. 2005 May 24;111(20):2605-10. doi: 10.1161/CIRCULATIONAHA.104.510461. Epub 2005 May 16.
citation: Agata J, Ura N, Yoshida H, Shinshi Y, Sasaki H, Hyakkoku M, Taniguchi S, Shimamoto K. Olmesartan is an angiotensin II receptor blocker with an inhibitory effect on angiotensin-converting enzyme. Hypertens Res. 2006 Nov;29(11):865-74. doi: 10.1291/hypres.29.865.
citation: Kuster GM, Pfister O, Burkard T, Zhou Q, Twerenbold R, Haaf P, Widmer AF, Osswald S. SARS-CoV2: should inhibitors of the renin-angiotensin system be withdrawn in patients with COVID-19? Eur Heart J. 2020 May 14;41(19):1801-1803. doi: 10.1093/eurheartj/ehaa235. No abstract available.
citation: Sharma A, Bhatt DL, Calvo G, Brown NJ, Zannad F, Mentz RJ. Heart failure event definitions in drug trials in patients with type 2 diabetes. Lancet Diabetes Endocrinol. 2016 Apr;4(4):294-6. doi: 10.1016/S2213-8587(16)00049-8. No abstract available.
citation: Marquis-Gravel G, Roe MT, Turakhia MP, Boden W, Temple R, Sharma A, Hirshberg B, Slater P, Craft N, Stockbridge N, McDowell B, Waldstreicher J, Bourla A, Bansilal S, Wong JL, Meunier C, Kassahun H, Coran P, Bataille L, Patrick-Lake B, Hirsch B, Reites J, Mehta R, Muse ED, Chandross KJ, Silverstein JC, Silcox C, Overhage JM, Califf RM, Peterson ED. Technology-Enabled Clinical Trials: Transforming Medical Evidence Generation. Circulation. 2019 Oct 22;140(17):1426-1436. doi: 10.1161/CIRCULATIONAHA.119.040798. Epub 2019 Oct 21.
citation: Wu Z, McGoogan JM. Characteristics of and Important Lessons From the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72 314 Cases From the Chinese Center for Disease Control and Prevention. JAMA. 2020 Apr 7;323(13):1239-1242. doi: 10.1001/jama.2020.2648. No abstract available.
citation: Guan WJ, Ni ZY, Hu Y, Liang WH, Ou CQ, He JX, Liu L, Shan H, Lei CL, Hui DSC, Du B, Li LJ, Zeng G, Yuen KY, Chen RC, Tang CL, Wang T, Chen PY, Xiang J, Li SY, Wang JL, Liang ZJ, Peng YX, Wei L, Liu Y, Hu YH, Peng P, Wang JM, Liu JY, Chen Z, Li G, Zheng ZJ, Qiu SQ, Luo J, Ye CJ, Zhu SY, Zhong NS; China Medical Treatment Expert Group for Covid-19. Clinical Characteristics of Coronavirus Disease 2019 in China. N Engl J Med. 2020 Apr 30;382(18):1708-1720. doi: 10.1056/NEJMoa2002032. Epub 2020 Feb 28.
citation: Arentz M, Yim E, Klaff L, Lokhandwala S, Riedo FX, Chong M, Lee M. Characteristics and Outcomes of 21 Critically Ill Patients With COVID-19 in Washington State. JAMA. 2020 Apr 28;323(16):1612-1614. doi: 10.1001/jama.2020.4326.
citation: Ye M, Wysocki J, William J, Soler MJ, Cokic I, Batlle D. Glomerular localization and expression of Angiotensin-converting enzyme 2 and Angiotensin-converting enzyme: implications for albuminuria in diabetes. J Am Soc Nephrol. 2006 Nov;17(11):3067-75. doi: 10.1681/ASN.2006050423. Epub 2006 Oct 4.
citation: Soler MJ, Ye M, Wysocki J, William J, Lloveras J, Batlle D. Localization of ACE2 in the renal vasculature: amplification by angiotensin II type 1 receptor blockade using telmisartan. Am J Physiol Renal Physiol. 2009 Feb;296(2):F398-405. doi: 10.1152/ajprenal.90488.2008. Epub 2008 Nov 12.
citation: Vuille-dit-Bille RN, Camargo SM, Emmenegger L, Sasse T, Kummer E, Jando J, Hamie QM, Meier CF, Hunziker S, Forras-Kaufmann Z, Kuyumcu S, Fox M, Schwizer W, Fried M, Lindenmeyer M, Gotze O, Verrey F. Human intestine luminal ACE2 and amino acid transporter expression increased by ACE-inhibitors. Amino Acids. 2015 Apr;47(4):693-705. doi: 10.1007/s00726-014-1889-6. Epub 2014 Dec 23.
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.
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: Zhang P, Zhu L, Cai J, Lei F, Qin JJ, Xie J, Liu YM, Zhao YC, Huang X, Lin L, Xia M, Chen MM, Cheng X, Zhang X, Guo D, Peng Y, Ji YX, Chen J, She ZG, Wang Y, Xu Q, Tan R, Wang H, Lin J, Luo P, Fu S, Cai H, Ye P, Xiao B, Mao W, Liu L, Yan Y, Liu M, Chen M, Zhang XJ, Wang X, Touyz RM, Xia J, Zhang BH, Huang X, Yuan Y, Loomba R, Liu PP, Li H. Association of Inpatient Use of Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers With Mortality Among Patients With Hypertension Hospitalized With COVID-19. Circ Res. 2020 Jun 5;126(12):1671-1681. doi: 10.1161/CIRCRESAHA.120.317134. Epub 2020 Apr 17.
citation: Guo J, Huang Z, Lin L, Lv J. Coronavirus Disease 2019 (COVID-19) and Cardiovascular Disease: A Viewpoint on the Potential Influence of Angiotensin-Converting Enzyme Inhibitors/Angiotensin Receptor Blockers on Onset and Severity of Severe Acute Respiratory Syndrome Coronavirus 2 Infection. J Am Heart Assoc. 2020 Apr 7;9(7):e016219. doi: 10.1161/JAHA.120.016219. Epub 2020 Apr 1. No abstract available.
citation: Sun H, Davison BA, Cotter G, Pencina MJ, Koch GG. Evaluating treatment efficacy by multiple end points in phase II acute heart failure clinical trials: analyzing data using a global method. Circ Heart Fail. 2012 Nov;5(6):742-9. doi: 10.1161/CIRCHEARTFAILURE.112.969154. Epub 2012 Oct 11.
citation: Felker GM, Maisel AS. A global rank end point for clinical trials in acute heart failure. Circ Heart Fail. 2010 Sep;3(5):643-6. doi: 10.1161/CIRCHEARTFAILURE.109.926030. No abstract available.
citation: Margulies KB, Hernandez AF, Redfield MM, Givertz MM, Oliveira GH, Cole R, Mann DL, Whellan DJ, Kiernan MS, Felker GM, McNulty SE, Anstrom KJ, Shah MR, Braunwald E, Cappola TP; NHLBI Heart Failure Clinical Research Network. Effects of Liraglutide on Clinical Stability Among Patients With Advanced Heart Failure and Reduced Ejection Fraction: A Randomized Clinical Trial. JAMA. 2016 Aug 2;316(5):500-8. doi: 10.1001/jama.2016.10260.
citation: 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.
citation: Sharma A, Hijazi Z, Andersson U, Al-Khatib SM, Lopes RD, Alexander JH, Held C, Hylek EM, Leonardi S, Hanna M, Ezekowitz JA, Siegbahn A, Granger CB, Wallentin L. Use of Biomarkers to Predict Specific Causes of Death in Patients With Atrial Fibrillation. Circulation. 2018 Oct 16;138(16):1666-1676. doi: 10.1161/CIRCULATIONAHA.118.034125.
citation: Clerkin KJ, Fried JA, Raikhelkar J, Sayer G, Griffin JM, Masoumi A, Jain SS, Burkhoff D, Kumaraiah D, Rabbani L, Schwartz A, Uriel N. COVID-19 and Cardiovascular Disease. Circulation. 2020 May 19;141(20):1648-1655. doi: 10.1161/CIRCULATIONAHA.120.046941. Epub 2020 Mar 21.
citation: Nerenberg KA, Zarnke KB, Leung AA, Dasgupta K, Butalia S, McBrien K, Harris KC, Nakhla M, Cloutier L, Gelfer M, Lamarre-Cliche M, Milot A, Bolli P, Tremblay G, McLean D, Padwal RS, Tran KC, Grover S, Rabkin SW, Moe GW, Howlett JG, Lindsay P, Hill MD, Sharma M, Field T, Wein TH, Shoamanesh A, Dresser GK, Hamet P, Herman RJ, Burgess E, Gryn SE, Gregoire JC, Lewanczuk R, Poirier L, Campbell TS, Feldman RD, Lavoie KL, Tsuyuki RT, Honos G, Prebtani APH, Kline G, Schiffrin EL, Don-Wauchope A, Tobe SW, Gilbert RE, Leiter LA, Jones C, Woo V, Hegele RA, Selby P, Pipe A, McFarlane PA, Oh P, Gupta M, Bacon SL, Kaczorowski J, Trudeau L, Campbell NRC, Hiremath S, Roerecke M, Arcand J, Ruzicka M, Prasad GVR, Vallee M, Edwards C, Sivapalan P, Penner SB, Fournier A, Benoit G, Feber J, Dionne J, Magee LA, Logan AG, Cote AM, Rey E, Firoz T, Kuyper LM, Gabor JY, Townsend RR, Rabi DM, Daskalopoulou SS; Hypertension Canada. Hypertension Canada's 2018 Guidelines for Diagnosis, Risk Assessment, Prevention, and Treatment of Hypertension in Adults and Children. Can J Cardiol. 2018 May;34(5):506-525. doi: 10.1016/j.cjca.2018.02.022. Epub 2018 Mar 1.
citation: Sharma A, Elharram M, Afilalo J, Flannery A, Afilalo M, Tselios C, Ni J, Ezekowitz JA, Cheng MP, Ambrosy AP, Zannad F, Brophy JM, Giannetti N, Bessissow A, Kronfli N, Marelli A, Aziz H, Alqahtani M, Aflaki M, Craig M, Lopes RD, Ferreira JP. A randomized controlled trial of renin-angiotensin-aldosterone system inhibitor management in patients admitted in hospital with COVID-19. Am Heart J. 2022 May;247:76-89. doi: 10.1016/j.ahj.2022.01.015. Epub 2022 Feb 7.
citation: Aflaki M, Flannery A, Ferreira JP, Cheng MP, Kronfli N, Marelli A, Zannad F, Brophy J, Afillalo J, Huynh T, Giannetti N, Bessissow A, Ezekowitz JA, Lopes RD, Ambrosy AP, Craig M, Sharma A. Management of Renin-Angiotensin-Aldosterone System blockade in patients admitted to hospital with confirmed coronavirus disease (COVID-19) infection (The McGill RAAS-COVID- 19): A structured summary of a study protocol for a randomized controlled trial. Trials. 2021 Feb 5;22(1):115. doi: 10.1186/s13063-021-05080-4.