Role of commonly used blood pressure medications in treatment of COVID-19 (CLARITY 2.0)

Phase 2

Conditions: Coronavirus as the cause of diseases classified elsewhere,

Registration Number: CTRI/2021/10/037468

Lead Sponsor: The University of Sydney

Brief Summary: The major cause of mortality from COVID-19 has beenlife-threatening pneumonia and acute respiratory distress syndrome (ARDS).Elevated levels of a number of pro-inflammatory cytokines, includinginterleukin-6 (IL-6) and monocyte chemoattractant protein-1 (MCP-1, also knownas C-C Motif Chemokine Ligand 2 [CCL2]) have been reported in patients withsevere COVID-19, suggesting involvement of a hyper-inflammatory immuneresponse. MCP-1 is a chemokine with a key role in macrophage recruitment andactivation and is the natural ligand for Chemokine Receptor Type 2(CCR2). The capacity of CCR2 in the setting of COVID-19 has not beentested with most programs testing CCR2 in the setting of chronic disease suchas renal disease.

Alongside the role of chemokines in inducing thehyperinflammatory response, there is good evidence that the renin-angiotensinsystem (RAS) may also play a role in the pathophysiology of COVID-19. The RASis responsible for regulating haemodynamic, inflammatory, and fibroticprocesses, and includes two main cross-regulating axes: the vasoconstrictive,pro-inflammatory, pro-fibrotic ACE-Ang II-AT1R axis, and the vasodilatory,anti-inflammatory, anti-fibrotic ACE2-Ang1-7-MasR and ACE2-Ang1-9-AT2R axis.SARS-CoV-2 responsible for COVID-19 appears to bind and downregulateangiotensin converting enzyme type 2 (ACE2). Animal studies of therelated SARS-CoV-1 suggest that this downregulation of ACE2 is sufficient forcausing lung pathology and is reversed by treatment with an AngiotensinReceptor Blocker (ARB). Several randomised controlled trials areunderway to assess the effectiveness of ARBs in limiting the severity ofCOVID-19.

CLARITY 2.0 is an investigator-initiated trial that willevaluate the safety and efficacy of dual treatment with repagermanium, a CCR2antagonist and candesartan, an ARB, in patients hospitalised with COVID-19disease.

Detailed Description: Not available

Recruitment & Eligibility

Status: Other

Sex: All

Target Recruitment: 80

Inclusion Criteria

1.Adults aged â‰¥ 18 years 2.Laboratory-confirmed diagnosis of SARS-CoV-2 infection within 10 days prior to randomisation (Confirmation through appropriate approved laboratory or Point of Care testing method, including Polymerase Chain Reaction (PCR) or other public health assay.) 3.Systolic Blood Pressure (SBP) â‰¥ 120 mmHg OR SBP â‰¥ 115 mmHg and currently treated with a non-RAASi BP lowering agent that can be ceased.
4.Willing and able to comply with all study requirements, including treatment, timing and/or nature of required assessments.
5.Documented informed consent.

Exclusion Criteria

1.Currently treated with an ACEi, ARB or aldosterone antagonist, aliskiren, or ARNi 2.Intolerance of ARBs 3.Serum potassium >5.5 mmol/L 4.An estimated Glomerular Filtration Rate (eGFR) <30ml/min/1.732m 5.Known biliary obstruction, known severe hepatic impairment (Child-Pugh-Turcotte score 10-15) 6.Pregnancy, lactation, or inadequate contraception.
o Female participants must be either post-menopausal, infertile or use a reliable means of contraception for at least 60 days after the last dose of investigational product or refrain.
Where they are of childbearing potential, female participants must also have a negative pregnancy test result within 7 days prior to registration.
o Male participants must have been surgically sterilised or use a (double if required) barrier method of contraception during the treatment period and for at least 60 days after the last dose of investigational product or refrain from donating sperm during this period.
7.Participation in a study of a novel investigational product within 28 days prior to randomisation.
8.Plans to participate in another study of a novel investigational product during this study.

Study & Design

Study Type: Interventional

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
The primary endpoint is a Clinical Health Score, determined within a 7-point ordinal scale of clinical health status which is a modified version of the 9-point score developed by the WHO for Coronavirus Disease 2019 (COVID-19) trials.	Day 1-14

Secondary Outcome Measures

Name	Time	Method
ICU admission	Day 0-28
Incidence of Respiratory Failure	Day 0-28
Length of hospitalisation	From admission to discharge/death
Length of ICU admission	From ICU admission to discharge to ward/death
Requirement of ventilatory support	Days 0-28
Requirement of dialysis	Days 0-28
Clinical Health Score	Day 28
Death	Day 0-28
Time to death	Between hospital admission and death
Incidence of Acute Kidney Injury	Day 0-28

Trial Locations

Locations (10): All India Institute of Medical Sciences
🇮🇳
Raipur, CHHATTISGARH, India
Amrita Institute of Medical Sciences
🇮🇳
Kozhikode, KERALA, India
DM Wayanad Institute of Medical Sciences
🇮🇳
Wayanad, KERALA, India
Government Medical College and Hospital
🇮🇳
Chandigarh, CHANDIGARH, India
Jawaharlal Nehru Medical College and Hospital
🇮🇳
Aligarh, UTTAR PRADESH, India
Jivanrekha Multispecialty Hospital
🇮🇳
Pune, MAHARASHTRA, India
Kasturba Medical College
🇮🇳
Udupi, KARNATAKA, India
Maharaja Agrasen Multispeciality Hospital
🇮🇳
Jaipur, RAJASTHAN, India
Samishta Hospital and Research Institute
🇮🇳
Guntur, ANDHRA PRADESH, India
Sterling Multispecialty Hospital
🇮🇳
Pune, MAHARASHTRA, India
All India Institute of Medical Sciences
🇮🇳Raipur, CHHATTISGARH, India
Dr Vinay Rathore
Principal investigator
9914699651
vinayrathoremd@gmail.com