Controlled Trial of Angiotensin Receptor Blocker (ARB) & Chemokine Receptor Type 2 (CCR2) Antagonist for the Treatment of COVID-19 (CLARITY 2)

An Investigator Initiated, International Multi-Centre, Multi-Arm, Multi-Stage Randomised Double Blind Placebo Controlled Trial of Angiotensin Receptor Blocker (ARB) & Chemokine Receptor Type 2 (CCR2) Antagonist for the Treatment of COVID-19

CLARITY 2.0 is an investigator-initiated trial that will evaluate the safety and efficacy of dual treatment with repagermanium, a CCR2 antagonist, and candesartan, an ARB, in patients hospitalised with COVID-19 disease.

Study Overview

• Status: Terminated
• Conditions: COVID-19; SARS-CoV2 Infection
• Intervention / Treatment: Drug: Candesartan Cilexetil; Drug: Repagermanium; Drug: Repagermanium Placebo; Drug: Candesartan Placebo

• Study Type: Interventional
• Enrollment (Actual): 49
• Phase: Phase 2

Contacts and Locations

Study Locations

• India
  • Aligarh, India
    • Jawaharlal Nehru Medical College and Hospital
  • Chandigarh, India
    • Government Medical College and Hospital
  • Guntur, India
    • Samishta Hospital and Research Institute
  • Jaipur, India
    • Maharaja Agrasen Hospital
  • Kochi, India
    • Amrita Institute Of Medical Science
  • Mangaluru, India
    • Kasturba Medical College
  • Meppadi, India
    • DM Wayanad Institute of Medical Sciences
  • Nigdi, India
    • Sterling Hospital
  • Pune, India
    • Jivanrekha Multi-Speciality Hospital
  • Raipur, India
    • All India Institute of Medical Sciences, Raipur

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Adults aged ≥ 18 years (maximum 65 years old in India).
2. Laboratory-confirmed diagnosis of SARS-CoV-2 infection within 10 days prior to randomisation. (Confirmation must be through Reverse Transcription Polymerase Chain Reaction [RT-PCR] method)
3. Intended for hospital admission for management of COVID-19.
4. Patients with moderate (respiratory rate of ≥ 24/minute or SPO2: 90% to ≤ 93% on room air) or severe (respiratory rate of ≥ 30/minute or SPO2: <90% on room air) COVID-19.
5. Systolic Blood Pressure (SBP) ≥ 120 mmHg OR SBP ≥ 115 mmHg and currently treated with a non-RAASi BP lowering agent that can be ceased.
6. Willing and able to comply with all study requirements, including treatment, timing and/or nature of required assessments.
7. 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.
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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Interventional Arm; Titratable candesartan with commencing dose 4mg tablets twice daily (daily dose 8 mg) + fixed dose repagermanium one x 120mg immediate release capsule twice daily (total daily dose 240mg). Treatment will continue for 28 days.	Drug: Candesartan Cilexetil; Angiotensin Receptor Blocker (ARB); Drug: Repagermanium; C-C chemokine receptor type 2 (CCR2) antagonist; Other Names: DMX-200
Placebo Comparator: Control Arm #1; Titratable candesartan with commencing dose 4mg tablets twice daily (daily dose 8 mg) + matched placebo repagermanium one capsule twice daily. Treatment will continue for 28 days.	Drug: Candesartan Cilexetil; Angiotensin Receptor Blocker (ARB); Drug: Repagermanium Placebo; C-C chemokine receptor type 2 (CCR2) antagonist placebo
Placebo Comparator: Control Arm #2; Titratable matched placebo candesartan one tablet twice daily + matched placebo repagermanium one capsule twice daily. Treatment will continue for 28 days.	Drug: Repagermanium Placebo; C-C chemokine receptor type 2 (CCR2) antagonist placebo; Drug: Candesartan Placebo; Angiotensin Receptor Blocker (ARB) placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical Health Score at day 14	The primary objective is to evaluate the safety and efficacy of dual treatment with repagermanium and candesartan in patients hospitalised with COVID-19 disease, assessed by the Clinical Health Score at day 14, which is determined within an 8-point ordinal scale of health status: Not hospitalised, no limitations on activities.; Not hospitalised, limitation on activities.; Hospitalised, not requiring supplemental oxygen.; Hospitalised, requiring supplemental oxygen by mask or nasal prongs.; Hospitalised, on non-invasive ventilation or high-flow oxygen devices.; Hospitalised, requiring intubation and mechanical ventilation.; Hospitalised, on invasive mechanical ventilation and additional organ support (ECMO).; Death.	14 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical Health Score at day 28	The primary objective is to evaluate the safety and efficacy of dual treatment with repagermanium and candesartan in patients hospitalised with COVID-19 disease, assessed by the Clinical Health Score at day 28, which is determined within an 8-point ordinal scale of health status: Not hospitalised, no limitations on activities.; Not hospitalised, limitation on activities.; Hospitalised, not requiring supplemental oxygen.; Hospitalised, requiring supplemental oxygen by mask or nasal prongs.; Hospitalised, on non-invasive ventilation or high-flow oxygen devices.; Hospitalised, requiring intubation and mechanical ventilation.; Hospitalised, on invasive mechanical ventilation and additional organ support (ECMO).; Death.	28 days
ICU admission	The secondary objectives are to evaluate the safety and efficacy of dual treatment with repagermanium and candesartan in patients hospitalised with COVID-19 disease, assessed by incidence of ICU admission in days 0-28.	28 days
Death	The secondary objectives are to evaluate the safety and efficacy of dual treatment with repagermanium and candesartan in patients hospitalised with COVID-19 disease, assessed by incidence of deaths in days 0-28.	28 days
Time to death	The secondary objectives are to evaluate the safety and efficacy of dual treatment with repagermanium and candesartan in patients hospitalised with COVID-19 disease, assessed from hospital admission to death.	28 days
Acute Kidney Injury	The secondary objectives are to evaluate the safety and efficacy of dual treatment with repagermanium and candesartan in patients hospitalised with COVID-19 disease, assessed by incidence of acute kidney injury in days 0-28.	28 days
Respiratory Failure	The secondary objectives are to evaluate the safety and efficacy of dual treatment with repagermanium and candesartan in patients hospitalised with COVID-19 disease, assessed by incidence of respiratory failure in days 0-28.	28 days
Length of hospital admission	The secondary objectives are to evaluate the safety and efficacy of dual treatment with repagermanium and candesartan in patients hospitalised with COVID-19 disease, assessed by days of inpatient stay from admission to discharge or death.	28 days
Length of ICU Admission	The secondary objectives are to evaluate the safety and efficacy of dual treatment with repagermanium and candesartan in patients hospitalised with COVID-19 disease, assessed by days in ICU from admission to transfer to ward or death.	28 days
Requirement of ventilatory support	The secondary objectives are to evaluate the safety and efficacy of dual treatment with repagermanium and candesartan in patients hospitalised with COVID-19 disease, assessed by count of days with ventilation in days 0-28.	28 days
Requirement of dialysis	The secondary objectives are to evaluate the safety and efficacy of dual treatment with repagermanium and candesartan in patients hospitalised with COVID-19 disease, assessed by count of days with dialysis in days 0-28.	28 days
Clinical Health Score at day 60	The primary objective is to evaluate the safety and efficacy of dual treatment with repagermanium and candesartan in patients hospitalised with COVID-19 disease, assessed by the Clinical Health Score at day 60, which is determined within an 8-point ordinal scale of health status: Not hospitalised, no limitations on activities.; Not hospitalised, limitation on activities.; Hospitalised, not requiring supplemental oxygen.; Hospitalised, requiring supplemental oxygen by mask or nasal prongs.; Hospitalised, on non-invasive ventilation or high-flow oxygen devices.; Hospitalised, requiring intubation and mechanical ventilation.; Hospitalised, on invasive mechanical ventilation and additional organ support (ECMO).; Death.	60 days
Clinical Health Score at day 90	The primary objective is to evaluate the safety and efficacy of dual treatment with repagermanium and candesartan in patients hospitalised with COVID-19 disease, assessed by the Clinical Health Score at day 90, which is determined within an 8-point ordinal scale of health status: Not hospitalised, no limitations on activities.; Not hospitalised, limitation on activities.; Hospitalised, not requiring supplemental oxygen.; Hospitalised, requiring supplemental oxygen by mask or nasal prongs.; Hospitalised, on non-invasive ventilation or high-flow oxygen devices.; Hospitalised, requiring intubation and mechanical ventilation.; Hospitalised, on invasive mechanical ventilation and additional organ support (ECMO).; Death.	90 days
Clinical Health Score at day 180	The primary objective is to evaluate the safety and efficacy of dual treatment with repagermanium and candesartan in patients hospitalised with COVID-19 disease, assessed by the Clinical Health Score at day 180, which is determined within an 8-point ordinal scale of health status: Not hospitalised, no limitations on activities.; Not hospitalised, limitation on activities.; Hospitalised, not requiring supplemental oxygen.; Hospitalised, requiring supplemental oxygen by mask or nasal prongs.; Hospitalised, on non-invasive ventilation or high-flow oxygen devices.; Hospitalised, requiring intubation and mechanical ventilation.; Hospitalised, on invasive mechanical ventilation and additional organ support (ECMO).; Death.	180 days

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of Hypotension	The specific safety objectives are to evaluate the safety of dual treatment with repagermanium and candesartan in patients hospitalised with COVID-19 disease, assessed by incidence of hypotension in days 0-28.	28 days
Incidence of Hyperkalemia	The specific safety objectives are to evaluate the safety of dual treatment with repagermanium and candesartan in patients hospitalised with COVID-19 disease, assessed by incidence of hyperkalemia in days 0-28.	28 days
Incidence of Deranged Liver Function Tests	The specific safety objectives are to evaluate the safety of dual treatment with repagermanium and candesartan in patients hospitalised with COVID-19 disease, assessed by incidence of deranged liver function tests in days 0-28.	28 days
Total Serious Adverse Events (SAEs)	The specific safety objectives are to evaluate the safety of dual treatment with repagermanium and candesartan in patients hospitalised with COVID-19 disease, assessed by total number of SAEs in days 0-28.	28 days
Incidence of hospital readmission	Admission for overnight stay up to day 90 following initial hospital discharge.	90 days

Collaborators and Investigators

• Sponsor: University of Sydney
• Collaborators: The George Institute for Global Health, India
• Investigators: Study Chair: Meg Jardine, NHMRC Clinical Trials Centre, The University of Sydney; Study Chair: Vivekanand Jha, The George Institute for Global Health, India

Study record dates

Study Major Dates

• Study Start (Actual): January 7, 2022
• Primary Completion (Actual): August 15, 2022
• Study Completion (Actual): January 28, 2023

Study Registration Dates

• First Submitted: November 14, 2021
• First Submitted That Met QC Criteria: November 14, 2021
• First Posted (Actual): November 16, 2021

Study Record Updates

• Last Update Posted (Actual): September 15, 2023
• Last Update Submitted That Met QC Criteria: September 13, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Keywords: COVID-19; SARS-CoV2; Angiotensin Receptor Blocker (ARB); C-C chemokine receptor type 2 (CCR2) antagonist
• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; COVID-19; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Antineoplastic Agents; Immunologic Factors; Angiotensin II Type 1 Receptor Blockers; Angiotensin Receptor Antagonists; Interferon Inducers; Candesartan; Candesartan cilexetil; Propagermanium
• Other Study ID Numbers: CTC0312

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Trial data will be disseminated in the form of a publication to a relevant clinical journal and presentation at appropriate scientific conferences.

Individual participant data that underlie the results reported, after de-identification (text, tables, figures, and appendices), may be shared with Investigators whose proposed use of the data has been approved by an independent review committee ("learned intermediary") identified for this purpose.

IPD Sharing Access Criteria

Data will be available after publication for an indefinite time / for a finite time (specify dates) All data requests will be considered by the primary sponsor on a case-by-case basis. Requests must include a methodologically sound proposal. Specific conditions of use may apply and will be specified in a data sharing agreement that the requester must agree to before access is granted.

Access can be requested via the Health Data Australia catalogue

• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; ICF; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No