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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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COVID-19, SARS-CoV2 Infection

Intervention / Treatment
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* Drug: Candesartan Cilexetil
* Drug: Repagermanium
* Drug: Candesartan Placebo
* Drug: Repagermanium Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adults aged ≥ 18 years (maximum 65 years old in India). 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) Intended for hospital admission for management of COVID-19. 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. Systolic Blood Pressure (SBP) ≥ 120 mmHg OR SBP ≥ 115 mmHg and currently treated with a non-RAASi BP lowering agent that can be ceased. Willing and able to comply with all study requirements, including treatment, timing and/or nature of required assessments. Documented informed consent. Exclusion Criteria: Currently treated with an ACEi, ARB or aldosterone antagonist, aliskiren, or ARNi Intolerance of ARBs Serum potassium >5.5 mmol/L An estimated Glomerular Filtration Rate (eGFR) <30ml/min/1.732m Known biliary obstruction, known severe hepatic impairment (Child-Pugh-Turcotte score 10-15) Pregnancy, lactation, or inadequate contraception. Participation in a study of a novel investigational product within 28 days prior to randomisation. Plans to participate in another study of a novel investigational product during this study.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Interventional Arm<br>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<br>* Angiotensin Receptor Blocker (ARB)<br>Drug: Repagermanium<br>* C-C chemokine receptor type 2 (CCR2) antagonist<br>* Other names: DMX-200;|
| Placebo Comparator: Control Arm #1<br>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<br>* Angiotensin Receptor Blocker (ARB)<br>Drug: Repagermanium Placebo<br>* C-C chemokine receptor type 2 (CCR2) antagonist placebo<br>|
| Placebo Comparator: Control Arm #2<br>Titratable matched placebo candesartan one tablet twice daily + matched placebo repagermanium one capsule twice daily. Treatment will continue for 28 days. | Drug: Candesartan Placebo<br>* Angiotensin Receptor Blocker (ARB) placebo<br>Drug: Repagermanium Placebo<br>* C-C chemokine receptor type 2 (CCR2) antagonist placebo<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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COVID-19, SARS-CoV2, Angiotensin Receptor Blocker (ARB), C-C chemokine receptor type 2 (CCR2) antagonist