Multicentric, Randomized Study to Assess Safety and Efficacy of Centhaquine in COVID-19 Patients With ARDS

Study Overview
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Brief Summary
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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel coronavirus causing coronavirus disease 2019 (COVID-19), which has been a global pandemic since March 2020. According to WHO, more than 289 million cases have been confirmed worldwide, with just over 5.4 million reported deaths as of January 2022. SARS-CoV-2 variants continue to emerge, with the omicron variant causing the increased surge in cases. Currently, Johns Hopkins University of Medicine reports a case fatality rate of 1.5% for the United States. COVID-19 infections may be asymptomatic in some cases, while most cases cause mild to moderate illness with respiratory and flu-like symptoms. However, a significant number of COVID-19 cases develop severe life-threatening illness involving severe pneumonia and acute respiratory distress syndrome (ARDS), requiring admission to the intensive care unit (ICU) Although there have been breakthroughs in the treatment for COVID-19, most of these are directed at mild-to-moderate disease rather than patients with severe disease on mechanical ventilators. There is still a need for novel and effective treatment options in severe COVID-19 illness with continued vaccine hesitancy, decreased social distancing, and new emerging variants. Centhaquine is a first-in-class resuscitative agent for the hypovolemic shock that is approved for marketing in India. Centhaquine has been found to be an effective resuscitative agent in rat, rabbit, and swine models of hemorrhagic shock. Its safety and tolerability have been demonstrated in a human phase I study in 25 subjects (CTRI/2014/06/004647). Clinical phase II (CTRI/2017/03/008184) and phase III (CTRI/2019/01/017196) results indicate that centhaquine is a novel first-in-class, highly effective resuscitative agent for hypovolemic shock. Centhaquine provided hemodynamic stability and significantly improved acute respiratory distress syndrome (ARDS) and multiple organ dysfunction score (MODS) in clinical trials conducted in India. A total of 155 patients with hypovolemic shock have been studied (combined phase II and III). Centhaquine is safe and reduced the mortality from 10.71% in patients receiving standard treatment to 2.20% in patients that received centhaquine (odds ratio 5.340; 95% CI 1.270-26.50; P=0.0271). In a phase 3 study of hypovolemic shock, ARDS and MODS were secondary endpoints, and centhaquine reduced both with a significant p-value.

Detailed Description
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This is a multicentric, randomized, double-blind, placebo-controlled phase-II clinical study to assess the safety and efficacy of centhaquine as an adjuvant to the standard of care in critically ill COVID-19 patients with ARDS. For an individual patient, the duration of the study will be 1 month (28 days), including 2 study visits: visit 1/Day 1 (screening/randomization/baseline/treatment visit) and visit 2/End of Study (Day 28 ). At visit 1, eligible patients will be randomized into 2 groups: Group 1: Centhaquine (Dose: 0.01 mg/kg) + Standard of care Group 2: Placebo (Dose: equal volume saline) + Standard of care In both treatment groups, patients will be provided the standard of care. Centhaquine or placebo will be administered intravenously after randomization to COVID-19 patients meeting inclusion criteria. In the centhaquine group, centhaquine (0.01 mg/kg) dose will be administered as an intravenous (IV) infusion over 1 hour in 100 mL of normal saline. An additional dose of centhaquine will be administered if oxygenation is required or SBP remains or falls below or equal to 90 mmHg but not before 24 hours of the previous dose. In the control group, placebo (equal volume of normal saline) will be administered as intravenous (IV) infusion over 1 hour in 100 mL of normal saline post-randomization. Conditions of administration will remain the same as for the centhaquine group. All subjects will be closely monitored during and after infusion. Vital signs will be monitored every 10 minutes during infusion. In the event of worsening hemodynamics or respiratory status, the infusion will be discontinued. Each subject will also be monitored closely throughout his/her hospitalization and will be followed until discharge from randomization. Each subject will be assessed for efficacy and safety parameters over 28 days from randomization.

Official Title
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A Multicentric Randomized, Double-blind, Placebo-controlled Study to Assess the Safety and Efficacy of Centhaquine as an Adjuvant to the Standard of Care in COVID-19 Patients With Moderate to Severe Acute Respiratory Distress Syndrome

Conditions
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COVID-19 Acute Respiratory Distress Syndrome

Intervention / Treatment
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* Drug: Normal Saline
* Drug: Centhaquine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: A subject will be eligible for inclusion in the study if he/she fulfils the following criteria: Adult males or females aged 18 years or older RT-PCR confirmation for SARS-CoV2 infection from respiratory tract specimens) Currently hospitalized and intubated COVID-19 patients P/F ratio of <100 mmHg with PEEP ≥ 5 cm H20 Systolic blood pressure below 90 mmHg Written informed consent Exclusion Criteria: A subject will not be eligible for inclusion in this study if he/she meets any of the following exclusion criteria: Patients with confirmed pregnancy Breast feeding patients Patient is participating in another interventional study Patient developing ARDS due to fluid overload or congestive heart failure Patients with alternative causes of hypotension not related to COVID-19 (e.g., hypovolemia, neurogenic, iatrogenic) Patients with renal impairment (eGFR < 60 ml/min/1.73 m2) Patients with hepatic impairment (Child Pugh scores B and C)

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 |
| --- | --- |
| Placebo Comparator: Normal saline<br>Placebo (Dose: equal volume saline) + Standard of care | Drug: Normal Saline<br>* Placebo (Dose: equal volume saline) + Standard of care<br>* Other names: Vehicle;|
| Active Comparator: Centhaquine<br>Centhaquine (Dose: 0.01 mg/kg) + Standard of care | Drug: Centhaquine<br>* Centhaquine (Dose: 0.01 mg/kg) + Standard of care<br>* Other names: PMZ-2010;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical improvement of ARDS in critically ill COVID-19 patients | • The study's primary objective is to determine the clinical improvement of moderate to severe ARDS in COVID-19 patients | 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 28-day all-cause mortality | Incidence of 28-day all-cause mortality | 28 days | 
| Time to clinical improvement on WHO 8-point ordinal scale | Time to clinical improvement on WHO 8-point ordinal scale (ranging from 1-Ambulatory to 8-Death) | 28 days | 
| Days in hospital | Days in hospital [Time frame: The number of days beginning with the day of randomization counted as Day 1 through Day 28 during which the patient is being cared in the hospital] | 28 days | 
| Days in ICU | Days in ICU [Time frame: The number of days beginning with the day of randomization counted as Day 1 through Day 28 during which the patient is being cared in the ICU] | 28 days | 
| Ventilator free days (VFDs) | Ventilator free days (VFDs) in hospital [Time frame: The number of days beginning with the day of the episode counted as Day 1 through Day 28, during which the patient is being cared for in the hospital] | 28 days | 
| Days on organ support therapeutic procedures (renal replacement therapy, cardiovascular support) | Days on organ support therapeutic procedures (renal replacement therapy, cardiovascular support) [Time frame: The number of days beginning with the day of randomization counted as Day 1 through Day 28, during which the patient is being cared on renal replacement therapy, cardiovascular support] | 28 days | 
| Amount of total vasopressor(s) infused. | Amounts of total vasopressor(s) infused; Mean through from the time of randomization till Day 9 [Time frame: from the time of randomization till Day 9] | 9 days | 
| Change in Multiple Organ Dysfunction Syndrome Score (MODS) | Multiple Organ Dysfunction Syndrome Score (MODS); Mean through from the time of randomization till Day 9 [Time frame: from the time of randomization till Day 9] | 9 days | 
| Adverse events (AEs) and serious adverse events (SAEs) | Proportion of patients with adverse events (AEs) and serious adverse events (SAEs) | 28 days |