A Study to Assess Safety and Efficacy of Centhaquine as a Resuscitative Agent

Study Overview
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Brief Summary
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This protocol is designed to develop a novel first-in-class treatment for use in critical care and life-threatening condition of hypovolemic shock with unmet need and is of national interest. Shock is a life-threatening condition of circulatory failure. It is a state of cellular and tissue hypoxia due to reduced oxygen delivery and/or increased oxygen consumption or inadequate oxygen utilization. Shock most commonly occurs when there is circulatory failure leading to reduced tissue perfusion. There are four types of shock: distributive, cardiogenic, hypovolemic, and obstructive. However, these are not exclusive, and many patients with circulatory failure have a combination of more than one form of shock (multifactorial shock).

Detailed Description
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Despite advances in medical science, treatments for hypovolemic shock have changed little in the past 30-40 years. A wounded soldier bleeding on the battlefield, or a trauma victim, is treated today largely as the patient would have been treated in 1970. The primary goal when treating traumatic hemorrhage is to control blood loss, support ventilation and oxygenation, and maintain cardiovascular function to preserve organ blood perfusion. Rapid volume repletion is indicated in patients with severe hypovolemic shock. Delayed therapy can lead to ischemic injury and possibly to irreversible shock and multiorgan system failure. Although resuscitation with intravenous fluids and blood products has remained the gold standard over the last twenty years, vigorous volume resuscitation may not be curative and has been associated with the development of serious complications including coagulopathy, acute lung injury, and abdominal compartment syndrome. Massive resuscitation also profoundly alters the neuroendocrine milieu needed to maintain vasomotor tone and may lead to a state of recalcitrant hypotension, multi-organ failure, and ultimately death in severely injured patients. Vasopressors are generally used to increase blood pressure and cardiac output, but sometimes they are not recommended since they do not correct the primary problem and tend to reduce tissue perfusion further. This study seeks to address the impact of centhaquine on the patient population with hypovolemic shock (prehospital SBP ≤ 90 mmHg). The inclusion of centhaquine during resuscitation could potentially prevent the profound hypotension seen in late-stage shock, limit the need for aggressive volume and blood product resuscitation, and decrease the incidence of resuscitation-associated complications. This study will investigate if early use of centhaquine during the resuscitation of hypovolemic shock results in improved survival at Day 28, fewer blood transfusions, a decreased need for crystalloid resuscitation, and a lower incidence of resuscitation related complications. In animal models of hypovolemic shock, low doses (0.006 to 0.05 mg/kg) of centhaquine proved to be highly effective in resuscitation. Centhaquine significantly decreased blood lactate and increased mean arterial pressure (MAP), pulse pressure, and cardiac output (CO), as well as decreased mortality and increased the survival time of animals with severe blood loss. Furthermore, its resuscitative effect was significantly greater compared to presently used resuscitative solutions. The proposed mechanism of action of centhaquine is that in low doses, it acts on α2B adrenergic receptors to produce venous constriction and a consequent increase in venous return to the heart, and stimulation of sodium sense in the brain to increase the intravascular blood volume. These effects increase cardiac output and tissue blood perfusion, which may be responsible for its resuscitative action. 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. Clinical phase II and III results indicate that centhaquine is a novel first-in-class, highly effective resuscitative agent for hypovolemic shock due to blood loss. Safety and highly significant efficacy in improving blood pressure, lactate levels, base deficit, and reduction in the use of vasopressors and reduced mortality obtained in phase II and III studies in patients of hypovolemic shock are convincing. Therefore, a phase III clinical study in the United States and Europe will be conducted in patients of hypovolemic shock patients. The present multi-centric, randomized, double-blind, placebo-controlled phase-III study aims to assess the efficacy and safety of centhaquine as a resuscitative agent to be used as an adjuvant to standard treatment of hypovolemic shock.

Official Title
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A Multi-Centric, Randomized, Double-Blind, Placebo-controlled, Phase-III Study to Assess Safety and Efficacy of Centhaquine as a Resuscitative Agent to be Used as an Adjuvant to Standard Treatment of Hypovolemic Shock

Conditions
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Hypovolemic Shock

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. Subjects with hypovolemic shock admitted to the hospital with systolic blood pressure ≤ 90 mm Hg at presentation, Mean Arterial Pressor (MAP) ≤ 65 mm Hg and continue to receive standard treatment of shock (endotracheal intubation; fluid resuscitation and vasopressors). Standard of care to be provided to the subject shall be the one used in that hospital. Blood lactate level indicative of hypovolemic shock with lactate level more than 2 mmol/L. Exclusion Criteria: A subject will not be eligible for inclusion in this study if he/she meets any of the following exclusion criteria: Subject with illness clinically defined as septic shock (Procalcitonin plasma levels of ≥0.5 ng/mL) or cardiogenic shock or neurogenic shock. Subject for whom an etiology for hypovolemic shock cannot be determined on initial evaluation. Hypovolemic shock due to traumatic brain injury, traumatic tamponade, traumatic tension pneumothorax, ventricular wall rupture. Patient with altered consciousness not due to hypovolemic shock. Subject with confirmed pregnancy. Cardiopulmonary resuscitation (CPR) before randomization. Presence of a do not resuscitate order. Patient is participating in another interventional study. Patients with systemic diseases which were already present before having trauma, such as: cancer, chronic renal failure, liver failure, decompensated heart failure or AIDS.

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
Interventional Model Description: This is a multi-centric, randomized, double-blind, placebo-controlled phase-III clinical study to assess the safety and efficacy of centhaquine therapy in patients with hypovolemic shock with systolic arterial blood pressure ≤ 90 mmHg at presentation and continue to receive standard treatment of shock. This protocol is designed to develop a novel first-in-class treatment for use in critical care and life-threatening condition of hypovolemic shock with unmet need and is of national interest.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Normal saline<br>Hypovolemic shock patients will be provided the standard of care. Following randomization 100 ml (equal volume to experimental arm) of normal saline will be administered intravenously over 1 hour. | Drug: Normal Saline<br>* Normal Saline to be Used as Vehicle in the Phase-III Study to Assess Efficacy of Centhaquine as a Resuscitative Agent for Hypovolemic Shock<br>* Other names: Vehicle;|
| Experimental: Centhaquine<br>Hypovolemic shock patients will be provided the standard of care. Following randomization centhaquine (0.01 mg/kg) will be administered intravenously over 1 hour in 100 mL of normal saline. | Drug: Centhaquine<br>* Phase-III Study to Assess Efficacy of Centhaquine as a Resuscitative Agent for Hypovolemic Shock<br>* Other names: PMZ-2010;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of subjects with all-cause mortality [Time frame: Day 0 through day 28]. | Incidence of mortality | Day 0 through day 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of subjects with all-cause mortality within 48 hours | Proportion of subjects with all-cause mortality within 48 hours | 48 hours | 
| Change in Mean Arterial Pressure (MAP) from baseline of at least 10 mm Hg; Mean through 48 hours and at the time of discharge or day 7 | Change in Mean Arterial Pressure (MAP) from baseline of at least 10 mm Hg; Mean through 48 hours and at the time of discharge or day 7 | First 48 hours and at the time of discharge or day 7 | 
| Time (hours) to decrease blood lactate level to <2 mmol/L | Time (hours) to decrease blood lactate level to <2 mmol/L; Mean through 2 hours for the first 12 hours, then every 6 hours for the next 36 hours. | 48 hours | 
| Proportion of patients with adverse events (AEs) and serious adverse events (SAEs) | Proportion of patients with adverse events (AEs) and serious adverse events (SAEs) | Day 0 through day 28 |