Efficacy of PMZ-2010 (Centhaquine) a Resuscitative Agent for Hypovolemic Shock

Study Overview
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Brief Summary
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This is a prospective, multi-centric, randomized, double-blind, parallel, controlled phase-III efficacy clinical study of PMZ-2010 therapy in patients with hypovolemic shock. Centhaquine (previously used names, centhaquin and PMZ-2010; International Non-proprietary Name (INN) recently approved by WHO is centhaquine) has been found to be an effective resuscitative agent in rat, rabbit and swine models of hemorrhagic shock, it decreased blood lactate, increased mean arterial pressure, cardiac output, and decreased mortality. An increase in cardiac output during resuscitation is mainly attributed to an increase in stroke volume. Centhaquine acts on the venous α2B-adrenergic receptors and enhances venous return to the heart, in addition, it produces arterial dilatation by acting on central α2A-adrenergic receptors to reduce sympathetic activity and systemic vascular resistance.

Detailed Description
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Approximately 105 patients will be randomized 2:1 into 2 treatment groups after meeting the eligibility criteria. Total 70 patients will be enrolled in PMZ-2010 group (Group 1) and in Normal Saline group (Group 2) total 35 patients will be enrolled. Group 1: PMZ-2010 (Dose: 0.01 mg/kg) + Standard of care Group 2: Normal Saline (Dose: Equal volume) + Standard of care In both treatment groups, patients will be provided the standard of care. PMZ-2010 or Normal Saline will be administered intravenously after randomization to hypovolemic shock patients with systolic arterial blood pressure ≤ 90 mmHg at presentation and continue to receive standard Shock Treatment. In PMZ-2010 group, dose of PMZ-2010 (0.01 mg/kg) will be administered as an intravenous (IV) infusion over 1 hour in 100 mL of normal saline. Second dose of PMZ-2010 will be administered if SBP falls below or remains below or equal to 90 mmHg but not before 4 hours of previous dose and total doses per day (in 24 hours) will not exceed 3 doses. PMZ-2010 administration if needed will continue for two days post randomization. Minimum 1 dose or maximum 6 doses of PMZ-2010 will be administered within first 48 hours. post randomization. In Control group, single dose of equal volume of Normal Saline will be administered as intravenous (IV) infusion over 1 hour in 100 mL of normal saline post randomization. Condition of administration will remain same as for PMZ-2010 group. Each patient will be monitored closely throughout his/her hospitalization and will be followed until discharge from randomization. Each patient will be assessed for efficacy parameters over 28 days from randomization to a clinic visit.

Official Title
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A Prospective, Multi-Centric, Randomized, Double-Blind, Parallel, Phase-III Study to Assess Efficacy of PMZ-2010 as a Resuscitative Agent for Hypovolemic Shock to be Used as an Adjuvant to Standard Shock Treatment

Conditions
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Hypovolemic Shock

Intervention / Treatment
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* Drug: Normal saline + Standard Treatment
* Drug: Centhaquine + Standard Treatment


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with hypovolemic shock admitted to the emergency room or ICU with systolic blood pressure ≤ 90 mmHg at presentation and continue to receive standard shock treatment. Blood Lactate level indicative of hypovolemic shock (>2.0 mmol/L). Exclusion Criteria: Development of any other terminal illness not associated with Hypovolemic shock during the 28-day observation period. Patient with altered consciousness not due to Hypovolemic shock. Known 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
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 + Standard Treatment<br>* Normal Saline to be Used as Vehicle in the Phase-III Study to Assess Efficacy of PMZ-2010 as a Resuscitative Agent for Hypovolemic Shock<br>* Other names: Vehicle;|
| Experimental: PMZ-2010 (centhaquine)<br>Hypovolemic shock patients will be provided the standard of care. Following randomization PMZ-2010 (0.01 mg/kg) will be administered intravenously over 1 hour in 100 mL of normal saline. | Drug: Centhaquine + Standard Treatment<br>* Phase-III Study to Assess Efficacy of PMZ-2010 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 |
| --- | --- | --- |
| Change in systolic and diastolic blood pressure | Change in systolic and diastolic blood pressure - Mean through 48 hours | 48 hours | 
| Change in blood lactate level | Change in blood lactate level - Mean through 48 hours | 48 hours | 
| Change in base-deficit | Change in Base-deficit - Mean through 48 hours | 48 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total Urine Output | Total volume of urine output - Mean through 48 hours | 48 hours | 
| Vasopressor(s) infused | Amount of total vasopressor(s) infused - Mean through 48 hours | 48 hours | 
| Volume of fluid administered | Total volume of fluid administered - Mean through 48 hours | 48 hours | 
| Doses of study drug | Number of doses of study drug administered in first 48 hours post randomization | 48 hours | 
| Incidence of mortality | Proportion of patients with all-cause mortality at 48 hours and 28 days | 28 days | 
| Stay in hospital, in ICU and/or on Ventilator | Days in hospital, in ICU and/or on Ventilator - Mean through 28 days | 28 days | 
| Change in Multiple Organ Dysfunction Syndrome Score | Change in Multiple Organ Dysfunction Syndrome Score (MODS) - Mean through 28 days. MODS is a 5 grade scale from 0 to 4, where 0 is the best and 4 is the worst outcome. | 28 days | 
| Change in Acute Respiratory Distress Syndrome | Change in Acute Respiratory Distress Syndrome (ARDS) - Mean through 28 days. ARDS will be determined using Murray Score for Acute Lung Injury which is based upon radiological findings, oxygenation status, ventilation status of the patient. A lower score of 0 is the best and about 2.5 is the worst outcome. | 28 days | 
| Change in Glasgow coma score | Change in Glasgow coma score (GCS) - Mean through 28 days. GCS is a 15 point scale to assess the level of consciousness of patients where less than 3 is comatose state and 15 is fully awake. | 28 days | 
| Incidence of adverse events | Proportion of patients with drug related adverse events during 28 days | 28 days |