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

Primary Purpose

Hypovolemic Shock

Status
Not yet recruiting
Phase
Phase 3
Locations
Study Type
Interventional
Intervention
Normal Saline
Centhaquine
Sponsored by
Pharmazz, Inc.
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Hypovolemic Shock

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

A subject will be eligible for inclusion in the study if he/she fulfils the following criteria:

  1. Adult males or females aged 18 years or older.
  2. 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.
  3. 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:

  1. Subject with illness clinically defined as septic shock (Procalcitonin plasma levels of ≥0.5 ng/mL) or cardiogenic shock or neurogenic shock.
  2. Subject for whom an etiology for hypovolemic shock cannot be determined on initial evaluation.
  3. Hypovolemic shock due to traumatic brain injury, traumatic tamponade, traumatic tension pneumothorax, ventricular wall rupture.
  4. Patient with altered consciousness not due to hypovolemic shock.
  5. Subject with confirmed pregnancy.
  6. Cardiopulmonary resuscitation (CPR) before randomization.
  7. Presence of a do not resuscitate order.
  8. Patient is participating in another interventional study.
  9. Patients with systemic diseases which were already present before having trauma, such as: cancer, chronic renal failure, liver failure, decompensated heart failure or AIDS.

Sites / Locations

    Arms of the Study

    Arm 1

    Arm 2

    Arm Type

    Active Comparator

    Experimental

    Arm Label

    Normal saline

    Centhaquine

    Arm Description

    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.

    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.

    Outcomes

    Primary Outcome Measures

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

    Secondary Outcome Measures

    Proportion of subjects with all-cause mortality within 48 hours
    Proportion of subjects with all-cause mortality within 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
    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.
    Proportion of patients with adverse events (AEs) and serious adverse events (SAEs)
    Proportion of patients with adverse events (AEs) and serious adverse events (SAEs)

    Full Information

    First Posted
    February 11, 2022
    Last Updated
    June 19, 2023
    Sponsor
    Pharmazz, Inc.
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    1. Study Identification

    Unique Protocol Identification Number
    NCT05251181
    Brief Title
    A Study to Assess Safety and Efficacy of Centhaquine as a Resuscitative Agent
    Official Title
    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
    Study Type
    Interventional

    2. Study Status

    Record Verification Date
    June 2023
    Overall Recruitment Status
    Not yet recruiting
    Study Start Date
    October 2023 (Anticipated)
    Primary Completion Date
    October 2025 (Anticipated)
    Study Completion Date
    October 2025 (Anticipated)

    3. Sponsor/Collaborators

    Responsible Party, by Official Title
    Sponsor
    Name of the Sponsor
    Pharmazz, Inc.

    4. Oversight

    Studies a U.S. FDA-regulated Drug Product
    Yes
    Studies a U.S. FDA-regulated Device Product
    No

    5. Study Description

    Brief Summary
    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
    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.

    6. Conditions and Keywords

    Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
    Hypovolemic Shock

    7. Study Design

    Primary Purpose
    Treatment
    Study Phase
    Phase 3
    Interventional Study Model
    Parallel Assignment
    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
    ParticipantCare ProviderInvestigatorOutcomes Assessor
    Masking Description
    In this double-blind study, the subject and all relevant personnel involved with the conduct and interpretation of the study (including investigator, investigational site personnel, and the sponsor or designee's staff) will remain blinded to the identity of the Investigational Product (IP) assigned and the randomization codes. The final randomization list will be kept strictly confidential, filed securely by the independent biostatistician, and accessible only to authorized persons as per the sponsor's standard operating procedures until the completion of the study.
    Allocation
    Randomized
    Enrollment
    430 (Anticipated)

    8. Arms, Groups, and Interventions

    Arm Title
    Normal saline
    Arm Type
    Active Comparator
    Arm Description
    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.
    Arm Title
    Centhaquine
    Arm Type
    Experimental
    Arm Description
    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.
    Intervention Type
    Drug
    Intervention Name(s)
    Normal Saline
    Other Intervention Name(s)
    Vehicle
    Intervention Description
    Normal Saline to be Used as Vehicle in the Phase-III Study to Assess Efficacy of Centhaquine as a Resuscitative Agent for Hypovolemic Shock
    Intervention Type
    Drug
    Intervention Name(s)
    Centhaquine
    Other Intervention Name(s)
    PMZ-2010
    Intervention Description
    Phase-III Study to Assess Efficacy of Centhaquine as a Resuscitative Agent for Hypovolemic Shock
    Primary Outcome Measure Information:
    Title
    Proportion of subjects with all-cause mortality [Time frame: Day 0 through day 28].
    Description
    Incidence of mortality
    Time Frame
    Day 0 through day 28
    Secondary Outcome Measure Information:
    Title
    Proportion of subjects with all-cause mortality within 48 hours
    Description
    Proportion of subjects with all-cause mortality within 48 hours
    Time Frame
    48 hours
    Title
    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
    Description
    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
    Time Frame
    First 48 hours and at the time of discharge or day 7
    Title
    Time (hours) to decrease blood lactate level to <2 mmol/L
    Description
    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.
    Time Frame
    48 hours
    Title
    Proportion of patients with adverse events (AEs) and serious adverse events (SAEs)
    Description
    Proportion of patients with adverse events (AEs) and serious adverse events (SAEs)
    Time Frame
    Day 0 through day 28

    10. Eligibility

    Sex
    All
    Minimum Age & Unit of Time
    18 Years
    Accepts Healthy Volunteers
    No
    Eligibility Criteria
    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.

    12. IPD Sharing Statement

    Citations:
    PubMed Identifier
    34061314
    Citation
    Gulati A, Choudhuri R, Gupta A, Singh S, Ali SKN, Sidhu GK, Haque PD, Rahate P, Bothra AR, Singh GP, Maheshwari S, Jeswani D, Haveri S, Agarwal A, Agrawal NR. A Multicentric, Randomized, Controlled Phase III Study of Centhaquine (Lyfaquin(R)) as a Resuscitative Agent in Hypovolemic Shock Patients. Drugs. 2021 Jun;81(9):1079-1100. doi: 10.1007/s40265-021-01547-5. Epub 2021 Jun 1.
    Results Reference
    result
    PubMed Identifier
    33970455
    Citation
    Gulati A, Jain D, Agrawal NR, Rahate P, Choudhuri R, Das S, Dhibar DP, Prabhu M, Haveri S, Agarwal R, Lavhale MS. Resuscitative Effect of Centhaquine (Lyfaquin(R)) in Hypovolemic Shock Patients: A Randomized, Multicentric, Controlled Trial. Adv Ther. 2021 Jun;38(6):3223-3265. doi: 10.1007/s12325-021-01760-4. Epub 2021 May 10.
    Results Reference
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    PubMed Identifier
    30006694
    Citation
    Kontouli Z, Staikou C, Iacovidou N, Mamais I, Kouskouni E, Papalois A, Papapanagiotou P, Gulati A, Chalkias A, Xanthos T. Resuscitation with centhaquin and 6% hydroxyethyl starch 130/0.4 improves survival in a swine model of hemorrhagic shock: a randomized experimental study. Eur J Trauma Emerg Surg. 2019 Dec;45(6):1077-1085. doi: 10.1007/s00068-018-0980-1. Epub 2018 Jul 13.
    Results Reference
    result
    PubMed Identifier
    34012389
    Citation
    Ranjan AK, Zhang Z, Briyal S, Gulati A. Centhaquine Restores Renal Blood Flow and Protects Tissue Damage After Hemorrhagic Shock and Renal Ischemia. Front Pharmacol. 2021 May 3;12:616253. doi: 10.3389/fphar.2021.616253. eCollection 2021.
    Results Reference
    result
    PubMed Identifier
    28385449
    Citation
    Papalexopoulou K, Chalkias A, Pliatsika P, Papalois A, Papapanagiotou P, Papadopoulos G, Arnaoutoglou E, Petrou A, Gulati A, Xanthos T. Centhaquin Effects in a Swine Model of Ventricular Fibrillation: Centhaquin and Cardiac Arrest. Heart Lung Circ. 2017 Aug;26(8):856-863. doi: 10.1016/j.hlc.2016.11.008. Epub 2016 Dec 19.
    Results Reference
    result
    PubMed Identifier
    27109141
    Citation
    O'Donnell JN, O'Donnell EP, Kumar EJ, Lavhale MS, Andurkar SV, Gulati A, Scheetz MH. Pharmacokinetics of centhaquin citrate in a dog model. J Pharm Pharmacol. 2016 Jun;68(6):803-9. doi: 10.1111/jphp.12554. Epub 2016 Apr 25.
    Results Reference
    result
    PubMed Identifier
    26725913
    Citation
    O'Donnell JN, Gulati A, Lavhale MS, Sharma SS, Patel AJ, Rhodes NJ, Scheetz MH. Pharmacokinetics of centhaquin citrate in a rat model. J Pharm Pharmacol. 2016 Jan;68(1):56-62. doi: 10.1111/jphp.12498. Epub 2016 Jan 4.
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    PubMed Identifier
    26216751
    Citation
    Papapanagiotou P, Xanthos T, Gulati A, Chalkias A, Papalois A, Kontouli Z, Alegakis A, Iacovidou N. Centhaquin improves survival in a swine model of hemorrhagic shock. J Surg Res. 2016 Jan;200(1):227-35. doi: 10.1016/j.jss.2015.06.056. Epub 2015 Jun 29.
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    PubMed Identifier
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    Citation
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    Citation
    Lavhale MS, Havalad S, Gulati A. Resuscitative effect of centhaquin after hemorrhagic shock in rats. J Surg Res. 2013 Jan;179(1):115-24. doi: 10.1016/j.jss.2012.08.042. Epub 2012 Sep 2.
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    Citation
    Gulati A, Lavhale MS, Garcia DJ, Havalad S. Centhaquin improves resuscitative effect of hypertonic saline in hemorrhaged rats. J Surg Res. 2012 Nov;178(1):415-23. doi: 10.1016/j.jss.2012.02.005. Epub 2012 Apr 2.
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    A Study to Assess Safety and Efficacy of Centhaquine as a Resuscitative Agent

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