A Study to Assess the Safety and Efficacy of Centhaquine in Hypovolemic Shock Patients

Official title

A Prospective, Multi-centric, Open-labeled, Phase-IV Study to Assess Safety and Efficacy of LYFAQUIN™ (Centhaquine Citrate) as a Resuscitative Agent for Hypovolemic Shock to be Used as an Adjuvant to Standard Treatment of Shock

Overview

This is a prospective, multi-centric, open-labeled, phase-IV clinical study to evaluate the safety and efficacy of centhaquine citrate (LYFAQUIN™), a first-in-class drug for treating hypovolemic shock, a life-threatening condition caused by severe blood or fluid loss. Centhaquine has been found to be an effective resuscitative agent in rat, rabbit, and swine models of hemorrhagic shock. It has demonstrated the ability to decrease blood lactate levels, increase mean arterial pressure, enhance cardiac output, and reduce mortality rates. The increase in cardiac output during resuscitation is primarily attributed to an augmentation in stroke volume. Centhaquine exerts its effects by acting on the venous α2B-adrenergic receptors, which enhances venous return to the heart. Additionally, it produces arterial dilation by targeting central α2A-adrenergic receptors, thereby reducing sympathetic activity and systemic vascular resistance.

Detailed description

This study will enroll approximately 400 patients aged 18 years or older with hypovolemic shock and a systolic blood pressure of 90 mmHg or lower upon admission to the hospital. These patients will continue to receive standard shock treatment, including endotracheal intubation, fluid resuscitation, and vasopressors. The trial seeks to answer several key questions: Is centhaquine safe to use in patients with hypovolemic shock? Can centhaquine improve blood pressure, lactate levels, and base deficit, and reduce mortality? Participants will receive centhaquine in addition to the standard of care. Centhaquine will be administered intravenously in 100 mL of normal saline at a dose of 0.01 mg/kg of body weight over a period of one hour. A second dose will be given if the systolic blood pressure remains at or below 90 mmHg, but not before 4 hours have passed since the previous dose. The total number of doses within 24 hours will not exceed 3, and centhaquine administration may continue for up to two days after enrollment. Each patient will be closely monitored throughout their hospitalization and followed until discharge or up to seven days from enrollment, whichever comes first. The trial will assess safety and efficacy parameters according to a predefined schedule of visits. The baseline characteristics of the patients in different groups will be compared using statistical tests such as the Chi-square test for categorical variables and the Unpaired t-test for continuous variables. Changes in dichotomous variables between groups from baseline to follow-ups will be analyzed using McNemar's test. Survival rates will be measured using Kaplan-Meier survival analysis, and univariate and multiple Cox-regression analysis will be employed to determine hazard ratios and their 95% confidence intervals for patient survival. The trial results will be presented as mean±SEM (median, minimum, and maximum) values and percentages.

Interventions

• Drug Centhaquine
  Centhaquine (LYFAQUIN™ or centhaquine citrate) is a novel, first-in-class, highly effective resuscitative agent for hypovolemic shock. Phase II results demonstrate highly significant efficacy in improving blood pressure (p\<0.0001), lactate levels (p=0.0012) and base-deficit (p\<0.0001). There was also improvement in reduction in use of vasopressors and reduced mortality. Similarly, results of phase III study confirmed the safety and efficacy of centhaquine as an adjuvant to standard of care for

Primary outcome measures

• Proportion of patients with adverse events (AEs) and serious adverse events (SAEs) [Time frame: Up to 7 days]

Secondary outcome measures (10)

• Systolic and diastolic blood pressure [Time frame: Up to 7 days]
• Blood lactate [Time frame: 48 hours]
• Base-deficit [Time frame: 48 hours]
• Time in intensive care unit (ICU) [Time frame: Up to 7 days]
• Time on ventilator [Time frame: Up to 7 days]
• Urine output [Time frame: 48 hours]
• Incidence of mortality [Time frame: 7 days]
• Multiple Organ Dysfunction Syndrome score (MODS) [Time frame: Up to 7 days]
• Acute Respiratory Distress Syndrome (ARDS) [Time frame: Up to 7 days]
• Glasgow Coma Scale (GCS) [Time frame: Up to 7 days]

Eligibility criteria

Inclusion criteria

• Adult hypovolemic shock patients aged 18 years or older 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 study duration.
• Patient with altered consciousness not due to hypovolemic shock and comatose patient. • Known pregnancy.
• Cardiopulmonary resuscitation (CPR) before enrollment.
• 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 sepsis, cancer, chronic renal failure, liver failure, decompensated heart failure, or AIDS.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

India · 17 centers

• ACSR Government Medical College and Hospital — Nellore
• All India Institute of Medical Sciences (AIIMS) — Raipur
• Aman Hospital — Vadodara
• New Era Hospital — Nagpur
• Seven Star Hospital — Nagpur
• Meditrina Hospital — Nagpur
• Sri Guru Ram Das University of Health Sciences (SGRDH) — Amritsar
• Dayanand Medical College & Hospital (DMCH) — Ludhiana
• … and 9 more centers

Publications

• 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. PMID 22964270
• Geevarghese M 3rd, Patel K, Gulati A, Ranjan AK. Role of adrenergic receptors in shock. Front Physiol. 2023 Jan 16;14:1094591. doi: 10.3389/fphys.2023.1094591. eCollection 2023. PMID 36726848
• 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. PMID 26216751
• 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. PMID 22487389
• Gulati A, Zhang Z, Murphy A, Lavhale MS. Efficacy of centhaquin as a small volume resuscitative agent in severely hemorrhaged rats. Am J Emerg Med. 2013 Sep;31(9):1315-21. doi: 10.1016/j.ajem.2013.05.032. Epub 2013 Jul 19. PMID 23871440
• 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. PMID 30006694
• 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. PMID 34012389
• 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. PMID 33970455

Identifiers

NCT: NCT05956418 · PMZ-2010/CT-4.1/2019

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗