Clinical trial NCT05956418: 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE4
Conditions: Hypovolemic Shock
Keywords: Shock
Hypovolemia
Hemorrhage
Blood Pressure
Resuscitation
Centhaquine
Adrenergic
Lead sponsor: Pharmazz, Inc.
Sponsor class: INDUSTRY
First posted: 2023-07-21
Enrollment: 400
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: This is a prospective, multi-centric, open-labeled, single-arm and phase-IV study in 400 hypovolemic shock patients with a systolic arterial blood pressure ≤ 90 mmHg. The study duration will be approximately 15 months, including a 12-month enrollment period. All patients in the single group of the study will receive treatment with "Centhaquine (Dose: 0.01 mg/kg) + Standard of care." A second dose of centhaquine may be given if the systolic blood pressure remains low. However, the maximum number of doses per day should not exceed 3, and if needed the treatment will continue for the 2nd day of enrollment. Within the first 48 hours post-enrollment, a minimum of 1 dose and a maximum of 6 doses of centhaquine will be administered. Each patient will be closely monitored throughout their hospitalization and followed until discharge or day 7 (whichever comes earlier) from enrollment.
Primary purpose: TREATMENT

Brief summary: 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.

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.

Primary outcomes:
measure: Proportion of patients with adverse events (AEs) and serious adverse events (SAEs)
timeFrame: Up to 7 days
Secondary outcomes:
measure: Systolic and diastolic blood pressure
timeFrame: Up to 7 days
measure: Blood lactate
timeFrame: 48 hours
measure: Base-deficit
timeFrame: 48 hours
measure: Time in intensive care unit (ICU)
timeFrame: Up to 7 days
measure: Time on ventilator
timeFrame: Up to 7 days
measure: Urine output
timeFrame: 48 hours
measure: Incidence of mortality
timeFrame: 7 days
measure: Multiple Organ Dysfunction Syndrome score (MODS)
timeFrame: Up to 7 days
measure: Acute Respiratory Distress Syndrome (ARDS)
timeFrame: Up to 7 days
measure: Glasgow Coma Scale (GCS)
timeFrame: Up to 7 days
Other outcomes:
Locations:
city: Nellore
country: India
facility: ACSR Government Medical College and Hospital
state: Andhra Pradesh
city: Raipur
country: India
facility: All India Institute of Medical Sciences (AIIMS)
state: Chhattisgarh
city: Vadodara
country: India
facility: Aman Hospital
state: Gujarat
city: Nagpur
country: India
facility: New Era Hospital
state: Maharashtra
city: Nagpur
country: India
facility: Seven Star Hospital
state: Maharashtra
city: Nagpur
country: India
facility: Meditrina Hospital
state: Maharashtra
city: Amritsar
country: India
facility: Sri Guru Ram Das University of Health Sciences (SGRDH)
state: Punjab
city: Ludhiāna
country: India
facility: Dayanand Medical College & Hospital (DMCH)
state: Punjab
city: Ludhiāna
country: India
facility: Christian Medical College and Hospital (CMC)
state: Punjab
city: Kota
country: India
facility: Government Medical College
state: Rajasthan
city: Coimbatore
country: India
facility: KG Hospital
state: Tamil Nadu
city: Agra
country: India
facility: Pushpanjali Hospital
state: UP
city: Jhansi
country: India
facility: Maharani Laxmi Bai Medical College (MLBMC)
state: UP
city: Jhānsi
country: India
facility: Nirmal Hospital
state: UP
city: Kanpur
country: India
facility: Ganesh Shankar Vidyarthi Memorial Medical College (GSVM)
state: UP
city: Varanasi
country: India
facility: Janta Hospital
state: UP
city: Kolkata
country: India
facility: IPGMER & SSKM Hospital
state: West Bengal
Study officials:
affiliation: Pharmazz India
name: Manish Lavhale, Ph.D.
role: STUDY_DIRECTOR
References:
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.
citation: 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.
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.
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.
citation: 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.
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.
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.
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.
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.