Clinical trial NCT04045327: Efficacy of PMZ-2010 (Centhaquine) a Resuscitative Agent for Hypovolemic Shock
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Hypovolemic Shock
Lead sponsor: Pharmazz, Inc.
Sponsor class: INDUSTRY
First posted: 2019-08-05
Enrollment: 105
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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:

1. Development of any other terminal illness not associated with Hypovolemic shock during the 28-day observation period.
2. Patient with altered consciousness not due to Hypovolemic shock.
3. Known pregnancy.
4. Cardiopulmonary resuscitation (CPR) before randomization.
5. Presence of a do not resuscitate order.
6. Patient is participating in another interventional study.
7. Patients with systemic diseases which were already present before having trauma, such as: cancer, chronic renal failure, liver failure, decompensated heart failure or AIDS.

Primary outcomes:
measure: Change in systolic and diastolic blood pressure
timeFrame: 48 hours
measure: Change in blood lactate level
timeFrame: 48 hours
measure: Change in base-deficit
timeFrame: 48 hours
Secondary outcomes:
measure: Total Urine Output
timeFrame: 48 hours
measure: Vasopressor(s) infused
timeFrame: 48 hours
measure: Volume of fluid administered
timeFrame: 48 hours
measure: Doses of study drug
timeFrame: 48 hours
measure: Incidence of mortality
timeFrame: 28 days
measure: Stay in hospital, in ICU and/or on Ventilator
timeFrame: 28 days
measure: Change in Multiple Organ Dysfunction Syndrome Score
timeFrame: 28 days
measure: Change in Acute Respiratory Distress Syndrome
timeFrame: 28 days
measure: Change in Glasgow coma score
timeFrame: 28 days
measure: Incidence of adverse events
timeFrame: 28 days
Other outcomes:
Locations:
city: Nagpur
country: India
facility: Seven Star Hospital
state: Maha
city: Ajmer
country: India
facility: Jawahar Lal Nehru Medical College & Attached Hospitals
city: Amravati
country: India
facility: Radiant Superspeciality Hospital
city: Bangalore
country: India
facility: People Tree Hospitals
city: Belgaum
country: India
facility: KLE's Dr. Prabhakar Kore Hospital & Medical Research Centre
city: Dehradun
country: India
facility: Shri Guru Ram Rai Institute of Medical & Health Sciences
city: Kanpur
country: India
facility: Department of Surgery, GSVM Medical College
city: Kolkata
country: India
facility: Institute of Postgraduate Medical Education & Research and SSKM Hospital
city: Lucknow
country: India
facility: King George's Medical University
city: Ludhiana
country: India
facility: Christian Medical College & Hospital
city: Ludhiana
country: India
facility: Sidhu Hospital Pvt. Ltd.
city: Mysuru
country: India
facility: Department of General Medicine, JSS Hospital
city: Nagpur
country: India
facility: New Era Hospital & Research Institute
city: Nagpur
country: India
facility: Rahate Surgical Hospital & ICU
city: Nagpur
country: India
facility: Criticare Hospital & Research Institute
city: Nellore
country: India
facility: ACSR Government Medical College & Hospital
city: New Delhi
country: India
facility: Maulana Azad Medical College and associated Lok Nayak Hospital
city: Varanasi
country: India
facility: Institute of Medical Sciences, Banaras Hindu University
Study officials:
affiliation: Pharmazz, Inc.
name: Anil Gulati, MD, PhD
role: STUDY_CHAIR
References:
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: 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.
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, 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: 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: 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: Anil Gulati, Dinesh Jain, Nilesh Agrawal, Prashant Rahate, Soumen Das, Rajat Chowdhuri, Deba Dhibar, Madhav Prabhu, Sameer Haveri, Rohit Agarwal, Manish Lavhale. Clinical Phase II Results Of PMZ-2010 (centhaquin) As A Resuscitative Agent For Hypovolemic Shock. Critical Care Medicine Volume 47, Issue 1, Page 12.
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.
citation: Gulati A, Choudhuri R, Gupta A, Singh S, Noushad Ali SK, 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. medRxiv [Preprint]. 2021 May 9:2020.07.30.20068114. doi: 10.1101/2020.07.30.20068114.