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

Hypovolemic Shock Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04045327
• Other study ID #: PMZ-2010/CT-3.1/2018
• Secondary ID: CTRI/2019/01/017
• Status: Completed
• Phase: Phase 3
• Start date: January 31, 2019
• Est. completion date: September 27, 2019

Study information

• Verified date: October 2019
• Source: Pharmazz, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 105
• Est. completion date: September 27, 2019
• Est. primary completion date: September 23, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Hypovolemia
• Hypovolemic Shock
• Shock

Intervention

Drug:
• Normal saline + Standard Treatment
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
• Centhaquine + Standard Treatment
Phase-III Study to Assess Efficacy of PMZ-2010 as a Resuscitative Agent for Hypovolemic Shock

Locations

Country	Name	City	State
India	Jawahar Lal Nehru Medical College & Attached Hospitals	Ajmer
India	Radiant Superspeciality Hospital	Amravati
India	People Tree Hospitals	Bangalore
India	KLE's Dr. Prabhakar Kore Hospital & Medical Research Centre	Belgaum
India	Shri Guru Ram Rai Institute of Medical & Health Sciences	Dehradun
India	Department of Surgery, GSVM Medical College	Kanpur
India	Institute of Postgraduate Medical Education & Research and SSKM Hospital	Kolkata
India	King George's Medical University	Lucknow
India	Christian Medical College & Hospital	Ludhiana
India	Sidhu Hospital Pvt. Ltd.	Ludhiana
India	Department of General Medicine, JSS Hospital	Mysuru
India	Criticare Hospital & Research Institute	Nagpur
India	New Era Hospital & Research Institute	Nagpur
India	Rahate Surgical Hospital & ICU	Nagpur
India	Seven Star Hospital	Nagpur	Maha
India	ACSR Government Medical College & Hospital	Nellore
India	Maulana Azad Medical College and associated Lok Nayak Hospital	New Delhi
India	Institute of Medical Sciences, Banaras Hindu University	Varanasi

Sponsors (1)

Lead Sponsor	Collaborator
Pharmazz, Inc.

Country where clinical trial is conducted

India, 

References & Publications (7)

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 S

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. — View 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. — View 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. 2018 Jul 13. doi: 10.1007/s00068-018-0980-1. [Epub ahead of print] — View 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. — View 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. — View 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change in systolic and diastolic blood pressure	Change in systolic and diastolic blood pressure - Mean through 48 hours	48 hours
Primary	Change in blood lactate level	Change in blood lactate level - Mean through 48 hours	48 hours
Primary	Change in base-deficit	Change in Base-deficit - Mean through 48 hours	48 hours
Secondary	Total Urine Output	Total volume of urine output - Mean through 48 hours	48 hours
Secondary	Vasopressor(s) infused	Amount of total vasopressor(s) infused - Mean through 48 hours	48 hours
Secondary	Volume of fluid administered	Total volume of fluid administered - Mean through 48 hours	48 hours
Secondary	Doses of study drug	Number of doses of study drug administered in first 48 hours post randomization	48 hours
Secondary	Incidence of mortality	Proportion of patients with all-cause mortality at 48 hours and 28 days	28 days
Secondary	Stay in hospital, in ICU and/or on Ventilator	Days in hospital, in ICU and/or on Ventilator - Mean through 28 days	28 days
Secondary	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
Secondary	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
Secondary	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
Secondary	Incidence of adverse events	Proportion of patients with drug related adverse events during 28 days	28 days