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

Blood Loss Clinical Trial

Official title:

A Prospective, Multi-centric, Randomized, Double-blind, Parallel, Saline Controlled Phase II Safety and Efficacy Study of PMZ-2010 as a Resuscitative Agent for Hypovolemic Shock to be Used Along With Standard Shock Treatment.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04056065
• Other study ID #: PMZ-02 Version 03 2017
• Secondary ID: CTRI/2017/03/008
• Status: Completed
• Phase: Phase 2
• Start date: May 29, 2017
• Est. completion date: October 21, 2018

Study information

• Verified date: August 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-II efficacy clinical study of PMZ-2010 therapy in patients with hypovolemic shock.

Centhaquine is highly safe and well tolerated. Toxicological studies showed high safety margin in preclinical studies. Its safety and tolerability has been demonstrated in a human phase I study in 25 subjects (CTRI/2014/06/004647; NCT02408731).

Description:

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.

Unlike presently used vasopressors, centhaquine increased mean arterial pressure by increasing stroke volume and cardiac output, and it decreased systemic vascular resistance. The most common adverse effects of vasopressors as a class include arrhythmias, fluid extravasation, and ischemia. Centhaquine does NOT act on beta-adrenergic receptors, and therefore the risk of arrhythmias is mitigated. It is NOT a vasopressor; however, it increases blood pressure and cardiac output by augmenting venous blood return to the heart and enhanced tissue perfusion by arterial dilatation. Enhancing tissue perfusion is a significant advantage over existing vasopressors.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 50
• Est. completion date: October 21, 2018
• Est. primary completion date: September 19, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 70 Years

Eligibility

Inclusion Criteria:

• Adult males or females aged 18-70 years.

• Patients with Hypovolemic shock due to blood loss admitted to the emergency room or ICU with systolic blood pressure = 90 mmHg at presentation and continue to receive standard shock treatment (endotracheal intubation; fluid resuscitation and vasopressors). Standard of care to be provided to the patients shall be the one used in the particular hospital setup.

• Body weight 45 kg - 85 kg.

• Female subject is either: (1) Not of childbearing potential, defined as postmenopausal for at least 1 year or surgically sterile (bilateral tubal ligation, bilateral oophorectomy or hysterectomy) or, (2) If of childbearing potential, agrees to use any of the following effective separate forms of contraception throughout the study, up to and including the follow-up visits: Condoms, sponge, foams, jellies, diaphragm or intrauterine device, or A vasectomised partner OR abstinence.

Exclusion Criteria:

• Terminal illness

• Development of any other terminal illness not associated with Hypovolemic shock due to blood loss during the 28 day observation period

• Patient with severe brain injury or with a Glasgow Coma Scale (GCS) < 8

• Type of injury is not known

• Inability to obtain intravenous access

• Known pregnancy

• Cardiopulmonary resuscitation (CPR) before randomization

• Presence of a do not resuscitate order

• Patient taking beta adrenergic antagonists

• Untreated tension pneumothorax

• Untreated cardiac tamponade

• Bilateral absent pupillary light reflex (both pupils fixed and dilated)

• 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

Related Conditions & MeSH terms

• Blood Loss
• Hypovolemia
• Hypovolemic Shock
• Shock

Intervention

Drug:
• Normal Saline
In addition to standard of care normal saline to be used as vehicle in the phase-II study to assess efficacy of PMZ-2010 as a resuscitative agent for hypovolemic shock
• Centhaquine
In addition to standard of care PMZ-2010 to be used as an experimental drug in the phase-II study to assess its efficacy as a resuscitative agent for hypovolemic shock

Locations

Country	Name	City	State
India	KLE's Dr. Prabhakar Kore Hospital & Medical Research Centre	Belgaum
India	Post Graduate Institute of Medical Education and Research	Chandigarh
India	Institute of Postgraduate Medical Education & Research and SSKM Hospital	Kolkata
India	Dayanand Medical College & Hospital	Ludhiana
India	New Era Hospital & Research Institute	Nagpur
India	Seven Star Hospital	Nagpur	Maha
India	ORIANA Hospital	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	Incidence of PMZ-2010 related adverse events	The primary objective of the study is to determine incidence of drug (PMZ-2010) related adverse events.	28 days
Secondary	Volume of fluid administered	Total volume of fluid administered - Mean through 48 hours	48 hours
Secondary	Volume of blood products administered	Total volume of blood products administered - Mean through 48 hours	48 hours
Secondary	Vasopressor(s) infused	Amount of total vasopressor(s) infused - 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	Change in systolic and diastolic blood pressure	Change in systolic and diastolic blood pressure - Mean through 48 hours	48 hours
Secondary	Change in blood lactate level	Change in blood lactate level - Mean through 48 hours	48 hours
Secondary	Change in base-deficit	Change in Base-deficit - Mean through 48 hours	48 hours
Secondary	Change in platelet count	Change in platelet count as part of coagulation parameters mean through 48 hours. Platelets are parts of the blood that helps the blood clot. Average platelet counts are 150,000 to 450,000 number of platelets per microliter.	48 hours
Secondary	Change in prothrombin time	Change in prothrombin time as part of coagulation parameters mean through 48 hours. Prothrombin time (PT) is a blood test that measures the time it takes for the blood to clot. The average time range for blood to clot is about 10 to 14 seconds.	48 hours
Secondary	Change in international normalized ratio (INR)	Change in international normalized ratio (INR) as part of coagulation parameters mean through 48 hours. The results of the prothrombin time test vary from laboratory to laboratory, therefore, a ratio called the international normalized ratio (INR) is calculated. It allows for differences in laboratories across the world so that test results become more relevant and can be compared. The average INR range is 0.8 to 1.1.	48 hours
Secondary	Change in fibrinogen	Change in fibrinogen as part of coagulation parameters mean through 48 hours. Fibrinogen is a protein, specifically a clotting factor (factor I), that is essential for proper blood clot formation. The reference range for fibrinogen is 150-400 mg/dL	48 hours
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	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	Incidence of mortality	Proportion of patients with all-cause mortality at 48 hours and 28 days	28 days