Clinical trial NCT04056065: PMZ-2010 (Centhaquine) as a Resuscitative Agent for Hypovolemic Shock
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.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Hypovolemic Shock
Blood Loss
Keywords: Resuscitative agent
Vasopressor
Lead sponsor: Pharmazz, Inc.
Sponsor class: INDUSTRY
First posted: 2019-08-14
Enrollment: 50
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
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-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).

Detailed 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.

Eligibility criteria: 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

Primary outcomes:
measure: Incidence of PMZ-2010 related adverse events
timeFrame: 28 days
Secondary outcomes:
measure: Volume of fluid administered
timeFrame: 48 hours
measure: Volume of blood products administered
timeFrame: 48 hours
measure: Vasopressor(s) infused
timeFrame: 48 hours
measure: Doses of study drug
timeFrame: 48 hours
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
measure: Change in platelet count
timeFrame: 48 hours
measure: Change in prothrombin time
timeFrame: 48 hours
measure: Change in international normalized ratio (INR)
timeFrame: 48 hours
measure: Change in fibrinogen
timeFrame: 48 hours
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: Stay in hospital, in ICU and/or on Ventilator
timeFrame: 28 days
measure: Incidence of mortality
timeFrame: 28 days
Other outcomes:
Locations:
city: Nagpur
country: India
facility: Seven Star Hospital
state: Maha
city: Belgaum
country: India
facility: KLE's Dr. Prabhakar Kore Hospital & Medical Research Centre
city: Chandigarh
country: India
facility: Post Graduate Institute of Medical Education and Research
city: Kolkata
country: India
facility: Institute of Postgraduate Medical Education & Research and SSKM Hospital
city: Ludhiana
country: India
facility: Dayanand Medical College & Hospital
city: Nagpur
country: India
facility: New Era Hospital & Research Institute
city: Varanasi
country: India
facility: ORIANA Hospital
Study officials:
affiliation: Pharmazz, Inc.
name: Anil Gulati
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, 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.