Anil Gulati1, Rajat Choudhuri2, Ajay Gupta3, Saurabh Singh4, S K Noushad Ali5, Gursaran Kaur Sidhu6, Parvez David Haque7, Prashant Rahate8, Aditya R Bothra9, Gyan P Singh10, Sanjiv Maheshwari11, Deepak Jeswani12, Sameer Haveri13, Apurva Agarwal14, Nilesh Radheshyam Agrawal15. 1. Pharmazz, Inc., 50 West 75th Street, Suite 105, Willowbrook, IL, 60527, USA. anil.gulati@pharmazz.com. 2. Institute of Postgraduate Medical Education and Research/SSKM Hospital, Kolkata, West Bengal, India. 3. Chiranjeev Medical Centre, Jhansi, Uttar Pradesh, India. 4. Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India. 5. ACSR Government Medical College and Hospital, Nellore, Andhra Pradesh, India. 6. Sidhu Hospital Pvt. Ltd., Ludhiana, Punjab, India. 7. Christian Medical College and Hospital, Ludhiana, Punjab, India. 8. Seven Star Hospital, Nagpur, Maharashtra, India. 9. Rahate Surgical Hospital and ICU, Nagpur, Maharashtra, India. 10. King George's Medical University, Lucknow, Uttar Pradesh, India. 11. Jawahar Lal Nehru Medical College and Attached Hospital, Ajmer, Rajasthan, India. 12. Criticare Hospital and Research Institute, Nagpur, Maharashtra, India. 13. KLE's Dr. Prabhakar Kore Hospital and Medical Research Centre, Belgaum, Karnataka, India. 14. GSVM Medical College, Uttar Pradesh, Kanpur, India. 15. New Era Hospital, Nagpur, Maharashtra, India.
Abstract
INTRODUCTION:Centhaquine (Lyfaquin®) showed significant safety and efficacy in preclinical and clinical phase I and II studies. METHODS: A prospective, multicentric, randomized phase III study was conducted in patients with hypovolemic shock, systolic blood pressure (SBP) ≤ 90mmHg, and blood lactate levels ≥ 2 mmol/L. Patients were randomized in a 2:1 ratio to the centhaquine group (n = 71) or the control (saline) group (n = 34). Every patient received standard of care (SOC) and was followed for 28 days. The study drug (normal saline or centhaquine 0.01 mg/kg) was administered in 100 mL of normal saline infusion over 1 h. The primary objectives were to determine changes (mean through 48 h) in SBP, diastolic blood pressure (DBP), blood lactate levels, and base deficit. The secondary objectives included the amount of fluids, blood products, and vasopressors administered in the first 48 h, duration of hospital stay, time in intensive care units, time on ventilator support, change in acute respiratory distress syndrome (ARDS), multiple organ dysfunction syndrome (MODS), and the proportion of patients with 28-day all-cause mortality. RESULTS: The demographics of patients and baseline vitals in both groups were comparable. The cause of hypovolemic shock was trauma in 29.4 and 47.1% of control group and centhaquine group patients, respectively, and gastroenteritis in 44.1 and 29.4%, respectively. Shock index (SI) and quick sequential organ failure assessment at baseline were similar in the two groups. An equal amount of fluids and blood products were administered in both groups during the first 48 h of resuscitation. A lesser amount of vasopressors was needed in the first 48 h of resuscitation in the centhaquine group. An increase in SBP from baseline was consistently higher up to 48 h (12.9% increase in area under the curve from 0 to 48 h [AUC0-48]) in the centhaquine group than in the control group. A significant increase in pulse pressure (48.1% increase in AUC0-48) in the centhaquine group compared with the control group suggests improved stroke volume due to centhaquine. The SI was significantly lower in the centhaquine group from 1 h (p = 0.032) to 4 h (p = 0.049) of resuscitation. Resuscitation with centhaquine resulted in a significantly greater number of patients with improved blood lactate (control 46.9%; centhaquine 69.3%; p = 0.03) and the base deficit (control 43.7%; centhaquine 69.8%; p = 0.01) than in the control group. ARDS and MODS improved with centhaquine, and an 8.8% absolute reduction in 28-day all-cause mortality was observed in the centhaquine group. CONCLUSION:Centhaquine is an efficacious resuscitative agent for treating hypovolemic shock. The efficacy of centhaquine in distributive shock is being explored. TRIAL REGISTRATION: Clinical Trials Registry, India; ctri.icmr.org.in, CTRI/2019/01/017196; clinicaltrials.gov, NCT04045327.
RCT Entities:
INTRODUCTION:Centhaquine (Lyfaquin®) showed significant safety and efficacy in preclinical and clinical phase I and II studies. METHODS: A prospective, multicentric, randomized phase III study was conducted in patients with hypovolemic shock, systolic blood pressure (SBP) ≤ 90 mmHg, and blood lactate levels ≥ 2 mmol/L. Patients were randomized in a 2:1 ratio to the centhaquine group (n = 71) or the control (saline) group (n = 34). Every patient received standard of care (SOC) and was followed for 28 days. The study drug (normal saline or centhaquine 0.01 mg/kg) was administered in 100 mL of normal saline infusion over 1 h. The primary objectives were to determine changes (mean through 48 h) in SBP, diastolic blood pressure (DBP), blood lactate levels, and base deficit. The secondary objectives included the amount of fluids, blood products, and vasopressors administered in the first 48 h, duration of hospital stay, time in intensive care units, time on ventilator support, change in acute respiratory distress syndrome (ARDS), multiple organ dysfunction syndrome (MODS), and the proportion of patients with 28-day all-cause mortality. RESULTS: The demographics of patients and baseline vitals in both groups were comparable. The cause of hypovolemic shock was trauma in 29.4 and 47.1% of control group and centhaquine group patients, respectively, and gastroenteritis in 44.1 and 29.4%, respectively. Shock index (SI) and quick sequential organ failure assessment at baseline were similar in the two groups. An equal amount of fluids and blood products were administered in both groups during the first 48 h of resuscitation. A lesser amount of vasopressors was needed in the first 48 h of resuscitation in the centhaquine group. An increase in SBP from baseline was consistently higher up to 48 h (12.9% increase in area under the curve from 0 to 48 h [AUC0-48]) in the centhaquine group than in the control group. A significant increase in pulse pressure (48.1% increase in AUC0-48) in the centhaquine group compared with the control group suggests improved stroke volume due to centhaquine. The SI was significantly lower in the centhaquine group from 1 h (p = 0.032) to 4 h (p = 0.049) of resuscitation. Resuscitation with centhaquine resulted in a significantly greater number of patients with improved blood lactate (control 46.9%; centhaquine 69.3%; p = 0.03) and the base deficit (control 43.7%; centhaquine 69.8%; p = 0.01) than in the control group. ARDS and MODS improved with centhaquine, and an 8.8% absolute reduction in 28-day all-cause mortality was observed in the centhaquine group. CONCLUSION:Centhaquine is an efficacious resuscitative agent for treating hypovolemic shock. The efficacy of centhaquine in distributive shock is being explored. TRIAL REGISTRATION: Clinical Trials Registry, India; ctri.icmr.org.in, CTRI/2019/01/017196; clinicaltrials.gov, NCT04045327.
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