A Multicentric, Randomized, Controlled Phase III Study of Centhaquine (Lyfaquin®) as a Resuscitative Agent in Hypovolemic Shock Patients

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) ≤ 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.

Conflict of interest statement

Anil Gulati has issued and pending patents and is an employee and stockholder of Pharmazz, Inc. Rajat Choudhuri, Ajay Gupta, Saurabh Singh, S.K. Noushad Ali, Gursaran Kaur Sidhu, Parvez David Haque, Prashant Rahate, Aditya R. Bothra, Gyan P. Singh, Sanjiv Maheshwari, Deepak Jeswani, Sameer Haveri, Apurva Agarwal, and Nilesh Radheshyam Agrawal have no conflicts of interest that are directly relevant to the content of this article.

Figures

Fig. 1

Patient enrolment, randomization, and trial completion

Fig. 2

Total volume of fluid, blood products, and vasopressors administered during the first 48 h in the control and centhaquine groups. Total urine output in the first 48 h in the control and centhaquine groups. Data are presented as mean ± standard error

Fig. 3

Systolic BP during the first 48 h in the control and centhaquine groups. The upper panel shows data as the mean ± SEM. The lower panel indicates the number of patients with improved systolic BP at 12, 24, and 48 h of resuscitation. BP blood pressure, SEM standard error of the mean

Fig. 4

Diastolic BP during the first 48 h in the control and centhaquine groups. The upper panel shows data as the mean ± SEM. The lower panel indicates the number of patients with improved diastolic BP at 12, 24, and 48 h of resuscitation. BP blood pressure, SEM standard error of the mean

Fig. 5

Mean difference from baseline to 48 h at various time intervals plotted to determine the AUC for systolic blood pressure, diastolic blood pressure, and pulse pressure. Compared with the control group, the AUC0–48 for systolic blood pressure was higher by 12.99%, diastolic blood pressure was lower by 7.44%, and pulse pressure was higher by 48.14% in the centhaquine group. A significant increase in pulse pressure in the centhaquine group strongly suggests increased stroke volume. AUC area under the curve

Fig. 6

Shock index (HR/SBP), an important indicator of cardiac performance (left ventricular stroke work) in early hemorrhage, was significantly improved by centhaquine in the first 4 h of resuscitation. CI confidence interval, Diff. difference, HR heart rate, SBP systolic blood pressure

Fig. 7

Blood lactate levels in the control and centhaquine groups on day 3 of resuscitation (upper panel). Changes in blood lactate levels following resuscitation of patients with hypovolemic shock in control and centhaquine groups (lower panel)

Fig. 8

Base deficit in control and centhaquine groups on day 3 of resuscitation (upper panel). Changes in base deficit following resuscitation of patients with hypovolemic shock in control and centhaquine groups of individual patients (lower panel)

Fig. 9

ARDS was compared between day 1 (before resuscitation) and day 3 of resuscitation. Centhaquine treatment significantly improved ARDS following resuscitation, whereas improvement was minor in the control group. MODS was compared between day 3 and day 7 of resuscitation. In the control group, MODS worsened from 1.138 to 1.727, whereas it improved from 1.367 to 0.8182 in the centhaquine group. ARDS acute respiratory distress syndrome, MODS multiple organ dysfunction syndrome