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

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.

Resuscitative Effect of Centhaquine (Lyfaquin®) in Hypovolemic Shock Patients: A Randomized, Multicentric, Controlled Trial.

INTRODUCTION: Centhaquine (Lyfaquin®) showed significant efficacy as a resuscitative agent in animal models of haemorrhagic shock. Its safety and tolerability were confirmed in healthy human volunteers. In this study, our primary objective was to determine the safety, and the secondary objective was to assess the efficacy of centhaquine in patients with hypovolemic shock. METHODS: A prospective, multicentre, randomized phase II study was conducted in male and female patients aged 18-70 years with hypovolemic shock having systolic BP ≤ 90 mmHg. Patients were randomized in a 1:1 ratio to either the control or centhaquine group. The control group received 100 ml of normal saline infusion over 1 h, while the centhaquine group received 0.01 mg/kg of centhaquine in 100 ml normal saline infusion over 1 h. Every patient received standard of care (SOC) and was followed for 28 days. RESULTS: Fifty patients were included, and 45 completed the trial: 22 in the control group and 23 in the centhaquine group. The demographics of patients in both groups were comparable. No adverse event related to centhaquine was recorded in the 28-day observation period. The baseline, Injury Scoring System score, haemoglobin, and haematocrit were similar in both groups. However, 91% of the patients in the centhaquine group needed major surgery, whereas only 68% in the control group (p = 0.0526). Twenty-eight-day all-cause mortality was 0/23 in the centhaquine group and 2/22 in the control group. The percent time in ICU and ventilator support was less in the centhaquine group than in the control group. The total amount of vasopressors needed in the first 48 h of resuscitation was lower in the centhaquine group than in the control group (3.12 ± 2.18 vs. 9.39 ± 4.28 mg). An increase in systolic and diastolic BP from baseline through 48 h was more marked in the centhaquine group than in the control group. Compared with the control group, blood lactate level was lower by 1.75 ± 1.07 mmol/l in the centhaquine group on day 3 of resuscitation. Improvements in base deficit, multiple organ dysfunction syndrome (MODS) score and adult respiratory distress syndrome (ARDS) were greater in the centhaquine group than in the control group. CONCLUSION: When added to SOC, centhaquine is a well-tolerated and effective resuscitative agent. It improves the clinical outcome of patients with hypovolemic shock. TRIAL REGISTRATION: ClinicalTrials.gov identifier number: NCT04056065.

A multicentric, randomized, controlled phase III study of centhaquine (Lyfaquin ® ) as a resuscitative agent in hypovolemic shock patients.

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 having systolic blood pressure (SBP) of ≤90 mm Hg and blood lactate levels of ≥2 mmol/L. Patients were randomized in a 2:1 ratio, 71 patients to the centhaquine group and 34 patients to the control (saline) group. 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 hour. The primary objectives were to determine changes (mean through 48 hours) in SBP, diastolic blood pressure (DBP), blood lactate levels, and base deficit. The secondary objectives included the amount of fluids, blood products, vasopressors administered in the first 48 hours, duration of hospital stay, time in ICU, time on the ventilator support, change in patient's Acute Respiratory Distress Syndrome (ARDS), Multiple Organ Dysfunction Syndrome (MODS) scores, and the proportion of patients with 28-day all-cause mortality. RESULTS: The demographics of patients and baseline vitals in both groups were comparable. Trauma was the cause of hypovolemic shock in 29.41% of control and 47.06% of centhaquine, gastroenteritis in 44.12% of control, and 29.41% of centhaquine patients. An equal amount of fluids and blood products were administered in both groups during the first 48 hours of resuscitation. A lesser amount of vasopressors was needed in the first 48 hours of resuscitation in the centhaquine group. An increase in SBP from the baseline was consistently higher in the centhaquine group than in the control. A significant increase in pulse pressure in the centhaquine group than the control group suggests improved stroke volume due to centhaquine. The shock index was significantly lower in the centhaquine group than control from 1 hour (p=0.0320) till 4 hours (p=0.0494) of resuscitation. Resuscitation with centhaquine had a significantly greater number of patients with improved blood lactate and the base deficit than 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 a highly efficacious resuscitative agent for treating hypovolemic shock. The efficacy of centhaquine in distributive shock due to sepsis and COVID-19 is being explored. TRIAL REGISTRATION: Clinical Trials Registry, India; ctri.icmr.org.in, CTRI/2019/01/017196; clinicaltrials.gov, NCT04045327 . KEY SUMMARY POINTS: A multicentric, randomized, controlled trial was conducted to evaluate the efficacy of centhaquine in hypovolemic shock patients.One hundred and five patients were randomized 2:1 to receive centhaquine or saline. Centhaquine was administered at a dose of 0.01 mg/kg in 100 mL saline and infused over 1 hour. The control group received 100 mL of saline over a 1-hour infusion.Centhaquine improved blood pressure, shock index, reduced blood lactate levels, and improved base deficit. Acute Respiratory Distress Syndrome (ARDS) and Multiple Organ Dysfunction Syndrome (MODS) score improved with centhaquine.An 8.8% absolute reduction in 28-day all-cause mortality was observed in the centhaquine group. There were no drug-related adverse events in the study.