Introduction: Centhaquine (Lyfaquin Ò ) 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 B 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

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 [AUC 0–48 ]) in the centhaquine group than in the control group. A significant increase in pulse pressure (48.1% increase in AUC 0–48 ) 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 e...

Background Sovateltide (IRL-1620, PMZ-1620), an endothelin-B receptor agonist, has been previously shown to increase cerebral blood flow, have anti-apoptotic activity and produce neurovascular remodeling when administered intravenously following acute cerebral ischemic stroke in rats. Its safety and tolerability were confirmed in healthy human volunteers (CTRI/2016/11/007509). Objective Our objective was to determine the safety, tolerability and efficacy of sovateltide as an addition to standard of care (SOC) in patients with acute cerebral ischemic stroke. Methods A prospective, multicentric, randomized, double-blind, placebo-controlled study was conducted to compare the safety (primary objective) and efficacy (secondary objective) of sovateltide in patients with acute cerebral ischemic stroke. Adult males or females aged 18–70 years who had experienced a radiologically confirmed ischemic stroke within the last 24 h were included in the study. Patients with intracranial hemorrhage and those receiving endovascular therapy were excluded. Patients randomized to the sovateltide group received three doses of sovateltide (each dose 0.3 µg/kg) administered as an intravenous bolus over 1 min at an interval of 3 ± 1 h on day 1, day 3 and day 6 (total dose of 0.9 µg/kg/day). Patients randomized to the placebo group received an equal volume of saline. Every patient in both groups received SOC for stroke. Efficacy was evaluated using neurological outcomes based on National Institute of Health Stroke Scale (NIHSS), modified Rankin Scale (mRS) and Barthel Index (BI) scores from day 1 through day 90. Quality of life was measured using the EuroQoL-5 Dimensions (EQ-5D) and Stroke-Specific Quality of Life (SSQoL) at 60 and 90 days of follow-up. Results A total of 40 patients with acute cerebral ischemic stroke were enrolled in this study, of whom 36 completed the 90-day follow-up. Patients received saline ( n = 18; 11 male and 7 female) or sovateltide ( n = 18; 15 male and 3 female) within 24 h of onset of stroke. The number of patients receiving investigational drug within 20 h of onset of stroke was 14/18 in the saline group and 10/18 in the sovateltide group. The baseline characteristics and SOC in both cohorts was similar. Sovateltide was well-tolerated, and all patients received complete treatment with no incidence of drug-related adverse events. Hemodynamic, biochemical or hematological parameters were not affected by sovateltide. Sovateltide treatment resulted in improved mRS and BI scores on day 6 compared with day 1 ( p < 0.0001), an effect not seen in the saline group. Sovateltide increased the frequency of favorable outcomes at 3 months. An improvement of ≥ 2 points on the mRS was observed in 60 and 40% of patients in the sovateltide and saline groups, respectively ( p = 0.0519; odds ratio [OR] 5.25). An impro...

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Centhaquine is a novel, first-in-class resuscitative agent for the treatment of hypovolemic shock. Efficacy of centhaquine for the treatment of hypovolemic shock as an adjuvant to standard of care (SOC) was evaluated in a prospective, multi-center, randomized, double-blind, placebo-controlled Phase 3 study. Key inclusion criteria were; systolic blood pressure of ≤90 mm Hg, blood lactate levels of ≥2 mmol/L and patients receiving SOC in a hospital or ICU setting. Patients were randomized in a 2:1 ratio either to the centhaquine group receiving centhaquine dose of 0.01 mg/kg by IV infusion along with SOC or to the control group receiving SOC plus saline. Primary endpoints of the study were change in systolic blood pressure (SBP) and diastolic blood pressure (DBP), change in blood lactate levels and change in base deficit. Mortality through day 28 was the key secondary endpoint. A total of 197 patients were screened, of which 105 patients met the eligibility criteria and were included in the study. Out of 105 patients, 71 patients were randomized to centhaquine group and 34 patients to control group. Demographics and baseline characteristics of patients in both groups was comparable. Hemoglobin level was 9.38 ± 0.71 g/dL and 8.73 ± 0.55 g/dL in control and centhaquine groups, respectively at the time of inclusion in the study. At 24 hours of resuscitation, SBP of more than 110 mmHg was in 59.38% patients of control and 81.82% patients of centhaquine group (P=0.00842). Similarly, at 24 hours of resuscitation, DBP of more than 70 mmHg was in 50.00% patients in control group and 78.46% patients in centhaquine group (P=0.002175). The number of patients with blood lactate levels of 1.5 mmol/L or less were 46.88% in the group with standard treatment compared to 69.35% in centhaquine group (P=0.0168). The number of patients with base-deficit of less than minus 2 were 46.88% in standard treatment group compared to 68.25% in those receiving centhaquine (P=0.0217). Centhaquine treatment significantly reduced 28-day all-cause mortality. In the control group, the mortality rate was 11.76% compared to 2.94% in the centhaquine group (odds ratio: 4.4; 95% CI 0.9651 to 23.74 and P=0.037). No drug related adverse event was reported. Centhaquine (Lyfaquin®) is a highly efficacious resuscitative agent for the treatment of hypovolemic shock as an adjuvant to SOC. The study protocol (PMZ-2010/CT-3.1/2018) was approved by the Drug Controller General of India (DCGI), Ministry of Health and Family Welfare, Government of India and Institutional Ethics Committee of all the 14 Institutions.