Dalargin for Prevention of Organ Disfunction in High-Risk Abdominal Surgery (Dal-PROTECT)

A Randomized, Double-Blind, Placebo-Controlled Trial of Dalargin for the Prevention of Postoperative Organ Dysfunction in Patients Undergoing High-Risk Abdominal Surgery

Major abdominal surgeries (e.g., gastrectomy, pancreatectomy, colectomy) carry a high risk of life-threatening postoperative complications, including multiorgan disfunction syndrome (MODS), acute kidney injur (AKI), miocardial injury after non-cardiac surgery (MINS) and severe infections. These complications are driven by ischemia-reperfusion injury, leading to oxidative stress and a systemic inflammatory response. Despite advances in surgical and anesthetic techniques, there are no effective pharmacological strategies for personalized prevention of these events, which adversely affect recovery and survival.

In this context, opioid receptor agonist, particularly senthetic analogs of Leu-enkephalin such as Dalargin, have emerged as promising agents for pharmacologica preconditioning. Preclinical evidence suggests their ability to mitigate oxidative stress and inflammation by moduating key signaling pathways . The potential for these peptides to protect andothelial function and reduce organ damage presents a novel therapeutic avenue.

This study aims to clinically test the hypothesis that perioperative intravenous infusion of Dalargin reduce the incidence and severity of postoperative organ dysfunction. Patients undergoing high-risk abdominal surgery will be randomized to receive either a 72-hour continuous of Dalargin (following a defined dosage regimen) or an identical placebo infusion. the study will also integrate an assessment of genetic polymorphism ( e.g., in NRF2, OLR1, TLR9 genes) to explore personalized approaches to risk stratification and prevention.

Study Overview

• Status: Active, not recruiting
• Conditions: Postoperative Complications; Abdominal Surgery; Multiple Organ Failure
• Intervention / Treatment: Drug: Dalargin; Other: 0.9 % NaCl

Detailed Description

This is a prospective, randomized, double-blind, placebo-controlled clinical trial. The study investigates the effects of a synthetic leucine-enkephalin analog (Dalargin) on oxidative distress, systemic inflammatory response, organ failure, and infectious complications in patients undergoing high-risk abdominal surgery (e.g. on the stomach, pancreas, or colon).

Objectives: The primary objective is to evaluate whether perioperative infusion of Dalargin reduces the incidence of a composite endpoint of postoperative organ dysfunction (including acute respiratory destress syndrome, acute kidney injury, and sepsis) . Secondary objectives include assessing its effects on biomarkers of oxidative stress (malondialdehyde, carbonylated proteins), inflammation (procalcitonin, interleukin-6, HMGB-1), and myocardial injury (high-sensitivity troponin T), as well asthe length of ICU and hospital stay.

Methods: A total of 200 patients aged 18-85 years (ASA I-III) scheduled for elective high-risk abdominal surgery ander general anesthesia will be randomized to recieve either Dalargin or placebo (0,9% sodium chloride). The study drug will be administered as a continious intravenous: 8 ml/hour for the first 24 hour, followed be 4 ml/hour for the next 48 hours, startinf after anesthesia induction. Patient outcomes will be evaluated using clinical scales (e.g., CPIS, KDIGO, APACHE II) and laboratory assessments. Additionally, genetic polymorphismis (NRF2, OLR1, TLR9, AGTR1, AQP1) will be analyzed to identify predictors of organ dysfunction and enable personalized risk stratification.

Scientific Navelty: This is the first study to comprehensively evaluate the organoprotective potential a synthetic enkephalin analog via pharmacological preconditioning in high-risk non-cardiac surgery, combining clinical endpoints with biomarker and genetic analysis to develop a personalized prevention strategy.

Sample Size Justification: The sample size of 200 participants (100/group) was calculated based on the anticipated incidence of the primary composite endpoint (postoperative organ dysfunction) in the control group. Based on previous similar studies and meta-analyses, we assume an event rate of 35% in the placebo group. We hypothesize that Dalargin will reduce this incidence to 20% (absolut risk reduction of 15%). With a two-sided alpha of 0.05 and 80% power, using a chisquared test, the required sample size is 178 participants. To account for a potential dropout rate of approximately 10%, the total sample size was increased to 200 partipitants. This sample size also provides adequate power (>80%) to detect clinically meaningful differences in key secondary endpoints, including the incidence of MINS (Myocardial Injury after non-cardiac Surgery) and changes in biomarker levels (e.g., interleukin-6)

• Study Type: Interventional
• Enrollment (Actual): 200
• Phase: Phase 3

Contacts and Locations

Study Locations

• Russia
  • Moscow, Russia, 125284
    • S.P. Botkin Moscow Multidisciplinary Scientific and Clinical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Male or female patients aged 18 to 85 years.
• Scheduled for elective high-risk abdominal surgery (e.g., gastrectome, pancreatectomy, colectomy) under general anesthesia.
• American Society of Anesthesiologists (ASA) physical status class I-III.
• Able to provide written informed consent.

Exclusion Criteria:

• ASA physical status class IV or V.
• Acute myocardial infarction within the past 6 month.
• Acute stroke within the past 6 month.
• Chronic heart failure NYHA class IV.
• Chronic kidney disease stage 3a or higher (according KDIGO)
• Active infectious disease.
• Any diagnosed phychiatric disorder (according ICD-10) confirmed be a psychiatrist.
• Any neuromuscular disease (according to ICD-10)
• Pregnancy or breastfeeding.
• Inability to undergo preoperative assessment.
• Previous enrollment in this trial.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dalargin; Patients in this arm receive a continuous intravenous of the study drug Dalargin (synthetic leucine-enkephalin analog) according to the predefined protocol	Drug: Dalargin; Dalargin is a synthetic analog of the endogenous opioid peptide leucine-enkephalin. It is supplied as a lyophilized powder in vials containing 30 mg. For administration, the contents of one vial are reconstituted and diluted to a total volume of 300 ml with 0,9% sodium chloride (normal saline). The solution is administered as a continious intravenous infusion via an elastomeric infusion pump. The infusion starts after induction of anesthesia and continues for a total of 72 hours according to the following regimen: 8ml/hour (delivering 0.8 mg/hour) for the first 24 hours, followed by 4 ml/hour (delivering 0.4 mg/hour) for the subsequent 48 hours.
Placebo Comparator: Placebo; Patients in this arm recive a continious intravenous infusion of 0.9% sodium chloride as a placebo, matching the volume and administration schedule of the active arm.	Other: 0.9 % NaCl; A continious intravenous infusion of 0.9%sodium chloride used as a placebo control. It is prepared and administered in an identical manner (volume, duration, infusion device) as the active drug (Dalargin) to maintain blinding; Other Names: Placebo; Normal saline; 0.9% sodium chloride

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of Major Postoperative Complications	Composite endpoin defined as the occurrence of at leats one of the follwing within the first 7 days after surgery: Miocardial injury after non-cardiac Surgery (MINS) (defined as an elevated high-sensitivity cardiac troponin T value with an ischemic feature, without requiring ischemic symptoms), Acute Kidney Injury (according to KDIGO criteria), Acute Respiratory Distress Syndrome (according to Berlin definition) or Sepsis (according to Sepsis - 3 criteria),	7 days postoperatively

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incident of acute respiratory distress syndrome (ARDS)	Diagnosed according to the Berlin Definition (timing, origin, chest imaging, oxygenation)	7 days postoperatively
Incidence of acute kidney injury (AKI)	Defined and staged according to the kidney disease: improving Global Outcomes (KDIGO) criteris, based on serum creatinine and urine output.	7 days postoperatively
Incident of sepsis	Defined accorging to hte Sepsis-3 criteria as a life-threatening organ dysfunction caused by a dysregulated host response to infection	7 days postoperatively
Plasma level of Interleukin-6 (IL-6)	Concentration measured in picograms per milliliter (pg/ml) using enzyme-linked immunosorbent assay (ELISA).	24 hours postoperatively
Plasma level of procalcitonin	Concentration measured in nanograms per milliliter (ng/ml)	24 hours postoperatively
Length of intensive care unit (ICU) stay	Total number of days spent in ICU from the day of surgery until discharge	From surgery until ICU discharge, up to 30 days
Length of hospital stay	Total numbers of days spent in the hospital from the day of surgery until discharge.	From surgery until hospital discharge, 30 days.
30-days all-cause mortality	Death from any cause occurring within 30 days after the index surgery	30 days postoperatively
Incidence of postoperative delirium	Assessed using the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) or the 3-Minute Diagnostic Interview for (3D-CAM)	7 days postoperatively
Level of oxidative stress marker (Malondialdehyde, MDA)	Plasma concentration of malondialdehyde measured in micromoles per liter as a marker of lipid peroxidation	2 days postoperatively
Chande in insulin resistance (HOMA-IR)	Change in the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) index from baseline to the postoperative period.	5 days postoperatively

Collaborators and Investigators

• Sponsor: Botkin Hospital

Study record dates

Study Major Dates

• Study Start (Actual): May 13, 2025
• Primary Completion (Estimated): July 20, 2026
• Study Completion (Estimated): December 20, 2026

Study Registration Dates

• First Submitted: February 5, 2026
• First Submitted That Met QC Criteria: February 5, 2026
• First Posted (Actual): February 11, 2026

Study Record Updates

• Last Update Posted (Actual): February 11, 2026
• Last Update Submitted That Met QC Criteria: February 5, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Keywords: Oxidative stress; Organ protection; Dalargin; Leu-enkephalin; Pharmacological preconditioning; Genetic polymorphis; High-risk surgery
• Additional Relevant MeSH Terms: Pathologic Processes; Shock; Pathological Conditions, Signs and Symptoms; Multiple Organ Failure; Postoperative Complications; Spinocerebellar ataxia 23; Pharmaceutical Preparations; Inorganic Chemicals; Chlorine Compounds; Crystalloid Solutions; Isotonic Solutions; Solutions; Sodium Compounds; Chlorides; Hydrochloric Acid; Saline Solution; Sodium Chloride; enkephalin-Leu, Ala(2)-Arg(6)-
• Other Study ID Numbers: BOTKIN-DAL-PROTECT-01; EC #6/25/5 (Other Grant/Funding Number: Independ Ethics Committee of the S.P. Botkin Moscow Multidisciplinary Sccientific and Clinical Center)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No