A Randomized, Double-Blind, Placebo-Controlled Trial of Dalargin for the Prevention of Postoperative Organ Dysfunction in Patients Undergoing High-Risk Abdominal Surgery
试验速览
- 阶段
- 3 期
- 状态
- 进行中（未招募）
- 发起方
- 入组人数
- 200
- 试验地点
- 1
- 主要终点
- Incidence of Major Postoperative Complications
研究概览
简要总结
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.
详细描述
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)
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Prevention
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 85 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
排除标准
- •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.
研究组 & 干预措施
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.
干预措施: 0.9 % NaCl (Other)
Dalargin
Patients in this arm receive a continuous intravenous of the study drug Dalargin (synthetic leucine-enkephalin analog) according to the predefined protocol
干预措施: Dalargin (Drug)
结局指标
主要结局
Incidence of Major Postoperative Complications
时间窗: 7 days postoperatively
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),
次要结局
- Incident of acute respiratory distress syndrome (ARDS)(7 days postoperatively)
- Incidence of acute kidney injury (AKI)(7 days postoperatively)
- Incident of sepsis(7 days postoperatively)
- Plasma level of Interleukin-6 (IL-6)(24 hours postoperatively)
- Plasma level of procalcitonin(24 hours postoperatively)
- Length of intensive care unit (ICU) stay(From surgery until ICU discharge, up to 30 days)
- Length of hospital stay(From surgery until hospital discharge, 30 days.)
- 30-days all-cause mortality(30 days postoperatively)
- Incidence of postoperative delirium(7 days postoperatively)
- Level of oxidative stress marker (Malondialdehyde, MDA)(2 days postoperatively)
- Chande in insulin resistance (HOMA-IR)(5 days postoperatively)
研究者
Anatolii Anatolievich Malyshev
Candidate og Medical Sciences, Head of the Department of Anesthesiology and Resuscitationa №62, role in study - principal Investigator
Botkin Hospital