Remaxol® in Malignant Mechanical Jaundice

Study Overview
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Brief Summary
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The trial intends to study the safety and efficacy of Remaxol® (succinate + methionine + inosine + nicotinamide; POLYSAN Ltd., Russia),solution for infusion for the reduction of hyperbilirubinemia in patients with obstructive jaundice caused by tumor (malignancy).

Detailed Description
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The study will recruit in-hospital surgical patients with obstructive jaundice caused by malignancies of pancreatic and hepatobiliary zone. The study consists of the following periods: Screening - preliminary examination of patients (duration up to 3 days). Period of therapy (including surgery and postoperative period) - treatment with the investigational product Remaxol®, solution for infusions, (NTFF POLYSAN Ltd., Russia) or placebo, as part of standard infusion therapy during the postoperative period of patients with mechanical jaundice of malignant origin (duration 10 days). The period of follow-up (duration - 3 weeks after the end of treatment). After the screening, patients who meet the inclusion criteria and do not have exclusion criteria will be randomly assigned to three groups (1:1:1): Group I: treatment with Remaxol® 400 ml IV, and placebo (Ringer solution) 400 ml IV, once a day for 10 days, along with standard infusion therapy. Group II: treatment Remaxol® 800 ml IV, once a day for 10 days, along with standard infusion therapy. Group III: patients will receive placebo ((Ringer solution) 800 ml IV, once a day for 10 days, along with standard infusion therapy. Assessment will include physical examination data, vital signs, blood tests (CBC, biochemistry - protein, albumin, AST, ALT, APG, GGTP, LDH, total bilirubin, direct bilirubin, amylase, glucose, electrolytes, creatinine, urea, uric acid, C -reactive protein, lipid profile; coagulogram; urine samples), ECOG assessment, repeated abdominal ultrasound, neurophysiological test for the evaluation of encephalopathy, record of bile volume by drainage (if applicable). All patients will be followed up for 31 days.

Official Title
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A Multicenter, Double-blind, Placebo-controlled, Randomized Trial of the Efficacy and Safety of Remaxol®, a Solution for Infusions Produced by STPF POLYSAN (Russia), in Patients With Malignant Mechanical Jaundice

Conditions
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Jaundice; Malignant

Intervention / Treatment
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* Drug: Remaxol®
* Drug: Ringer's Solution


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Presence of signed informed consent for participation in the study. Men and women over 18 years of age (incl.). Demonstrated by one or several instrumental methods (ultrasound, cholangiography, CT or MRI) enlargement of intrahepatic bile ducts with visualized obturation of the main bile ducts caused by tumor. Duration of mechanical jaundice less than 30 days, including the first day of the screening period. The status by the classifications Eastern Cooperative Oncology Group (ECOG) scale is 0-2. Life expectancy of more than 3 months. Laboratory data corresponding to the following cutoff limits : hemoglobin ≥90 g / l; neutrophils ≥ 1.5x109 / l; Platelets ≥ 75 x 109 / L; AsAT and / or AlAT above 3 х normal but less than 25 х normal Serum creatinine not exceeding 2 × normal, Serum potassium within normal limits Negative urine test for pregnancy in women of reproductive age. For reproductive age: consent to use adequate methods of contraception or for complete abstinence from sexual activity for the period of the study. Exclusion Criteria: Radical surgery planned within 10 days from the date of randomization. Liver metastases with the biliary block at the level of segmental ducts. Suspicion of metastases in the central nervous system or metastatic arachnoiditis during physical examination; clinically significant ascites. Acute destructive pancreatitis, diffuse peritonitis, ongoing bleeding of any etiology, sepsis (procalcitonin test of 10 ng / ml and above). Liver cirrhosis Presence of clinically significant cardiovascular diseases: chronic cardiac insufficiency III-IV functional class by NYHA, uncontrolled arterial hypertension, acute stroke or acute myocardial infarction in the previous 3 months, unstable angina, uncontrolled arrhythmia and severe heart rhythm disturbances. Pregnancy or lactation. Hypersensitivity to any component of the study drug / placebo and / or intolerance to any component of the study drug / placebo. Regular intake of medications prohibited or not permitted by the study protocol within 4 weeks prior to enrollment or medical indication tio start any medication prohibited or not permitted by the study protocol Concomitant chronic systemic immune or hormonal therapy. Gout. Alcohol and/or drug dependence. Active tuberculosis, HIV infection, syphilis, acute viral hepatitis. Any other conditions / diseases that may interfere with the patient's compliance with the requirements of the Protocol. Mental, physical and other reasons that do not allow the patient to comply with the requirements of the study protocol. Any other significant (by judgement of the investigator) condition that prevents the patient from entering the study. Participation in any clinical trial in the previous 3 months. Staff of the research center and their family members.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Remaxol® 400 ml + Placebo 400 ml<br>Treatment with Remaxol® 400 ml IV + Ringer solution 400 ml IV for 10 days. Drug: Remaxol (succinate + methionine + inosine + nicotinamide) | Drug: Remaxol®<br>* Solution for intravenous infusions, containing succinate, methionine, inosine, and nicotinamide in 400 ml glass bottle<br>* Other names: Remaxol (succinate + methionine + inosine + nicotinamide);Drug: Ringer's Solution<br>* Solution for intravenous infusion, 400 or 800 ml<br>* Other names: Placebo;|
| Experimental: Remaxol® 800 ml<br>Treatment with Remaxol® 800 ml IV for 10 days. Drug: Remaxol (succinate + methionine + inosine + nicotinamide) | Drug: Remaxol®<br>* Solution for intravenous infusions, containing succinate, methionine, inosine, and nicotinamide in 400 ml glass bottle<br>* Other names: Remaxol (succinate + methionine + inosine + nicotinamide);|
| Placebo Comparator: Control<br>Treatment with Ringer's solution 800 ml IV for 7 days. Drug: Ringer's solution | Drug: Ringer's Solution<br>* Solution for intravenous infusion, 400 or 800 ml<br>* Other names: Placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to regression of jaundice | The time (days) from the day of the drainage operation to the reduction of the total bilirubin level down to 90 μmol / l, in experimental (Remaxol®) vs. control (Placebo) groups | 21 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Regression of cytolysis (normal alanine aminotransferase and aspartate aminotransferase serum levels) | Proportion of patients in study groups who reached normal serum levels of alanine aminotransferase and aspartate aminotransferase on day 11 from the start of treatment | 11 days | 
| Regression of cholestasis | Proportion of patients in study groups who reached normal serum levels of alkaline phosphatase, GGTP, total bilirubin, and direct bilirubin on day 11 from the start of treatment | 11 days | 
| Regression of encephalopathy | Proportion of patients in study groups who had normal brain functioning on day 11, as reflected by the neurophysiological test for the evaluation of the degree of encephalopathy | 11 days | 
| Serum bilirubin | Dynamics of total and direct bilirubin serum levels against baseline values and between visits in the study groups | 21 days | 
| Serum alkaline phosphatase | Dynamics of serum alkaline phosphatase level against baseline values and between visits in the study groups | 21 days | 
| Serum GGTP | Dynamics of serum gamma-glutamyltranspeptidase level against baseline values and between visits in the study groups | 21 days | 
| Serum alanine aminotransferase | Dynamics of serum alanine aminotransferase level against baseline values and between visits in the study groups | 21 days | 
| Serum aspartate aminotransferase | Dynamics of serum aspartate aminotransferase level against baseline values and between visits in the study groups | 21 days | 
| Liver function | State of liver protein synthesis function (as reflected by serum levels of total protein, albumin, INR, PT, PTI, APTT, fibrinogen) against baseline values and/or between visits | 21 days | 
| Kidney function | State of kidney function (creatinine serum level) against baseline values and/or between visits | 21 days | 
| Proportion of patients with complications of jaundice | The number of patients in the study groups who developed complications in the postoperative period which were, according to the researcher's assessment, causally related to the obstructive jaundice (for example, purulent cholangitis, sepsis, kidney failure) | 21 days | 
| Eastern Cooperative Oncology Group (ECOG) Performance Status | Status of patients in the study groups by ECOG (Eastern Cooperative Oncology Group) grades at the end of the study. ECOG Performance Status consists of the following grades: 0 - fully active, able to carry on all pre-disease performance without restriction; - restricted but ambulatory and able to carry out work of a light or sedentary nature; - ambulatory and capable of all selfcare but unable to carry out any work activities; - capable of only limited selfcare; partially confined to bed or chair; - completely disabled; cannot carry on any selfcare; - Dead | 31 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Jaundice, obstructive, Methionine, Succinic acid