Remaxol® in Mechanical Jaundice of Non-malignant Origin

Study Overview
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Brief Summary
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The purpose of this study is to assess the safety and efficacy of Remaxol (succinate + methionine + inosine + nicotinamide; POLYSAN Ltd., Russia) infusions at dose 400 and 800 ml to treat mechanical jaundice of non-tumor cause during the first week after surgery.

Detailed Description
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The study will be performed in in-hospital patients with obstructive jaundice cause by conditions other than tumor (predominantly by cholelithiasis; ICD-10 codes K80 and K83.1). The patients will be screened in the 15 days preceeding the appointed drainage surgery. The treatment will be started in the first 6 hours after the drainage surgery and continue for 7 days. Following screening, patients who meet the inclusion criteria and have no criteria for exclusion will be randomly assigned into three study groups in the proportion of 1: 1: 1): Group I: treatment with Remaxol 400 ml IV + Ringer solution 400 ml IV for 7 days. Group II: treatment with Remaxol 800 ml IV for 7 days. Group III (control): Ringer solution 800 ml IV for 7 days. Physical examination data, vital signs, biochemistry panel (including bilirubin, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, GGTP) will be assessed on days 1-8, on day 11 and day 14. Diagnostic abdominal ultrasound will be performed before surgery and on days 3 and 8. Neurophysiological test for the evaluation of the degree of encephalopathy will be performed before surgery, on days 3, 5, 8, and 14. All patients will be followed up for 14 days.

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

Conditions
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Jaundice, Obstructive

Intervention / Treatment
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* Drug: Remaxol (succinate + methionine + inosine + nicotinamide)
* 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 the age of 18 (incl.). Obstructive jaundice, verified by enlargement of intrahepatic bile ducts with proven non-tumor obstruction of extrahepatic bile ducts. Duration of mechanical jaundice 15 days or less. The level of total bilirubin in the blood from 5-fold to 20-fold exceeding normal. 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 20 х normal Serum creatinine not exceeding 2 × normal, Serum potassium within normal limits Negative urine test for pregnancy in women of reproductive age. Consent to use adequate methods of contraception or for complete abstinence from sexual activity for the period of the study. Consent to abstain completely from alcohol intake during the study period. Exclusion Criteria: Tumor causing the obstruction of the bile ducts or the presence of any other malignancy at the time of randomization. The need for another radical surgery within 2 weeks from the planned date of randomization. Acute destructive pancreatitis, diffuse or diffuse peritonitis, sepsis. Preexisting liver cirrhosis. Exacerbation of the chronic peptic ulcer. Ongoing bleeding. 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. Any other decompensated disease. Pregnancy or lactation. Hypersensitivity to any component of the study drug / placebo and / or intolerance to any component of the study drug / placebo. Regular admission of medications prohibited or not permitted by the study protocol within 4 weeks prior to enrollment. 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<br>Group I: treatment with Remaxol 400 ml IV + Ringer solution 400 ml IV for 7 days. Drug: Remaxol (succinate + methionine + inosine + nicotinamide) | Drug: Remaxol (succinate + methionine + inosine + nicotinamide)<br>* Solution for intravenous infusions, containing succinate, methionine, inosine, and nicotinamide in 400 ml glass bottle<br>* Other names: Remaxol®;Drug: Ringer's Solution<br>* Intravenous infusion, 400 or 800 ml<br>* Other names: Placebo;|
| Experimental: Remaxol 800 ml<br>Group II: treatment with Remaxol 800 ml IV for 7 days. Drug: Remaxol (succinate + methionine + inosine + nicotinamide) | Drug: Remaxol (succinate + methionine + inosine + nicotinamide)<br>* Solution for intravenous infusions, containing succinate, methionine, inosine, and nicotinamide in 400 ml glass bottle<br>* Other names: Remaxol®;|
| Placebo Comparator: Control<br>Group III: Ringer's solution 800 ml IV for 7 days. Drug: Ringer's solution | Drug: Ringer's Solution<br>* 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 |
| --- | --- | --- |
| Days to regression of jaundice | Time (days) from the date of drainage surgery to the reduction of the total bilirubin level down to 50 μmol / l, in experimental (Remaxol®) and control (Placebo) groups | 14 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disappearance of cytolysis (normal alanine aminotransferase and aspartate aminotransferase serum levels) on day 5 | Proportion of patients in study groups who reached normal serum levels of alanine aminotransferase and aspartate aminotransferase on day 5 from the start of treatment | 5 days | 
| Disappearance of cholestasis on day 5 | Proportion of patients in study groups who reached normal serum levels of alkaline phosphatase, GGTP, total bilirubin, and direct bilirubin on day 5 from the start of treatment | 5 days | 
| Disappearance of encephalopathy on day 5 | Proportion of patients in study groups who had normal brain functioning on day 5, as reflected by the neurophysiological test for the evaluation of the degree of encephalopathy | 5 days | 
| Serum bilirubin | Dynamics of total and direct bilirubin serum levels against baseline values and between visits in the study groups | 14 days | 
| Serum enzymes | Dynamics of serum alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and GGTP against baseline values and between visits in the study groups | 14 days | 
| Liver function | State of liver protein synthesis function (as reflected by serum levels of total protein, albumin, fibrinogen) against baseline values and/or between visits | 14 days | 
| Kidney function | State of kidney function (serum creatinine) against baseline values and/or between visits | 14 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). | 14 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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obstructive jaundice, non-malignant, mechanical jaundice, non-malignant, Methionine, Succinic acid