Remaxol® in Malignant Mechanical Jaundice

Phase 3

Completed

• Conditions: Jaundice; Malignant
• Interventions: Drug: Ringer's Solution; Drug: Remaxol®

• Registration Number: NCT03416062
• Lead Sponsor: POLYSAN Scientific & Technological Pharmaceutical Company

Brief Summary

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

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.

Study Timeline

• Study Start: 2017-04-03
• Study First Submitted: 2018-01-23
• Study First Submitted QC: 2018-01-29
• Study First Posted: 2018-01-30
• Primary Completion: 2020-02-03
• Study Completion: 2020-03-04
• Status Verified: 2020-07
• Last Update Submitted: 2020-07-09
• Last Update Posted: 2020-07-10

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 240

Inclusion Criteria

1. Presence of signed informed consent for participation in the study.

2. Men and women over 18 years of age (incl.).

3. 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.

4. Duration of mechanical jaundice less than 30 days, including the first day of the screening period.

5. The status by the classifications Eastern Cooperative Oncology Group (ECOG) scale is 0-2.

6. Life expectancy of more than 3 months.

7. 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

8. Negative urine test for pregnancy in women of reproductive age.

9. For reproductive age: consent to use adequate methods of contraception or for complete abstinence from sexual activity for the period of the study.

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Exclusion Criteria

1. Radical surgery planned within 10 days from the date of randomization.
2. Liver metastases with the biliary block at the level of segmental ducts.
3. Suspicion of metastases in the central nervous system or metastatic arachnoiditis during physical examination; clinically significant ascites.
4. Acute destructive pancreatitis, diffuse peritonitis, ongoing bleeding of any etiology, sepsis (procalcitonin test of 10 ng / ml and above).
5. Liver cirrhosis
6. 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.
7. Pregnancy or lactation.
8. Hypersensitivity to any component of the study drug / placebo and / or intolerance to any component of the study drug / placebo.
9. 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
10. Concomitant chronic systemic immune or hormonal therapy.
11. Gout.
12. Alcohol and/or drug dependence.
13. Active tuberculosis, HIV infection, syphilis, acute viral hepatitis.
14. Any other conditions / diseases that may interfere with the patient's compliance with the requirements of the Protocol.
15. Mental, physical and other reasons that do not allow the patient to comply with the requirements of the study protocol.
16. Any other significant (by judgement of the investigator) condition that prevents the patient from entering the study.
17. Participation in any clinical trial in the previous 3 months.
18. Staff of the research center and their family members.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Control	Ringer's Solution	Treatment with Ringer's solution 800 ml IV for 7 days. Drug: Ringer's solution
Remaxol® 400 ml + Placebo 400 ml	Remaxol®	Treatment with Remaxol® 400 ml IV + Ringer solution 400 ml IV for 10 days. Drug: Remaxol (succinate + methionine + inosine + nicotinamide)
Remaxol® 400 ml + Placebo 400 ml	Ringer's Solution	Treatment with Remaxol® 400 ml IV + Ringer solution 400 ml IV for 10 days. Drug: Remaxol (succinate + methionine + inosine + nicotinamide)
Remaxol® 800 ml	Remaxol®	Treatment with Remaxol® 800 ml IV for 10 days. Drug: Remaxol (succinate + methionine + inosine + nicotinamide)

Primary Outcome Measures

Name	Time	Method
Time to regression of jaundice	21 days	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

Secondary Outcome Measures

Name	Time	Method
Serum bilirubin	21 days	Dynamics of total and direct bilirubin serum levels against baseline values and between visits in the study groups
Regression of cholestasis	11 days	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
Serum aspartate aminotransferase	21 days	Dynamics of serum aspartate aminotransferase level against baseline values and between visits in the study groups
Liver function	21 days	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
Kidney function	21 days	State of kidney function (creatinine serum level) against baseline values and/or between visits
Eastern Cooperative Oncology Group (ECOG) Performance Status	31 days	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; 1. - restricted but ambulatory and able to carry out work of a light or sedentary nature; 2. - ambulatory and capable of all selfcare but unable to carry out any work activities; 3. - capable of only limited selfcare; partially confined to bed or chair; 4. - completely disabled; cannot carry on any selfcare; 5. - Dead
Regression of cytolysis (normal alanine aminotransferase and aspartate aminotransferase serum levels)	11 days	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
Serum alanine aminotransferase	21 days	Dynamics of serum alanine aminotransferase level against baseline values and between visits in the study groups
Regression of encephalopathy	11 days	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
Serum alkaline phosphatase	21 days	Dynamics of serum alkaline phosphatase level against baseline values and between visits in the study groups
Serum GGTP	21 days	Dynamics of serum gamma-glutamyltranspeptidase level against baseline values and between visits in the study groups
Proportion of patients with complications of jaundice	21 days	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)

Trial Locations

Locations (18)

City Clinical Hospital of Emergency Care; 🇷🇺 Ryazan, Russian Federation

SPb GBUZ 'City Mariinskaya Hospital'; 🇷🇺 Saint Petersburg, Russian Federation

Omsk Regional Clinical Oncology Center; 🇷🇺 Omsk, Russian Federation

SPb GBUZ "City Hospital №26"; 🇷🇺 Saint Petersburg, Russian Federation

Siberian State Medical University; 🇷🇺 Tomsk, Russian Federation

Moscow City Clinical Hospital #1 n.a.N.I.Pirogov; 🇷🇺 Moscow, Russian Federation

GBUZ 'Leningrad Regional Oncology Center'; 🇷🇺 Saint Petersburg, Russian Federation

GBUZ "Penza Regional Clinical Hospital na N.N.Burdenko"; 🇷🇺 Penza, Russian Federation

North-West State Medical University named after I.I. Mechnikov; 🇷🇺 Saint Petersburg, Russian Federation

OGAUZ "Tomsk Regional Clinical Hospital"; 🇷🇺 Tomsk, Russian Federation

Moscow City Clinical Hospital #29 n.a.N.A.Bauman; 🇷🇺 Moscow, Russian Federation

GBUZ 'Bryansk City Hospital #1'; 🇷🇺 Bryansk, Russian Federation

KBUZ 'Regional Clinical Hospital'; 🇷🇺 Krasnoyarsk, Russian Federation

Regional Clinical Hospital of Emergency Care n.a.M.A.Podgorbunsky; 🇷🇺 Kemerovo, Russian Federation

OBUZ 'Kursy Regional Clinical Oncology Dispensary' of Kursky Regional Healthcare Department; 🇷🇺 Kursk, Russian Federation

GBUZ Leningrad Regional Clinical Hospital; 🇷🇺 Saint Petersburg, Russian Federation

Hospital for War Veterans; 🇷🇺 Saint Petersburg, Russian Federation

Saint-Petersburg I.I.Dzanelidze Research Institute of Emergency Medicine; 🇷🇺 Saint Petersburg, Russian Federation