The results of phase III multicenter open randomized controlled study REM-Chol-III-16 in patients with intrahepatic cholestasis syndrome caused by chronic diffuse liver diseases
- Authors: Stel'makh V.V.1, Kovalenko A.L.2, Popova V.B.3, Uspenskiy Y.P.4, Morozov V.G.5, Belikova T.N.6, Rafalskiy V.V.7, Antonova E.A.8
-
Affiliations:
- Mechnikov North-Western State Medical University
- Golikov Scientific Clinical Center of Toxicology
- Medical center "Reavita Med SPb"
- Saint Petersburg State Paediatric Medical University
- Medical company "Hepatologist"
- Togliatti City Clinical Hospital №1
- Immanuel Kant Baltic Federal University
- "Modern Medical Technologies" Clinic
- Issue: Vol 93, No 12 (2021)
- Pages: 1470-1476
- Section: Original articles
- URL: https://journals.rcsi.science/0040-3660/article/view/96444
- DOI: https://doi.org/10.26442/00403660.2021.12.201266
- ID: 96444
Cite item
Full Text
Abstract
Aim. To assess the safety and efficacy of Remaxol®, solution for infusion, compared with parenteral form of S-adenosyl-L-methionine, in the treatment of patients with intrahepatic cholestasis syndrome accompanying chronic diffuse liver diseases of various etiology.
Materials and methods. In a multicenter open-label comparative study of the safety and efficacy of Remaxol® (inosine + meglumine + methionine + nicotinamide + succinic acid) 317 patients aged 18 to 65 years were randomized into 2 groups: patients of the experimental group (n=168) received intravenous Remaxol®, solution for infusion, 400 ml, and patients of the control group (n=149) – Heptral® (S-adenosyl-L-methionine) 800 mg. The duration of treatment was 10 days. The primary efficacy endpoint was the proportion of patients who responded to therapy, as demonstrated by dynamics of laboratory parameters of liver functional status: decrease in gamma glutamyl transpeptidase level by ≥40%, and/or alkaline phosphatase level by ≥30%, and/or decrease total bilirubin level by ≥30% from baseline by the end of the treatment course.
Results. The proportion of responders was 51% in the Remaxol® group vs. 44.9% in the Heptral® group (p=0.303); the lower limit of the one-sided 95% confidence interval for the difference in the proportions of responders was -4.01%, which exceeds the non-inferiority margin pre-defined by the study protocol, thus, the non-inferiority hypothesis was proven, i.e. Remaxol at a dose of 400 ml/day demonstrates similar efficacy to Heptral at a dose of 800 mg/day in patients with intrahepatic cholestasis syndrome associated with chronic diffuse liver diseases. Similar positive trends in the levels of transaminases, total bilirubin and the severity of pruritus were revealed in both treatment groups. We did not reveal statistically significant between-group differences in the frequency of adverse events definitely related to the study treatment.
Conclusion. Administration of Remaxol® as a part of the pathogenetic therapy of patients with intrahepatic cholestasis syndrome who need hepatoprotection is justified.
Full Text
##article.viewOnOriginalSite##About the authors
Viktoriia V. Stel'makh
Mechnikov North-Western State Medical University
Author for correspondence.
Email: lednik-07@mail.ru
ORCID iD: 0000-0001-7942-1227
канд. мед. наук, доц. каф. внутренних болезней, клинической фармакологии и нефрологии
Russian Federation, Saint PetersburgAleksey L. Kovalenko
Golikov Scientific Clinical Center of Toxicology
Email: lednik-07@mail.ru
ORCID iD: 0000-0003-3695-2671
д-р биол. наук, канд. хим. наук, вед. науч. сотр.
Russian Federation, Saint PetersburgVeronika B. Popova
Medical center "Reavita Med SPb"
Email: lednik-07@mail.ru
ORCID iD: 0000-0001-8235-5654
канд. мед. наук, ген. дир.
Russian Federation, Saint PetersburgYury P. Uspenskiy
Saint Petersburg State Paediatric Medical University
Email: lednik-07@mail.ru
ORCID iD: 0000-0001-6434-1267
д-р мед. наук, проф., зав. каф. факультетской терапии им. проф. В.А. Вальдмана
Russian Federation, Saint PetersburgViacheslav G. Morozov
Medical company "Hepatologist"
Email: lednik-07@mail.ru
ORCID iD: 0000-0002-4451-7891
д-р мед. наук, проф., дир.
Russian Federation, SamaraTatiana N. Belikova
Togliatti City Clinical Hospital №1
Email: lednik-07@mail.ru
ORCID iD: 0000-0002-8662-9373
зам. глав. врача
Russian Federation, TogliattiVladimir V. Rafalskiy
Immanuel Kant Baltic Federal University
Email: lednik-07@mail.ru
ORCID iD: 0000-0002-2503-9580
д-р мед. наук, проф., дир. Центра клинических исследований
Russian Federation, KaliningradElizaveta A. Antonova
"Modern Medical Technologies" Clinic
Email: lednik-07@mail.ru
ORCID iD: 0000-0002-5455-299X
врач-терапевт, клинический фармаколог
Russian Federation, Saint PetersburgReferences
- Ивашкин В.Т., Широкова Е.Н., Маевская М.В., и др. Клинические рекомендации по диагностике и лечению холестаза. М., 2013 [Ivashkin VT, Shirokova EN, Mayevskaya MV, et al. Klinicheskie rekomendatsii po diagnostike i lecheniiu kholestaza. Moscow, 2013 (in Russian)].
- Подымова С.Д. Болезни печени. М.: Медицина, 2005 [Podymova SD. Bolezni pecheni. Moscow: Medicina, 2005 (in Russian)].
- Голованова Е.В., Петраков А.В., Носкова К.К. Внутрипеченочный холестаз при хронических заболеваниях печени. Экспериментальная и клиническая гастроэнтерология. 2011;2:58-67 [Golovanova EV, Petrakov AV, Noskova KK. Intrahepatic cholestasis in chronic liver diseases. Eksperimental'naya i klinicheskaya gastroenterologiya. 2011; 2: 58-67 (in Russian)].
- Минушкин О.Н. Лечение основных проявлений болезней печени. Клиническая фармакология и терапия. 1996;1:4-8 [Minushkin ON. Treatment of the main manifestations of liver disease. Klinicheskaya farmakologiya i terapiya. 1996;1:4-8 (in Russian)].
- Успенский Ю.П., Барышникова Н.В., Фоминых Ю.А. Опыт применения урсодезоксихолевой кислоты у пациентов с гастроэнтерологическими кластерами метаболического синдрома, ассоциированными с явлениями холестаза. Медицина: теория и практика. 2018;3(1):96-7 [Uspensky YuP., Baryshnikova NV, Fominykh YuA. Experience of using ursodeoxycholic acid in patients with gastroenterological clusters of metabolic syndrome associated with cholestasis. Meditsina: teoriya i praktika. 2018;3(1):96-7 (in Russian)]
- Sherlock S, Dooley J. Diseasеs of the liver and biliary system. 10th Blackwell Sci. Publications. Oxford, 1997; p. 217-38.
- Almasio P, Bortolini M, Pagliaro L, Coltorti M. Role of S-adenosyl-L-methionine in the treatment of intrahepatic cholestasis. Drugs. 1990;40(3):111-23. doi: 10.2165/00003495-199000403-00011
- Frezza M. A meta-analysis of therapeutic trials with ademetionine in the treatment of intrahepatic cholestasis. Ann Ital Med Interna Organo Uff Della Soc Ital Med Interna. 1993;8:48-51.
- Сологуб Т.В., Горячева Л.Г., Суханов Д.С., и др. Гепатопротективная активность ремаксола при хронических поражениях печени. Клиническая медицина. 2010;1(88):62-6 [Sologub TV, Goryacheva LG, Sukhanov DS, et al. Hepatoprotective activity of Remaxol in chronic liver damage. Klinicheskaya meditsina. 2010;1(88):62-6 (in Russian)].
- Стельмах В.В., Козлов В.К., Иванова В.Ф., Самусенко И.А. Эффективность инфузионного гепатопротекторного препарата Ремаксол в патогенетической терапии хронических вирусных гепатитов на цирротической стадии. Терапевтический архив. 2015;87(8):67-72 [Stelmakh VV, Kozlov VK, Ivanova VF, Samusenko IA. The efficacy of the hepatoprotective infusion drug Remaxol in the pathogenetic therapy of chronic viral hepatitis at the cirrhotic stage. Terapevticheskii Arkhiv (Ter. Arkh.). 2015;87(8):67-72 (in Russian)]. doi: 10.17116/terarkh201587867-72
- Стельмах В.В., Некрасова А.С., Козлов В.К., и др. Эффективность комбинированной терапии сукцинат содержащими лекарственными препаратами неалкогольной жировой болезни печени. Клиническая медицина 2016;11(94):836-42 [Stelmakh VV, Nekrasova AS, Kozlov VK, et al. Efficiency of combination therapy with succinate containing medicinal products of non-alcoholic fatty liver disease. Klinicheskaya meditsina. 2016;11(94):836-42 (in Russian)]. doi: 10.18821/0023-2149-2016-94-11-836-842
- Ильченко Л.Ю., Оковитый С.В. Ремаксол: механизмы действия и применение в клинической практике. Архивъ внутренней медицины. 2016;6(2):16-21 [Ilchenko LYu, Okovityy SV. Remaxol: mechanisms of action and application in clinical practice. Arkhiv" vnutrenney meditsiny. 2016;6(2):16-21 (in Russian)]. doi: 10.20514/2226-6704-2016-6-2-16-21
- Филиппова Н.В., Барыльник Ю.Б., Шульдяков А.А. Применение Ремаксола в качестве гепатопротектора при длительной психофармакотерапии. Журнал неврологии и психиатрии им. C.C. Корсакова. 2019;119(4):43-6 [Filippova NV, Barylnik YuB, Shuldyakov AA. The use of Remaxol as a hepatoprotector in long-term psychopharmacotherapy. Zhurnal nevrologii i psikhiatrii im. C.C. Korsakova. 2019;119(4):43-6 (in Russian)]. doi: 10.17116/jnevro201911901143
- Коваленко А.Л., Петров А.Ю., Суханов Д.С., и др. Ремаксол – препарат для восстановления системы антиоксидантной защиты при поражении печени циклофосфаном в эксперименте. Экспериментальная и клиническая фармакология. 2011;1(74):32-5 [Kovalenko AL, Petrov AYu, Sukhanov DS, et al. Remaxol is a drug for restoring the antioxidant defense system in case of liver damage by cyclophosphamide in experiment. Eksperimental'naya i klinicheskaya farmakologiya. 2011;1(74):32-5 (in Russian)]. doi: 10.30906/0869-2092-2011-74-1-32-35
- Суханов Д.С., Петров А.Ю., Коваленко А.Л., Романцов М.Г. Индукция S-аденозил-L-метионина в гепатоцитах при фармакотерапии токсических и лекарственных поражений печени в эксперименте. Экспериментальная и клиническая фармакология. 2011;74(1):32-5 [Sukhanov DS, Petrov AYu, Kovalenko AL, Romantsov MG. Induction of S-adenosyl-L-methionine in hepatocytes during pharmacotherapy of toxic and drug-induced liver lesions in experiment. Eksperimental'naya i klinicheskaya farmakologiya. 2011;74(1):32-5 (in Russian)]. doi: 10.30906/0869-2092-2011-74-10-34-38
- Яковенко Э.П., Григорьев П.Я., Агафонова Н.А., Яковенко А.В. Внутрипеченочный холестаз: от патогенеза до лечения. Практикующий врач. 1998;13:20. [Yakovenko EP, Grigoriev PYa, Agafonova NA, Yakovenko AV. Intrahepatic cholestasis: from pathogenesis to treatment. Praktikuyushchiy vrach. 1998;13:20 (in Russian)].
- Bogert PT, LaRusso NF. Cholangiocyte biology. Curr Opin Gastroenterol. 2007;23(3):299-305. doi: 10.1097/MOG.0b013e3280b079fb
Supplementary files
![](/img/style/loading.gif)