Technologically-Treated Polyclonal Affinity-Purified Antibodies to the Tumor Necrosis Factor-α, Brain Specific S-100 Protein and Histamine in Treatment of Functional Dyspepsia: Results of the Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial

The aim of the study was to evaluate the efficacy and safety of Kolofort® (a complex medicine containing technologically processed forms of antibodies to S-100 protein, tumor necrosis factor-α and histamine) in the management of functional dyspepsia (FD) in outpatient clinical practice.

Methods: Outpatients (N = 309) at the age of 18–45 in whom FD was diagnosed according to the Rome IV criteria were enrolled in a multicenter, double-blind, placebo-controlled, randomized clinical trial. Patients were randomized in two groups receiving Kolofort^® or placebo 2 tablets tid for 8 weeks. The primary endpoint of the study was a change in the FD symptoms severity score according to the Gastrointestinal symptom score (GIS) at week 8. ITT and [PP] analysis were performed.

Results: at week 8 the reduction in GIS sum score was observed in Kolofort® group and placebo group (by 7.2 ± 3.3 [7.2 ± 3.4] and 6.3 ± 4.6 [6.2 ± 4.5], respectively, p = 0.041 [0.039]). The proportion of cases with GIS score reduction by ≥4 was 88,1 % [88.6 %] and 79.1 % [79.6 %] in Kolofort® group and placebo group, respectively (p = 0.046 [p = 0.051]). None of the patients in Kolofort^® group had progression of FD symptoms or required additional therapy. There were 29 adverse events (AEs) recorded in 25 patients including 16 cases in 13 (8.6 %) patients in Kolofort® group and 13 AEs in 12 (7.6 %) patients in placebo group.

Conclusion: the clinical trial demonstrates the positive effect of Kolofort^® in FD with a favorable safety profile.

1. Aziz I., Palsson O.S., Törnblom H., Sperber A.D., Whitehead W.E., Simrén M. Epidemiology, clinical characteristics, and associations for symptom-based Rome IV functional dyspepsia in adults in the USA, Canada, and the UK: a cross-sectional population-based study. Lancet Gastroenterol Hepatol. 2018;3(4):252–62. DOI: 10.1016/S2468-1253(18)30003-7

2. Mukhtar K., Nawaz H., Abid S. Functional gastrointestinal disorders and gut-brain axis: What does the future hold? World J Gastroenterol. 2019;25(5):52–566. DOI:10.3748/wjg.v25.i5.552

3. Azer S.A., Akhondi H. Gastritis. In: StatPearls. Treasure Island (FL): StatPearls Publishing; 2021 Jan. Available from: https://www.ncbi.nlm.nih.gov/books/NBK544250/

4. Zullo A., Hassan C., De Francesco V., Repici A., Manta R., Tomao S., et al. Helicobacter pylori and functional dyspepsia: an unsolved issue? World J Gastroenterol. 2014;20(27):8957–63. DOI: 10.3748/wjg.v20.i27.8957

5. Sugano K., Tack J., Kuipers E.J., Graham D.Y., ElOmar E.M., Miura S., et al. Kyoto global consensus report on Helicobacter pylori gastritis. Gut. 2015;64:133– 67. DOI: 10.1136/gutjnl-2015-309252

6. Malfertheiner P., Megraud F., O’Morain C.A., Gisbert J.P., Kuipers E.J., Axon A.T., et al. Management of Helicobacter pylori infection the Maastricht V/Florence Consensus Report. Gut. 2017;66(1):6–30. DOI: 10.1136/gutjnl-2016-312288

7. Ivashkin V.T., Mayev I.V., Sheptulin A.A., Lapina T.L., Trukhmanov A.S., Kartavenko I.M., et al. Diagnosis and treatment of the functional dyspepsia: clinical guidelines of the Russian Gastroenterological Association. Rus J Gastroenterol Hepatol Coloproctol. 2017;27(1):50–61 (In Russ.). DOI: 10.22416/1382-4376-2017-27-1-50-61

8. Yamawaki H., Futagami S., Wakabayashi M., Sakasegawa N., Agawa S., Higuchi K., et al. Management of functional dyspepsia: state of the art and emerging therapies. Ther Adv Chronic Dis. 2018;9(1):23–32. DOI: 10.1177/2040622317725479

9. Sayuk G.S., Gyawali C.P. Functional Dyspepsia: Diagnostic and Therapeutic Approaches. Drugs. 2020;80(13):1319–36. DOI: 10.1007/s40265-020-01362-4

10. Luo L., Du L., Shen J., Cen M., Dai N. Benefit of small dose antidepressants for functional dyspepsia: Experience from a tertiary center in eastern China. Medicine (Baltimore). 2019; 98(41):e17501. DOI: 10.1097/MD.0000000000017501

11. Инструкция по медицинскому применению лекарственного препарата Колофорт® ЛП-N (000027) — (РГ-RU). https://grls.rosminzdrav.ru/Grls_View_v2.aspx?routingGuid=58b244a0-60a5-4a1e-8e0a-cdc7edf6b06a&t=

12. Gudkov S.V., Penkov N.V., Baimler I.V., Lyakhov G.A., Pustovoy V.I., Simakin A.V., et al. Effect of Mechanical Shaking on the Physicochemical Properties of Aqueous Solutions. Int J Mol Sci. 2020;21(21):8033. DOI: 10.3390/ijms21218033

13. Gudkov S.V., Baimler I.V., Uvarov O.V., Smirnova V.V., Volkov M.Yu., Semenova A.A., et al. Influence of the Concentration of Fe and Cu Nanoparticles on the dynamics of the Size Distribution of Nanoparticles. Frontiers of Physics. 2020b;8;622551. DOI: 10.3389/fphy.2020.622551

14. Ryzhkina I.S., Murtazina L.I., Kiseleva Yu.V., Konovalov A.I. Self-organization and physicochemical properties of aqueous solutions of the antibodies to interferon gamma at ultrahigh dilution. Doklady Physical Chemistry. 2015;462(1);110–4 (In Russ.). DOI: 10.1134/S0012501615050048

15. Woods K.N. New insights into the microscopic interactions associated with the physical mechanism of action of highly diluted biologics. Scientific Reports. 2021;11(1);13774. DOI: 10.1038/s41598-021-93326-1

16. Epstein O. The spatial homeostasis hypothesis. Symmetry. 2018;10(4);103. DOI: 10.3390/sym10040103

17. Tarasov S.A., Gorbunov E.A., Don E.S., Emelyanova A.G., Kovalchuk A.L., Yanamala N., et al. Insights into the mechanism of action of highly diluted biologics. J Immunol. 2020;205(5);1345–54. DOI: 10.4049/jimmunol.2000098

18. Gudkov S.V., Lyakhov G.A., Pustovoy V.I., Shcherbakov I.A. Influence of Mechanical Effects on the Hydrogen Peroxide Concentration in Aqueous Solutions. Physics of Wave Phenomena. 2019;27(2);141–4. DOI: 10.1021/acsomega.0c01444

19. Bunkin N.F., Shkirin A.V., Ninham B.W., Chirikov S.N., Chaikov L.L., Penkov N.V., et al. Shaking-Induced Aggregation and Flotation in Immunoglobulin Dispersions: Differences between Water and Water-Ethanol Mixtures. ACS Omega. 2020;5(24);14689–701. DOI: 10.1021/acsomega.0c01444

20. Shcherbakov I.A. Influence of External Impacts on the Properties of Aqueous Solutions. Physics of Wave Phenomena. 2021;29(2);89–93. DOI: 10.3103/S1541308X21020114

21. Shcherbakov I.A. Specific Features of the Concentration Dependences of Impurities in Condensed Media. Physics of Wave Phenomena. 2020;28(2);83–7. DOI: 10.3103/S1541308X20020156

22. Lyakhov G.A., Shcherbakov I.A. Approaches to the Physical Mechanisms and Theories of Low-Concentration Effects in Aqueous Solutions. Physics of Wave Phenomena. 2019;27(2);79–86.

23. Emelianova A.G., Petrova N.V., Fremez C., Fontanié M., Tarasov S.А., Epstein O.I. Therapeutic potential of highly diluted antibodies in antibiotic-resistant infection. Eur J Pharm Sci. 2022;173.106161. DOI: 10.1016/j.ejps.2022.106161

24. Rafalsky V., Averyanov A., Bart B., Minina E., Putilovskiy M., Andrianova E., et al. Efficacy and safety of Ergoferon versus oseltamivir in adult outpatients with seasonal influenza virus infection: a multicenter, open-label, randomized trial. Int J Infect Dis. 2016;51;47–55. DOI: 10.1016/j.ijid.2016.09.002

25. Mkrtumyan A., Romantsova T., Vorobiev S., Volkova A., Vorokhobina N., Tarasov S., et al. Efficacy and safety of Subetta add-on therapy in type 1 diabetes mellitus: The results of a multicenter, double-blind, placebo-controlled, randomized clinical trial. Diabetes Res Clin Pract. 2018;142;1–9. DOI: 10.1016/j.diabres.2018.04.044

26. Pushkar D., Vinarov A., Spivak L., Kolontarev K., Putilovskiy M., Andrianova E., et al. Efficacy and safety of Afalaza in men with symptomatic benign prostatic hyperplasia at risk of progression: a multicenter, double-blind, placebo-controlled, randomized clinical trial. Cent European J Urol. 2018;71(4);427–35. DOI: 10.5173/ceju.2018.1803

27. Nikiforov V.V., Ruzhentsova T.A. Clinical efficacy and safety of Ergoferon in flu and other acute respiratory viral infections: a critical evaluation from the standpoint of evidence-based medicine. Infektsionnye bolezni: novosti, mneniya, obuchenie. 2019;8(4);84–97 (In Russ.). DOI: 10.24411/2305-3496-2019-14011

28. Geppe N.A., Zaplatnikov A.L., Kondyurina E.G., Afanasyeva O.I., Pshenichnaya N.Yu., Blokhin B.M., et al. Efficacy and safety of Anaferon for children and Anaferon for the prevention and treatment of influenza and other acute respiratory viral infections: systematic review and meta-analysis. RMJ. Medical Review. 2021;5(5);335–47 (In Russ.). DOI: 10.32364/2587-6821-2021-5-5-335-347

29. Avalueva E.B., Adasheva T.V., Babaeva A.R., Burdina E.G., Kireeva N.V., Lenskaya L.G., et al. Efficacy and safety of preparation Kolofort in treatment of irritable bowel syndrome: results of multicentral double blind placebo controlled clinical trial. Consilium Medicum Gastrojenterologija. 2014;1: 43–50 (In Russ.).

30. Jertuzun I.A., Zueva E.P., Krylova S.G., Efimova L.A., Dugina J.L., Jepshtejn O.I. Experimental study of preparation Kolofort — a novel drug for treatment of irritable bowel syndrome and other functional gastrointestinal disorders. Journal of Volgograd State Medical University. 2012;4(44);25–27 (In Russ.).

31. Stanghellini V., Chan F.K., Hasler W.L., Malagelada J.R., Suzuki H., Tack J., et al. Gastroduodenal Disorders. Gastroenterology. 2016;150(6);1380–92. DOI: 10.1053/j.gastro.2016.02.011

32. Adam B., Liebregts T., Saadat-Gilani K., Vinson B., Holtmann G. Validation of the gastrointestinal symptom score for the assessment of symptoms in patients with functional dyspepsia. Aliment Pharmacol Ther. 2005;22(4);357–63. DOI: 10.1111/j.1365-2036.2005.02572.x

33. Pittayanon R., Yuan Y., Bollegala N.P., Khanna R., Leontiadis G.I., et al. Prokinetics for functional dyspepsia. Cochrane Database of Systematic Reviews. 2018;10. DOI: 10.1002/14651858.CD009431.pub3

34. Samsonov A.A., Lobanova E.G., Mikheeva O.M., Yashina A.V., Axelrod A.G. Modern approaches to the treatment of the functional gastrointestinal disorder and overlap syndrome. Consilium Medicum. 2017;19(8.2);17– 26 (In Russ.).

35. Ivashkin V.T., Poluektova E.A., Glazunov A.B., Putilovskiy M.A., Epstein O.I. Pathogenetic approach to the treatment of functional disorders of the gastrointestinal tract and their intersection: results of the Russian observation retrospective program COMFORT. BMC Gastroenterol. 2019;20(1):2. doi: 10.1186/s12876-019-1143-5

36. Wei J., Man Q., Guo F. Precise and systematic survey of the efficacy of multicomponent drugs against functional dyspepsia. Sci Rep. 2019;9;10713. DOI: 10.1038/s41598-019-47300-7