Efficacy, Safety, and Tolerability of 4-MUST Tablets in Chronic Cholecystitis and Biliary Dyskinesia

Phase 2

Recruiting

• Conditions: Chronic Cholecystitis; Biliary Dyskinesia
• Interventions: Drug: 4-MUST; Drug: Placebo

• Registration Number: NCT06842966
• Lead Sponsor: Valenta Pharm JSC

Brief Summary

A study of the efficacy, safety, and tolerability of the drug 4-MUST at various doses compared to placebo in patients with chronic cholecystitis and biliary dyskinesia

Detailed Description

Not available

Study Timeline

• Study Start: 2024-10-17
• Status Verified: 2025-02
• Study First Submitted: 2025-02-17
• Study First Submitted QC: 2025-02-17
• Study First Posted: 2025-02-24
• Last Update Submitted: 2025-02-27
• Last Update Posted: 2025-03-04
• Primary Completion: 2026-12-31
• Study Completion: 2026-12-31

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 300

Inclusion Criteria

1. Men and women aged 18-70 years.
2. Presence of established gastrointestinal diseases: Chronic cholecystitis (K81.1); Dyskinesia of the bile duct or gallbladder (K82.8).
3. Presence of pain/discomfort in the upper abdomen combined with at least one of the following symptoms: Heartburn; Belching; Nausea; Abdominal bloating; Borborygmi (stomach rumbling); Flatulence; Constipation; Diarrhea.
4. Maximum severity of pain/discomfort in the upper abdomen over the past week is 40 mm or more on the VAS (Visual Analog Scale).
5. Severity of gastrointestinal symptoms according to the GSRS (Gastrointestinal Symptom Rating Scale) questionnaire is at least 30 points.
6. Women who are not sexually active, or women using effective contraception methods (intrauterine devices, oral contraceptives, contraceptive patches, long-acting injectable contraceptives, double barrier methods) for 8 weeks prior to and during 3 weeks after the end of the study and have a negative pregnancy test, as well as women unable to conceive (documented conditions: hysterectomy, tubal ligation, infertility, menopause for more than 1 year) or men using barrier contraceptives throughout the study and for 3 weeks after its completion, or men unable to conceive (documented conditions: vasectomy, infertility).
7. Presence of a signed and dated informed consent from the patient to participate in the study.

Non-inclusion Criteria:

1. Peptic ulcer disease, duodenal ulcer, erosive GERD.
2. Toxic megacolon.
3. Paralytic ileus.
4. Gilbert's syndrome.
5. Abdominal adhesion disease.
6. Blood in stool, unexplained weight loss, fever, anemia.
7. Inflammatory and erosive gastrointestinal diseases.
8. Irritable bowel syndrome, non-specific ulcerative colitis, Crohn's disease.
9. Oncological diseases of the gastrointestinal tract, including in history.
10. Surgical interventions on the gastrointestinal tract in history, including endoscopic papillotomy, cholecystectomy (excluding appendectomy).
11. Use of prohibited therapy medications within 3 days prior to randomization.
12. History of mental illnesses.
13. Presence of chronic heart failure IIb-III stages and/or III-IV functional classes according to NYHA, angina pectoris III-IV functional classes.
14. Chronic kidney disease stage IIIa-V (according to NKF/KDOQI, 2006).
15. Established diagnosis of liver failure, including in history and/or changes in liver enzyme activity: Increase in AST, ALT, ALP and/or γ-GTP more than 3 times above the upper limit of normal; Increase in total bilirubin more than 2 times above the upper limit of normal or development of jaundice.
16. Presence of HIV, syphilis, viral hepatitis B or C, including in history.
17. Lactose intolerance, lactase deficiency, and glucose-galactose malabsorption syndrome.
18. Liver cirrhosis.
19. Increased sensitivity to active and excipient substances of the drug 4-MUST.
20. Severe, decompensated or unstable somatic diseases (any diseases or conditions that threaten the patient's life or worsen their prognosis and make it impossible for the patient to participate in clinical research).
21. Diabetes mellitus in a state of subcompensation and decompensation.
22. Systemic connective tissue diseases.
23. Autoimmune diseases.
24. Need for surgical and/or endovascular treatment and/or necessity for hemodialysis procedures.
25. Epilepsy or seizures of unclear etiology, including in history.
26. Alcoholism, substance abuse or drug addiction, including in history.
27. Uncorrected electrolyte disturbances.
28. States following surgical interventions if less than 6 months have passed since the intervention.
29. Women during pregnancy or lactation; women planning pregnancy within the next 6 months.
30. Patients who require prohibited concomitant therapy within this study framework.
31. Participation in another clinical trial within the last 3 months prior to the screening visit date.
32. Lack of willingness to cooperate from the patient's side.
33. Other conditions that, in the opinion of the investigator, prevent the inclusion of the patient in the study.

Exclusion Criteria

1. Erroneous inclusion of a patient in the study (not meeting inclusion/exclusion criteria at the time of randomization).
2. Ineffectiveness of therapy. The therapy will be deemed ineffective if there is no clinical improvement by visit 3 (15±1 days of therapy) - persistence or increase in the severity of pain/discomfort in the upper abdomen on the VAS compared to baseline. If excluded, the patient will be assigned alternative treatment at the discretion of the investigator.
3. Patient non-compliance (a compliant patient is defined as one who has taken at least 202 and no more than 303 tablets).
4. Need for prohibited concomitant therapy.
5. If the investigator believes that further participation in the study would harm the patient.
6. Pregnancy of the patient, necessity for breastfeeding.
7. Gross violation by the patient of the study protocol procedures presented in the patient information sheet (PIS).
8. Withdrawal of informed consent (patient's unwillingness to continue participation in the study).
9. Loss of contact with the patient (inability to reach the patient via mobile and home phone (if applicable), as well as through a contact person; there must be at least three documented attempts to contact the patient).
10. Emergence during the study of any diseases or conditions that worsen the patient's prognosis, making it impossible for the patient to continue participating in this clinical trial.
11. Any other reasons, including administrative ones, that in the investigator's opinion would prevent the subject from completing the study.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
4-MUST, 128 mg	4-MUST	Patients will receive 1 tablet of the drug 4-MUST (128 mg of trimebutine 4-methylumbelliferyl sulfate) and 2 placebo tablets three times a day.
4-MUST, 128 mg	Placebo	Patients will receive 1 tablet of the drug 4-MUST (128 mg of trimebutine 4-methylumbelliferyl sulfate) and 2 placebo tablets three times a day.
4-MUST, 256 mg	4-MUST	Patients will receive 2 tablets of the drug 4-MUST (256 mg of trimebutine 4-methylumbelliferyl sulfate) and 1 placebo tablet three times a day.
4-MUST, 256 mg	Placebo	Patients will receive 2 tablets of the drug 4-MUST (256 mg of trimebutine 4-methylumbelliferyl sulfate) and 1 placebo tablet three times a day.
4-MUST, 384 mg	4-MUST	Patients will receive 3 tablets of the drug 4-MUST (384 mg of trimebutine 4-methylumbelliferyl sulfate) three times a day.
Placebo	Placebo	Patients will receive 3 placebo tablets three times a day.

Primary Outcome Measures

Name	Time	Method
Average reduction in the severity of pain/discomfort in the upper abdomen on the VAS by day 29 from the start of therapy	Day 29 ± 1	Visual analogue scale (VAS) from 0 to 100 mm, where 0 is "no pain", and 100 is "the worst pain one can imagine"

Secondary Outcome Measures

Name	Time	Method
Change in the total score of gastrointestinal symptom severity according to the GSRS questionnaire on days 8, 15, 22, and 29 from the start of therapy	Day 8 ± 1, 15 ± 1, 22 ± 1, and 29 ± 1	The Gastrointestinal Symptom Rating Scale (GSRS) is a self-administered questionnaire designed to assess gastrointestinal symptoms and their severity. It consists of 15 items categorized into five domains: Abdominal pain (including stomach pain and nausea), Reflux (heartburn and acid reflux), Indigestion (bloating, burping, and flatulence), Constipation (hard stools and incomplete evacuation), Diarrhea (loose stools and urgency). Respondents rate their symptoms on a 7-point Likert scale, where 1 indicates no discomfort and 7 indicates very severe discomfort.
Response rate to therapy (proportion of patients in the group showing a reduction in pain/discomfort in the upper abdomen on the VAS by more than 30%) by day 29 from the start of therapy	Day 29 ± 1	Visual analogue scale (VAS) from 0 to 100 mm, where 0 is "no pain", and 100 is "the worst pain one can imagine"
Response rate to therapy (proportion of patients in the group showing a reduction in pain/discomfort in the upper abdomen on the VAS by 50% or more) by day 29 from the start of therapy	Day 29 ± 1	Visual analogue scale (VAS) from 0 to 100 mm, where 0 is "no pain", and 100 is "the worst pain one can imagine"
Change in manifestations of dyspeptic disorders according to the GSRS questionnaire scores on days 8, 15, 22, and 29 from the start of treatment	Day 8 ± 1, 15 ± 1, 22 ± 1, and 29 ± 1	The Gastrointestinal Symptom Rating Scale (GSRS) is a self-administered questionnaire designed to assess gastrointestinal symptoms and their severity. It consists of 15 items categorized into five domains: Abdominal pain (including stomach pain and nausea), Reflux (heartburn and acid reflux), Indigestion (bloating, burping, and flatulence), Constipation (hard stools and incomplete evacuation), Diarrhea (loose stools and urgency). Respondents rate their symptoms on a 7-point Likert scale, where 1 indicates no discomfort and 7 indicates very severe discomfort.
Change in quality of life based on the total score from the SF-36 questionnaire by day 29 from the start of therapy;	Day 29 ± 1	SF-36 (Short Form 36 Health Survey) is a self-reported questionnaire. It consists of 36 items that cover eight health domains: Physical functioning, Role limitations due to physical health, Role limitations due to emotional problems, Bodily pain, General health perceptions, Vitality (energy and fatigue), Social functioning, Mental health. SF-36 produces a profile of scores for each domain, which can be summarized into two main components: the Physical Component Summary (PCS) and the Mental Component Summary (MCS). Scores range from 0 to 100, where lower scores indicate greater disability and higher scores indicate better health.
Average reduction in pain/discomfort severity in the upper abdomen on the VAS by days 8, 15, and 22 from the start of treatment	Day 8 ± 1, 15 ± 1, 22 ± 1, and 29 ± 1	Visual analogue scale (VAS) from 0 to 100 mm, where 0 is "no pain", and 100 is "the worst pain one can imagine"
Safety and Tolerability: adverse event (AE) rate	From the date of screening (and signing informed consent form) to the end of the study or to an early termination visit, whichever came first, assessed up to day 36 ± 2 for each participant	Frequency of adverse events (AEs) or serious AEs (SAEs)
Safety and Tolerability: adverse event (AE) number	From the date of screening (and signing informed consent form) to the end of the study or to an early termination visit, whichever came first, assessed up to day 36 ± 2 for each participant	Number of adverse events (AEs) or serious AEs (SAEs)
Safety and Tolerability: AEs associated with the study drug	From the date of screening (and signing informed consent form) to the end of the study or to an early termination visit, whichever came first, assessed up to day 36 ± 2 for each participant	Number and frequency of AEs associated with the study drug
Safety and Tolerability: SAEs associated with the study drug	From the date of screening (and signing informed consent form) to the end of the study or to an early termination visit, whichever came first, assessed up to day 36 ± 2 for each participant	Number and frequency of SAEs associated with the study drug
Safety and Tolerability: treatment discontinuation	From the date of screening (and signing informed consent form) to the end of the study or to an early termination visit, whichever came first, assessed up to day 36 ± 2 for each participant	Percentage of patients who discontinued treatment due to the occurrence of AEs/SAEs
Safety and Tolerability: vital signs - systolic blood pressure (SBP)	Screening, day 1, day 8 ± 1, day 15 ± 1, day 22 ± 1, day 29 ± 1	SBP, mmHg
Safety and Tolerability: vital signs - diastolic blood pressure (DBP)	Screening, day 1, day 8 ± 1, day 15 ± 1, day 22 ± 1, day 29 ± 1	DBP, mmHg
Safety and Tolerability: vital signs - respiratory rate (RR)	Screening, day 1, day 8 ± 1, day 15 ± 1, day 22 ± 1, day 29 ± 1	RR, breaths per minute
Safety and Tolerability: vital signs - heart rate (HR)	Screening, day 1, day 8 ± 1, day 15 ± 1, day 22 ± 1, day 29 ± 1	HR, beats per minute
Safety and Tolerability: vital signs - body temperature	Screening, day 1, day 8 ± 1, day 15 ± 1, day 22 ± 1, day 29 ± 1	Body temperature, Celsius scale
Physical examination results: cardiovascular system	Screening, day 1, day 8 ± 1, day 15 ± 1, day 22 ± 1, day 29 ± 1	An assessment of the condition of the cardiovascular system on physical examination (normal condition or list of abnormal conditions, if any)
Physical examination results: respiratory system	Screening, day 1, day 8 ± 1, day 15 ± 1, day 22 ± 1, day 29 ± 1	An assessment of the condition of the respiratory system on physical examination (normal condition or list of abnormal conditions, if any)(normal condition or list of abnormal conditions, if any)
Physical examination results: digestive tract	Screening, day 1, day 8 ± 1, day 15 ± 1, day 22 ± 1, day 29 ± 1	An assessment of the condition of the digestive tract on physical examination (normal condition or list of abnormal conditions, if any)
Physical examination results: endocrine system	Screening, day 1, day 8 ± 1, day 15 ± 1, day 22 ± 1, day 29 ± 1	An assessment of the condition of the endocrine system on physical examination (normal condition or list of abnormal conditions, if any)
Physical examination results: musculoskeletal system	Screening, day 1, day 8 ± 1, day 15 ± 1, day 22 ± 1, day 29 ± 1	An assessment of the condition of the musculoskeletal system on physical examination (normal condition or list of abnormal conditions, if any)
Physical examination results: nervous system	Screening, day 1, day 8 ± 1, day 15 ± 1, day 22 ± 1, day 29 ± 1	An assessment of the condition of the nervous system on physical examination (normal condition or list of abnormal conditions, if any)
Physical examination results: sensory systems	Screening, day 1, day 8 ± 1, day 15 ± 1, day 22 ± 1, day 29 ± 1	An assessment of the condition of the sensory systems on physical examination (normal condition or list of abnormal conditions, if any)
Physical examination results: skin/visible mucous membranes	Screening, day 1, day 8 ± 1, day 15 ± 1, day 22 ± 1, day 29 ± 1	An assessment of the condition of the skin/visible mucous membranes on physical examination (normal condition or list of abnormal conditions, if any)
Results of laboratory and instrumental examinations: clinical blood test - hemoglobin	Screening, day 15 ± 1, day 29 ± 1	Hemoglobin (g/L)
Results of laboratory and instrumental examinations: clinical blood test - hematocrit	Screening, day 15 ± 1, day 29 ± 1	Hematocrit (%)
Results of laboratory and instrumental examinations: clinical blood test - red blood cell count	Screening, day 15 ± 1, day 29 ± 1	Red blood cell count (cells/L)
Results of laboratory and instrumental examinations: clinical blood test - platelet count	Screening, day 15 ± 1, day 29 ± 1	Platelet count (cells/L)
Results of laboratory and instrumental examinations: clinical blood test - leukocyte count	Screening, day 15 ± 1, day 29 ± 1	Leukocyte count (cells/L)
Results of laboratory and instrumental examinations: clinical blood test - erythrocyte sedimentation rate	Screening, day 15 ± 1, day 29 ± 1	Erythrocyte sedimentation rate (mm/h)
Results of laboratory and instrumental examinations: clinical blood test - myelocytes	Screening, day 15 ± 1, day 29 ± 1	Leukocyte formula (myelocytes, %)
Results of laboratory and instrumental examinations: clinical blood test - band neutrophils	Screening, day 15 ± 1, day 29 ± 1	Leukocyte formula (band neutrophils, %)
Results of laboratory and instrumental examinations: clinical blood test - segmented neutrophils	Screening, day 15 ± 1, day 29 ± 1	Leukocyte formula (segmented neutrophils, %)
Results of laboratory and instrumental examinations: clinical blood test - eosinophils	Screening, day 15 ± 1, day 29 ± 1	Leukocyte formula (eosinophils, %)
Results of laboratory and instrumental examinations: clinical blood test - basophils	Screening, day 15 ± 1, day 29 ± 1	Leukocyte formula (basophils, %)
Results of laboratory and instrumental examinations: clinical blood test - monocytes	Screening, day 15 ± 1, day 29 ± 1	Leukocyte formula (monocytes, %)
Results of laboratory and instrumental examinations: clinical blood test - lymphocytes	Screening, day 15 ± 1, day 29 ± 1	Leukocyte formula (lymphocytes, %)
Results of laboratory and instrumental examinations: blood chemistry - glucose	Screening, day 15 ± 1, day 29 ± 1	Glucose concentration (mmol/L)
Results of laboratory and instrumental examinations: blood chemistry - cholesterol	Screening, day 15 ± 1, day 29 ± 1	Total cholesterol concentration (mmol/L)
Results of laboratory and instrumental examinations: blood chemistry - protein	Screening, day 15 ± 1, day 29 ± 1	Total protein concentration (g/L)
Results of laboratory and instrumental examinations: blood chemistry - bilirubin	Screening, day 15 ± 1, day 29 ± 1	Total bilirubin concentration (micromol/L)
Results of laboratory and instrumental examinations: blood chemistry - creatinine	Screening, day 15 ± 1, day 29 ± 1	Creatinine concentration (micromol/L)
Results of laboratory and instrumental examinations: blood chemistry - alkaline phosphatase	Screening, day 15 ± 1, day 29 ± 1	Alkaline phosphatase activity (U/L)
Results of laboratory and instrumental examinations: blood chemistry - alanine transaminase	Screening, day 15 ± 1, day 29 ± 1	Alanine transaminase activity (U/L)
Results of laboratory and instrumental examinations: blood chemistry - aspartate transaminase	Screening, day 15 ± 1, day 29 ± 1	Aspartate transaminase activity (U/L)
Results of laboratory and instrumental examinations: blood chemistry - gamma-GTP	Screening, day 15 ± 1, day 29 ± 1	Gamma-glutaryl transpeptidase activity (U/L)
Results of laboratory and instrumental examinations: urinalysis - specific gravity	Screening, day 15 ± 1, day 29 ± 1	Specific gravity of the urine
Results of laboratory and instrumental examinations: urinalysis - pH	Screening, day 15 ± 1, day 29 ± 1	pH of the urine
Results of laboratory and instrumental examinations: urinalysis - protein	Screening, day 15 ± 1, day 29 ± 1	Protein concentration (g/L)
Results of laboratory and instrumental examinations: urinalysis - glucose	Screening, day 15 ± 1, day 29 ± 1	Glucose concentration (mmol/L)
Results of laboratory and instrumental examinations: urinalysis - red blood cells	Screening, day 15 ± 1, day 29 ± 1	Red blood cell content (number in sight)
Results of laboratory and instrumental examinations: urinalysis - white blood cells	Screening, day 15 ± 1, day 29 ± 1	White blood cell content (number in sight)
Safety and Tolerability: 12-lead electrocardiogram (ECG) - heart rate	Screening, day 1, day 8 ± 1, day 15 ± 1, day 22 ± 1, day 29 ± 1	12-lead ECG (I, II, III, aVR-enhanced unipolar abduction from the right arm , aVL-enhanced unipolar abduction from the left arm, aVF - enhanced unipolar abduction from the left leg, V1-V6) taken while lying down: heart rate (beats per minute)
Safety and Tolerability: 12-lead electrocardiogram (ECG) - PQ interval	Screening, day 1, day 8 ± 1, day 15 ± 1, day 22 ± 1, day 29 ± 1	12-lead ECG (I, II, III, aVR-enhanced unipolar abduction from the right arm , aVL-enhanced unipolar abduction from the left arm, aVF - enhanced unipolar abduction from the left leg, V1-V6) taken while lying down: PQ interval (is the period, measured in milliseconds, that extends from the beginning of the P wave (the onset of atrial depolarization) until the beginning of the QRS complex)
Safety and Tolerability: 12-lead electrocardiogram (ECG) - QRS complex	Screening, day 1, day 8 ± 1, day 15 ± 1, day 22 ± 1, day 29 ± 1	12-lead ECG (I, II, III, aVR-enhanced unipolar abduction from the right arm , aVL-enhanced unipolar abduction from the left arm, aVF - enhanced unipolar abduction from the left leg, V1-V6) taken while lying down: QRS complex (the QRS complex is the combination of three of the graphical deflections seen on a typical electrocardiogram)
Safety and Tolerability: 12-lead electrocardiogram (ECG) - corrected QT interval	Screening, day 1, day 8 ± 1, day 15 ± 1, day 22 ± 1, day 29 ± 1	12-lead ECG (I, II, III, aVR-enhanced unipolar abduction from the right arm , aVL-enhanced unipolar abduction from the left arm, aVF - enhanced unipolar abduction from the left leg, V1-V6) taken while lying down: corrected QT interval (distance from the beginning of the QRS complex to the end of the T wave) (Frederica correction)

Trial Locations

Locations (17)

State autonomous health care institution "Engels City Clinical Hospital No. 1"; 🇷🇺 Engels, Russian Federation

Ivanovo Kuvaev Clinical Hospital; 🇷🇺 Ivanovo, Russian Federation

State Budgetary Institution of Healthcare of Moscow "City Polyclinic No. 2 of the Moscow Department of Healthcare"; 🇷🇺 Moscow, Russian Federation

Unimed-C Jsc; 🇷🇺 Moscow, Russian Federation

The State Budgetary Healthcare Institution of the Moscow Region "Moscow Regional Research Clinical Institute named after M.F. Vladimirsky"; 🇷🇺 Moscow, Russian Federation

Limited Liability Company "ErSi Medical"; 🇷🇺 Novosibirsk, Russian Federation

Professors' Clinic LLC.; 🇷🇺 Perm, Russian Federation

Limited Liability Company "Energy of Health"; 🇷🇺 Saint Petersburg, Russian Federation

St. Petersburg State Budgetary Healthcare Institution "City Polyclinic No. 117"; 🇷🇺 Saint Petersburg, Russian Federation

Limited Liability Company "Clinic Zvezdnaya"; 🇷🇺 Saint Petersburg, Russian Federation

Limited Liability Company "Meili"; 🇷🇺 Saint Petersburg, Russian Federation

State Budgetary Institution "St. Petersburg Research Institute of Emergency Care named after I.I. Djanelidze"; 🇷🇺 Saint Petersburg, Russian Federation

Private institution of higher education "Medical University 'Reavis'"; 🇷🇺 Samara, Russian Federation

Limited Liability Company "Medical Center Eco-Safety"; 🇷🇺 St. Petersburg, Russian Federation

Association "Regional Medical Center 'Open Medicine'"; 🇷🇺 Tol'yatti, Russian Federation

LLC "Polyclinic Polimedika Veliky Novgorod"; 🇷🇺 Veliky Novgorod, Russian Federation

Limited Liability Company "Medical Center for Diagnosis and Prevention Plus"; 🇷🇺 Yaroslavl, Russian Federation