Efficacy, Safety, and Tolerability of 4-MUST, 128 mg Tablets in Chronic Cholecystitis and Biliary Dyskinesia

Phase 3RecruitingNCT07595003

Valenta Pharm JSC300 enrolled

Overview

The aim of the study is to evaluate the efficacy, safety, and tolerability of 4-MUST, 128 mg tablets compared to placebo in patients with chronic cholecystitis and biliary dyskinesia.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

DOUBLE

Enrollment

300

Conditions

Chronic Cholecystitis Biliary Dyskinesia

Interventions

4-MUSTDRUG

128 mg of trimebutine 4-methylumbelliferyl sulfate tablet.

PlaceboDRUG

Placebo tablet.

Eligibility

Sex: ALLMin age: 18 YearsMax age: 70 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. Males and females aged 18-70 years. 2. Diagnosed with chronic cholecystitis (K81.1) and/or dyskinesia of the cystic duct or gallbladder (K82.8) prior to enrollment; diagnosis supported by clinical history of exacerbations and remissions and/or imaging/laboratory findings. 3. Upper abdominal pain or discomfort attributable to gallbladder or biliary tract dysfunction (per investigator assessment), accompanied by ≥1 of the following: heartburn, belching, nausea, abdominal bloating, borborygmi (stomach rumbling), flatulence, constipation, or 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. The total bilirubin level does not exceed 2 times the upper limit of normal (no more than 42 μmol/L). 7. Women who are either sexually abstinent or using effective contraception methods (e.g. intrauterine devices, contraceptive patches, long-acting injectable contraceptives, or double barrier methods) for at least 8 weeks before and 3 weeks after the end of the study, with a confirmed negative pregnancy test, as well as women with documented infertility or non-childbearing status (e.g. hysterectomy, tubal ligation, infertility or 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). 8. Signed and dated informed consent from. Non-inclusion Criteria: 1. Gastric or duodenal ulcer, erosive gastroesophageal reflux disease (GERD), or other inflammatory/erosive gastrointestinal diseases in the acute stage, unless stable remission for ≥ 1 year since the last exacerbation. 2. Indication for surgical or endoscopic intervention due to exacerbation of chronic cholecystitis or complications of biliary tract dyskinesia. 3. Toxic megacolon. 4. Paralytic ileus. 5. Gilbert's syndrome. 6. Choledocholithiasis (or a high risk of its development, as determined by the investigator); 7. Impaired bile outflow due to adhesions in the abdominal cavity.Abdominal adhesion disease. 8. Irritable bowel syndrome, non-specific ulcerative colitis, Crohn's disease. 9. Gastrointestinal malignancy (including history of) or suspected gastrointestinal malignancy (e.g., blood in stool, unexplained weight loss, fever, anemia). 10. Any other oncological diseases known at the time of screening, or suspicion thereof. 11. History of gastrointestinal surgery, including cholecystectomy or endoscopic sphincterotomy (appendectomy excluded). 12. Use of prohibited therapy medications within 3 days prior to randomization. 13. History of mental illnesses. 14. Chronic heart failure IIb-III stages and/or III-IV functional classes according to NYHA, angina pectoris III-IV functional classes. 15. Chronic kidney disease stage IIIa-V (according to NKF/KDOQI, 2006). 16. History of or current hepatic impairment; or liver test abnormalities: AST, ALT, ALP, or GGT \>3 above the upper limit of normal (ULN); total bilirubin \>2 ULN or clinical jaundice. 17. HIV, syphilis, viral hepatitis B or C, including in history. 18. Lactose intolerance, lactase deficiency, and glucose-galactose malabsorption syndrome. 19. Liver cirrhosis. 20. Hypersensitivity to the active ingridient or any of the excipients of the drug 4-MUST. 21. Severe, decompensated, or unstable somatic conditions that are life-threatening, worsen prognosis, or preclude safe study participation. 22. Diabetes mellitus in a state of subcompensation and decompensation. 23. Systemic connective tissue diseases. 24. Autoimmune diseases. 25. Indication for hemodialysis procedures. 26. Epilepsy or seizures of unclear etiology, including in history. 27. Alcoholism, substance abuse or drug addiction, including in history. 28. Uncorrected electrolyte disturbances. 29. QTcF interval on a 12-lead electrocardiogram (ECG) ≥430 ms in men and ≥450 ms in women. 30. Episodes of constipation during the last 3 months that required the prescription of drug therapy. 31. History of surgery within 6 month prior to screening. 32. Women during pregnancy or lactation; women planning to become pregnant within the next 6 months. 33. Patients who require prohibited concomitant therapy within this study framework. 34. Participation in another clinical trial within the last 3 months prior to the screening visit date. 35. Unwillingness or inability to comply with study procedures and protocol requirements.. 36. Other conditions that, in the investigator's judgement, may preclude the patient's participation in the study. Exclusion Criteria: 1. Incorrect enrollment of a patient in the study (failure to meet inclusion/exclusion criteria at the time of randomization). 2. Lack of Efficacy. Study treatment will be discontinued if no clinical improvement is observed by Visit 3 (Day 15 ± 1), defined as persistence or worsening of upper abdominal pain/discomfort (assessed by Visual Analog Scale \[VAS\]) compared to baseline. Upon discontinuation, alternative therapy will be initiated at the investigator's discretion. 3. Patient non-compliance (a compliant patient is defined as one who has taken at least 202 and no more than 303 tablets). 4. Requirement for prohibited concomitant therapy. 5. Use of Duspatalin® (INN: mebeverine) for more than 3 consecutive days or for more than 5 days in total throughout the study. 6. If the investigator judges that comtinued participation in the study would harm the patient. 7. Pregnancy or the need for breastfeeding. 8. Major protocol deviation by the subject with respect to procedures outlined in the Informed Consent Form (ICF). 9. Withdrawal of informed consent by the subject (decision to discontinue study participation). 10. Lost to follow-up: Inability to contact the subject after ≥3 documented attempts via mobile phone, landline (if applicable), and designated emergency contact. 11. 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. 12. Any other reasons, including administrative issues, that in the investigator's judgement may interfere with subject's ability to comlete the study.

Locations (10)

State Budgetary Institution of Healthcare of Moscow "City Polyclinic No. 2 of the Moscow Department of Healthcare"

Moscow, Russia

RECRUITING

Unimed-C Jsc

Moscow, Russia

Outcomes

Primary Outcomes

Mean reduction in the severity of pain/discomfort in the upper abdomen on the VAS by day 29 compared to baseline

Visual analogue scale (VAS) from 0 to 100 mm, where 0 is "no pain", and 100 is "the worst pain one can imagine"

Time frame: Day 29 ± 1

Secondary Outcomes

Mean reduction in the severity of pain/discomfort in the upper abdomen according to VAS by days 2-28 from the start of therapy

Visual analogue scale (VAS) from 0 to 100 mm, where 0 is "no pain", and 100 is "the worst pain one can imagine"

Time frame: Day 2 - Day 28

Frequency of response to therapy (proportion of patients in the group with a reduction in the severity of pain/discomfort in the upper abdomen according to VAS by 30% or more) by days 8, 15, 22, and 29 following treatment initiation.

Visual analogue scale (VAS) from 0 to 100 mm, where 0 is "no pain", and 100 is "the worst pain one can imagine"

Time frame: Day 8 ± 1, 15 ± 1, 22 ± 1, and 29 ± 1

Frequency of response to therapy (proportion of patients in the group with a reduction in the severity of pain/discomfort in the upper abdomen according to VAS by 50% or more) by days 8, 15, 22, and 29 following treatment initiation.

Visual analogue scale (VAS) from 0 to 100 mm, where 0 is "no pain", and 100 is "the worst pain one can imagine"

Time frame: Day 8 ± 1, 15 ± 1, 22 ± 1, and 29 ± 1

Time to therapeutic response (reduction in the severity of pain/discomfort in the upper abdomen according to VAS by 30% or more)

Visual analogue scale (VAS) from 0 to 100 mm, where 0 is "no pain", and 100 is "the worst pain one can imagine"

Time frame: Day 29 ± 1

Time to therapeutic response (reduction in the severity of pain/discomfort in the upper abdomen according to VAS by 50% or more)

Data from ClinicalTrials.gov

This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.

The State Budgetary Healthcare Institution of the Moscow Region "Moscow Regional Research Clinical Institute named after M.F. Vladimirsky"

Moscow, Russia

RECRUITING

Limited Liability Company "ErSi Medical"

Novosibirsk, Russia

RECRUITING

Federal State Budgetary Educational Institution of Higher Education "Academician E.A. Wagner Perm State Medical University" of the Ministry of Healthcare of the Russian Federation

Perm, Russia

RECRUITING

St. Petersburg State Budgetary Healthcare Institution "City Polyclinic No. 117"

Saint Petersburg, Russia

RECRUITING

Limited Liability Company "Research Center Eco-Safety"

Saint Petersburg, Russia

RECRUITING

Limited Liability Company "Research Center Eco-Safety"

Saint Petersburg, Russia

RECRUITING

Limited Liability Company "Clinic Zvezdnaya"

Saint Petersburg, Russia

RECRUITING

State Healthcare Institution "Saratov City Clinical Hospital No. 5"

Saratov, Russia

RECRUITING

Visual analogue scale (VAS) from 0 to 100 mm, where 0 is "no pain", and 100 is "the worst pain one can imagine"

Time frame: Day 29 ± 1

Frequency of clinical recovery (proportion of patients in the group with a reduction in the severity of pain/discomfort in the upper abdomen according to VAS to 10 mm or less) by days 8, 15, 22, and 29 following treatment initiation.

Visual analogue scale (VAS) from 0 to 100 mm, where 0 is "no pain", and 100 is "the worst pain one can imagine"

Time frame: Day 8 ± 1, 15 ± 1, 22 ± 1, and 29 ± 1

Time to clinical recovery (reduction in the severity of pain/discomfort in the upper abdomen according to VAS to 10 mm or less)

Visual analogue scale (VAS) from 0 to 100 mm, where 0 is "no pain", and 100 is "the worst pain one can imagine"

Time frame: Day 29 ± 1

Change in the total score of gastroenterological symptom severity according to the GSRS questionnaire by days 8, 15, 22, and 29 following treatment initiation.

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.

Time frame: Day 8 ± 1, 15 ± 1, 22 ± 1, and 29 ± 1

Change in dyspeptic symptom severity, as assessed by the GSRS, expressed as score changes from baseline in the Abdominal Pain, Reflux, Indigestion, Diarrhea, and Constipation syndrome subscales at Days 8, 15, 22, and 29 following treatment initiation.

Time frame: Day 8 ± 1, 15 ± 1, 22 ± 1, and 29 ± 1

Change in the severity of individual symptoms of dyspeptic disorders according to the GSRS questionnaire in points by days 8, 15, 22, and 29 following treatment initiation.

Time frame: Day 8 ± 1, 15 ± 1, 22 ± 1, and 29 ± 1

Change in quality of life according to the total score on the SF-36 questionnaire by day 29 from treatment initiation.

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.

Time frame: Day 29 ± 1

Change in the total score on the PAGI-SYM questionnaire by days 15 and 29 from treatment initiation.

PAGI-SYM (Patient Assessment of Upper Gastrointestinal Disorders-Symptom Severity Index) is a patient-reported questionnaire designed to assess the severity of symptoms in upper gastrointestinal disorders (GERD, dyspepsia, and gastroparesis). It consists of 20 items grouped into six subscales: Heartburn/Regurgitation, Fullness/Early Satiety, Nausea/Vomiting, Bloating, Upper Abdominal Pain, and Lower Abdominal Pain. Each symptom is rated on a 6-point Likert scale from 0 (none) to 5 (very severe). The questionnaire provides a profile of scores for each subscale, as well as a total score. Higher scores indicate greater symptom severity.

Time frame: Day 15 ± 1, and 29 ± 1

change in the total score on the Visceral Sensitivity Index questionnaire by days 15 and 29 from the start of therapy

VSI (Visceral Sensitivity Index) is a patient-reported questionnaire measuring gastrointestinal-specific anxiety (cognitive, affective, and behavioral responses to GI sensations). It consists of 15 items rated on a 6-point scale, producing a total score from 0 to 75. Higher scores indicate greater GI-specific anxiety. Originally validated in IBS patients, it is now used across various GI disorders.

Time frame: Day 15 ± 1, and 29 ± 1

Change in the total score on the Emotional Distress - Depression - Short Form 4a questionnaire by days 8, 15, 22, and 29 from the start of therapy

Emotional Distress - Depression - Short Form 4a (PROMIS Depression SF 4a) is a patient-reported questionnaire assessing depression symptoms over the past 7 days. It consists of 4 items rated on a 5-point scale. Raw scores (4-20) are converted to a standardized T-score (mean=50, SD=10). Higher scores indicate greater depression severity.

Time frame: Day 8 ± 1, 15 ± 1, 22 ± 1, and 29 ± 1

Safety and Tolerability: adverse event (AE) rate

Frequency of adverse events (AEs) or serious AEs (SAEs)

Time frame: From screening (and signing informed consent form) to the end of the study (Day 36 ± 2)

Safety and Tolerability: adverse event (AE) number

Number of adverse events (AEs) or serious AEs (SAEs)

Time frame: From screening (and signing informed consent form) to the end of the study (Day 36 ± 2)

Safety and Tolerability: AEs associated with the study drug

Number and frequency of AEs associated with the study drug

Time frame: From screening (and signing informed consent form) to the end of the study (Day 36 ± 2)

Safety and Tolerability: SAEs associated with the study drug

Number and frequency of SAEs associated with the study drug

Time frame: From screening (and signing informed consent form) to the end of the study (Day 36 ± 2)

Safety and Tolerability: treatment discontinuation

Percentage of patients who discontinued treatment due to the occurrence of AEs/SAEs

Time frame: From screening (and signing informed consent form) to the end of the study (Day 36 ± 2)

Safety and Tolerability: vital signs - systolic blood pressure (SBP)

SBP, mmHg

Time frame: Screening, day 1, day 8 ± 1, day 15 ± 1, day 22 ± 1, day 29 ± 1

Safety and Tolerability: vital signs - diastolic blood pressure (DBP)

DBP, mmHg

Time frame: Screening, day 1, day 8 ± 1, day 15 ± 1, day 22 ± 1, day 29 ± 1

Safety and Tolerability: vital signs - respiratory rate (RR)

RR, breaths per minute

Time frame: Screening, day 1, day 8 ± 1, day 15 ± 1, day 22 ± 1, day 29 ± 1

Safety and Tolerability: vital signs - heart rate (HR)

HR, beats per minute

Time frame: Screening, day 1, day 8 ± 1, day 15 ± 1, day 22 ± 1, day 29 ± 1

Safety and Tolerability: vital signs - body temperature

Body temperature, Celsius scale

Time frame: Screening, day 1, day 8 ± 1, day 15 ± 1, day 22 ± 1, day 29 ± 1

Physical examination results: cardiovascular system

An assessment of the condition of the cardiovascular system on physical examination (normal condition or list of abnormal conditions, if any)

Time frame: Screening, day 1, day 8 ± 1, day 15 ± 1, day 22 ± 1, day 29 ± 1

Physical examination results: respiratory system

An assessment of the condition of the respiratory system on physical examination (normal condition or list of abnormal conditions, if any)

Time frame: Screening, day 1, day 8 ± 1, day 15 ± 1, day 22 ± 1, day 29 ± 1

Physical examination results: digestive tract

An assessment of the condition of the digestive tract on physical examination (normal condition or list of abnormal conditions, if any)

Time frame: Screening, day 1, day 8 ± 1, day 15 ± 1, day 22 ± 1, day 29 ± 1

Physical examination results: endocrine system

An assessment of the condition of the endocrine system on physical examination (normal condition or list of abnormal conditions, if any)

Time frame: Screening, day 1, day 8 ± 1, day 15 ± 1, day 22 ± 1, day 29 ± 1

Physical examination results: musculoskeletal system

An assessment of the condition of the musculoskeletal system on physical examination (normal condition or list of abnormal conditions, if any)

Time frame: Screening, day 1, day 8 ± 1, day 15 ± 1, day 22 ± 1, day 29 ± 1

Physical examination results: nervous system

An assessment of the condition of the nervous system on physical examination (normal condition or list of abnormal conditions, if any)

Time frame: Screening, day 1, day 8 ± 1, day 15 ± 1, day 22 ± 1, day 29 ± 1

Physical examination results: sensory systems

An assessment of the condition of the sensory systems on physical examination (normal condition or list of abnormal conditions, if any)

Time frame: Screening, day 1, day 8 ± 1, day 15 ± 1, day 22 ± 1, day 29 ± 1

Physical examination results: skin/visible mucous membranes

An assessment of the condition of the skin/visible mucous membranes on physical examination (normal condition or list of abnormal conditions, if any)

Time frame: Screening, day 1, day 8 ± 1, day 15 ± 1, day 22 ± 1, day 29 ± 1

Results of laboratory and instrumental examinations: clinical blood test - hemoglobin

Hemoglobin (g/L)