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

Official title

Multicenter, Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study to Evaluate the Efficacy, Safety, and Tolerability of 4-MUST, 128 mg Tablets in Patients With Chronic Cholecystitis and Biliary Tract Dyskinesia

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.

Interventions

• Drug 4-MUST
  128 mg of trimebutine 4-methylumbelliferyl sulfate tablet.
• Drug Placebo
  Placebo tablet.

Primary outcome measures

• Mean reduction in the severity of pain/discomfort in the upper abdomen on the VAS by day 29 compared to baseline [Time frame: Day 29 ± 1]

Secondary outcome measures (12)

• Mean reduction in the severity of pain/discomfort in the upper abdomen according to VAS by days 2-28 from the start of therapy [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. [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. [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) [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) [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. [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) [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. [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. [Time frame: Day 29 ± 1]
• Change in the total score on the PAGI-SYM questionnaire by days 15 and 29 from treatment initiation. [Time frame: Day 15 ± 1, and 29 ± 1]

Eligibility criteria

Inclusion criteria

• Males and females aged 18-70 years.
• 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.
• 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.
• Maximum severity of pain/discomfort in the upper abdomen over the past week is 40 mm or more on the VAS (Visual Analog Scale).
• Severity of gastrointestinal symptoms according to the GSRS (Gastrointestinal Symptom Rating Scale) questionnaire is at least 30 points.
• The total bilirubin level does not exceed 2 times the upper limit of normal (no more than 42 μmol/L).
• 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).
• Signed and dated informed consent from.

Non-inclusion Criteria:

• 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.
• Indication for surgical or endoscopic intervention due to exacerbation of chronic cholecystitis or complications of biliary tract dyskinesia.
• Toxic megacolon.
• Paralytic ileus.
• Gilbert's syndrome.
• Choledocholithiasis (or a high risk of its development, as determined by the investigator);
• Impaired bile outflow due to adhesions in the abdominal cavity.Abdominal adhesion disease.
• Irritable bowel syndrome, non-specific ulcerative colitis, Crohn's disease.
• Gastrointestinal malignancy (including history of) or suspected gastrointestinal malignancy (e.g., blood in stool, unexplained weight loss, fever, anemia).
• Any other oncological diseases known at the time of screening, or suspicion thereof.
• History of gastrointestinal surgery, including cholecystectomy or endoscopic sphincterotomy (appendectomy excluded).
• Use of prohibited therapy medications within 3 days prior to randomization.
• History of mental illnesses.
• Chronic heart failure IIb-III stages and/or III-IV functional classes according to NYHA, angina pectoris III-IV functional classes.
• Chronic kidney disease stage IIIa-V (according to NKF/KDOQI, 2006).
• 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.
• HIV, syphilis, viral hepatitis B or C, including in history.
• Lactose intolerance, lactase deficiency, and glucose-galactose malabsorption syndrome.
• Liver cirrhosis.
• Hypersensitivity to the active ingridient or any of the excipients of the drug 4-MUST.
• Severe, decompensated, or unstable somatic conditions that are life-threatening, worsen prognosis, or preclude safe study participation.
• Diabetes mellitus in a state of subcompensation and decompensation.
• Systemic connective tissue diseases.
• Autoimmune diseases.
• Indication for hemodialysis procedures.
• Epilepsy or seizures of unclear etiology, including in history.
• Alcoholism, substance abuse or drug addiction, including in history.
• Uncorrected electrolyte disturbances.
• QTcF interval on a 12-lead electrocardiogram (ECG) ≥430 ms in men and ≥450 ms in women.
• Episodes of constipation during the last 3 months that required the prescription of drug therapy.
• History of surgery within 6 month prior to screening.
• Women during pregnancy or lactation; women planning to become pregnant within the next 6 months.
• Patients who require prohibited concomitant therapy within this study framework.
• Participation in another clinical trial within the last 3 months prior to the screening visit date.
• Unwillingness or inability to comply with study procedures and protocol requirements..
• Other conditions that, in the investigator's judgement, may preclude the patient's participation in the study.

Exclusion criteria

• Incorrect enrollment of a patient in the study (failure to meet inclusion/exclusion criteria at the time of randomization).
• 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.
• Patient non-compliance (a compliant patient is defined as one who has taken at least 202 and no more than 303 tablets).
• Requirement for prohibited concomitant therapy.
• Use of Duspatalin® (INN: mebeverine) for more than 3 consecutive days or for more than 5 days in total throughout the study.
• If the investigator judges that comtinued participation in the study would harm the patient.
• Pregnancy or the need for breastfeeding.
• Major protocol deviation by the subject with respect to procedures outlined in the Informed Consent Form (ICF).
• Withdrawal of informed consent by the subject (decision to discontinue study participation).
• Lost to follow-up: Inability to contact the subject after ≥3 documented attempts via mobile phone, landline (if applicable), and designated emergency contact.
• 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.
• Any other reasons, including administrative issues, that in the investigator's judgement may interfere with subject's ability to comlete the study.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Double blind

Primary purpose

Treatment

Study locations

Russia · 10 centers

• State Budgetary Institution of Healthcare of Moscow "City Polyclinic No. 2 of the Moscow D — Moscow
• Unimed-C Jsc — Moscow
• The State Budgetary Healthcare Institution of the Moscow Region "Moscow Regional Research — Moscow
• Limited Liability Company "ErSi Medical" — Novosibirsk
• Federal State Budgetary Educational Institution of Higher Education "Academician E.A. Wagn — Perm
• St. Petersburg State Budgetary Healthcare Institution "City Polyclinic No. 117" — Saint Petersburg
• Limited Liability Company "Research Center Eco-Safety" — Saint Petersburg
• Limited Liability Company "Research Center Eco-Safety" — Saint Petersburg
• … and 2 more centers

Identifiers

NCT: NCT07595003 · GIB-03-04-2025

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗