Biliary Dyskinesia, Chronic Cholecystitis
Conditions
Brief summary
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
DRUG4-MUST
128 mg of trimebutine 4-methylumbelliferyl sulfate tablet.
DRUGPlacebo
Placebo tablet.
Sponsors
Valenta Pharm JSC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
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/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean reduction in the severity of pain/discomfort in the upper abdomen on the VAS by day 29 compared to baseline | 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
| Measure | Time frame | Description |
|---|---|---|
| Mean reduction in the severity of pain/discomfort in the upper abdomen according to VAS by days 2-28 from the start of therapy | Day 2 - Day 28 | Visual analogue scale (VAS) from 0 to 100 mm, where 0 is "no pain", and 100 is "the worst pain one can imagine" |
| 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. | 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" |
| 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. | 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" |
| Time to therapeutic response (reduction in the severity of pain/discomfort in the upper abdomen according to VAS by 30% or more) | 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" |
| Time to therapeutic response (reduction in the severity of pain/discomfort in the upper abdomen according to VAS by 50% or more) | 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" |
| 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. | 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" |
| Time to clinical recovery (reduction in the severity of pain/discomfort in the upper abdomen according to VAS to 10 mm or less) | 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 the total score of gastroenterological symptom severity according to the GSRS questionnaire by days 8, 15, 22, and 29 following treatment initiation. | 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 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. | 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 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. | 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 according to the total score on the SF-36 questionnaire by day 29 from treatment initiation. | 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. |
| Change in the total score on the PAGI-SYM questionnaire by days 15 and 29 from treatment initiation. | Day 15 ± 1, and 29 ± 1 | 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. |
| change in the total score on the Visceral Sensitivity Index questionnaire by days 15 and 29 from the start of therapy | Day 15 ± 1, and 29 ± 1 | 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. |
| 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 | Day 8 ± 1, 15 ± 1, 22 ± 1, and 29 ± 1 | 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. |
| Safety and Tolerability: adverse event (AE) rate | From screening (and signing informed consent form) to the end of the study (Day 36 ± 2) | Frequency of adverse events (AEs) or serious AEs (SAEs) |
| Safety and Tolerability: adverse event (AE) number | From screening (and signing informed consent form) to the end of the study (Day 36 ± 2) | Number of adverse events (AEs) or serious AEs (SAEs) |
| Safety and Tolerability: AEs associated with the study drug | From screening (and signing informed consent form) to the end of the study (Day 36 ± 2) | Number and frequency of AEs associated with the study drug |
| Safety and Tolerability: SAEs associated with the study drug | From screening (and signing informed consent form) to the end of the study (Day 36 ± 2) | Number and frequency of SAEs associated with the study drug |
| Safety and Tolerability: treatment discontinuation | From screening (and signing informed consent form) to the end of the study (Day 36 ± 2) | 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) |
| 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: blood chemistry - CRP | Screening, day 15 ± 1, day 29 ± 1 | C-reactive protein, CRP (mg/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 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 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 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 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) |
Countries
Russia
Outcome results
None listed