Conditions: Functional Bowel Disorder
Keywords: Mebeverine+Simethicone Duspatalin abdominal pain bloating/flatulence functional bowel disorder fixed dose combination NRS11
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 465
Healthy volunteers: no

Brief summary:
The parallel three-group study of efficacy and safety was planned to investigate the reduction in abdominal pain and bloating during treatment with the fixed-dose combination of Mebeverine + Simethicone versus Duspatalin® and Espumisan® as a monotherapy (Protocol No. MESI3001).

Detailed description:

Arms:
arm 1: three times a day per os arm 2: three times a day per os arm 3: 80 mg (2 capsules 40 mg) three times a day per os

Interventions: intervention 1: Mebeverine+Simethicone intervention 2: Mebeverine intervention 3: Simethicone
Intervention descriptions: intervention 1: fixed-dose combination, film-coated tablets, 135 mg + 80 mg intervention 2: Duspatalin®, coated tablets 135 mg intervention 3: Espumisan® capsules 40 mg

Protocol document:
Prot_000.pdf: 
ClinicalTrials.gov Identifier: 
NCT05175131 


Mebeverine+Simethicone 
 
Abbott Product Operations AG 
Protocol MESI3001 Amendment 1 dated 07 April 2021 
 
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CLINICAL STUDY PROTOCOL 
MESI3001 
Study title: 
Multicenter, randomized, parallel-group, open-label, comparative 
clinical 
study 
to 
evaluate 
efficacy 
and 
safety 
of 
Mebeverine+Simethicone 
fixed-dose 
combination 
versus 
Duspatalin® (mebeverine) and versus Espumisan® (simethicone) in 
patients with functional bowel disorders with abdominal pain and 
excess gas formation 
 
Study number: 
MESI3001 
Study phase: 
III 
Study drug name: 
Mebeverine+Simethicone 
Planned Indication: 
Symptomatic treatment of pain, spasms dysfunction and abdomen 
discomfort associated with functional bowel diseases. Symptoms 
may include abdominal pain, cramps, bloating and flatulence, 
changes in stool frequency (diarrhea, constipation, or alternating 
diarrhea/constipation) and consistency. 
 
 
Sponsor: 
Abbott Products Operations AG 
 
Contact person: 
 
 
 
 
 
 
 
Protocol date: 
Amendment 1.0 dated 07 April 2021 
 
 
 
 
 
 
 
 
 
 
 


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Protocol MESI3001 Amendment 1 dated 07 April 2021 
 
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PROTOCOL APPROVAL PAGE 
 
 
Signature_______________________________ 
 
 
 
 
 
Date_________________________ 
 
 
Signature_______________________________ 
 
  
 
 
 
 
Date_________________________ 
 
 
 
Signature_______________________________ 
 
  
Date_________________________ 
 
 
Signature_______________________________ 
 
  
 
 
 
 
Date_________________________ 


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Protocol MESI3001 Amendment 1 dated 07 April 2021 
 
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PRINCIPAL INVESTIGATOR STATEMENT 
Name: 
 
I, the undersigned certify that I have read and understood the Protocol. I give consent to 
following Protocol MESI3001: Multicenter, randomized, parallel-group, open-label, 
comparative clinical study to evaluate efficacy and safety of Mebeverine+Simethicone fixed-
dose combination versus Duspatalin® (mebeverine) and versus Espumisan® (simethicone) in 
patients with functional bowel disorders with abdominal pain and excess gas formation. 
 
I undertake to conduct this study in accordance with the requirements of International 
Conference on Harmonization Good Clinical Practice Guideline (ICH GCP(E6)) and Resolution 
№ 79 “Concerning adoption of the Good clinical practice of Eurasian Economic Union (EEU)”, 
principles provided in Helsinki Declaration, as well as in accordance with the applicable 
legislation and regulations of the Russian Federation. 
Date: 
 
Signature: 
 
 
 


Mebeverine+Simethicone 
 
Abbott Product Operations AG 
Protocol MESI3001 Amendment 1 dated 07 April 2021 
 
Confidential 
 
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CONTACT INFORMATION ON CLINICAL STUDY 
SPONSOR, 
PHARMACOVIGILANCE 
Abbott Product Operations AG 
 
 
 
 
 
 
CRO, MEDICAL EXPERTISE, 
DATA MANAGEMENT, 
BIOSTATISTICS  
  
 
  
  
  
  
 
 
 
 
 
 
 
  
  
   
 
 
  
  
 
 
  
  
 
 
  
 
 
  
 
 
DEPOT 
  
 
 
  
 
 
 
 
LABORATORY  
  
 
 


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Protocol MESI3001 Amendment 1 dated 07 April 2021 
 
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Page 5 of 94 
 
 
 
  
 
 
CLINICAL SITES 
According to list of approved sites 
 
 


Mebeverine+Simethicone 
 
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SYNOPSIS 
Sponsor: 
Abbott 
Product Operations AG 
Study drug: 
Mebeverine+Simethicone 
Active substance: 
Mebeverine hydrochloride and 
Simethicone 
Study title: 
Multicenter, randomized, parallel-group, open-label, comparative clinical study to evaluate 
efficacy and safety of Mebeverine+Simethicone fixed-dose combination versus Duspatalin® 
(mebeverine) and versus Espumisan® (simethicone) in patients with functional bowel disorders 
with abdominal pain and excess gas formation. 
Study centers (planned): 
 
Study duration: 
Approximately 9 months (from the first visit of the first 
patient until the last visit of the last patient) 
Study phase:  
III 
Study objectives: 
Primary objectives: 
To assess the efficacy of Mebeverine+Simethicone fixed-dose combination versus 
Duspatalin® (mebeverin) and Espumisan® (simethicone) based on the change of abdominal pain 
and bloating/flatulence intensity, assessed with NRS-11 scales after 4 weeks of treatment in 
patients with functional bowel disorders with abdominal pain and bloating/flatulence.Secondary 
objectives:  
To evaluate the following efficacy and safety parameters of Mebeverine+Simethicone fixed-
dose combination versus Duspatalin® (mebeverin) and versus Espumisan® (simethicone) in 
patients with functional bowel disorders with abdominal pain and excess gas formation 
(bloating/flatulence), including analysis in subgroups (patients with IBS and other functional 
bowel diseases, patients with constipation, diarrhea, both constipation and diarrhea, neither of 
them): 
• Change from baseline of NRS-11 pain intensity after 4 weeks of treatment  
• Proportion of patients with the NRS-11 pain intensity reduction of ≥30% versus baseline 
during at least 50% of treatment weeks over treatment period 
• Proportion of patients with the NRS-11 pain intensity reduction of ≥ 50% versus baseline 
during at least 50% of treatment weeks over treatment period. 
• Proportion of patients with the abdominal pain assessed in the Patient Dairy completely 
resolved during at least 50% of treatment weeks over treatment period (NRS-11 0 
assessment). 
• Change from baseline of NRS-11 bloating/flatulence intensity after 4 weeks of treatment 
• Proportion of patients with the NRS-11 bloating/flatulence intensity reduction of ≥30% 
versus baseline during at least 50% of treatment weeks over treatment period. 
• Proportion of patients with the NRS-11 bloating/flatulence intensity reduction of ≥ 50% 
versus baseline during at least 50% of treatment weeks over treatment period.  


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• Proportion of patients with the bloating/flatulence assessed in the Patient Dairy 
completely resolved during at least 50% of treatment weeks over treatment period (NRS-
11 0 assessment). 
• For patients with constipation: proportion of patients with any increase in number of 
CSBM per week versus baseline during at least 50% of treatment weeks. 
• For patients with diarrhea: proportion of patients with any decrease in the number of days 
per week with at least one stool consistency of Type 6 or Type 7 BSS versus baseline 
during at least 50% of treatment weeks. 
• Change in number of days per week during study treatment period when drotaverine was 
taken. 
• Change in quality of life evaluation using IBSQOL questionnaire versus baseline. 
• The incidence and severity of adverse events (AE) and serious adverse events (SAE), 
physical examination, vital signs and lab results. 
Study methodology: 
Study design: 
An open-label, randomized, comparative Phase III clinical study. The study is performed to 
evaluate efficacy and safety of Mebeverine+Simethicone fixed-dose combination versus 
Duspatalin ® (mebeverin) and versus Espumisan ® (simethicone) after 4 weeks of treatment in 
patients with functional bowel disorders with abdominal pain and excess gas formation. 
The study will be conducted at approximately 45 clinical sites in Russia. 
A total of 465 patients with functional bowel disorders with abdominal pain and excess gas 
formation will be randomized in the study at a 1:1:1 ratio (155 patients in each of the three 
groups).  
Taking into account a possible screen-failure rate approximately 30%, up to 665 patients will 
be screened to include 465 patients in study.  
Clinical study will include three periods: Screening and Run-in period (1 week), study 
treatment period (4 weeks), and follow-up period (1 week). 
Screening and run-in period 
On the Visit 1 (Week -1, Day -7) after signing the Patient Information Leaflet and the 
Informed Consent Form, screening procedures will be performed, including collection of 
demographic data and medical history, physical examination, height and body weight 
measurements, BMI determination, vital signs assessment, sampling of biological material for 
hematology and biochemistry blood tests, urinalysis, test for fecal calprotectin. For patients older 
than 501 years old who have not had a colonoscopy performed during the cause of the last 12 
months prior to screening which confirms the absence of significant pathological changes, this 
procedure will be performed as part of the screening examination. Screening period will be 
prolonged for 2 more weeks (up to 3 weeks) for these patients. Colonoscopy should be performed 
not later than 10 days before the randomization visit. Assessment of abdominal pain and 
bloating/flatulence intensities will be performed using an 11-point Numeric Rating Scale (NRS-
11). An ECG and urine pregnancy test for women of childbearing potential will be performed.  
The drotaverin intake not more than 80 mg 1 – 3 times a day during one day after pain episode  
will be allowed for intensive abdominal pain during the study; No-spa® will be recommended to 
the patients for this purpose. Other drugs for abdominal pain and bloating/flatulence treatment 


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will be prohibited. Any changes in diet and probiotic therapy (including drug and dose regimen 
changes) will be also prohibited.  
Patients will be given Patient Diaries for daily self-assessment of abdominal pain, 
bloating/flatulence severity with NRS-11 (the most severe episode during last 24 hours), study 
drug and drotaverin intake, stool frequency and consistency with Bristol Stool Chart (BSC). 
Women with childbearing potential will register menstrual bleeding days.   
At the end of the Screening and Run-in period, patients will be invited to the center to assess 
the abdominal pain and bloating/flatulence intensities and confirm compliance with the 
inclusion/exclusion criteria. The baseline abdominal pain and bloating/flatulence intensity for the 
inclusion/exclusion criteria assessment will be determined as average daily NRS-11 abdominal 
pain and bloating/flatulence score during last week of screening period (7 days before 
randomization). 
Study treatment period 
On Visit 2 (Week 0, Day 1) patients who meets all inclusion/exclusion criteria, will be 
randomized into one of the three groups at a 1:1:1 ratio. Vital signs and body weight will be 
evaluated. Patients will assess their quality of life by completing IBSQOL. 
Group 
Study product 
Number of patients 
1 
Mebeverine+Simethicone, 135 mg+80 mg, three times 
a day 
155 
2 
Duspatalin® 135 mg three times a day 
155 
3 
Espumisan®, 80 mg (2 capsules 40 mg) three times a 
day 
155 
 
The study will be open, with no treatment blinding.  
Throughout the study, patients will keep diaries for daily recordings of the abdominal pain 
and bloating/flatulence intensities on the NRS scale (the most intensive episode during last 24 
hours), study drug and drotaverin intake which will be allowed as rescue medication not more 
than 80 mg 1 – 3 times a day during one day for intensive pain episode; patients will also evaluate 
the frequency and consistency of stools, women with childbearing potential will register 
menstrual bleeding days. 
Study treatment period duration will be 4 weeks. On Week 2, Day 15, the telephone contact 
(TC) for adverse events (AEs) and concomitant medications assessment will be performed. 
On Visit 3 (Week 4, Day 29) the abdominal pain and bloating/flatulence intensities 
registration according to the Patient Diary will be checked by investigator, as well as the 
frequency and consistency of stool, drotaverin intake, the adverse events and concomitant 
medications. Physical examination, vital signs, and body weight will be assessed, blood and urine 
for haematology and biochemistry tests and urinalysis will be sampled. Patients will assess their 
quality of life by completing IBSQOL. At this visit study treatment will be completed and patients 
will receive recommendations for further treatment of abdominal functional disorder.  
Follow-up period 
Follow-up period will last for 1 more week after study treatment completion. At Week 5, Day 
36, the TC will be performed to assess the adverse events and concomitant medications.  


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Main inclusion and exclusion criteria: 
Inclusion criteria 
1. Signed Informed Consent Form; 
2. Males and females aged 18 to 75 years old (inclusive);  
3. Abdominal pain and bloating/flatulence due to functional bowel disorder (including IBS, 
chronic functional constipation, chronic functional diarrhea or functional abdominal 
bloating); 
4. Episodes of abdominal pain for at least 3 months, with a frequency of at least 3 times a 
month; 
5. Abdominal pain intensity of 4 to 9 points (inclusive) when assessed on the NRS-11 scale 
(i.e. weekly average, with daily recording of the worst pain for the last 24 hours during 
last week of Screening and Run-in period);  
6. Bloating/flatulence intensity of of 4 to 9 points (inclusive) when assessed on the NRS-11 
scale (i.e. weekly average, with daily recording of the worst bloating episode for the last 
24 hours during last week of Screening and Run-in period); 
7. Patients' consent to use adequate contraception methods throughout the study. Adequate 
contraception methods include:  
a. oral contraceptives or contraceptive patches,  
b. condom or diaphragm (barrier method) with spermicide, or  
c. an intrauterine device 
Exclusion criteria: 
1. Hypersensitivity to mebeverine, simethicone, drotaverine, excipients of the studied 
products, or contraindications; 
2. Intake of tricyclic antidepressants, eluxadoline, linaclotide, selective serotonin re-
uptake inhibitors, rifaximin, lubriprostone within the last week before screening; 
3. New prescription or any change in probiotic drug therapy (including change in the 
drug or dosage regimen) during the last month before screening; 
4. History of intestinal obstruction, stricture, toxic megacolon, GI (gastro-intestinal) 
perforation, fecal impaction, gastric banding, bariatric surgery, adhesions, ischemic 
colitis, or impaired intestinal circulation (e.g. aorto-iliac disease); 
5. History of major gastric, hepatic, pancreatic or intestinal surgery (appendectomy, 
hemorrhoidectomy, or polypectomy allowed as long as occurred > 3 months prior to 
trial screening; uncomplicated laparoscopic or open cholecystectomy is allowed if no 
history of post-operative biliary tract pain and surgery occurred > 3 months prior to 
screening); 
6. Significant and progressive enlargement of the liver, spleen, lymph nodes; ascites; 
palpable tumor formation in the abdominal cavity / pelvis according to physical 
examination, hepatic cirrhosis; 
7. Significant concomitant acute or chronic disease (cardiovascular, gastrointestinal, 
endocrine, immunological, metabolic, bronchopulmonary, urinary system) or any 


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condition that, according to Investigator, is a contraindication for the patient to 
participate in the study if interference with the study performance; 
8. Any inflammatory bowel disease (Crohn’s disease, ulcerative colitis, any infection 
including bacterial, viral, protozoa, helminthosis); 
9. Elevated fecal calprotectin level 1 month before or at screening which indicates the 
presence of inflammatory GIT disease; 
10. Unexplained GI bleeding within 3 months prior to screening; 
11. Confirmed diagnosis of bile acids malabsorption; 
12. History of any malignant disease except basal cell carcinoma of skin and vesical 
cervix carcinoma in situ which were cured ≥ 5 years ago;  
13. Confirmed diagnosis of celiac disease; 
14. Confirmed hereditary galactose or fructose intolerance , total lactase deficiency, 
sucrase-isomaltose insufficiency, glucose-galactose malabsorption syndrome; 
15. Diet changes (e.g, switching to fermented foods, a gluten-free diet) within the 1 
months prior to screening; 
16. Planned elective surgery during the study; 
17. Pancreatic exocrine insufficiency or acute pancreatitis; 
18. Endometriosis in women; 
19. Positive results of tests for HIV, hepatitis B or C, at the moment of screening; 
20. Drugs or alcohol abuse at screening or in the past, which, in the Investigator's opinion, 
makes the patient not eligible for participation in the study; 
21. Participation in another clinical study or another study drug administration within 30 
days prior to screening; 
22. Pregnant or lactating women, or women planning to get pregnant during the clinical 
study; women of child-bearing potential (including those without history of surgical 
sterilization and women with <2 years post-menopause) not using adequate 
contraception methods; 
23. Inability to read or right; unwillingness to understand and comply with Protocol 
procedures; non-compliance with medication dosing regimen or procedures which, in 
the Investigator’s opinion, may affect study results or the patient’s safety and prevent 
the patient’s participation in the study; any other concomitant diseases or severe 
mental disorders, which make the patient ineligible for study participation, limit the 
legal basis for Informed Consent procedure, or may affect the patient’s ability to 
participate in the study. 
Study product, dosage, and route of administration: 
Name: Mebeverine+Simethicone 
Drug substances: mebeverine hydrochloride and simethicone  
Drug formulation: film-coated tablets  
Dosage: 135 mg + 80 mg 
Route of administration: orally 1 tablet 3 times a day before meal 
Storage conditions: In a light-protected place at a temperature not above 25°C. 


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Manufacturer: 
 
Comparator products, dosage, and route of administration: 
Duspatalin® 
Drug substance: mebeverine hydrochloride  
Drug formulation: film coated tablets 
Dosage: 135 mg 
Route of administration: orally  
Dosing regimen: 135 mg three times a day in before meals 
Storage conditions: at a temperature below 30˚С 
 
 
Espumisan® 
Active substance: Simethicone  
Drug formulation: capsules 
Dosage: 40 mg 
Route of administration: orally 2 capsules 3 times a day with and without meals 
Storage conditions: at a temperature below 30˚С  
 
 
Treatment duration: 
Each patient will be participating in the study for approximately 6 weeks, including 1 week 
of screening and run-in period, 4 weeks of study treatment, and 1 follow-up week.  
Start of patient enrollment is scheduled for November 2020. All patients are planned to 
complete all study visits until April 2021, and the study is planned to be completed in August 
2021. 
Assessment criteria: 
Efficacy assessment 
Primary endpoint: 
• Change from baseline of sum of NRS-11 abdominal pain and bloating/flatulence intensity 
scores after 4 weeks of treatment.  
The baseline abdominal pain and bloating/flatulence intensity will be determined as the 
average of the NRS-11 daily assessment during 7 days before randomization (weekly average of 
last week of screening and run-in period). The Week 4 assessment is the same (data from last 7 
days of the corresponding week). 
Secondary end points: 
• Change from baseline of NRS-11 pain intensity after 4 weeks of treatment  


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• Proportion of patients with the NRS-11 pain intensity reduction of ≥30% versus baseline 
during at least 50% of treatment weeks over treatment period 
• Proportion of patients with the NRS-11 pain intensity reduction of ≥ 50% versus baseline 
during at least 50% of treatment weeks over treatment period. 
• Proportion of patients with the abdominal pain assessed in the Patient Dairy completely 
resolved during at least 50% of treatment weeks over treatment period (NRS-11 0 
assessment). 
• Change from baseline of NRS-11 bloating/flatulence intensity after 4 weeks of treatment 
• Proportion of patients with the NRS-11 bloating/flatulence intensity reduction of ≥30% 
versus baseline during at least 50% of treatment weeks over treatment period. 
• Proportion of patients with the NRS-11 bloating/flatulence intensity reduction of ≥ 50% 
versus baseline during at least 50% of treatment weeks over treatment period.  
• Proportion of patients with the bloating/flatulence assessed in the Patient Dairy 
completely resolved during at least 50% of treatment weeks over treatment period (NRS-
11 0 assessment). 
• For patients with constipation: proportion of patients with any increase in number of 
CSBM per week versus baseline during at least 50% of treatment weeks. 
• For patients with diarrhea: proportion of patients with any decrease in the number of days 
per week with at least one stool consistency of Type 6 or Type 7 BSS versus baseline 
during at least 50% of treatment weeks. 
• Change in number of days per week during study treatment period when drotaverine was 
taken. 
• Change in quality of life evaluation using IBSQOL questionnaire versus baseline. 
• The incidence and severity of adverse events (AE) and serious adverse events (SAE), 
physical examination, vital signs and lab results. 
The baseline abdominal pain and bloating/flatulence intensity will be determined as average 
of the worst daily episodes NRS-11 assessment during 7 days before randomization (last week of 
screening and run-in period). The data from last week of screening and run-in period will be also 
used for baseline assessment of stool frequency and consistency and number of days of drotaverin 
intake. Week 1, Week 2, Week3 and Week 4 assessments are the same (data from the last 7 days 
of the corresponding week). 
Safety assessment 
Safety will be assessed per treatment arm, based on the incidence and severity of AE and 
SAE, physical examination, vital signs and lab results. 
Statistical Analysis methods 
Statistical analysis will be performed according to the Statistical Analysis Plan created and 
finalized before the database lock. 
The Safety Population will consist of all randomized patients who received at least one dose 
of the study product. 
The Full Analysis Set (FAS) will consist of all randomized patients who received at least one 
dose of the study product and have at least one post-baseline assessment of the efficacy 
parameters. 


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Per Protocol set (PP) will consist of all FAS patients who completed study treatment and had 
no significant protocol violations. 
Also, secondary endpoint analysis will be performed in the following subgroups: 
• Patients with IBS 
• Patients with other functional bowel diseases 
• Patients with constipation 
• Patients with diarrhea 
• Patients with both constipation and diarrhea 
Patients with neither constipation nor diarrhea. 
Primary efficacy endpoint analysis 
The FAS will be the main sample for efficacy assessment in this study performed to confirm 
superiority. Additional analysis of the primary efficacy endpoint will be performed in the per 
protocol (PP) set.  
For the difference of changes in sum scores of NRS-11 pain and bloating/flatulence 
intensities 
after 
4 
weeks 
of 
treatment 
versus 
baseline 
between 
the 
groups 
Mebeverine+Simethicone 
versus 
Duspatalin® 
and 
Mebeverine+Simethicone 
versus 
Espumisan®, a two-sided 95% confidence interval (CI) will be constructed, which is equivalent 
to a 97.5% one-sided CI. The confidence interval will be constructed using ANCOVA, which 
will include treatment and site as fixed effect, and baseline parameter will be included in the 
model as covariate. To test the hypothesis of superiority of the FDC Mebeverine+Simethicone 
versus every comparator (Duspatalin® and Espumisan®), the upper confidence limit will be 
used. The null hypothesis (H0: no difference in change from baseline of sum of bloating/flatulence 
and pain scores between the FDC and corresponding comparator, will be rejected in favor of the 
alternative hypothesis (Ha: larger change from baseline of sum of bloating/flatulence and pain 
scores in the fixed-dose combination Mebeverine+Simethicone group) only if the upper limit of 
two-sided 95% CI does not contain the value 0. In addition the study will be considered successful 
in case the both superiority hypothesizes are proven, i. e. upper limit of two-sided 95% CI does 
not contain the value 0 for both constructed confidence intervals. In this case, a conclusion will 
be drawn on the fixed-dose combination of Mebeverine+Simethicone is superior versus 
Duspatalin® (mebeverin) and Espumisan® (simethicone) for the pooled decrease of pain and 
bloating/flatulence intensity. 
Secondary endpoint analysis 
Intergroup comparisons will also be performed for secondary efficacy endpoints using the 
χ2/Fisher exact test and 95% confidence intervals for differences in proportions will be given. 
Additionally, the proportion of patients with reduced severity of pain in the bowel region and 
bloating/flatulence during each week of the 4-week treatment period charts will be constructed. 
ANCOVA model, which will include treatment and site as fixed effect, and baseline value as 
covariate, will be used for continuous covariates comparison presenting treatment effect 
estimates and associated 95% CIs. 
Safety endpoint analysis 
The safety sample will be used for the analysis of the safety and tolerability data. 
Treatment Emergent Adverse Events (TEAEs) including AE and SAE will be presented by 
frequencies (number of patients with AEs and number of events) and are summarized by unique 
treatment (Mebeverine+Simethicone, Duspatali®, Espumisan®), primary System Organ Class 


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(SOC) and Preferred terms (PT) and relation to the study drug and severity. Severity and drug-
event relationship of the treatment emergent AEs are summarized separately.  
Laboratory values and vital signs by visit and their changes from baseline will be summarized 
in tables of descriptive statistics. Abnormal values (according to the reference ranges) will be 
presented in frequency tables (low, normal and high values). 
Patient distribution, demographic characteristics, and analysis of baseline 
characteristics 
Patient distribution, demographic and baseline characteristics will be summarized using 
descriptive statistics. The number and proportion (%) of patients receiving concomitant 
medication will be provided in frequency tables by the 2 and 4 level ATC codes. The number and 
proportion (%) of patients with prior medical conditions will be provided. Information on dosing, 
including daily doses, exposure time, and total dose, will be presented descriptively for each 
group. 
Sample size 
There are no published data on bloating/flatulence and abdominal pain assessment with NRS-
11 for simethicone versus placebo and mebeverin versus placebo. Comparison of Linaclotide 
treatment versus placebo for bloating decrease in chronic constipation patients was assessed with 
NRS-11 and found out 1.0 point difference between groups with approximately 2.5 standard 
deviation.2 Comparison of B. coagulans Unique IS2 treatment versus placebo for pain decrease 
in IBS patients was assessed with NRS-11 and found out 3.2 point difference between groups 
with 2.5 standard deviation.3 
An assumption was taken that Mebeverin+Simethicone fixed dose combination will decrease 
the sum of pain and bloating/flatulence scores on average at least 1.0 point more than simethicone 
or mebeverine as monotherapy. 
For primary endpoint to demonstrate the superiority of the FDC versus separately each 
mono-component assuming an expected 1.0 point difference between the two treatment groups 
and standard deviation 2.5 with type I error α = 0.05 (two-sided) and power 90% for each 
comparison individually in a group-sequential design with one interim stage at information 
fraction 40%, about 132 patients should be included in both groups. The overall power to 
demonstrate superiority for both comparisons (FDC vs mebeverine monotherapy and FDC vs 
simethicone monotherapy) is about 80%. 
Thus, 396 should be included into the analysis. 
1. mebeverin 
superiority 
/sum 
NRS-11 scores for 
pain 
and 
bloating/flatulene 
intensity 
α = 0.05 (two-sided) 
β = 0.1 
Power = 90% 
Mean diff. = 1.0 
SD = 2.5 
Alpha spending function: 
O'Brien-Fleming 
Beta spending function (non-binding): 
O'Brien-Fleming 
Max. num, of stages = 2 
Info. proportion at Interim stage = 0.40 
n1 = n2 = 132 
2. simethicone 
superiority 
/sum 
NRS-11 scores for 
pain 
and 
bloating/flatulene 
intensity 
α = 0.05 (two-sided) 
β = 0.1 
Power = 90% 
Mean diff. = 1.0 
SD = 2.5 
Alpha spending function: O'Brien-Fleming 
n1 = n2 = 132  


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Beta spending function (non-binding): 
O'Brien-Fleming 
Max. num, of stages = 2 
Info. proportion at Interim stage = 0.40 
Thus, taking into account a 15% drop-out rate, about 155 patients should be included in each 
group. A total of 465 patients should be randomized. 
Randomization  
Patients will be randomized into three equal groups (1:1:1) using the IWRS system.  
Protocol version number and date:  
Protocol MESI3001 Amendment 1 dated 07 April 2021 
 


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TABLE OF CONTENTS 
PROTOCOL APPROVAL PAGE ............................................................................................ 2 
PRINCIPAL INVESTIGATOR STATEMENT ....................................................................... 3 
CONTACT INFORMATION ON CLINICAL STUDY .......................................................... 4 
SYNOPSIS ................................................................................................................................ 6 
TABLE OF CONTENTS ........................................................................................................ 16 
LIST OF TABLES .................................................................................................................. 20 
LIST OF FIGURES ................................................................................................................. 20 
LIST OF ABBREVIATIONS ................................................................................................. 21 
1. 
INTRODUCTION ........................................................................................................... 22 
1.1. FREQUENCY AND PREVALENCE OF CHRONIC ABDOMINAL PAIN AND 
ABDOMINAL BLOATING . ......................................................................................... 22 
1.2. MECHANISMS OF ORIGIN, TYPES AND CHARACTERISTICS OF ABDOMINAL PAIN
 ......................................................................................................................................... 22 
1.3. ABDOMINAL PAIN AND BLOATING IN FUNCTIONAL BOWEL DISORDERS
 ......................................................................................................................................... 22 
1.4. FUNCTIONAL BOWEL DISORDERS: EPIDEMIOLOGY AND SOCIAL 
SIGNIFICANCE, EVOLUTION OF TERMINOLOGY, LIMITATIONS OF THE ROME 
CRITERIA IV EDITION ................................................................................................ 23 
1.5. SPASMOLYTICS, SIMETHICONE AND THEIR COMBINATION IN FBD THERAPY
 ......................................................................................................................................... 25 
1.6. FIXED-DOSE COMBINATION MEBEVERINE + SIMETHICONE .......................... 26 
1.6.1. 
INDICATIONS AND DOSAGE........................................................................... 26 
1.6.2. 
CONTRAINDICATIONS ..................................................................................... 26 
1.6.3. 
REFERENCE SAFETY INFORMATION ........................................................... 26 
2. 
STUDY AIMS ................................................................................................................. 26 
2.1. PRIMARY OBJECTIVES .............................................................................................. 26 
2.2. SECONDARY OBJECTIVES: ....................................................................................... 27 
3. 
STUDY DESIGN ............................................................................................................ 27 
3.1. OVERALL STUDY DESIGN......................................................................................... 27 
3.2. SCREENING AND RUN-IN PERIOD ........................................................................... 28 
3.2.1. 
VISIT 1 (WEEK -1, DAY -7, FOR COLONOSCOPY PATIENTS WEEK -3, DAY -
21) 
28 
3.3. STUDY TREATMENT PERIOD ................................................................................... 28 
3.3.1. 
VISIT 2, RANDOMIZATION (WEEK 0, DAY 1) .............................................. 28 
3.3.2. 
TELEPHONE CONTACT 1 (WEEK 2, DAY 15) ............................................... 29 
3.3.3. 
VISIT 3, END OF STUDY TREATMENT (WEEK 4, DAY 29) ........................ 29 
3.4. FOLLOW UP PERIOD ................................................................................................... 29 
3.4.1. 
TELEPHONE CONTACT 2 (WEEK 5, DAY 36) ............................................... 29 
3.5. STUDY DESIGN RATIONALE .................................................................................... 31 
3.5.1. 
ASSESSMENT OF SUPERIOR EFFICACY OF MEBEVERINE+SIMETHICONE 
FIXED-DOSE COMBINATION VERSUS ANY OF IT’S MONO-COMPONENT. ... 31 
3.5.2. 
STUDY TREATMENT DURATION AND DOSAGE REGIMEN ..................... 32 


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3.5.3. 
EFFICACY AND SAFETY ASSESSMENT PARAMETERS ............................ 32 
3.6. PREVIOUS EXPERIENCE ............................................................................................ 33 
3.6.1. 
MEBEVERINE ..................................................................................................... 33 
3.6.1.1. 
MECHANISM OF ACTION OF MEBEVERINE ................................................ 33 
3.6.1.2. 
CLINICAL STUDIES TO EVALUATE EFFICACY OF MEBEVERINE ......... 33 
3.6.1.3. 
SAFETY OF MEBEVERINE ............................................................................... 35 
3.6.2. 
SIMETHICONE .................................................................................................... 37 
3.6.2.1. 
MECHANISM OF ACTION OF SIMETHICONE .............................................. 37 
3.6.2.2. 
CLINICAL EFFICACY OF SIMETHICONE ...................................................... 37 
3.6.2.3. 
SAFETY OF SIMETHICONE .............................................................................. 39 
3.7. COMBINED USE OF ANTISPASMODICS AND SIMETHICONE ............................ 39 
3.7.1. 
CONCLUSION ON THE COMBINED USE OF ANTISPASMODICS AND 
SIMETHICONE .............................................................................................................. 41 
3.7.2. 
APPROVED COMBINATIONS OF SIMETHICONE AND ANTISPASMODICS
 
41 
3.8. FIXED-DOSE COMBINATION MEBEVERINE+SIMETHICONE ............................ 41 
3.8.1. 
RISK/BENEFIT RATIO ....................................................................................... 44 
3.8.2. 
CLINICAL PROGRAM FOR FIXED DOSE COMBINATION 
MEBEVERINE+SIMETHICONE DEVELOPMENT ................................................... 45 
4. 
SELECTION OF STUDY POPULATION ..................................................................... 47 
4.1. STUDY POPULATION .................................................................................................. 47 
4.2. INCLUSION CRITERIA ................................................................................................ 47 
4.3. EXCLUSION CRITERIA ............................................................................................... 47 
4.4. EXCLUSION OF PATIENTS FROM THE STUDY AFTER RANDOMIZATION .... 49 
4.5. RE-TESTS AND RE-SCREENING ............................................................................... 49 
5. 
STUDY DRUG ............................................................................................................... 50 
5.1. DESCRIPTION OF THE INVESTIGATED DRUGS .................................................... 50 
5.1.1. 
FIXED-DOSE COMBINATION MEBEVERINE + SIMETHICONE ................ 50 
5.1.2. 
DUSPATALIN ® .................................................................................................. 50 
5.1.3. 
ESPUMISAN® ..................................................................................................... 50 
5.2. ADMINISTRATION OF THE STUDY DRUG AND RANDOMIZATION ................ 51 
5.3. COMPLIANCE OF THE THERAPY CONDUCTION ................................................. 51 
5.4. PACKING AND LABELING OF THE STUDY DRUGS ............................................. 52 
Label of blister (Label 5829-L01) ..................................................................................... 52 
Label of secondary pack (Label 5829-L02) ...................................................................... 52 
Label of blister (Label 5829-L03) ..................................................................................... 53 
Label of secondary pack (Label 5829-L04) ...................................................................... 53 
Label of blister (Label 5829-L05) 
 (simple white label) ............................................ 53 
Label of secondary pack (Label 5829-L06) 
 (simple white label) ........................ 54 
5.5. ACCOUNTING OF THE STUDY DRUG ..................................................................... 54 
5.6. STUDY DRUG STORAGE IN THE STUDY SITE ...................................................... 54 
5.7. CONCOMITANT MEDICATION ................................................................................. 54 


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5.8. PROHIBITED MEDICATIONS ..................................................................................... 55 
5.9. RESTRICTIONS ON THE PATIENT’S DIET AND PHYSICAL ACTIVITY ............ 55 
6. 
DESCRIPTION OF THE PROCEDURES ..................................................................... 55 
6.1. INFORMED CONSENT ................................................................................................. 56 
6.2. PATIENT REGISTRATION .......................................................................................... 56 
6.3. DEMOGRAPHIC DATA AND MEDICAL HISTORY ................................................ 56 
6.4. PHYSICAL EXAMINATION ........................................................................................ 56 
6.5. VITAL SIGNS, HEIGHT AND WEIGHT ..................................................................... 56 
6.6. ELECTROCARDIOGRAPHY ....................................................................................... 56 
6.7. COLONOSCOPY ............................................................................................................ 56 
6.8. NUMERIC RANGE SCALE (NRS-11) ......................................................................... 57 
6.9. BRISTOL STOOL CHART (BSC) ................................................................................. 57 
6.10. ........... QUALITY OF LIFE EVALUATION USING THE IBSQOL QUESTIONNAIRE
 ......................................................................................................................................... 58 
6.11. .............................................................................................. LABORATORY PARAMETERS
 ......................................................................................................................................... 58 
6.12. ............ REQUIREMENTS FOR COLLECTING, RECORDING AND REPORTING OF 
ADVERSE EVENTS ...................................................................................................... 59 
6.12.1. 
ADVERSE EVENTS ............................................................................................ 59 
6.12.1.1. DEFINITION OF ADVERSE EVENT ................................................................. 59 
6.12.1.2. RECORDING OF ADVERSE EVENTS .............................................................. 60 
6.12.1.3. SEVERITY ............................................................................................................ 60 
6.12.1.4. DRUG-EVENT RELATIONSHIP ........................................................................ 60 
6.12.1.5. OUTCOME ........................................................................................................... 61 
6.12.1.6. FOLLOW-UP OF ADVERSE EVENTS .............................................................. 61 
6.12.1.7. SERIOUS ADVERSE EVENTS (SAES) ............................................................. 61 
6.12.1.8. REPORTING SERIOUS ADVERSE EVENTS ................................................... 62 
6.12.2. 
PREGNANCY ....................................................................................................... 62 
6.13. ......................................................................... EMERGENCY SITUATION PROCEDURES
 ......................................................................................................................................... 63 
6.14. ................................................................. SUBJECT WITHDRAWAL FROM THE STUDY
 ......................................................................................................................................... 63 
6.15. ................................................................................ THE VALIDITY OF MEASUREMENTS
 ......................................................................................................................................... 64 
7. 
STUDY PROCEDURES ................................................................................................. 64 
7.1. SCREENING AND RUN-IN PERIOD (VISIT 1, WEEK – 1, DAY -7) ....................... 64 
7.2. TREATMENT PERIOD ................................................................................................. 65 
7.2.1. 
RANDOMIZATION (VISIT 2 WEEK 0, DAY 1). .............................................. 65 
7.2.2. 
TELEPHONE CONTACT 1 (WEEK 2, DAY 15) ............................................... 65 
7.2.3. 
END OF TREATMENT (VISIT 3, WEEK 4, DAY 29) ...................................... 65 
7.3. FOLLOW-UP PERIOD ................................................................................................... 66 
7.3.1. 
TELEPHONE CONTACT 2 (WEEK 5, DAY 36) ............................................... 66 
7.4. UNSCHEDULED VISITS .............................................................................................. 66 


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7.5. EARLY DISCONTINUATION VISIT ........................................................................... 66 
8. 
QUALITY ASSURANCE ............................................................................................... 66 
9. 
STATISTICAL METHODS PLANNED ........................................................................ 67 
9.1. GENERAL PROVISIONS .............................................................................................. 67 
9.2. SAMPLING SIZE IDENTIFICATION .......................................................................... 67 
9.3. RANDOMIZATION ....................................................................................................... 68 
9.4. STATISTICAL METHODS ........................................................................................... 68 
9.5. PATIENT DISTRIBUTION, DEMOGRAPHIC AND BASELINE CHARACTERISTICS
 ......................................................................................................................................... 68 
9.6. STUDY DRUG INTAKE ................................................................................................ 68 
9.7. EFFICACY ANALYSIS ................................................................................................. 69 
9.7.1. 
PRIMARY EFFICACY END POINT ................................................................... 69 
9.7.2. 
PRIMARY END POINTS ANALYSIS ................................................................ 69 
9.7.3. 
SECONDARY EFFICACY END POINTS .......................................................... 69 
9.7.4. 
SECONDARY EFFICACY END POINTS ANALYSIS ..................................... 70 
9.8. SAFETY ANALYSIS ..................................................................................................... 70 
9.8.1. 
SAFETY END POINTS: ....................................................................................... 70 
9.8.2. 
SAFETY END POINTS ANALYSIS ................................................................... 70 
9.9. PROCEDURES TO RECORD MISSING, NOT SUBJECT TO ANALYSIS AND 
DUBIOUS DATA ........................................................................................................... 70 
9.10.REPORTING OF ANY DEVIATIONS FROM THE ORIGINAL STATISTICAL PLAN
 ......................................................................................................................................... 71 
10. ADMINISTRATIVE PROCEDURES ............................................................................ 71 
10.1. ....................................................................................................................... LEGAL ASPECTS
 ......................................................................................................................................... 71 
10.2. .............................................................................. INVESTIGATOR’S RESPONSIBILITIES
 ......................................................................................................................................... 71 
10.3. ................................................................................................ MONITORING PROCEDURES
 ......................................................................................................................................... 71 
10.4. ....................................................................................... STORAGE OF DOCUMENTATION
 ......................................................................................................................................... 72 
10.5. ................................................................................................................... ETHICAL ASPECTS
 ......................................................................................................................................... 72 
10.5.1. 
INDEPENDENT ETHICS COMMITTEE ............................................................ 72 
10.5.2. 
ETHICAL CONDUCT OF CLINICAL STUDY .................................................. 72 
10.5.3. 
INFORMED CONSENT ....................................................................................... 72 
10.6. .................................................................................................. FINANCING OF THE STUDY
 ......................................................................................................................................... 73 
10.7. ....................................................................................................... PLAN OF PUBLICATIONS
 ......................................................................................................................................... 73 
11. APPENDICIES ................................................................................................................ 74 
 
 


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12. REFERENCES ................................................................................................................ 89 
 
LIST OF TABLES 
Table 1 
MESI3001 study chart ................................................................................. 30 
Table 2 The most frequent (> 3%) adverse events (safety population, study MEB003) .. 36 
Table 4. Descriptive statistics for PK parameters of DMAC in healthy volunteers after single 
dose of Duspatalin® [R] and FDC Mebeverine+Simethicone [T] ............................ 43 
Table 5. Comparative bioavailability (% R) and 90% CI.................................................. 43 
Table 5. Bristol Stool Chart. .............................................................................................. 58 
Table 6 
Laboratory  tests .......................................................................................... 59 
 
LIST OF FIGURES 
Figure 1. Clinical study MESI3001design ........................................................................ 29 
Figure 2 Average PK curves for DMAC after Duspatalin® 135 mg [R] and 
Mebeverine+Simethicone 135 mg+80 mg [T]. ......................................................... 43 
 


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LIST OF ABBREVIATIONS 
 
FAS 
Full analysis set 
IBSQOL 
Irritable bowel syndrome quality of life 
MedDRA 
Medical Dictionary for Regulatory Activities 
NRS-11 
11-point Numeric Rating Scale 
PP 
Population per protocol 
TEAE 
Treatment emergent adverse events 
BSS 
Bristol stool score 
VAS 
Visual Analogue Scale 
HIV 
Human immunodeficiency virus 
WHO 
World Health Organization 
ED 
Early discontinuation 
CI 
Confident interval 
EAEU 
Eurasian Economic Union 
GIT 
Gastrointestinal tract 
BMI 
Body mass index 
IP 
Investigational product 
eCRF 
Electronic Case Report Form(s) 
SOC 
System organ class 
AR 
Adverse reaction 
IEC 
Independent Ethics Committee 
AE(s) 
Adverse event(s)  
ET 
End of treatment 
PT 
Preferred term 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
SAR 
Serious Adverse Reaction 
SAE 
Serious Adverse Event 
SOP 
Standard Operating Procedures 
IBS 
Irritable bowel syndrome 
TC 
Telephone contact 
FGID 
Functional gastrointestinal disease 
FBD 
Functional bowel disease 
HR 
Heart rate  
ECG 
Electrocardiogram 


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1. INTRODUCTION  
1.1. Frequency and prevalence of chronic abdominal pain and abdominal bloating . 
Abdominal pain has been and remains a serious problem of internal diseases and 
gastroenterology.4 
According to R. Hunt et al., the frequency of abdominal pain associated with spasm of 
smooth musculature of the hollow organs of the digestive system is 10-46% regardless of age. 
However, women are more likely to suffer from such pains5 
In a fairly large epidemiological study (S.A. Kurilovich and co-authors) conducted in 
Novosibirsk, in a random sample of 416 men and 473 women between the ages of 45 and 70, the 
frequency of chronic abdominal pain was 17.3%, disturbing women more often than men (23.5 
and 10.5% respectively).6 
In the general population, the frequency of complaints of bloating and overcrowding 
was 30%, and in the population of patients with irritable bowel syndrome the frequency 
of such complaints is close to 100%7 
1.2. Mechanisms of origin, types and characteristics of abdominal pain 
In general, 4 main types of abdominal pain are distinguished by the mechanism of 
formation: visceral, parietal, radiating and psychogenic 4 
One of the variants of abdominal pain due to organic causes may be parietal pain resulting 
from the involvement of the peritoneum in the pathological process.  
Due to the large number of synapses between neurons, double innervation often occurs, 
which underlies the irradiation of pain.  
Psychogenic pain occurs in the absence of somatic causes and is caused by a deficiency 
of inhibitory factors and/or amplification of normal incoming afferent signals due to lesions 
of central control mechanisms and/or reduction in synthesis of biologically active 
substances. This pain is constant, acutely reducing the quality of life and not associated with 
dysmotility, eating, intestinal peristalsis, defecation and other physiological processes. 
The most frequent mechanism of abdominal pain is visceral pain, which caused by 
increased pressure, distension, tension, local circulatory disorder, which is usually based on 
the development of spastic contraction of the smooth muscles of the hollow organ. Spasm that 
causes pain may also be the result of organic diseases, but most often it is the main 
manifestation of functional pathology of the GIT organs. Pain is usually dull, spastic, burning 
and has no clear localisation. 
1.3. Abdominal pain and bloating in functional bowel disorders 
In functional bowel disorders (FBD) the mechanisms of pain formation are different and 
may be isolated or combined: visceral genesis is often combined with radiating and/or 
psychogenic mechanisms. It is characteristic that spastic pain in the FBD disturbs patients 
while they are awake and rarely occurs during sleep5,8 
Management of the abdominal pain is a serious separate problem, even if the main cause of 
its occurrence is correctly and promptly diagnosed. The choice of a drug depends on both, the 
mechanism of pain and the specific nosological form. In everyday practice, considering the often 
combined character of pain, it is not unusual to use a combination of different medicines. 
Spasmolytic drugs are used to relieve visceral abdominal pain of any genesis - both 
organic and functional. They not only relieve pain, but also help to recover the blood flow 
affected by spasm, mucous membrane trophicity, the passage of intestinal contents and the 
absorption of nutrients and gas, leading to a feeling of overflow and laceration in the 


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abdomen.4 The prescription of spasmolytics is not accompanied by direct intervention in the 
mechanisms of pain sensitivity and does not complicate the recognition of acute surgical 
pathology, can be very often effective to eliminate the pain and improve the quality of life of 
patients suffering from recurrent abdominal pain associated with the FBD, which determines 
their widespread use. 5,9 
Essential to the patient's quality of life is to get rid of pain. Appropriate symptomatic therapy, 
even if it does not have an etiopathogenetic focus, but relieves pain, is crucial. Another fact that 
should be taken into consideration is that the prescription of spasmolytics reduces pain during 
endoscopic examination which allows to conduct various diagnostic procedures. 
Muscle spasm it is a universal reaction of smooth muscles to any pathological effects, 
which inevitably leads to excitation of nociceptors located in the gastrointestinal muscular 
layer. It is the muscle spasm that is one of the key mechanisms underlying the most commonly 
occurring variant of abdominal pain - visceral pain. Considering the importance of spasm as 
a universal link in the development and other symptoms of many gastroenterological diseases, 
it must be admitted that spasmolytic treatment is pathogenetically justified. 5,10 
1.4. Functional bowel disorders: epidemiology and social significance, evolution of 
terminology, limitations of the Rome criteria IV edition 
According to the latest version (IV) of the Rome criteria for Functional Gastrointestinal 
Disorders (FGID), approved in 2016,11 the FBD includes: 
• Irritable bowel syndrome (constipation predominant IBS, diarrhea predominant IBS, 
mixed IBS, unclassified IBS) 
• Functional constipation  
• Functional diarrhea  
• Functional abdominal bloating/distension  
• Nonspecific functional intestinal syndrome  
• 
Opioid-induced constipation  
Population studies show that the prevalence of IBS is 10% - 20%, the frequency of detection 
of new cases - 1% - 2% per year12 Only 10% - 20% of patients with IBS seek medical help.  
The prevalence of other FBDs is less studied. In the adult population, the frequency of 
functional constipation is 14% on average and ranges widely from 1.9% to 40.1%, with the 
frequency of simple complaints about constipation significantly higher than the frequency of 
diagnoses according to the Rome criteria.13 
The prevalence of functional diarrhea ranges from 1.5% to 17%14,15,16,17,18 
The prevalence of functional bloating has not been examined in major prospective studies, but 
there is evidence of the prevalence of a symptom such as bloating. According to a telephone survey 
of 2,510 subjects in the U.S., 15.9% of those surveyed reported episodes of bloating during the 
last month.19 Patients with FGID often noted a concomitant symptom of bloating, especially 
patients with IBS and functional constipation.20,21,22,23,24,25 
Since the main manifestations of FBD are abdominal pain (the dominant symptom for IBS and 
may be present in other functional bowel disorders) and lifestyle changes due to a defecation 
disorder, people with FBD are more likely to lose wages because of absences from work due to 
the illness.26 The negative impact of FBD on the quality of life of patients has been clearly 
demonstrated.27 Many social activities, such as eating, traveling long distances, participating in 
festive activities, are significantly complicated by symptoms specific to FBD. 
The pathophysiology of the FBD, even the IBS (the most studied disease in this group), is not 
fully understood. There is evidence of multiple pathogenetic pathways: 28: visceral hypersensitivity 


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or autonomous dysfunction, 29,30,31,32 and also influence of psychological factors causing 
disturbance of the nervous system of intestine and disturbance of interconnection of brain and 
intestine that in any case leads to disorders of intestinal motility.33,34 
Prior to the creation of the Rome Foundation for the study of gastrointestinal functional 
pathology, the FBD group included the so-called "spastic constipation, chronic irritable bowel, 
mucous colitis, spastic colitis", etc., the symptoms of which could include: abdominal pain, 
spasms, a feeling of bloating and flatulence, change in stool frequency.  
In 1999, the Rome criteria II first presented a new scientific direction in gastroenterology called 
"neurogastroenterology", which began to study the fundamental and applied aspects of FGID. At 
the same time, a new concept of gastrointestinal diseases, motor disorders and FGID was proposed, 
based on three basic positions: 1) organic (structural) disorders (e.g., esophagitis, inflammatory 
bowel diseases, etc.) are classified within the framework of organic morphology; criteria for their 
diagnosis are based on macro- and microscopic changes; 2) motility disorders (e.g., gastroparesis, 
intestinal pseudo-obstruction) are classified within the framework of organ function and specific 
motility disorders. They are diagnosed on the basis of repeated physiological tests (e.g. measuring 
time of intestinal transit or gastric emptying); 3) FGID (e.g. functional dyspepsia, irritable bowel 
syndrome) depend on the patient's interpretation and perception of the disease, i.e. they are 
classified and diagnosed primarily on the basis of a set of symptoms. In the mid-1990s, the 
American pharmaceutical agency FDA recommended to use the Rome criteria for irritable bowel 
syndrome (IBS) in pharmacological studies, after which the Rome Foundation began to support 
leading pharmaceutical companies around the world. The Rome Criteria III were different from 
previous versions in that for the first time they were developed using approaches based on 
evidence-based medicine rather than consensus of experts. Since 2006, the Rome Criteria III have 
been considered worldwide as the fundamental diagnostic criteria of FGID for both clinicians and 
investigators. It is mentioned in Rome criteria III that there are certain limitations to their 
application, in particular: 1) the term FGID itself, although widely referenced in the literature, is 
not entirely accurate and has a degree of stigmatization; 2) whilst diagnostic criteria have been 
developed for use in clinical practice, they are not specific to examining the pathogenetic features 
of this pathology.  
The current criteria are the Rome criteria, IV edition. 
It is generally accepted that the Rome criteria version IV, based on symptoms, have their 
limitations in clinical practice, although they are widely used in clinical trials. Specifically, 
diagnoses established under these criteria may exclude patients who do not fully meet the Rome 
criteria, although they require the same treatment.  
These limitations had a particular impact on IBS. The concept of "discomfort" was excluded 
from the fourth edition of IBS diagnostic criteria as having different translations in different 
languages or not even being present in some of them; in the previous edition of the Rome criteria 
the frequency of abdominal pain was at least 3 times per month, the pain had to be episodically 
present for 12 weeks, not necessarily sequential; in the new edition the frequency of episodic pain 
was increased to 4 per month, and the duration of pain had to be at least 6 months. Thus, the 
acceptance of the new, fourth edition of the Rome criteria significantly reduced the patient 
population with IBS. Patients who were previously classified as suffering from IBS were no longer 
consistent with this diagnosis, their disease began to be classified as other functional bowel 
disorders. For example, patients with abdominal pain and bowel dysfunction for less than 6 months 
or with a frequency of less than 1 episode per week, or those who have less than 2 of the 3 criteria 
for association of abdominal pain with stool disorders, or those in whom abdominal pain is not 
associated with stool disorders, does not meet Rome criteria IV and they are not diagnosed with 
IBS, they have a diagnosis of functional diarrhea or constipation, and at some time may be included 
in the group of IBS with diarrhea or constipation in terms of pain frequency. 


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Thus, efficacy and safety studies of spasmolytics in patients with IBS, conducted prior to the 
approval of the Rome criteria IV, were carried out on a patient population which corresponds to a 
wider group of functional bowel disorders as per the IV edition of the Rome criteria, including 
functional constipation, functional diarrhea, functional bloating 
1.5. Spasmolytics, simethicone and their combination in FBD therapy 
Spasmolytics are included in the previous (before the acceptance of the Rome criteria IV) and 
the latest version of the Guidelines of the Russian Gastroenterological Association, Russian 
Association of Coloproctologists for the diagnosis and treatment of patients with irritable bowel 
syndrome as first-line therapy.35,36 According to the Guidelines of the World Organisation of 
Gastroenterologists for the treatment of IBS in 2015,1(i.e. also prepared within the framework of 
the previous version of the Rome criteria), first-line therapy for the treatment of this pathology 
also include spasmolytics, among which are: mebeverine, otilonium, hyoscine, cimetropium, 
pinaverium and dicyclomine.  
Although currently simethicone is not included in the guidelines for the treatment of patients 
with IBS due to a lack of clinical research data, it can be assumed that its addition to basic therapy 
would be effective and would bring relief to a significant number of patients since, according to 
the published data, virtually all FBD patients suffer from flatulence..20,21,22,23,24,25,37 Many 
investigators have emphasised the particularly negative role of flatulence in worsening the 
wellbeing of FBD patients, since this symptom, by changing its intensity, intensifies during the 
day, worsens after a meal, usually decreasing by night18,36,38 It is the simethicone, which has the 
properties of a defoamer, which reduces flatulence, discomfort and abdominal pain by increasing 
the gastrointestinal gas excretion.39,40 
Taking into consideration the important role of spasmolytics in the treatment of FBD, favorable 
effect of simethicone on one of the key symptoms of FBD, flatulence, it is obviously expedient to 
try to study the effectiveness of spasmolytics and simethicone co-use in patients with FBD, 
suffering from stool disorders, bloating and abdominal pain, expressed in different extents and 
thus having different diagnoses: one or another type of IBS, functional diarrhea, functional 
constipation. Such generalization can also be made by the idea of a single etiopathogenetic 
mechanism of the development of these diseases. It is assumed that their development is based on 
the changes in the gut-brain axis and is realized in the form of intestinal motility disorders,41 which 
are eliminated by mebeverine. These motility disorders are probably an important pathogenetic 
link in the formation of both diarrhea and constipation, as well as bloating 37,42 
Functional abdominal bloating is a common symptom of many forms of functional bowel 
pathology, with adverse effects on general well-being and quality of life. Symptomatic treatment 
of bloating according to modern ideas can be aimed not only at microbiota, visceral sensitivity and 
psychological concomitant pathology, but also at intestinal motility, its muscle tone. 42,43 
The currently available literature reviews on functional abdominal bloating indicate a wide 
practical use of spasmolytics and simethicone in everyday practice as the main symptomatic 
therapy for this group of patients. 7 At the same time, modern guidelines, acknowledging the low 
quality of evidence for the long-term effectiveness of these drugs, recommend their use in FBD. 
Two meta-analyses of clinical studies were conducted to assess bloating/distension. The first included 
6 clinical studies involving 885 patients and 5 different medicines.44 According to the meta-analysis 
data, spasmolytics were more likely to relieve bloating/distension symptoms in patients with IBS (the 
diagnosis was made according to the Rome criteria before the acceptance of version IV) compared to 
placebo (chance ratio = 1.46; 95% confidence interval: 1.10-1.94). According to the results of another 
meta-analysis, which included data from 7 clinical studies in 1419 patients receiving 4 different 
spasmolytics, administration of drugs was more effective than placebo (chance ratio 1.455; 95% 
confidence interval 1.17-1.81).45 


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In a prospective randomized placebo-controlled study in 285 patients with IBS (according to the 
Rome criteria of III edition), it was revealed that the combination of pinaverium bromide and 
simethicone decreased the severity of bloating and abdominal pain to a greater extent than placebo46 
Further research is needed to clarify the pathophysiological foundations of bloating formation. 
Clinical studies in which bloating and distension are endpoints are necessary to justify the use of 
safe medicines7 with already proven efficacy against other symptoms (e.g. mebeverine). 
Moreover, the inertness, local effect and lack of absorption of simethicone in the 
gastrointestinal tract suggests the absence of pharmacokinetic interaction between simethicone and 
other products. 
Thus, the addition of simethicone to spasmolytics provides an additional significant advantage 
in the treatment of patients, improving quality of life and reducing the severity of symptoms 
characteristic of FBD. 
1.6. Fixed-dose combination Mebeverine + Simethicone 
 
 
 
 
 
 
 
 
 
 
  
Fixed-dose combination was developed by 
 in one dosage: 
• Mebeverine + Simethicone, film-coated tablets, 135 mg + 80 mg 
1.6.1. Indications and dosage 
Fixed-dose combination Mebeverine + Simethicone is indicated for the symptomatic treatment 
of pain, spasms dysfunction and abdomen discomfort associated with functional bowel diseases. 
Symptoms may include abdominal pain, cramps, bloating and flatulence, changes in stool 
frequency (diarrhea, constipation, or alternating diarrhea/constipation) and consistency. 
Fixed-dose combination will be administered as 1 tablet 3 times per day before meal. The tablet 
of fixed-dose combination Mebeverine + Simethicone should be taken with water.  
1.6.2. Contraindications 
It should also be noted that, according to the instruction for use for individual drugs, 
mebeverine intake in a dose of 135 mg is contraindicated for children under 18 years of age, 
pregnant and lactating women, patients with hypersensitivity to any component of the drug. 
Simethicone is contraindicated in the presence of hypersensitivity to any component of the drug, 
for children under 6 years old, and in the presence of intestinal obstruction. Administration of the 
combination Mebeverine + Simethicone is contraindicated for children under 18 years of age, for 
pregnant and lactating women, in the case of hypersensitivity to any of the components of the drug, 
in the case of intestinal obstruction and in cases of hereditary galactose or fructose intolerance, 
total lactase deficiency, sucrase-isomaltose insufficiency, glucose-galactose malabsorption 
syndrome. 
1.6.3. Reference safety information 
At present the reference safety information for the FDC Mebeverine+Simethicone is based on 
the instructions for use for Duspatalin® (mebeverine) and Espumisan® (simethicone) which are 
presented in the Appendix 1, and also is described in the Investigator Brochure for the FDC 
Mebeverine+Simethicone. 
2. STUDY AIMS  
2.1. Primary objectives  
• To assess the efficacy of Mebeverine+Simethicone fixed-dose combination versus 
Duspatalin® (mebeverin) and Espumisan® (simethicone) based on the change of 


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abdominal pain and bloating/flatulence intensity, assessed with NRS-11 scales after 4 
weeks of treatment in patients with functional bowel disorders with abdominal pain 
and bloating/flatulence 
2.2. Secondary objectives:  
To evaluate the following efficacy and safety parameters of Mebeverine+Simethicone fixed-
dose combination versus Duspatalin® (mebeverin) and versus Espumisan® (simethicone) in 
patients with functional bowel disorders with abdominal pain and excess gas formation 
(bloating/flatulence), including analysis in subgroups (patients with IBS and other functional 
bowel diseases, patients with constipation, diarrhea, both constipation and diarrhea, neither of 
them): 
• Change from baseline of NRS-11 pain intensity after 4 weeks of treatment  
• Proportion of patients with the NRS-11 pain intensity reduction of ≥30% versus baseline 
during at least 50% of treatment weeks over treatment period 
• Proportion of patients with the NRS-11 pain intensity reduction of ≥ 50% versus baseline 
during at least 50% of treatment weeks over treatment period. 
• Proportion of patients with the abdominal pain assessed in the Patient Dairy completely 
resolved during at least 50% of treatment weeks over treatment period (NRS-11 0 
assessment). 
• Change from baseline of NRS-11 bloating/flatulence intensity after 4 weeks of treatment 
• Proportion of patients with the NRS-11 bloating/flatulence intensity reduction of ≥30% 
versus baseline during at least 50% of treatment weeks over treatment period. 
• Proportion of patients with the NRS-11 bloating/flatulence intensity reduction of ≥ 50% 
versus baseline during at least 50% of treatment weeks over treatment period.  
• Proportion of patients with the bloating/flatulence assessed in the Patient Dairy completely 
resolved during at least 50% of treatment weeks over treatment period (NRS-11 0 
assessment). 
• For patients with constipation: proportion of patients with any increase in number of 
CSBM per week versus baseline during at least 50% of treatment weeks. 
• For patients with diarrhea : proportion of patients with any decrease in the number of days 
per week with at least one stool consistency of Type 6 or Type 7 BSS versus baseline 
during at least 50% of treatment weeks. 
• Change in number of days per week during study treatment period when drotaverine was 
taken. 
• Change in quality of life evaluation using IBSQOL questionnaire versus baseline. 
• The incidence and severity of adverse events (AE) and serious adverse events (SAE), 
physical examination, vital signs and lab results. 
3. STUDY DESIGN 
3.1. Overall study design  
This study is an open-label randomized comparative clinical phase III study. The purpose of 
this study is to assess efficacy and safety of Mebeverine+Simethicone fixed-dose combination 
versus Duspatalin® (mebeverine) and versus Espumisan® (simethicone) after 4 weeks of 
treatment in patients with functional bowel disorders with abdominal pain and excess gas 


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formation (bloating/flatulence). 
The study will be conducted at approximately 45 sites in Russia. 
Clinical study will include three periods: Screening and Run-in period (1 week), study 
treatment period (4 weeks), and follow-up period (1 week). 
3.2. Screening and run-in period 
3.2.1. Visit 1 (Week -1, Day -7, for colonoscopy patients Week -3, Day -21) 
After signing the Patient Information Leaflet and the Informed Consent Form, screening 
procedures will be performed, including collection of demographic data and medical history, 
physical examination, height and body weight measurements, BMI determination, vital signs 
assessment, sampling of biological material for hematology and biochemistry blood tests, 
urinalysis, test for fecal calprotectin. For patients older than 50Error! Bookmark not defined. years old who 
have not had a colonoscopy conclusion in the last 12 months prior to screening which confirms 
the absence of significant pathological changes, this procedure will be performed as part of the 
screening examination. Screening period will be prolonged for 2 more weeks (up to 3 weeks) for 
these patients. Colonoscopy should be performed not later than 10 days before the randomization 
visit. Assessment of abdominal pain and bloating/flatulence intensities will be performed using an 
11-point Numeric Rating Scale (NRS-11). An ECG and urine pregnancy test for 
women of childbearing potential will be performed. The drotaverin intake drotaverin intake not 
more than 80 mg 1 – 3 times a day during one day after pain episode will be allowed for intensive 
abdominal pain during the study; No-spa® will be recommended to the patients for this purpose. 
Other drugs for abdominal pain and bloating/flatulence treatment will be prohibited. Any changes 
in diet and probiotic therapy (including drug and dose regimen changes) will be also prohibited. 
Patients will be given Patient Diaries for daily self-assessment of abdominal pain, 
bloating/flatulence severity with NRS-11 (the most severe episode during last 24 hours), study 
drug and drotaverin intake, stool frequency and consistency with Bristol Stool Chart (BSC). 
Women with childbearing potential will register menstrual bleeding days.  
At the end of the Screening and Run-in period, patients will be invited to the center to assess 
the abdominal pain and bloating/flatulence intensities and confirm compliance with the 
inclusion/exclusion criteria. The baseline abdominal pain and bloating/flatulence intensity for the 
inclusion/exclusion criteria assessment will be determined as average daily NRS-11 abdominal 
pain and bloating/flatulence score during last week of screening period (7 days before 
randomization). 
3.3. Study treatment period 
3.3.1. Visit 2, Randomization (Week 0, Day 1) 
On Visit 2 (Week 0, Day 1) patients who meets all inclusion/exclusion criteria, will be 
randomized into one of the three groups at a 1:1:1 ratio. Vital signs, body weight, AEs and 
concomitant medication will be evaluated. Patients will assess their quality of life by completing 
IBSQOL. 
Group 
Study product 
Number of patients 
1 
Mebeverine+Simethicone, 135 mg+80 mg, three times 
a day 
155 
2 
Duspatalin® 135 mg three times a day 
155 
3 
Espumisan®, 80 mg (2 capsules 40 mg) three times a 
day 
155 


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The study will be open, with no treatment blinding. 
3.3.2. Telephone contact 1 (Week 2, Day 15) 
Throughout the study, patients will keep diaries for daily recordings of the abdominal pain and 
bloating/flatulence intensities on the NRS scale (the most intensive episode during last 24 hours), 
study drug and drotaverin intake; patients will also evaluate the frequency and consistency of 
stools, women with childbearing potential will register menstrual bleeding days. 
During TC the Investigator will ask patients about possible AEs/SAEs, correctness of Patient 
Diary completion and study drug intake. 
3.3.3. Visit 3, End of study treatment (Week 4, Day 29)  
Duration of study treatment is 4 weeks.  
On Visit 3 (Week 4, Day 29) the abdominal pain and bloating/flatulence intensities registration 
according to the Patient Diary will be checked by investigator, as well as the frequency and 
consistency of stool, drotaverin intake, and the adverse events and concomitant medications. 
Physical examination, vital signs, and body weight will be assessed, blood and urine for 
haematology and biochemistry tests and urinalysis will be sampled. Patients will assess their 
quality of life by completing IBSQOL. At this visit study treatment will be completed and patients 
will receive recommendations for further treatment of abdominal functional disorder. 
3.4. Follow up period  
3.4.1. Telephone contact 2 (Week 5, Day 36) 
At Week 5, Day 36 the TC will be performed to assess the adverse events and concomitant 
medication. 
Clinical study design is presented on Figure 1 
Figure 1. Clinical study MESI3001design  
Screening and Run-in period 
Study treatment period 
Follow up period 
 
MEBEVERINE+SIMETHICONE 
N = 155 
 
 
 
 
 
 
 
 
 
 
 
 
DUSPATALIN (mebeverine) 
N = 155 
------------------------------ 
 
 
 
 
 
 
 
ESPUMISAN (simethicone) 
N = 155 
 
 
V1 
V2 (Randomization) 
ТC1 
V4 (EТ) 
ТC2 
W-1 
W0 
W2 
W4 
W5 
Abbreviations: EТ – end of treatment, V – Visit, ТC – telephone contact, W – Week  
 
 


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Table 1 
MESI3001 study chart 
Periods 
Screening 
and run-in 
period 
Treatment period 
Follow up  
ED 
Visits (V) 
V1 
V2 
TC1 
V3 
(ET) 
TC2 
 
Week 
W-11 
W0 
W2 
W4 
W5 
 
Day 
Day -7 
Day 1 
Day 15 
Day 29 
Day 36 
 
Visit window 
-21…-7 days 
 
±1 day 
±1 day 
+1 day 
 
Informed Consent Form, patient 
registration 
X 
 
 
 
 
 
Demography, medical history 
X 
 
 
 
 
 
Weight, Height (screening only), BMI 
X 
X 
 
X 
 
X 
Physical examination 
X 
 
 
X 
 
X 
Vital signs 
X 
X 
 
X 
 
X 
Hematology 
X 
 
 
X 
 
X 
Biochemistry  
X 
 
 
X 
 
X 
Pregnancy test2 
X 
 
 
 
 
 
Urinalysis 
X 
 
 
X 
 
X 
Tests for HIV, hepatitis B and C 
X 
 
 
 
 
 
Feces analysis for fecal calprotectin 
X 
 
 
 
 
 
Colonoscopy 3 
X 
 
 
 
 
 
ECG  
X 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
Abdominal pain intensity on the NRS-
11 scale4 
X 
X 
X 
X 
 
X 
Flatulence intensity on the NRS-11 
scale5 
X 
X 
X 
X 
 
X 
Stool frequency 
X 
X 
X 
X 
 
X 
Bristol stool scale 
X 
X 
X 
X 
 
X 
Patient diary distribution 
X 
X 
 
 
 
 
Patient diary assessment6  
 
X 
X 
X 
 
X 
Evaluate the quality of life (IBSQOL 
questionnaire) 
 
X 
 
X 
 
X 
Study drug dispense 
 
X 
 
 
 
 
Study drug accountability and 
compliance assessment 
 
 
 
X 
 
X 
Study drug return 
 
 
 
X 
 
 
Adverse events  
X 
X 
X 
X 
X 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
ET – End of treatment, ED – Early discontinuation, TC – Telephone contact, D – day, V – Visit 
 
1 Week -3 for patients undergo colonoscopy 
2 For women of child-bearing potential (including those without history of surgical sterilization and women with <2 years post-
menopause)  
3 For patients older than 50 years old, in case it was not done during last 12 months. Colonoscopy will be performed not later than 
10 days before randomization. 
4 Daily recording of the worst pain episode for the last 24 hours 
5 Daily recording of the worst bloating/flatulence episode for the last 24 hours 
6 Including NRS-11, Bristol stool scale, stool frequency, drotaverine and concomitant medications intake assessment and menstrual 
bleeding days) 


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3.5. Study design rationale 
This is a multicenter randomized open-label comparative clinical phase III study in parallel 
groups for assessment of efficacy and safety of Mebeverine+Simethicone fixed-dose combination 
versus Duspatalin® (mebeverine) and versus Espumisan® (simethicone) in patients with 
functional bowel disorders with abdominal pain and excess gas formation. 
3.5.1. Assessment of superior efficacy of Mebeverine+Simethicone fixed-dose 
combination versus any of it’s mono-component. 
Investigated fixed-dose combination Mebeverine+Simethicone include well known drugs with 
favorable safety profile; these drugs have long history of successful use in clinical practice.  
The bioequivalence of the FDC Mebeverine+Simethicone and Duspatalin® was confirmed in 
phase I clinical study.  
In line with EEU Guideline on fixed dose combinations preclinical and clinical development 
the randomized controlled clinical study in three groups in purpose to evaluate the superioriority 
of efficacy and acceptability of safety profile of the FDC Mebeverine+Simethicone versus 
Duspatalin® (mebeverine) and versus Espumisan® (simethicone) is planned.  
According to EMA Guidelines for development of pain medicines,47 visual analogue scales 
(VAS), numeric rating scales (NRS) and verbal rating scales (VRS) are used to assess pain in 
clinical studies. To confirm the efficacy of investigational product over time as a primary endpoint, 
it is recommended to use mean pain intensity differences from baseline (PID). Moreover, it is 
indicated that for long-term studies it is recommended to use as a primary endpoint a parameter 
such as the average pain intensity per week in a daily measurement compared to the baseline value. 
This Guidelines also recommend the use of Sum of Pain Intensity Differences (SPID) and its 
associated area under the pain intensity-time curve in most cases, but this parameter is intended to 
assess the effect over time of classic analgesics, after a single dose of anaesthetic. In the case of 
functional bowel disorders, this parameter does not seem applicable, as the pain is wave-like and 
may not occur every day. None of the components of the fixed combination of 
Mebeverine+Simethicone is a classic analgesic. 
For the self assessment of bloating/flatulence intensity by patient the numeric rating scale 
(NRS-11) will also be used. Such self assessment of bloating/flatulence intensity is being 
performed in clinical studies in patients with FBD.46  
It is assumed that comcomitant use of mebeverine and simethicone as a fixed dose 
combination will possibly lead to potentiation of their effects. As the assessed symptoms 
(abdominal pain and bloating/flatulence) are interrelated and sensation of their intensity may be 
assessed variously by different patients, it is reasonably to use co primary end point –change of 
sum of NRS-11  abdominal pain and bloating/flatulence intensity scores. Such approach is widely 
used in clinical studies in patients with functional bowel disorders. For example the IBS symptom 
severity scale (IBSS-SSS), which is the sum scores of 5 visual analogue scales for 5 main IBS 
symptoms, is used for the assessment of the efficacy of drugs with pathogenic mechanism of 
action.48 
Thus, according to the EMA's Guidelines for development of pain medicines47 (2016) and 
Guidelines of EAEU for clinical and preclinical development of combined medicines, 49 and aslo 
in line with the previous clinical studies experience in patients with functional bowel disorders 
(FBD), the design and methods of assessment were chosen to study the efficacy and safety of 
Mebeverine+Simethicone fixed combination. 


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3.5.2. Study treatment duration and dosage regimen 
To develop a fixed-dose combination, standard doses of Mebeverine and Simethicone studied 
in clinical trials and long used in clinical practice as per the Duspatalin® and Espumisan® 
prescribing information were used. 
FDC Mebeverin+Simethicone is designed for symptomatic treatment of abdominal pain and 
bloating in patients with FBD. The FDC is used in this patient population for the purpose of 
symptoms relief, but not for the resolution of the main cause of the disease. 
To improve the quality of life in patients with FBD it is necessary to decrease rapidly the main 
symptoms: abdominal pain and bloating. FDC Mebeverin+Simethicone is designed for relief of 
such symptoms as abdominal pain and bloating, and the quick therapeutic response is expected. 
The expectation of quick therapeutic response is based on the published data from clinical studies, 
which demonstrated that treatment with antispasmodic and simethicone in patients with IBS (in 
line with diagnostic criteria established before Rome IV classification, that is why this population 
includes not only patients with IBS but also patients with other functional bowel disorders as per 
Rome IV criteria)  leads to the pain and bloating decrease as early as after 4 weeks of 
therapy.50,51,52,53,54,55,56,57,58,59,60,61 These data are in consistence with published recommendations 
on clinical studies design in patients with functional GIT disorders, in which the minimal duration 
of study treatment for symptomatic drugs was defined as 4 weeks (but not for the drugs developed 
for the chronic long-term basic therapy.62 As the FDC Mebeverin+Simethicone was developed as 
symptomatic drug for patients with functional GIT disorders, the 4 weeks duration therapy was 
chosen for the planned study. Abdominal pain and bloating relief with the FDC 
Mebeverin+Simethicone treatment are expected at the end of 4 weeks period. The long-term study 
treatment with the FDC in comparison with mebeverin monotherapy and simethicone 
monotherapy seems to be not rational as the therapeutic effect of each mono-component occurs 
after first dose already, and treatment with simethicone and mebeverin as mono-components does 
not allow to control symptoms of the disease sufficiently and increases the risk for postponed 
abdominal pain and bloating relief. 
As a rescue therapy intake of droteverin in a dose of 80 mg 1-3 times a day will be allowed to 
stop intensive pain episode during one day after the episode. The drug effect is short, persists for 
8-10 hours; the drug is completely eliminated within 72 hours and will not affect the assessment 
of the efficacy of study product. 
3.5.3. Efficacy and safety assessment parameters 
Mebeverine and Simethicone affect two different key symptoms in patients with functional 
diseases of the colon: pain and bloating/flatulence. As the assessed symptoms are interrelated it 
was decided to use a coprimary end point (change of sum of NRS-11 every symptom intensity 
scores) as such approach is widely used in clinical studies in patients with FBD.48   
The study will also evaluate secondary efficacy parameters based on a numerical rating scale 
(NRS-11): the rate and degree of clinical symptoms relief, changes in the quality of life during 
treatment, need for additional antispasmodics. 
Although the previous studies and the long-term use of Mebeverine and Simethicone in clinical 
practice demonstrated a favorable safety profile comparable to that of placebo, the study provides 
a detailed assessment of the product safety, including physical examination, vital signs, laboratory 
blood tests and urinalysis (hematology and clinical chemistry, urinalysis) before and after the study 
treatment. Women of child-bearing potential will undergo a urine pregnancy strip test before the 
study. 


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3.6. Previous experience 
3.6.1. Mebeverine 
3.6.1.1. 
Mechanism of action of mebeverine 
 Mebeverine has a pronounced direct spasmolytic effect on the smooth muscle cells of the 
gastrointestinal tract, reducing spasm without affecting the normal intestinal motility. The exact 
mechanism of action of mebeverine is not clear. However previous studies showed that 
mebeverine reduces the permeability of ion channels, inhibits the reuptake of norepinephrine, has 
a local analgesic effect and changes the absorption of water in the gastrointestinal tract63, 64, 65, 66, 
67, 68, 69, 70, 71,. 
The direct antispasmodic effect of mebeverine on smooth muscle cells is not associated with 
impairment of gastrointestinal motility. The contraction of smooth muscle cells is mediated by an 
increase in intracellular calcium levels. Antispasmodics that act on smooth muscle cells inhibit the 
intracellular calcium currents in smooth muscle cells, blocking sodium channels. According to this 
mechanism of action, mebeverine reduces spasm and affects motility and sensitivity of the 
intestines72. Since the effect of mebeverine is not mediated by the autonomic nervous system, this 
drug does not have typical anticholinergic side effects 73. 
3.6.1.2. 
Clinical studies to evaluate efficacy of mebeverine 
Efficacy and safety of mebeverine used for symptomatic treatment of abdominal pain and 
spasms, dysfunction and discomfort in the intestine associated with FBD, as well as for treatment 
of secondary spasms in the gastrointestinal tract that occur in patients with chronic diseases were 
confirmed in many controlled clinical studies on more than 1500 patients. 
Many patients noted a significant improvement in well-being during the treatment with 
mebeverine; this is clinically significant benefit for patients with pain. Noteworthy, the main data 
on the clinical efficacy of mebeverine was obtained in studies conducted in the 1970s and 1980s, 
when the requirements for the design of clinical studies differed significantly from modern 
requirements and diagnostic criteria for IBD were wider and included symptoms which were 
classified within other FBDs in the last version of Rome criteria. 
Since 1965, in 9 placebo-controlled clinical studies the efficacy of mebeverine hydrochloride 
for treatment of IBS (in line with diagnostic criteria before Rome IV) was evaluated. In 4 of these 
studies 74, 75, 76, 77   100 mg tablets were used: in 1 study75 - in combination with 125 mg tablets), in 
2 studies78, 79  - 50 mg tablets, and in other 2 studies – 135 mg tablets53, 80. In 1 study52  the dose 
and formulation was not reported. In these studies, mebeverine was administered orally; total daily 
dose was up to 810 mg. 
In 8 of 9 these studies, the results were in favor of mebeverine; in 1 study77 no significant 
differences between mebeverine and placebo were noted. 
One placebo-controlled study was conducted with prolonged release capsules 200 mg 81. In this 
12-weeks study, 216 patients received treatment and ITT population was analyzed (106 patients 
received mebeverine, and 110 - placebo). 
In 1994 г. Poynard et al82 preformed meta-analysis of randomized controlled studies with 
antispasmodics for treatment of IBS (in line with diagnostic criteria before Rome IV), including 
mebeverine. This meta-analysis was performed by independent group and was not supported by 
pharmaceutical companies, federal agencies or any grants. Strict criteria were defined for inclusion 
to this meta-analysis: 1) the results are published as scientific articles; 2) randomization clearly 
described; 3) double-blind, placebo-controlled studies; 4) at least 51% patients with IBS included 
in the study; 5) at least 1 clinical endpoint of the following was used: 
• 
Global assessment of symptoms by patient or physician; 
• 
Abdominal pain; 


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• 
Constipation or 
• 
Abdominal distension. 
During the period from 1959 to 1992, a total of 148 clinical studies were found; 26 of them 
met inclusion criteria for this meta-analysis (total 8 drugs). Mebeverine was evaluated in 5 of these 
26 studies74, 76, 77, 80,83.  
Mebeverine significantly improved global symptom score as compared to placebo (odds ratio 
2.04, p<0.01). Mebeverine reduced abdominal pain; this result was not statistically significant due 
to relatively low number of mebeverine studies included to meta-analysis. Beneficial effect of 
mebeverine was similar to that for other antispasmodics. 
After this meta-analysis of Poynard et al in 1994 other meta-analyses were published. These 
studies analyzed placebo-controlled studies in which antispasmodics (including mebeverine) that 
induce smooth muscle relaxation were used for treatment of IBS. In general, mebeverine showed 
good  clinical efficacy and tolerability in patients with IBS. 
A total of 13 studies were conducted for evaluation of efficacy of standard tablets/capsules 
with active comparator. In 7 studies, 135 mg tablets were used, in 5 studies - 100 mg tablets, and 
in 1 study - 135 mg and 200 mg tablets. Treatment duration was from10 days to 12 weeks. In 7 
studies, there were no statistically significant differences between the treatment groups; in 4 
studies, the comparator was more effective, and in 2 studies mebeverine was more effective than 
active comparator55,57. 
In addition, efficacy of mebeverine in film-coated tablets was investigated in 8 non-controlled 
studies. In these studies, more than 1500 patients received therapy with mebeverine hydrochloride. 
Duration of the study treatment was from 15 days to 12 months. Different methods were used for 
assessment of efficacy; the results ranged 41% (no complaints) to 87% (general 
improvement)84,85,86,87,88,89,90,91 ). In 5 studies, mebeverine was administered in 100 mg tablets, in 
2 studies - 135 mg tablets; in the study of Boisson et al, 198791 there is no data on formulation. 
Daiuly dose of mebeverine hydrochloride in these studies ranged from 300 mg/day to 600 mg/day. 
Besides these 8 studies, in one study 92, only safety and tolerability were evaluated, without 
assessment of efficacy. In this study, mebeverine was administered to 7 healthy volunteers at 800 
mg/dose for 4 weeks. Mebeverine was well tolerated; any abnormalities in hematology, 
biochemistry, ECG and electroencephalogram (EEG) was not observed. 
In actively controlled studies, mebeverine, as well as different comparators, improved the 
symptoms, as compared to the baseline level. In most of the studies, improvements were similar 
in mebeverine and control groups. Open-label studies showed therapeutic efficacy of mebeverine 
assessed as clinical improvement from the baseline.  
Ilchenko investigated the efficacy of mebeverine in treatment of functional disorder of Oddi's 
sphincter in 20 patients with gallstone disease who underwent surgical intervention.93 The patients 
have complaints on pain in right hypochondrium, transient bitter taste in the mouth and nausea; 
therefore, the patients initially had pain and dyspepsia. All patients received mebeverine as 
monotherapy at 200 mg 2 times per day during 14 days. Clinical manifestations of disorder of 
Oddi's sphincter were assessed. In addition, the changes in biochemistry results and ultrasound 
examination were evaluated. Analysis of the results showed that treatment with mebeverine leads 
to a reduction in severity of pain or its complete disappearance, as well as a decrease in the 
manifestations of dyspepsia. Normalization of the function of Oddi's sphincter during the treatment 
with mebeverine was confirmed during an ultrasound study by narrowing of the common bile duct. 
Another study conducted by Lipnitsky et al in 200893 showed that the use of mebeverine in a 
dose of 200 mg 2 times a day was effective in the long-term treatment and prevention of 
postcholecystectomy syndrome. The study assessed the clinical manifestations and quality of life, 
as well as the composition of the microflora of the duodenal and large intestine in patients with 
calculous cholecystitis who were subjected to cholecystectomy. The study included 40 patients, of 
whom 20 were patients with acute calculous cholecystitis and 20 patients with chronic calculous 


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cholecystitis. All patients complained of pain of moderate intensity in the right hypochondrium 
that occurred after eating, or manifestations of dyspeptic syndrome (60% of patients), and bowel 
disorders (40% of patients). Half of patients received standard therapy, the other half received 
mebeverine in addition to standard therapy at a dose of 200 mg 2 times a day for 7 days before 
surgery and 3 months after surgery. Analysis of the research results showed that mebeverine is 
effective in the treatment and prevention of postcholecystectomy syndrome and dyspepsia in 100% 
and 95% of cases, respectively. Normalization of motility and evacuation function of the intestine 
were noted in 85% of patients. 
Mayev and co-authors in 200793 studied the efficacy of mebeverine in the treatment of patients 
with chronic non-calculous cholecystitis and primary functional disorders of the biliary tract. 
Patients (n = 191) were divided into three groups depending on the diagnosis: Group 1 - patients 
with non-calculous cholecystitis and functional disorders of the biliary tract; Group 2 - patients 
with a spastic primary functional disorder of the biliary tract; Group 3 - patients with primary 
gallbladder dysfunction (hypokinesia) without chronic non-calculous cholecystitis. 
Efficacy was assessed by the change in pain and manifestations of dyspeptic syndrome 
according to a questionnaire filled out by patients. The use of mebeverine in the complex therapy 
of patients with chronic non-calculosis cholecystitis and primary functional disorders of the biliary 
tract resulted in a more rapid relief of abdominal pain than standard therapy. In almost all studies 
of mebeverine, an improvement in general well-being was observed, as well as a decrease in the 
severity of symptoms, especially abdominal pain. 
It is important to stress that all of the above studies of the efficacy and safety of mebeverine 
were carried out in patients who were diagnosed with IBS in accordance with earlier versions of 
FBD diagnostic criteria and they certainly included patients who may be diagnosed with functional 
diarrhea, functional constipation and functional abdominal bloating by the current criteria of the 
fourth revision. 
After the approval of the fourth edition of the Rome diagnostic criteria, some patients for whom 
mebeverine has been shown to be effective in clinical studies, may theoretically be left without 
symptomatic therapy capable of significantly improving their well-being. In practice, patients with 
functional diarrhea and functional constipation, in addition to stool regulators, receive both 
spasmolytics and simethicone that can improve their general symptoms (primarily pain and 
bloating). Therefore, it is reasonable to conduct a clinical study of a fixed combination of 
Mebeverine+Simethicone involving patient population with functional bowel disorders, suffering 
from abdominal pain and bloating, but already divided into groups of functional bowel disorders, 
according to Rome Criteria IV. 
3.6.1.3. 
Safety of mebeverine  
Mebeverine, when properly administered, has a favorable safety profile. The adverse events 
that occurred during the use of mebeverine in clinical trials do not differ in frequency and nature 
from those in placebo groups. The most frequent adverse events include headache, nausea and 
other gastrointestinal symptoms of mild or moderate severity. Allergic reactions were mainly 
represented by skin reactions. Significant risks associated with the use of mebeverine in clinical 
practice other than allergic reactions were not identified during 50 years (Instruction for medical 
use for Duspatalin®, Appendix 1)  
In 2012, pooled analysis of adverse events was performed for clinical studies conducted in the 
period from 1968 to 201194. In the course of these studies, 1354 patients received mebeverine (353 
patients received mebeverine in studies with placebo control, 286 patients received placebo). In 
these studies, 121 healthy volunteers received mebeverine, and 11 healthy volunteers received 
placebo94  
During the course of the study, no deaths have been reported. Serious adverse events (SAE) 
were reported in 7 patients who received mebeverine and 1 patient who received placebo; all 


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observed SAEs were considered by the Investigator as not related to the study drug. Similar 
proportions (%) of patients discontinued the study drug because of the occurrence of one or more 
AEs: 4.3% (n = 58) in mebeverine group and 3.5% (n = 10) in placebo group. 94 
A total of 474 (35.0%) AEs were reported in 1354 study subjects who received mebeverine; 
61 of these AEs were assessed as related to the study drug (4.5%), while in the placebo group, AEs 
were recorded in 122 of 286 patients (42.7% / 15%); 43 of them were related to the study drug94 
In the largest controlled pivotal study Meb00395 mebeverine was administered in 200 mg 
capsules with prolonged release and film-coated tablets 135 mg. The information on the most 
frequent adverse events that were reported in this study is presented in Table 2 by preferred terms 
 
Table 2 The most frequent (> 3%) adverse events (safety population, study MEB003) 
Adverse event 
Mebeverine 
hydrochloride, 200 mg 
capsules, 2 times per day 
(N=106) 
Mebeverine 
hydrochloride, 135 mg 
tablets, 3 times per day 
(N=107) 
Abdominal pain 
16 (15%) 
10 (9%) 
Diarrhea 
12 (11%) 
4 (4%) 
Headache 
10 (9%) 
7 (7%) 
Vomiting 
7 (7%) 
2 (2%) 
Rhinitis 
6 (6%) 
2 (2%) 
Pain 
6 (6%) 
6 (6%) 
Nausea 
6 (6%) 
9 (8%) 
Constipation 
6 (6%) 
3 (3%) 
Pharyngitis 
4 (4%) 
3 (3%) 
Acne 
3 (3%) 
0 (0%) 
Depression 
3 (3%) 
1 (1%) 
Flatulence 
3 (3%) 
6 (6%) 
Dyspepsia 
3 (3%) 
5 (5%) 
Flu-like syndrome 
3 (3%) 
2 (2%) 
Migraine 
3 (3%) 
3 (3%) 
Bloating 
3 (3%) 
0 (0%) 
Pain in the neck 
1 (1%) 
3 (3%) 
Chest pain 
1 (1%) 
4 (4%) 
Backache 
0 (0%) 
3 (3%) 
 
The data provided in the table suggest that many of the AEs most frequently recorded in this 
study were associated with the gastrointestinal tract system and in fact were the usual symptoms 
of IBS. 


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The occurrence of gastrointestinal abnormalities (mainly abdominal pain, constipation, 
diarrhea and nausea) can be partially explained by the underlying disease, as well as by 
pharmacological action of mebeverine. 
The results of clinical safety studies showed that the safety profile of mebeverine is comparable 
to that of placebo; therefore, mebeverine can be considered to have a favorable safety and 
tolerability profile for symptomatic treatment of IBS when used in accordance with 
recommendations. 
For 50 years of use of mebeverine in clinical practice, any significant risks, except allergic 
reactions, were not identified. These allergic reactions were mainly limited to the skin: urticaria, 
angioedema, facial edema, exanthema, and hypersensitivity, including anaphylactic reactions. The 
frequency of allergic reactions that occur after treatment with mebeverine is impossible to 
estimate, since they have not been registered in clinical studies. Allergic reactions can appear after 
treatment with almost every drug and, therefore, are may not considered an important risk. 
The most frequent adverse drug reactions include Gastrointestinal Disorders (26.3%), Skin and 
Subcutaneous Tissue Disorders (22.0%), General Disorders and Administration Site Conditions 
(20.2%), and also Nervous System Disorders (16.1%) (Meb003)95. 
Often recorded gastrointestinal reactions, as well as numerous symptoms from other system 
organ classes, are considered as not related to mebeverine; these reactions were explained by the 
underlying disease. In IBS, pain syndromes of other origin besides the gastrointestinal tract, such 
as chest and back pain, are also observed. Psychiatric and neurological symptoms were also 
frequently observed in patients with IBS.     
Given the estimated cumulative effects of mebeverine in more than 233 million patients, the 
overall frequency of reported adverse events is very low. 
Thus, mebeverine, when properly administered, has a favorable safety profile.  
3.6.2. Simethicone 
Simethicone is an oral anti-foaming agent with a long history of use in clinical practice and 
diagnostics 96, 97, 98, 99, 100.   
3.6.2.1. 
Mechanism of action of Simethicone 
Simethicone reduces the amount of gas in the intestine. Simethicone has surface activity and 
is able to reduce the surface tension at the liquid / gas interface. This leads to fusion of gas bubbles 
and destruction of the foam. Therefore, released gas can be absorbed or removed naturally due to 
intestinal motility101 (Instruction for medical use for Espumisan®, Appendix 1). 
As suggested by Debray and co-workers over 40 years ago, Simethicone acts as a local barrier 
that protects the mucosa from irritants, such as hydrochloric acid, acetylsalicylic acid or bile salts 
102, 103. Simethicone probably interacts with endogenous surface active substances, protecting the 
intestinal mucosa. The effect of Simethicone is mediated by its action in the intestinal lumen, since 
it is not absorbed and does not have a toxic effect104. 
3.6.2.2. 
Clinical efficacy of Simethicone 
Some modern randomized prospective studies have shown the efficacy of Simethicone in 
patients with traveler's diarrhea 105 and functional dyspepsia 106, 107, 108, 109. In addition, the efficacy 
of the drug in preparation for diagnostic procedures is well known 110, 111, 112, 113, 114, 115, 116, 117, 118, 
119, 120, 121, 122.  
According to the results of randomized, placebo-controlled studies, treatment with probiotics 
and Simethicone reduces the severity of flatulence and abdominal discomfort in patients with IBS 
to whom the diagnosis was made in line with previous versions of Rome criteria 123.  
Anti-foaming effect is the main mechanism of action of Simethicone. As a result, patients who 
received Simethicone prior to the diagnostic procedure showed improved quality of visualization 


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during ultrasound examination of the gastrointestinal tract110, 111,112 and endoscopy 113, 114, 115, 116 
because Simethicone reduces bubbles and foam in the intestinal lumen. Addition of Simethicone 
in intestinal lavage or to laxatives also reduces the foam content in the colon and residual feces; 
this was confirmed by colonoscopy117, 118, 119, 120, 121 and by ultrasound examination of rectum122. 
A literature search revealed 13 comparative studies and 6 double-blind studies that meet 
modern requirements for clinical studies. More than 3,000 patients who received Simethicone in 
various formulations were included in these clinical studies of therapeutic efficacy of Simethicone. 
According to clinical studies, the most relevant to modern requirements, the effect of 
Simethicone in the treatment of patients with functional dyspepsia significantly exceeds the effect 
of placebo, as well as the effect of cisapride, which was used as a comparator drug106, 107, 108, 109. 
Both functional dyspepsia and IBS are characterized by abdominal pain; however, in patients 
with IBS, there is also abnormal defecation pattern. Simethicone is usually prescribed to patients 
with IBS to reduce the feeling of bloating and flatulence124, but there were no adequately 
conducted prospective comparative studies. 
When analyzing the published literature data, only two studies were identified, in which 80 
patients who received Simethicone and 54 patients who received placebo were included. Oswald 
et al. in 1961 published the results of a placebo controlled Simethicone study at a dose of 50 mg 
(tablets); the results showed that Simethicone was more effective than the comparators.125  In 1974, 
Weiss126  published a review and results of Simethicone study in 30 patients, also revealing the 
advantage of Simethicone. In more recent studies, the results of which are discussed below, in the 
section “Clinical studies of Simethicone as part of combination therapy,” the efficacy and safety 
of Simethicone were evaluated in combination with other drugs in patients with IBS. 
Urgesi R et al in 2014 published the results of a double-blind, randomized placebo -controlled 
study, which confirmed the efficacy of the combined use of probiotic and Simethicone. Patients 
were randomized to receive combination therapy with probiotic and Simethicone (n = 26) or 
placebo (n = 26); the duration of treatment was 4 weeks. Efficacy was evaluated at 2 weeks and 4 
weeks from the start of therapy.123. 
Combination therapy with probiotics and Simethicone led to improvement in the main IBS 
symptoms (in line with diagnostic criteria before Rome IV), such as flatulence, abdominal 
discomfort and altered defecation pattern. Noteworthy, significant difference was found between 
the test group and placebo in the degree of reduction of flatulence and abdominal discomfort. The 
severity of abdominal pain statistically significantly decreased in the combination therapy group 
as compared to the baseline. More powerful clinical studies are need to identify the differences 
between the treatment groups in the degree of abdominal pain reduction. 
Many patients with acute diarrhea, regardless of the cause, also complain on increased gas 
formation, cramps, abdominal pain, bloating, abdominal distension, flatulence, nausea and 
vomiting. In a double-blind placebo-controlled study, Kaplan et al compared the efficacy and 
safety of loperamide hydrochloride and Simethicone with Simethicone monotherapy, loperamide 
monotherapy and placebo in patients with acute diarrhea with abdominal discomfort caused by gas 
formation.105 The duration of therapy was 48 hours. The study included 493 patients. 124 patients 
were randomized to the combination therapy group (loperamide 2 mg and Simethicone 125 mg), 
123 patients were randomized loperamide 2 mg, 123 patients received Simethicone 125 mg, and 
123 patients received placebo. After randomization, these patients received 2 tablets of the study 
drug, then patients took one tablet of the prescribed drug after each episode of liquid stool, up to 
4 tablets for 24 hours.  
The primary end points were the time until the last liquid stool and the time until resolution of 
abdominal discomfort disappeared. An analysis of the results revealed that patients who received 
the combined treatment with loperamide and Simethicone have significantly (P <0.001) shorter 
time to the last liquid stool and abdominal discomfort disappears more quickly in comparison with 
both monotherapy group and the placebo group. Simethicone in monotherapy was significantly (P 
<0.01) more effective than placebo in alleviating general symptoms, alleviating diarrhea, 


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abdominal discomfort, reducing the number of bowel movements with a liquid stool over a period 
of 36-48 hours. 
In 2007, Hanauer et al published the results of a multicenter, double-blind study in patients 
with acute diarrhea127. The patients were randomized to receive two tablets, each contained either 
loperamide 2 mg and Simethicone 125 mg (n = 121), or loperamide 2 mg (n = 120), or Simethicone 
125 mg (n = 123), or placebo (n = 121). The duration of therapy was 48 hours. As well, as in the 
study of Kaplan105, the median time to the last liquid stool for group that received the combination 
therapy was significantly less than for loperamide, Simethicone and placebo groups (7.6 h, 11.5 h, 
26.0 h and 29.4 h, respectively, p <0.0232). The time to complete resolution of discomfort was 
lower in the combination therapy group as compared to the monotherapy and placebo groups (all 
p = 0.0001). 
Thus, co-administration of Simethicone and loperamide led to a more rapid resolution of acute 
nonspecific diarrhea and associated discomfort (abdominal pain, spasms, flatulence) in 
comparison with each drug as monotherapy or placebo; superiority of Simethicone monotherapy 
over placebo was also demonstrated105.  
Tolerability of the study treatment was good; none of the patients required rescue therapy.  
Thus, a number of modern randomized prospective studies have shown efficacy of Simethicone 
in patients with traveler's diarrhea, functional dyspepsia. In additional, the efficacy of treatment 
with Simethicone during preparation to diagnostic procedures is well known.  
According to randomized placebo controlled studies, therapy with a probiotic with 
Simethicone reduces the severity of flatulence and abdominal discomfort in patients with IBS (in 
line with diagnostic criteria before Rome IV).  
3.6.2.3. 
Safety of Simethicone 
Simethicone is usually well tolerated and has a favorable safety profile. No causal association 
of Simethicone with adverse events was found in published clinical studies. No systematic 
laboratory abnormalities, as well as laboratory abnormalities associated with Simethicone, have 
also been identified according to published data. 
In 2007, Rémy Meier and Michael Steuerwald published a review of clinical studies with 
Simethicone and noted that the comparison of Simethicone with placebo, cisapride, loperamide, 
combination of loperamide with Simethicone, in terms of incidence of adverse events, serious 
adverse events and early withdrawals due to adverse events was in favor of Simethicone.40 No 
causal relation of Simethicone with adverse events was found in published data from clinical 
studies. Systematic laboratory abnormalities, as well as laboratory abnormalities associated with 
Simethicone, were also not detected according to published data. 
According to Espumisan Instruction for use (Simethicone is the active substance), no adverse 
effects have been reported after treatment with this drug; some allergic reaction to the excipients 
drug may be expected. There is low likelihood of overdose with Simethicone. In a safety study 
conducted by Nair et al. In 2003, healthy volunteers received Simethicone at a dose of 30 grams 
per day for several days without developing adverse events and without laboratory abnormalities 
in biochemical parameters104. 
3.7. Combined use of antispasmodics and Simethicone 
In patients with FBD, a smooth muscle spasm of the gastrointestinal tract has an important role 
in the development of a pain symptoms.Error! Bookmark not defined. Antispasmodics are included in 
recommendations for the treatment of IBS as first-line line for the last decades 1, 35,36  
Simethicone is not currently included in recommendations for treatment of patients with IBS 
due to insufficient data from clinical studies. However, the results described above suggest that 
addition of Simethicone to the main therapy would be effective and would bring relief to a 
significant proportion of patients with FBD, because almost all of these patients suffer from 
flatulence.  


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Combined treatment with antispasmodic alverine and simethicone has lead to decrease in 
pain/discomfort intensity in patients with IBS, 39, 128 and also has lead to improvement in quality 
of life. It is important to note that in one study39 in which the majority of patients took 
antispasmodics, addition of simethicone to alverine resulted in additional statistically significant 
improvement in quality of life and reducing symptoms such as abdominal pain and 
bloating/flatulence. 
 
In 2011, Wittmann et al. published the results of a double-blind, randomized placebo-
controlled study of the efficacy and safety of the combined use of myotropic antispasmodic 
alverine and Simethicone in patients with IBS (in line with diagnostic criteria before Rome IV.39  
In this study, the patients with IBS (according to the Rome Criteria, revision III) were 
randomized to receive alverine citrate in combination with Simethicone or placebo. The treatment 
lasted 4 weeks. The primary endpoint was abdominal pain / discomfort intensity, assessed using 
Visual-Analogue Scale (VAS) after 4 weeks of therapy. In addition, the number of responders in 
both groups was compared. The response to treatment was defined as decrease in the number of 
points in the assessment of pain / discomfort on the VAS scale by 50% or more after 4 weeks of 
treatment. In the study, 207 patients were randomized to the combination therapy group and 205 
patients to the placebo group. 399 (97%) patients completed the study. The results showed that the 
intensity of abdominal pain / discomfort after 4 weeks of therapy was significantly lower in the 
combination therapy group compared to the placebo group (median 40 mm versus 50 mm in the 
combination therapy and placebo groups, respectively, p = 0.047). In addition, the response rate 
to the treatment was also significantly higher in the combination therapy group compared to the 
placebo group (46.8% compared to 34.3%, OR = 1.3; p = 0.01). The patients who received the 
combined therapy significantly improved the general medical condition in comparison with 
patients from the placebo group.  
The results on reduction in pain/discomfort after treatment with alverine and Simethicone 
showed that recovery rate was equal to 8; this is slightly less than the values obtained in previous 
studies for smooth muscles relaxants44 In addition, an improvement in overall well-being was 
noted; it was significantly more pronounced in the combination therapy group as compared to the 
placebo group. The effect of combination therapy on abdominal distension was not evaluated. 
Since there is no data on the comparative efficacy of combination therapy, alverine and 
Simethicone in monotherapy, it is difficult to determine which component contributes mote to 
observed the therapeutic effect of the combination. 
Thus, the use of antispasmodic combination therapy with alverine and Simethicone was 
effective in reducing the pain / discomfort in patients with IBS. 
Ducrotte et al conducted a long (6 months of therapy) double-blind randomized study that 
compared the efficacy and safety of episodic use of combination therapy with alverine and 
Simethicone when a pain attack occurred and the standard therapy chosen by the attending doctor 
for each patient128. Patients in the combination therapy group (n = 222) were instructed to take a 
capsule with a combined preparation 3 times a day before meals if a pain attack occurs and until 
it resolves. In the control group (n = 214), the doctor chose the tactics of treatment, it was forbidden 
only to prescribe the combination therapy with alverine and Simethicone. 
The primary endpoint in the study was the difference between groups in the change in the 
number of points on the questionnaire of quality of life from the initial to the end of therapy after 
6 months. 
Initially, the results of assessment of quality of life on a scale were comparable in both groups. 
Median dosing frequency in the combination therapy group was 75% days per month during the 
first month, 54% days per month for 2-3 months, and 45% days per month for 4-6 months. In the 
standard treatment group, 93.8% patients received at least one antispasmodic.  


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The improvement in the quality of life after assessing by Quality of Life scale during 6 months 
of therapy was significantly more pronounced in the combination therapy group (13.8 versus 8.4 
with a difference between 5.4 groups (95% CI: 2.3 - 8, 6; p = 0.0008. The percentage of 
improvement was also greater in the combined treatment group (28.5% compared to the 
conventional treatment group 18.6%; p = 0.04). According to the VAS score, abdominal pain 
decreased by 76.1% in the combination therapy group and by 59.2% in the conventional therapy 
group (p = 0.0001). In patients suffering from flatulence when included in the study, the severity 
of symptoms in the combination therapy group decreased by 76.6% compared with 57% in the 
standard therapy group (p <0.0001). 
Thus, the occasional use of combination therapy with alverine and Simethicone led to an 
improvement in the quality of life of patients with IBS (in line with diagnostic criteria before Rome 
IV), as well as to a reduction in the severity of symptoms, such as abdominal pain and flatulence, 
in comparison with standard therapy. In the comparison group, the vast majority of patients were 
treated with antispasmodics. Thus, addition of Simethicone to antispasmodics provides significant 
clinical advantage, improving the quality of life and reducing the severity of symptoms typical for 
FBD. 
3.7.1. Conclusion on the combined use of antispasmodics and Simethicone 
The use of antispasmodic combination therapy with altering and Simethicone led to a decrease 
in pain / discomfort in patients with IBS (in line with diagnostic criteria before Rome IV), as well 
as to an improvement in the quality of life of patients. Noteworthy, in one of the studies. in which 
the vast majority of patients received antispasmodics in the control group, addition of Simethicone 
to altering provided statistically significant advantage in improving the quality of life and reducing 
the severity of symptoms such as abdominal pain and flatulence. 
Thus, addition of Simethicone to antispasmodics provides a clinically significant advantage, 
improving the quality of life and reducing the severity of main symptoms of FBD. 
3.7.2. Approved combinations of Simethicone and antispasmodics 
Fixed-dose combination, Meteospasmil, which includes altering 60 mg and Simethicone 300 
mg, was approved in 1990 in Europe. The same combination of drugs was approved in the Russian 
Federation in 2007 (Meteospasmil). Meteospasmil is indicated for the treatment of functional 
disorders of the gastrointestinal tract, manifested by abdominal pain, increased gas formation, 
belching, nausea, constipation, diarrhea, or their alternation, as well as for preparation to X-ray, 
ultrasound or instrumental examination of the abdominal organs. 
3.8. Fixed-dose combination Mebeverine+Simethicone 
Fixed-dose combination Mebeverine + Simethicone, film-coated tablets 135 mg + 80 mg, is a 
new drug that contains mebeverine and Simethicone in one tablet. Currently, the drug has been 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  


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3.8.1. Risk/benefit ratio 
The study is aimed at the evaluation of comparative efficacy and safety of the fixed-dose 
combination of Mebeverine + Simethicone film-coated tablets 135mg + 80mg versus Duspatalin® 
film-coated tablets 135mg and Espumisan®, 40mg capsules (2 capsules). The study will include 
patients with functional diseases of the colon with abdominal pain and bloating/flatulence. 
Pain in patients with functional diseases of the colon is due to the spasm of intestine smooth 
muscles and excessive formation of gas. Spasmolytics being used for the decades are currently 
included into IBS treatment guideline as the first-line therapy. In accordance with the Clinical 
Guideline of Russian Association of Gastroenterology and Russian Association of Coloproctology 
on the diagnosis and treatment of irritable bowel syndrome, pain relief in IBS patients can be 
achieved with the use of various types of spasmolytics, i.e. blockers of M-cholinergic receptors, 
sodium and calcium channel blockers (Clinical Guideline of Russian Association of 
Gastroenterology, 2014). According to the IBS Treatment Guideline of the World 
Gastroenterology Association, the first-line therapy of this disease also includes spasmolytics, 
such as mebeverine, otilonium, hyoscine, cimetropium, pinaverium, and dicyclomine 
Simethicone is not included into IBS treatment guidelines due to the absence of sufficient 
clinical data, although it is suggested that its addition to the basic therapy would be effective and 
alleviating in many patients, as far as almost all of FBD patients experience flatulence according 
to the data published. Many authors emphasize a strong negative effect of flatulence in the 
compromised well-being of FBD patients, because this symptom changes the intensity: it is the 
most prominent during the daytime, worsens after meal and generally abates at night21,37,38. 
Simethicone, as an antifoaming agent, helps to reduce flatulence, discomfort and abdominal pain 
due to the improved gas evacuation from the GI tract39,40. 
The contribution of each component will be proven in a clinical study by studying co primary 
endpoint that will provide data on the pharmacodynamic effects of the components, as well as by 
studying the relevant secondary endpoints. 


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The risk associated with the use of Mebeverine in clinical studies is considered low, 
comparable to placebo, and is mostly limited to rare anaphylactic reactions, mainly, but not 
exclusively, limited to the skin, such as urticaria, angioedema, facial edema, exanthema, and 
hypersensitivity, including anaphylactic reactions. The frequency of anaphylactic reactions due to 
mebeverine cannot be assessed, because no such reactions were reported in the clinical studies. 
Anaphylactic reactions may be caused by any drug and are not considered an important risk during 
its use. 
Data of clinical safety studies show the comparability of safety profile of mebeverine to 
placebo, therefore, mebeverine can be considered to possess a favourable safety and tolerability 
profile for symptomatic treatment of FBD if used in accordance with the therapeutic guidelines. 
The most common post-marketing adverse reactions were the gastrointestinal tract disorders 
(26.3%), skin and subcutaneous tissues disorders (22.0%), general disorders and injection site 
conditions (20.2%), as well as the nervous system disorders (16.1%).92 
Common GIT reactions and multiple symptoms from other system and organ classes are not 
considered related to mebeverine and considered to be generally due to the underlying disease. 
IBS is often accompanied with other pain syndromes, besides gastrointestinal ones, such as back 
pain and chest pain.  Moreover, IBS is frequently associated with psychiatric and neurological 
symptoms. 
Therefore, if properly used, mebeverine generally demonstrates a favourable benefit-to-risk 
ratio. 
The risk associated with the use of Simethicone is extremely low. The drug is not absorbed in 
the gastrointestinal tract, has a local effect, and is eliminated unchanged. In the published clinical 
studies data, a causal relation of adverse events to Simethicone has not been identified. According 
to the published data, no systemic laboratory abnormalities or laboratory abnormalities related to 
Simethicone have been observed. 
According to the prescribing information for Espumisan® (simethicone), no adverse drug 
reactions have been reported; allergic reactions to the drug excepients are possible. 
Risks associated with rescue medication drotaverin is also low. 
The instruction on medical application for the No-spa® (drotaverin) is applied in Appendix 1. 
Drotaverine is an antispasmodic drug which is a phosphodiesterase IV inhibitor, it increases the 
cyclic adenosine monophosphate, inactivates the kinase of light myosin chain which leads to 
smooth muscles relaxation. Its effect is shown within 45-60 minutes and lasts for 8-10 hours. The 
product will be allowed only as a rescue therapy to relief intensive pain episode in a dose of 80 
mg 1 - 3 times a day during one day after the episode. 
Contraindications to drotaverine intake are hypersensitivity, severe renal failure, severe hepatic 
failure, severe heart failure, hereditary galactose or fructose intolerance, total lactase deficiency, 
sucrase-isomaltose insufficiency, glucose-galactose malabsorption syndrome. 
The side effects of drotaverin are rare, among them are: head ache, dizziness, insomnia, 
palpitation, hypotension, nausea, constipation, allergic reactions. 
3.8.2. Clinical program for fixed dose combination Mebeverine+Simethicone 
development 
The clinical program for the development of a fixed-dose combination of Mebeverine + 
Simethicone film-coated tablets 135 mg + 80 mg consists of a study of the pharmacokinetics and 
comparative bioavailability in healthy volunteers that confirmed the bioequivalence of the fixed-
dose combination versus Duspatalin®, and a study of the efficacy and safety in patients with 


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functional bowel disorders followed by intestinal pain and bloating. The parallel three-group study 
of efficacy and safety is planned to compare, according to the EAEU Guidelines for the 
Development of Fixed-Dose Combinations, the reduction in abdominal pain and bloating, as well 
as the rate of adverse events, during treatment the fixed-dose combination of Mebeverine + 
Simethicone versus Duspatalin® and Espumisan® as a monotherapy. 


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4. SELECTION OF STUDY POPULATION 
4.1. Study population 
465 patients with functional bowel disorders with abdominal pain and bloating/flatulence 
from 18 to 75 years old will be randomized into the study. 665 patients will be screened 
(approximately 30% screen failure rate).  
Patients will be randomized into three groups at the ration 1:1:1 (155 in every group):  
• Mebeverine + Simethicone, film coated tablets, 135 mg + 80 mg, one tablets 3 times a 
day during 4 weeks; 
• Duspatalin® film coated tablets, 135 mg, one tablets 3 times a day during 4 weeks; 
• Espumisan® capsules 40 mg, 2 capsules 3 times a day during 4 weeks. 
4.2. Inclusion criteria 
Patients should corresponds to all inclusion criteria listed below: 
1. Signed Informed Consent Form; 
2. Males and females aged 18 to 75 years old (inclusive);  
3. Abdominal pain and bloating/flatulence due to functional bowel disorder (including IBS, 
chronic functional constipation, chronic functional diarrhea or functional abdominal 
bloating); 
4. Episodes of abdominal pain for at least 3 months, with a frequency of at least 3 times a 
month; 
5. Abdominal pain intensity of 4 to 9 points (inclusive)  when assessed on the NRS-11 scale 
(i.e. weekly average, with daily recording of the worst pain for the last 24 hours during last 
week of Screening and Run-in period);  
6. Bloating/flatulence intensity of of  4 to 9 points (inclusive)  when assessed on the NRS-11 
scale (i.e. weekly average, with daily recording of the worst bloating episode for the last 
24 hours during last week of Screening and Run-in period); 
7. Patients' consent to use adequate contraception methods throughout the study. Adequate 
contraception methods include:  
a. oral contraceptives or contraceptive patches,  
b. condom or diaphragm (barrier method) with spermicide, or  
c. an intrauterine device 
4.3. Exclusion criteria 
Patients will be not eligible for participation in this study if he/she will meet at least one of the 
criteria described below: 
1. Hypersensitivity to mebeverine, simethicone, drotaverin, excipients of the studied 
products, or contraindications; 
2. Intake of tricyclic antidepressants, eluxadoline, linaclotide, selective serotonin re-uptake 
inhibitors, rifaximin, lubriprostone within the last week before screening; 
3. New prescription or any change in probiotic drug therapy (including change in the drug or 
dosage regimen) during the last month before screening; 
4. History of intestinal obstruction, stricture, toxic megacolon, GI (gastro-intestinal) 


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perforation, fecal impaction, gastric banding, bariatric surgery, adhesions, ischemic colitis, 
or impaired intestinal circulation (e.g. aorto-iliac disease); 
5. History of major gastric, hepatic, pancreatic or intestinal surgery (appendectomy, 
hemorrhoidectomy, or polypectomy allowed as long as occurred > 3 months prior to trial 
screening; uncomplicated laparoscopic or open cholecystectomy is allowed if no history 
of post-operative biliary tract pain and surgery occurred > 3 months prior to screening); 
6. Significant and progressive enlargement of the liver, spleen, lymph nodes; ascites; 
palpable tumor formation in the abdominal cavity / pelvis according to physical 
examination, hepatic cirrhosis; 
7. Significant concomitant acute or chronic disease (cardiovascular, gastrointestinal, 
endocrine, immunological, metabolic, bronchopulmonary, urinary system) or any 
condition that, according to Investigator, is a contraindication for the patient to participate 
in the study if interference with the study performance; 
8. Any inflammatory bowel disease (Crohn’s disease, ulcerative colitis, any infection 
including bacterial, viral, protozoa, helminthosis); 
9. Elevated fecal calprotectin level 1 month before or at screening which indicates the 
presence of inflammatory GIT disease; 
10. Unexplained GI bleeding within 3 months prior to screening; 
11. Confirmed diagnosis of bile acids malabsorption; 
12. History of any malignant disease except basal cell carcinoma of skin and vesical cervix 
carcinoma in situ which were cured ≥ 5 years ago;  
13. Confirmed diagnosis of celiac disease; 
14. Confirmed hereditary galactose or fructose intolerance , total lactase deficiency, sucrase-
isomaltose insufficiency, glucose-galactose malabsorption syndrome; 
15. Diet changes (e.g, switching to fermented foods, a gluten-free diet) within the 1 months 
prior to screening; 
16. Planned elective surgery during the study; 
17. Pancreatic exocrine insufficiency or acute pancreatitis; 
18. Endometriosis in women; 
19. Positive results of tests for HIV, hepatitis B or C, at the moment of screening; 
20. Drugs or alcohol abuse at screening or in the past, which, in the Investigator's opinion, 
makes the patient not eligible for participation in the study; 
21. Participation in another clinical study or another study drug administration within 30 days 
prior to screening; 
22. Pregnant or lactating women, or women planning to get pregnant during the clinical study; 
women of child-bearing potential (including those without history of surgical sterilization 
and women with <2 years post-menopause) not using adequate contraception methods; 
23. Inability to read or right; unwillingness to understand and comply with Protocol 
procedures; non-compliance with medication dosing regimen or procedures which, in the 
Investigator’s opinion, may affect study results or the patient’s safety and prevent the 
patient’s participation in the study; any other concomitant diseases or severe mental 
disorders, which make the patient ineligible for study participation, limit the legal basis 
for Informed Consent procedure, or may affect the patient’s ability to participate in the 
study. 


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4.4. Exclusion of patients from the study after randomization  
The patient can withdraw the consent any time without any explanations. In the event of 
significant deviations, which, according to the Investigator, could impede the patient’s 
participation in the study or interpretation of effectiveness or safety parameters, the patient should 
be excluded from the study. Criteria for early exclusion of patients from the study are provided in 
section 6.14 
4.5. Re-tests and re-screening 
In case of obtaining uncertain of doubtful results of laboratory testing during the screening 
examination repeated testing (re-test) may be conducted once in agreement with the Sponsor or its 
authorized representative 
The patients, who do not meet the inclusion/exclusion criteria due to manageable medical 
condition, can pass repeated Screening Visit after agreement from the Sponsor or his representative 
(re-screening). In this case, all screening procedures will be repeated, including the procedure for 
obtaining informed consent and assigning a new identification number. 


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5. STUDY DRUG 
5.1. Description of the investigated drugs 
5.1.1. Fixed-dose combination Mebeverine + Simethicone 
Study drug: 
Mebeverine + Simethicone, film-coated tablets, 135 mg + 80 mg  
Active substances: 
Mebeverine hydrochloride and Simethicone 
Pharmacological group 
Analgesics and antispasmodics. ATC code: A03AX (or A03E) 
Composition: 
Active substances: Mebeverine hydrochloride 135.00 mg and Simethicone 
EP-100%  84.43 mg, corresponding to  polydimethylsiloxane 80.00 mg 
 
 
 
 
 
 
  
Daily dose and dosing regimen: 
Orally 1 tablet 3 times a day before meal 
Package description: 
100 tablets (10 tablets in 10 Blisters PVC/PE/PVDC/Alu) 
Storage conditions 
In a light-protected place at a temperature not above 25°C. Keep out 
of the reach of children. 
Manufacturer: 
 
 
 
 
5.1.2. Duspatalin ® 
Study drug: 
Duspatalin® coated tablets 135 mg 
Active substance: 
Mebeverine hydrochloride 
Pharmacological group 
Antispasmodics. ATC code: А03АА04 
Composition: 
Coated tablets  
Active substance: Mebeverine hydrochloride 135,0 mg 
 
 
 
 
 
 
 
 
 
 
Daily dose and dosing regimen: 
Orally 1 tablet 135 mg three times a day before meals 
Package description: 
10 tablets in a blister from PVC / aluminum foil. 1 or 5 blisters in a carton 
pack with package insert. 
 
Storage conditions 
Store at a temperature not higher than 30˚С. Keep out of the reach of 
children. 
Manufacturer: 
Mylan Laboratories SAS, France 
5.1.3. Espumisan® 
Study drug: 
Espumisan®, 40 mg capsules 
Active substance: 
Simethicone  


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Pharmacological group 
Carminative ATH code: A03AH13 
Composition: 
40 mg capsules 
Active substance: Simethicone 40,0 mg 
 
 
Daily dose and dosing regimen: 
Orally 2 capsules 3  times a day after or before meal 
Package description: 
25 capsules in a PVC / aluminum foil blister. 
1, 2 and 4 blisters in a carton pack with Package Insert 
Storage conditions: 
Store at a temperature not higher than 30˚С. Keep out of the reach of children. 
Manufacturer: 
 
5.2. Administration of the study drug and randomization  
At the visit 2 Week 0, Day 1, all eligible patients will be randomized into three equal groups 
(1:1:1): 
• Mebeverine+Simethicone, 135 mg+80 mg, three times a day during 4 weeks  
• Duspatalin® 135 mg three times a day during 4 weeks 
• Espumisan®, 80 mg three times a day during 4 weeks 
Patients will take the study drugs during 4 weeks: Mebeverine+Simethicone  1 tablet three 
times a day before meal, Duspatali® 1 tablet three times a day before meal, Espumisan ® 2 
capsules 3 times a day after or before meal.  
The last dose has to be taken at the evening before the Visit 3 (Week 4, Day 29).  
The patients will register the study drug administration in the diary.  
5.3. Compliance of the therapy conduction  
The patient should take the first study drug dose at the Visit 2 day (Week 0). During telephone 
contact (TC 1, Week 2, Day 0), the Investigator checks the patient’s treatment compliance and 
whether he/she follows the recommendations on the Patient’s Diary filling, and, if necessary, 
conducts an additional conversation with the patient about the proper drug administration and 
filling out the Patient’s Diary. At Visit 3 (Week 4, Day 29), the patient should return all used and 
unused study drug packagings. The Investigator will check compliance with the recommendations 
for study drug self-administration at Visit 3 (Week 4, Day 29) based on the results of accounting 
for the returned study drug and the patient’s diary.  
The study drug compliance will be calculated at Visit 3 using the formula:  
Compliance = (N dispensed. – N returned.) / N calc. х 100% 
where N dispensed. = number of tablets/capsules dispensed, N returned. = number of 
tablets/capsules returned, N calc. = estimated number of tablets/capsules the volunteer was to 
receive since the previous visit.  
The compliance should be within the interval from 80% to 120%. 
 


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5.4. Packing and labeling of the study drugs 
The study drug will be packed and marked in accordance with current law and applicable 
regulatory requirements, in particular, Federal Law # 61-FZ On Circulation of Pharmaceutical 
products" dd. April, 12 2010. 
Label of investigational product is below: 
Label of blister (Label 5829-L01) 
 
 
 
Protocol no. MESI3001                             
 
 
 
 
 
 
Kit number: XXXXXX 
Packaging batch number: 5829-BB 
Tablet batch number: zzzzz    
Contents: 10 film-coated tablets Mebeverine+Simethicone, 135 mg+80 mg 
Sponsor: Abbott Product Operations AG 
 
 
 
 
Label of secondary pack (Label 5829-L02) 
 
 
 
 
 
 
 
 
 
 
 
FOR CLINICAL TRIAL USE ONLY                                                            
Protocol no. MESI3001                             
 
Kit number: XXXXXX 
 
Instructions for use and route of administration: oral use, 1 tablet 3 times a day, before meal 
 
Packaging batch number: 
 
Tablet batch number: zzzzz 
Not to be used after: MM/YYYY 
Contents:100 tablets (10 blisters with 10 tablets Mebeverine+Simethicone, 135 mg+80 mg each) 
Storage conditions: store in a light-protected place at a temperature not above 25°C 
 
Sponsor: Abbott Product Operations AG 
CRO: 
  
 
 
KEEP OUT OF THE REACH AND SIGHT OF CHILDREN 
 
For registered medication Duspatalin® in standard trade package and standard label additional 
label will be applied: 


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Label of blister (Label 5829-L03) 
 
 
 
Protocol no. MESI3001                             
 
 
 
 
 
 
Kit number: XXXXXX 
Packaging batch number: 
    
Contents: 10 tablets Duspatalin® 135 mg 
Abbott Product Operations AG 
 
 
 
 
 
Label of secondary pack (Label 5829-L04) 
 
 
 
 
 
 
 
 
 
 
 
FOR CLINICAL TRIAL USE ONLY                                                            
Protocol no. MESI3001                             
 
Kit number: XXXXXX 
 
Instructions for use and route of administration: oral use, 1 tablet 3 times a day, before meal 
 
Packaging batch number: 
 
Not to be used after: MM/YYYY 
Contents: 5 blisters with 10 tablets Duspatalin® 135 mg  
Storage conditions: at a temperature below 30˚С 
 
Abbott Product Operations AG 
CRO: 
  
 
 
KEEP OUT OF THE REACH AND SIGHT OF CHILDREN 
 
For registered medication Espumizan® in standard trade package and standard label 
additional label will be applied: 
Label of blister (Label 5829-L05)  
(simple white label) 
 
 
 
Protocol no. MESI3001                             
 
 
 
 
 
 
Kit number: XXXXXX 
Packaging batch number: 
    
Contents: 25 capsules Espumisan® 40 mg 
Abbott Product Operations AG 


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Label of secondary pack (Label 5829-L06) 
 
(simple white label) 
 
 
 
 
 
 
 
 
 
 
 
FOR CLINICAL TRIAL USE ONLY                                                            
Protocol no. MESI3001                             
 
Kit number: XXXXXX 
 
Instructions for use and route of administration: oral use, 2 capsules 3 times a day, after or before meal 
 
Packaging batch number:
 
Not to be used after: MM/YYYY 
Contents: 1 blister with 25 capsules Espumisan® 40 mg 
Storage conditions: store at a temperature below 30˚С  
 
Abbott Product Operations AG 
CRO: 
  
 
KEEP OUT OF THE REACH AND SIGHT OF CHILDREN 
 
5.5. Accounting of the study drug 
The Investigator will be responsible for proper accounting registration of the study drugs to 
provide their proper receiving, storage, distribution and return. The patients will be instructed to 
return all, both used and unused, packages of the study drugs to the investigational site at Visit 3. 
The returned materials will be checked, assessed the patient’s compliance. In case the patient loses 
the study drug package, an appropriate note should be written in the source documentation and in 
the study drugs accountability log. 
Upon completion of the study, all remaining study medications (Mebeverine+Simethicone, 
Duspatalin®, Espumisan®) should be returned to the local depot and destroyed. 
5.6. Study drug storage in the study site 
The Investigator will be responsible for the storage of the study drug in the study site 
throughout the entire period of the study. Restricted access and adequate temperature should be 
provided. Temperature monitoring should be carried out using thermometers, recording the 
minimum and maximum temperature during the reporting period. The temperature monitoring data 
should be recorded in the temperature registration log on a regularly basis. Upon the end of the 
study and the final calculation, the study drug Mebeverine+Simethicone is to be returned to the 
Sponsor or representatives. 
5.7. Concomitant Medication 
All the study drugs and concomitant medication including food supplements should be 
registered in the patient’s source documentation and in the electronic Case Report Form (eCRF). 
The Concomitant Medication also include allowed by the protocol rescue therapy applied to relief 
intensive pain episodes - drotaverin in a dose of 80 mg 1 - 3 times a day during one day after the 


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episode. This includes all medicinal products and food supplements that are not study medication 
taken by patients at any time during the clinical study. The patient’s source documentation and 
eCRF should contain the name (generic name of the active substance is preferable), dose, intake 
frequency, route of administration, indications for use (including the underlying disease, 
associated disease, adverse drug event or preventative treatment), date of the beginning and 
completion of a corresponding drug administration. Upon the study completion, the concomitant 
medication continues, a corresponding mark should be entered in the CRF 
5.8. Prohibited medications 
While taking part in the study, the patients are prohibited to take other study drugs, as well as 
medicines of the following groups: 
• Antibacterial therapy; 
• Systemic glucocorticosteroids; 
• Treatment for HIV, hepatitis B or C; 
• Treatment for HIV, hepatitis B or C; 
• Eluxadoline; 
• Linaclotid; 
• Selective serotonin re-uptake inhibitors; 
• Rifaximin; 
• Lubriprostone; 
• Antispasmodic therapy (including herbal, but excluding drotaverin to relief intensive pain 
episode in a dose of 80 mg 1 - 3 times a day during one day after the episode); 
• other drugs, herbal or supplements to eliminate intestinal pain and bloating/flatulence, 
except for those provided by the study protocol; 
• Any change in the dietary advise and probiotic drugs therapy (including the drug and 
dosage regimen). 
Drotaverine hydrochloride will be allowed for intensive abdominal pain. Drotaverine 
administration should be recorder in the patient's diary (including a dosage). 
5.9. Restrictions on the patient’s diet and physical activity 
Patients should maintain a pre-study food intake regimen and diet. There are no special 
restrictions on the  physical activity. 
Throughout the entire period of study the patient should use adequate contraceptive methods. 
Adequate contraceptive methods include:  
o Oral contraceptives or contraceptive patches or 
o Condoms or diaphragms (barrier method) together with a spermicide or 
o Intrauterine devices. 
6. DESCRIPTION OF THE PROCEDURES 
All the study procedures will be conducted in accordance with the requirements of 
International Conference on Harmonization Good Clinical Practice Guideline (ICH GCP(E6)) and 
Eurasian Economic Union (EEU), principles provided in Helsinki Declaration, as well as in 
accordance with the applicable legislation and regulations of the Russian Federation. The 
Investigator should agree to monitoring, audits and inspections in the study site and provide direct 


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access to the study for the Sponsor and representatives thereof, Independent Ethics Committee and 
regulatory authorities. 
6.1. Informed consent 
Written Informed consent will be obtained during the screening before any procedures related 
to the study are performed. 
6.2. Patient Registration  
Each patient, who has signed the Patient Information Form and the informed consent form, 
will be assigned an individual registration number, which consists of five digits: 
-
 
the first two digits indicate the number of the site, the other three refer to the sequence number of 
the patient in this site (001, 002, 003…010 etc.). The Investigator will be provided the instructions 
on the registration of patients prior to the study. 
6.3.  Demographic data and medical history  
To assess the eligibility/ non-eligibility of patients, demographic data (gender, age, race) and 
a complete medical history, including significant acute and chronic diseases and conditions (i.e. 
menopause), surgical procedures and allergic reactions should be collected. It is also necessary to 
ask the patient about any hospitalizations/surgical interventions scheduled for the period of study 
(if applicable). All new diagnoses and conditions identified in the screening should be included in 
the patient’s medical history. 
6.4. Physical examination 
Physical examination includes an assessment of general appearance, condition of the skin and 
mucous membranes, neck (including the thyroid gland), eyes, ears, nasopharynx, lungs, heart, 
abdomen, back, lymph nodes and neurologic status 
Any relevant findings from physical examination are to be recorded on the Medical History 
form in the eCRF (for findings from the screening evaluation that occurred prior to allocation to 
treatment). Any change versus baseline evaluation data considered to be an AE, should be 
registered appropriately in the eCRF and source documents. 
6.5.  Vital signs, height and weight 
This examination includes measurement of body temperature in the armpit, blood pressure in 
a sitting position, heart rate and respiration rate. Assessment of vital signs will be performed after 
10 minutes of rest. 
Weight and height of volunteer are measured without shoes. Height are measured only at 
Screening. Index body weight (BMI) is calculated according to the formula: 
BMI = weight / height2 (kg / m2). 
Changes in the vital signs regarding the data of the initial examination, regarded as AEs, 
should be recorded accordingly in the primary documentation and in CRFs. 
6.6. Electrocardiography 
Electrocardiography (ECG) in 12 leads will be performed in a supine position. The Investigator 
will examine ECG records, evaluate possible abnormalities, and then sign and date the conclusion. 
Changes on the ECG vs. baseline, regarded as AEs, should be recorded accordingly in primary 
documentation and in CRFs. The nest ECG parameters will be evaluated: heart rate, RR, PQ, QT, 
QRS and QTC. 
6.7. Colonoscopy  
Colonoscopy will be performed during screening in patients over 50 years of age who do not 
have a colonoscopy report on the absence of significant pathology in the last 12 months. 


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Colonoscopy should be performed after confirmation of the patient’s full compliance with other 
selection criteria. The procedure and the relevant preparation should be performed as per the 
standards adopted in the medical diagnostic center. The screening and induction period in the case 
of colonoscopy is to be extended to 3 weeks. 
6.8. Numeric range scale (NRS-11) 
NRS-11 is a Visual Analog Scale version (Visual Analog Scale for pain). The scale is a 
horizontal 10 cm line with the numbers from 0 to 10 located on it, where 0 is “no pain/bloating”, 
10 is “most severe pain/bloating you can imagine”. During Visit 1 (screening and run-in period), 
the Investigator will train the patient to select a number from 0 to 10 that corresponds to his/her 
worst pain in the last 24 hours and the greatest bloating/flatulence. Abdominal pain and 
bloating/flatulence according to the NRS-11 scales will be evaluated at the screening visit, then 
daily throughout the screening/run-in and study treatment periods (in the Patient’s Diary). The 
Patient’s Diary is to be returned to the Site at Visit 3 (Week 4) and stored along with the primary 
patient’s documents. The Investigator should enter the diary data into the eCRF. The baseline 
parameters of abdominal pain intensity and bloating/flatulence severity for the inclusion criteria 
assessment will be determined as the average daily NRS-11 scales scores 7 days before 
randomization (last week of the run-in period). 
NRS-11 scales for abdominal pain and bloating/flatulence are provided in Appendix 2. 
6.9. Bristol Stool Chart (BSC)  
Classification of stools according to the BSC is easily understood by patients and makes it 
possible to quickly identify the nature of stool disorders. In accordance with BSC, hard stool 
includes types 1 and 2, loose stool—types 6 and 7 (Table 5) 
At Visit 1 (Week -1), the Investigator will train patients to assess stool consistency using BSC. 
Assessment of stool consistency starts at Visit 1, then it is performed for every bowel movement 
daily until Visit 3 (Week 4). 


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Table 5. Bristol Stool Chart. 
 
6.10. Quality of life evaluation using the IBSQOL questionnaire 
Patients will be asked to evaluate the quality of life using the IBSQOL questionnaire at baseline 
at Visit 2 (Week 0) and at the end of the study treatment at Visit 3 (Week 4). A sample 
questionnaire is provided in Appendix 3. 
6.11. Laboratory parameters  
All laboratory tests under the protocol will be performed at the study sites local laboratories 
as per the approved standards. Testing for faecal calprotectin will be performed in the local 
laboratory or central laboratory (if test is not performed or delayed in local laboratory) if there is 
no result in 1 month before screening. Women of child-bearing potential will undergo a pregnancy 
strip test (including less than 2-year postmenopause). 
Before the study start, the local and central laboratories will provide the necessary certificates 
and laboratory standards. The laboratory is responsible for providing laboratory reports to the 
study sites. The Investigator will analyze the results of laboratory tests as per standard clinical 
practice. 
The required laboratory tests will be performed during visits in accordance with the study 
procedures schedule (TableTable 1). The table below (TableTable 6) provides laboratory 
parameters to be evaluated in the clinical study. Clinical relevance of the values outside the normal 
range (or abnormal results) is to be evaluated by the Investigator. 


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Table 6 
Laboratory tests 
Hematology 
Biochemistry tests 
Urinalysis 
Feces 
analysis 
Serology 
General 
Liver function 
Renal 
function 
 
Hemoglobin 
Hematocrit 
Red blood cells 
White 
blood 
cells 
Neutrophils * 
Lymphocytes * 
Monocytes * 
Eosinophils * 
Basophils * 
Platelets 
Glucose 
Total 
protein 
Sodium 
Potassium 
Chloride 
Total bilirubin 
Direct bilirubin 
Alkaline 
phosphatase 
ALT 
AST 
GGT 
Blood Urea 
Nitrogen 
Serum 
creatinine 
General 
properties: color, 
transparency, 
specific 
gravity, 
pH, 
protein, 
glucose, bilirubin, 
urobilinogen, 
ketone 
bodies, 
nitrites, 
hemoglobin 
Sediment 
microscopy: 
epithelium, 
red 
blood cells, white 
blood 
cells, 
cylinders, 
bacteria, salts 
 
Fecal 
calprotectin 
 
Anti-HIV 
antibodies 
Anti-HCV 
HBsAg 
  
Abbreviations: ALT - alanine aminotransferase, AST - aspartate aminotransferase, GGT - γ-
glutamyltransferase; HIV - human immunodeficiency virus, Anti-HCV - antibodies to hepatitis C 
virus, HBsAg - surface antigen of hepatitis B virus. 
The Investigator must review the laboratory report, evaluate possible abnormalities, and then 
sign and date the conclusion. Hematology (including absolute values of leukocyte formula) and 
blood chemistry results should be transferred into eCRF.  
Urinalysis results has to be accessed as normal/abnormal registered into eCRF. Clinical 
significance should be also evaluated.  Clinically significant laboratory abnormalities should be 
recorded as AE. Laboratory reports should be kept with primary patient documentation. 
6.12. Requirements for Collecting, Recording and Reporting of Adverse Events 
Each subject is to be evaluated at every visit. Should any AE be identified at termination visit, 
the investigator will continue to follow the subject as described in section 6.12.1.6. 
 The reference safety information of Mebeverine+Simethicone, Duspatalin® and Espumisan® 
for the expectedness assessment is contained in the Investigators’ Brochure, Instructions for 
medical use and section 1.5.3. 
Investigator will be notified by Sponsor’s representative in case any updates of IB or 
comparators labels (Instructions for medical use) become available. 
6.12.1. 
Adverse events 
6.12.1.1. Definition of Adverse Event 
Any untoward medical occurrence in a patient or clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding, for example), symptom (including an AE occurring from drug abuse, an AE 
occurring from drug withdrawal and any failure of expected pharmacological action), or disease 
temporally associated with the use of a pharmaceutical product, whether or not considered related 
to the pharmaceutical product. 


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An elective surgery/procedure scheduled to occur during a study will not be considered an 
adverse event if the surgery/procedure is being performed for a pre-existing condition and the 
surgery/procedure has been pre-planned prior to study entry. However, if the pre-existing 
condition deteriorates unexpectedly during the study (e.g., surgery performed earlier than 
planned), then the deterioration of the condition for which the elective surgery/procedure is being 
done will be considered an adverse event. 
6.12.1.2. Recording of Adverse Events 
Any AE should be recorded on the Adverse Events form in the eCRF and source documents. 
In order to avoid vague, ambiguous or colloquial expressions, the AE should be recorded in 
standard medical terminology rather than the subject’s own words. Whenever possible, the 
Investigator should group together into a single term signs and symptoms which constitute a single 
diagnosis. 
The existence of or change in an AE may be concluded due to the necessity to administer a 
concomitant medication, from a spontaneous report of the subject, from the physical examination 
or from special tests like laboratory assessments or other study specified tests (source of AE). 
For each subject that has signed the informed consent and prior to study drug allocation at any 
dose any change to medical status should be recorded in patient’s medical file in accordance to 
local requirements and the medical history eCRF only.  
Any change to medical status, which occurs after study drug allocation at any dose in the 
specified study AE collection period will be handled as an (S)AE.  
For each subject that has signed the informed consent but does not qualify for allocation to 
treatment, i.e. Screen Failure, any change to medical status (from the time of ICF signature until 
determination of non-qualification for the study) should be recorded in patient’s medical file 
according to local requirements. The related medical status change information will not be 
reviewed by Abbott or delegated staff, and will not qualify as a study (S)AE. 
The post-therapy AE collection period is defined as 30 days after the subject’s termination of 
study drug after the subject’s termination of study drug (collection of (S)AEs should be passive in 
this period unless otherwise specified) 
Each AE is to be evaluated for duration, severity, seriousness and causal relationship to the 
investigational drug. The action taken with study drug, the concomitant treatment/therapy 
introduced and the outcome as well as whether the event led to study termination will also be 
recorded. 
6.12.1.3. Severity 
The severity of the AE should be characterized as “mild, moderate or severe” according to the 
following definitions: 
− Mild events are usually transient and do not interfere with the subject’s daily activities. 
− Moderate events introduce a low level of inconvenience or concern to the subject and 
may interfere with daily activities. 
− Severe events interrupt the subject’s usual daily activity 
6.12.1.4. Drug-Event Relationship 
The causal relationship between the study drug and the AE should be characterized according 
to the following: 
− Unrelated – there is not a reasonable possibility that the study drug caused the AE. 


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− Unlikely – suggests that only a remote connection exists between the study drug and 
the event. Other conditions, including concurrent illness, progression or expression of 
the disease state or reaction to concomitant medication, appear to explain the AE. 
− Possible – suggests that the association of the AE with the study drug is unknown, 
however the event is not reasonably supported by other conditions. 
− Probable – suggests that a reasonable temporal sequence of the AE with drug 
administration exists and, in the Investigator’s clinical judgment, it is likely that a 
causal relationship exists between the drug administration and the AE, and other 
conditions (concurrent illness, progression or expression of the disease state, or 
concomitant medication reactions) do not appear to explain the AE. 
− Certain - clear evidence to suggest a causal relationship, and other possible 
contributing factors can be ruled out. The clinical event, including an abnormal 
laboratory test result, occurs in a plausible time relationship to drug administration and 
cannot be explained by concurrent disease or other drugs or chemicals. 
The relationship with COVID-19 will also be registered (in case it is ongoing at the moment 
of the study treatment phase). 
6.12.1.5. Outcome 
The outcome of the adverse event should be classified according to the following definitions: 
− Recovered / resolved: the event has resolved (no further symptoms are present and no 
treatment is being received by the subject). 
− Recovered / resolved with sequelae: the event has resolved but there may be lingering 
effects present (e.g., a scar following a cut or abrasion). 
− Fatal: the subject died as a result of the event. This code should only be used for the 
event that caused the death, not any event that was present at the time of the subject’s 
death. Fatal events require immediately reporting to the Sponsor (or an authorized 
representative). 
− Unknown: may only be used in the event that the subject is lost to follow-up and no 
reliable data can be obtained. 
All efforts should be made to classify the AE according to the above categories. 
Note: when the AE is ongoing, the outcome will remain blank on the Adverse Events form in 
the eCRF. 
6.12.1.6. Follow-up of Adverse Events  
All AEs occurring during the study are to be followed up in accordance with good medical 
practice until resolved or judged no longer clinically significant, or if a chronic condition, until 
fully characterized. All follow-up results are to be reported to the Sponsor (or an authorized 
representative). 
6.12.1.7. Serious Adverse Events (SAEs) 
Definitions of Serious Adverse Event (SAE) 
Any untoward medical occurrence that at any dose: 
− Results in death, 


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− Is life-threatening (an event in which the subject was at risk of death at the time of the 
event; it does not refer to an event which hypothetically might have caused death if it 
were more severe), 
− Requires inpatient hospitalization or prolongation of an existing hospitalization, 
− Results in persistent or significant disability/incapacity, 
− Is a congenital anomaly/birth defect, 
− Is any suspected transmission via a medicinal product of an infectious agent, 
− Is considered an important medical event (an event that may not be immediately life-
threatening or result in death or hospitalization, but based on medical judgment may 
jeopardize the subject and may require medical or surgical intervention to prevent any 
of the outcomes listed above (i.e., death of subject, life-threatening, hospitalization, 
prolongation of hospitalization, congenital anomaly, or persistent or significant 
disability/incapacity). Examples of such events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, blood dyscrasias or 
convulsions that do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse as well as spontaneous or elective abortions, stillbirths and 
ectopic pregnancies) 
6.12.1.8. Reporting Serious Adverse Events 
Any SAE (fatal or life-threatening SAE and other SAEs), whether or not related to the study 
drug, must be reported immediately within 24 hours of the investigator’s awareness of the event 
by telephone, faxing and email the appropriate SAE forms to the following numbers: 
Study Medical Monitor 
 
 
 
 
 
 
After office hours, the emergency telephone number is: 
 
6.12.2. 
Pregnancy 
If a subject should become pregnant during the study, the event will be reported within 1 day 
of the investigator’s knowledge of the pregnancy.  
 
 
If pregnancy occurs in a subject from the time of ICF signature who does not qualify for 
allocation to treatment, i.e. Screen Failure, the pregnancy should be recorded in patient’s medical 
file only, in accordance to local requirements. The pregnancy related medical status change 
information will not be reviewed by Abbott or delegated staff. The pregnancy will not qualify as 
a study (S)AE.  
If pregnancy occurs in a subject from the time of ICF signature who is not disqualified for 
allocation to treatment, the pregnancy should be recorded in patient’s medical file in accordance 
to local requirements and in Abbott’s pregnancy from. The pregnancy related medical status 


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change information will be reviewed by Abbott or delegated staff. The pregnancy will not qualify 
as a study (S)AE. 
The pregnancy evolution and outcome, i.e., the health status of the newborn, is to be reported 
on the Pregnancy Outcome Form
 
 
Pregnancy in a study subject is not considered an adverse event. However, the medical 
outcome of an elective or spontaneous abortion, stillbirth, ectopic pregnancy or congenital 
anomaly is considered a SAE and must be reported to
 within 24 hours of the 
investigator becoming aware of the event and followed-up as described in Section 6.12.2  
6.13. Emergency Situation Procedures 
The Investigator is responsible for obtaining information on all the patient’s emergency 
medical conditions in the course of the study. The text of the Patient Information Sheet and 
Informed Consent Form should contain the Investigator’s contact information. The patients will 
be recommended to contact the Investigator in the event of any emergency conditions occurring 
during the study.  
6.14. Subject Withdrawal from the Study  
All subjects are free to withdraw from participation in this study at any time, for any reason, 
specified or unspecified, and without penalty or loss of benefits to which the subject is otherwise 
entitled. 
The Study Termination form must be completed for all subjects who did not fail screening. 
In case of premature termination of the subject from the study, the primary reason for this 
premature termination is to be indicated according to the following definitions: 
• Adverse event: discontinuation due to any adverse event (AE) with a corresponding entry 
reflected on the Adverse Events form in the eCRF 
• Lack of efficacy: subject fails to respond to the study drug at an acceptable level where the 
subject or the Investigator feels it is in the best interests of the subject to seek another 
treatment. 
• Lost to follow-up: the subject fails to return to the study site for scheduled visits and does 
not respond to telephone or written attempts to contact. 
• Withdrew consent: subject decides to stop his/her participation in the study for any reason 
other than an AE, or is unable to complete the study as described in the clinical study 
protocol (e.g., subject is relocating to another location). 
• Administrative: the Sponsor decides to discontinue the study (either at the study site or the 
entire study), e.g., general safety problems leading the Sponsor to entirely stop the study. 
• Protocol violation – anything which is in direct violation of the clinical study protocol (e.g., 
inclusion/exclusion violation) 
If possible, the Investigator must first discuss the discontinuation with the Medical Monitor. 
Otherwise, the Investigator should discuss the issue of discontinuation with the Medical Monitor 
within 24 hours after discontinuation. 
The reason for the patient's discontinuation should be specified in the source documentation 
and on the electronic Case Report Form. If the patient discontinues participating in the study for 
more than one reason, the main reason should be given. Occurrence of an AE or SAE should be 
specified as the reason for the withdrawal of the patient’s consent due to such AE or SAE. 


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In addition, the Sponsor shall be entitled to terminate the study at any time. The Investigator 
is entitled to terminate the study at any time for medical or regulatory reasons. Termination of the 
study should be done after mutual consultations between the Investigator and the Sponsor only. 
If the study is terminated ahead of time, all patients should undergo early termination visit 
procedures, and all study documents must be returned to the Sponsor or its representative. 
Follow-up of AE, SAE and pregnancy continuing at the time of the study termination should 
be performed as per the Protocol, unless another procedure for the safety follow-up is agreed 
between the Investigator and the Sponsor. 
6.15. The validity of measurements 
Evaluations of the efficacy and safety of therapy in patients with functional diseases of the 
colon are standard and well known. A randomized, controlled, parallel-group clinical study will 
evaluate the safety and efficacy of the study drug versus reference drugs. 
Due to the COVID-19 pandemic, visits to the study site can be replaced by home visits by the 
site’s employees or the use of telemedicine opportunities. These changes, including the permissible 
amount of missing data, should be approved by the Sponsor and IEC and do not require 
amendments to the protocol (in case it is ongoing at the moment of the study treatment phase). 
7. STUDY PROCEDURES  
7.1. Screening and run-in period (Visit 1, Week – 1,1 Day -7) 
Visit window day -21….-7 
• 
The procedure for obtaining the informed consent 
• 
Patient Registration 
• 
Collection of demographic data, medical history and concomitant medication data 
• 
Physical examination  
• 
Assessment of vital signs 
• 
Measuring height, weight, BMI 
• 
Abdominal pain intensity on the NRS-11 scale evaluation (worst pain for the latest 3 
months) 
• 
Bloating/Flatulence intensity on the NRS-11 scale evaluation (worst bloating episode for 
the latest 3 months) 
• 
ECG 
• 
Blood sampling for safety laboratory tests (hematology and blood chemistry, tests for 
HIV, hepatitis B and C) 
• 
Urine collection for urinalysis 
• 
Feces sampling for Fecal calprotectin analysis (if there is no result in 1 month before 
screening) 
• 
The urine pregnancy test is carried out on women with child-bearing potential (including 
women in the menopausal period of less than two years) 
                                                 
1 Week -3, Day -21 in case of colonoscopy 


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• Assessment of inclusion/non-inclusion criteria 
• 
Patient diary dispense 
• Colonoscopy should be performed in patients over 50 years of age who do not have a 
colonoscopy report on the absence of significant colon pathology in the last 12 months who 
meet all inclusion/exclusion criteria (excluding Inclusion Criteria 5 and 6 that are to be 
evaluated at a randomization visit). Colonoscopy should be performed not later than 10 
days before the randomization visit. 
Patient questionnaires, tests, and scales should be completed according to the adopted clinical 
practice by the certified trained member of the Site study team before dosing. 
In case of ambiguous or controversial results of laboratory tests, a single repeated test (retest) 
may be performed, as agreed with the Sponsor or its representative.  
Patients that do not meet all inclusion/exclusion criteria will not be included in the study. 
Patients not enrolled in the study due to conditions which may be corrected may be re-screened 
one time, as agreed upon with the Sponsor or its representative. 
From this date intake of drugs prohibited by the protocol are not allowed. Intake of drotaverin 
in a dose of 80 mg 1-3 times a day will be allowed to stop intensive pain episode during one day 
after the episode. 
7.2. Treatment period  
7.2.1. 
Randomization (Visit 2 Week 0, Day 1). 
• 
Assessment of AE and concomitant medication 
• 
Measuring, weight, BMI 
• 
Assessment of vital signs 
• 
Abdominal pain and bloating/flatulence intensity on the NRS-11 scale evaluation  
• 
Patient diary assessment (Including stool consistency in line with the Bristol stool scale, 
stool frequency, drotaverine intake  and menstrual bleeding days) 
• Assessment of inclusion/non-inclusion criteria 
• 
Randomization  
• 
Evaluate the quality of life (IBSQOL questionnaire)  
• 
Study drug dispense 
7.2.2. Telephone contact 1 (Week 2, Day 15) 
Visit window ± 1 day 
• 
Assessment of AE and concomitant medication, study drug intake, interrogation for 
correctness of patient diary filling   
7.2.3. 
 End of treatment (Visit 3, Week 4, Day 29) 
Visit window ± 1 day 
• 
Assessment of AE and concomitant medication 
• 
Measuring, weight, BMI  
• 
Physical examination  


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• 
Assessment of vital signs 
• 
Blood sampling for safety laboratory tests (hematology and blood chemistry) 
• 
Urine collection for urinalysis  
• 
Patient diary assessment (daily data for 4 weeks, including abdominal pain and 
bloating/flatulence intensity, stool consistency in line with the Bristol stool scale, stool 
frequency, drotaverine intake  and menstrual bleeding days) 
• 
Evaluate the quality of life (IBSQOL questionnaire ) 
• 
Study drug return, accountability and compliance assessment 
At this point the period of the study therapy is completed. The patient will be given 
recommendations for further treatment as part of standard therapy 
7.3. Follow-up period 
7.3.1. Telephone contact 2 (Week 5, Day 36) 
Visit window +1 day 
• 
Assessment of AE and concomitant medication 
7.4. Unscheduled visits 
At the discretion of the Investigator, the patients may be invited for an unscheduled visit at 
any time in the course of the clinical study for safety reasons, in case a re-examination or repeated 
procedure is required, or to provide additional quantity of the study drug. During unscheduled 
visits, the Investigator may conduct the necessary procedures. Unscheduled visits should be 
registered in the source documentation and CRF. Unscheduled visits should not affect the schedule 
of planned visits provided by the Protocol of this clinical study 
7.5. Early discontinuation visit 
In case of early termination of participation, after Visit 2 (Week 0, Day 1) and before Visit 3 
(Week 4, Day 29), the patient should be invited to the study site to undergo an early discontinuation 
Visit (ED) assessments. The Investigator should make every effort to conduct ED  
ED Visit should include all procedures of Visit 3 (Week 4, Day 29). If ED Visit cannot be 
carried out in full, the Investigator should coordinate their actions with the Medical Monitor. On 
ED Visit the patient should return all used and unused packages of the study drug. The patient will 
be given recommendations for further treatment as part of standard therapy. 
If possible, the Investigator should discuss the patient's early discontinuation from the 
study with the Medical Monitor in advance. Otherwise, the Investigator should contact the 
Medical Monitor within 24 hours after the early discontinuation of the patient 
8. QUALITY ASSURANCE  
This clinical study will be conducted in accordance with Standard Operating Procedures (SOP) 
of the Sponsor and/or representatives thereof, the requirements of International Conference on 
Harmonization Good Clinical Practice Guidelines (ICH GCP(E6)) and Eurasian Economic Union 
(EEU), principles provided in Helsinki Declaration, as well as in accordance with the applicable 
legislation and regulations of the Russian Federation. Compliance with the requirements will be 
provided by audits of the study site and the data obtained in the study. 
The Investigator will enter the data required in accordance with this Protocol into the eCRF, 
provided by the Sponsor or the representative thereof. The monitors shall visit each study site at a 
frequency described in the monitoring plan to check the eCRFs for completeness and accuracy of 


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filling. Specifying question shall be asked concerning any differences between the source 
documentation and completed eCRFs, which the Investigator should answer and/or eliminate these 
inconsistencies.  When all the information required had been entered and all the specifying 
questions clarified, the Investigator should sign and date the eCRF of each patient. The completed 
pages of the eCRF will be checked during the monitoring visits.. 
Due to the COVID-19 pandemic, a centralized and remote monitoring model can be used in 
the study. All applicable principles will be described in the monitoring plan. 
9. STATISTICAL METHODS PLANNED 
9.1. General provisions 
This is clinical study to evaluate efficacy and safety of Mebeverine+Simethicone fixed-dose 
combination versus Duspatalin® (mebeverine) and versus Espumisan® (simethicone) in patients 
with functional bowel disorders with abdominal pain and excess gas formation. 
Statistical analysis, described in the following subsections, will be performed as specified in 
the Statistical analysis plan, which will be created and finalized before closing the database. The 
Statistical analysis plan will be included in the report on the clinical study for this Protocol. 
9.2. Sampling size identification 
In first amendment to protocol the pre-specified interim analysis was removed. However, as 
already all subjects were recruited no change in sample size was made. Note that a design without 
the interim analysis needs less patients to achieve the same power, so that deleting the interim did 
not have negative consequences to the power of the study while maintaining still the usual type 1 
error rate of 5% (two-sided). For sake of completeness below the original sample size rationale is 
given. 
There are no published data on bloating/flatulence and abdominal pain assessment with NRS-
11 for simethicone versus placebo and mebeverin versus placebo. Comparison of Linaclotide 
treatment versus placebo for bloating decrease in chronic constipation patients was assessed with 
NRS-11 and found out 1.0 point difference between groups with approximately 2.5 standard 
deviation.2Comparison of B. coagulans Unique IS2 treatment versus placebo for pain decrease in 
IBS patients was assessed with NRS-11 and found out 3.2 point difference between groups with 
2.5 standard deviation. 3 
An assumption was taken that Mebeverin+Simethicone fixed dose combination will decrease 
the sum of pain and bloating/flatulence scores on average at least 1.0 point more than simethicone 
or mebeverine as monotherapy. 
For primary endpoint to demonstrate the superiority of the FDC versus separately each mono-
component assuming an expected 1.0 point difference between the two treatment groups and 
standard deviation 2.5 with type I error α = 0.05 (two-sided) and a power 90% for each comparison 
individually in a group-sequential design with one interim stage at information fraction 40%, about 
132patients should be included in both groups. The overall power to demonstrate superiority for 
both comparisons (FDC vs mebeverine monotherapy and FDC vs simethicone monotherapy) is 
about 80%. 
Thus, 396 should be included into the analysis 
3. mebeverin 
superiority /sum NRS-
11 scores for pain and 
bloating/flatulene 
intensity 
α = 0.05 (two-sided) 
β = 0.1 
Power = 90% 
Mean diff. = 1.0 
SD = 2.5 
Alpha spending function: 
O'Brien-Fleming 
n1 = n2 = 132 


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Beta spending function (non-binding): 
O'Brien-Fleming 
Max. num, of stages = 2 
Info. proportion at Interim stage = 0.40 
4. simethicone 
superiority /sum NRS-
11 scores for pain and 
bloating/flatulene 
intensity 
α = 0.05 (two-sided) 
β = 0.1 
Power = 90% 
Mean diff. = 1.0 
SD = 2.5 
Alpha spending function: O'Brien-Fleming 
Beta spending function (non-binding): 
O'Brien-Fleming 
Max. num, of stages = 2 
Info. proportion at Interim stage = 0.40 
n1 = n2 = 132  
Thus, taking into account a 15% drop-out rate, about 155 patients should be included in each 
group. A total of 465 patients should be randomized.. 
9.3. Randomization 
Randomization will take place at Visit 2 (Week 0) with IWRS system which is described in 
the eCRF. Patients will be randomized into three equal groups (1:1:1) using the IWRS system (155 
patients per group).  
9.4. Statistical methods 
Statistical analysis will be performed according to the Statistical Analysis Plan created and 
finalized before the database lock. 
The Safety Population will consist of all randomized patients who received at least one dose 
of the study product. 
The Full Analysis Set (FAS) will consist of all randomized patients who received at least one 
dose of the study product and have at least one post-baseline assessment of the efficacy parameters. 
Per Protocol set (PP) will consist of all FAS patients who completed study treatment and had 
no significant protocol violations. 
Also, secondary endpoint analysis will be performed in the following subgroups: 
• Patients with IBS 
• Patients with other functional bowel diseases 
• Patients with constipation 
• Patients with diarrhea 
• Patients with both constipation and diarrhea 
• Patients with neither constipation nor diarrhea 
9.5. Patient distribution, demographic and baseline characteristics 
Patient distribution, demographic and baseline characteristics will be presented using 
descriptive statistics. The number and percentage of patients receiving concomitant medication 
will be presented in frequency tables according to the ATC class level 2 and 4. The number and 
percentage of patients with comorbidities and preceding conditions will also be specified. 
9.6. Study drug intake 
Information on dosage, including daily doses, duration of effect and total doses, will be 
presented in a descriptive way for each treatment group. 


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9.7. Efficacy analysis 
9.7.1. Primary efficacy end point 
• Change from baseline of sum of NRS-11 abdominal pain and bloating/flatulence 
intensity scores after 4 weeks of treatment.  
The baseline abdominal pain and bloating/flatulence intensity will be determined as the 
average of the NRS-11 daily assessment during 7 days before randomization (weekly average of 
last week of screening and run-in period). The Week 4 assessment is the same (data from last 7 
days of the corresponding week).. 
9.7.2. Primary end points analysis 
The FAS will be the main sample for efficacy assessment in this study performed to confirm 
superiority. Additional analysis of the primary efficacy endpoint will be performed in the per 
protocol (PP) set.  
For the difference of changes in sum scores of NRS-11 pain and bloating/flatulence intensities 
after 4 weeks of treatment versus baseline between the groups Mebeverine+Simethicone versus 
Duspatalin® and Mebeverine+Simethicone versus Espumisan®, a two-sided 95% confidence 
interval (CI) will be constructed, which is equivalent to a 97.5% one-sided CI. The confidence 
interval will be constructed using ANCOVA, which will include treatment and site as fixed effect, 
and baseline parameter will be included in the model as covariate. To test the hypothesis of 
superiority of the FDC Mebeverine+Simethicone versus every comparator (Duspatalin® and 
Espumisan®), the upper confidence limit will be used. The null hypothesis (H0: no difference in 
change from baseline of sum of bloating/flatulence and pain scores between the FDC and 
corresponding comparator, will be rejected in favor of the alternative hypothesis (Ha: larger change 
from baseline of sum of bloating/flatulence and pain scores in the fixed-dose combination 
Mebeverine+Simethicone group) only if the upper limit of two-sided 95% CI does not contain the 
value 0. In addition the study will be considered successful in case both superiority hypothesizes 
are proven, i. e. upper limit of two-sided 95% CI does not contain the value 0 for both constructed 
confidence intervals. In this case, the conclusion will be drawn on the fixed-dose combination of 
Mebeverine+Simethicone to be superior versus Duspatalin® (mebeverin) and Espumisan® 
(simethicone) for the decrease of both pain and bloating/flatulence intensity. 
9.7.3. Secondary efficacy end points 
• Change from baseline of NRS-11 pain intensity after 4 weeks of treatment  
• Proportion of patients with the NRS-11 pain intensity reduction of ≥30% versus 
baseline during at least 50% of treatment weeks over treatment period 
• Proportion of patients with the NRS-11 pain intensity reduction of ≥ 50% versus 
baseline during at least 50% of treatment weeks over treatment period. 
• Proportion of patients with the abdominal pain assessed in the Patient Dairy completely 
resolved during at least 50% of treatment weeks over treatment period (NRS-11 0 
assessment). 
• Change from baseline of NRS-11 bloating/flatulence intensity after 4 weeks of 
treatment 
• Proportion of patients with the NRS-11 bloating/flatulence intensity reduction of ≥30% 
versus baseline during at least 50% of treatment weeks over treatment period. 
• Proportion of patients with the NRS-11 bloating/flatulence intensity reduction of ≥ 
50% versus baseline during at least 50% of treatment weeks over treatment period.  


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• Proportion of patients with the bloating/flatulence assessed in the Patient Dairy 
completely resolved during at least 50% of treatment weeks over treatment period 
(NRS-11 0 assessment). 
• For patients with constipation: proportion of patients with any increase in number of 
CSBM per week versus baseline during at least 50% of treatment weeks. 
• For patients with diarrhea : proportion of patients with any decrease in the number of 
days per week with at least one stool consistency of Type 6 or Type 7 BSS versus 
baseline during at least 50% of treatment weeks. 
• Change in number of days per week during study treatment period when drotaverine 
was taken. 
• Change in quality of life evaluation using IBSQOL questionnaire versus baseline. 
The baseline abdominal pain and bloating/flatulence intensity will be determined as average 
of the worst daily episodes NRS-11 assessment during 7 days before randomization (last week of 
screening and run-in period). The data from last week of screening and run-in period will be also 
used for baseline assessment of stool frequency and consistency and number of days of drotaverin 
intake. Week 1, Week 2, Week3 and Week 4 assessments are the same (data from the last 7 days 
of the corresponding week). 
9.7.4. Secondary efficacy end points analysis 
Intergroup comparisons will also be performed for secondary efficacy endpoints using the 
χ2/Fisher exact test and 95% confidence intervals for differences in proportions will be given. 
Additionally, the proportion of patients with reduced severity of pain in the bowel region and 
bloating/flatulence during each week of the 4-week treatment period charts will be constructed. 
ANCOVA model, which will include treatment and site as fixed effect, and baseline value as 
covariate, will be used for continuous covariates comparison presenting treatment effect estimates 
and associated 95% CIs.  
9.8. Safety analysis 
9.8.1. Safety end points: 
• Safety will be assessed per treatment arm, based on the incidence and severity of AE and 
SAE, physical examination, vital signs and lab results. 
9.8.2. Safety end points analysis 
The safety sample will be used for the analysis of the safety and tolerability data. 
Treatment Emergent Adverse Events (TEAEs) including AE and SAE will be presented by 
frequencies (number of patients with AEs and number of events) and are summarized by unique 
treatment (Mebeverine+Simethicone, Duspatali®, Espumisan®), primary System Organ Class 
(SOC) and Preferred terms (PT) and relation to the study drug and severity. Severity and drug-
event relationship of the treatment emergent AEs are summarized separately.  
Laboratory values and vital signs by visit and their changes from baseline will be summarized 
in tables of descriptive statistics. Abnormal values (according to the reference ranges) will be 
presented in frequency tables (low, normal and high values). 
9.9. Procedures to record missing, not subject to analysis and dubious data 
No missing data will be added. To analyze the efficacy endpoints the last observation carry 
forward (LOCF) will be used. To determine the sensitivity of the evaluation: first the patients with 


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missing data will be analyzed, then the patients will be analyzed without replacing the missing 
data. 
9.10. Reporting of any deviations from the original statistical plan  
In case of any deviation from the planned statistical analysis all the changes compared to the 
methods described in the Protocol should be identified. Similarly, if there is a need for any 
additional changes, upon the completion of the analysis they should be specified in the Study 
report. 
10. ADMINISTRATIVE PROCEDURES 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
  
 
  
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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10.5. Ethical aspects 
10.5.1. 
Independent Ethics Committee  
Prior to the clinical study initiation, all study sites will obtain written approvals of independent 
Ethics committees (IECs) in accordance with International Conference on Harmonization Good 
Clinical Practice Guideline (ICH GCP(E6 R2)) and Eurasian Economic Union (EEU), principles 
provided in Helsinki Declaration, as well as in accordance with the applicable legislation and 
regulations of the Russian Federation. The following documents shall be submitted for IEC’s 
review: study protocol with amendments, patient’s information list and the informed consent form, 
written materials to be submitted to the patients, investigator’s brochure, information of safety of 
the study drug application, information on payments and other remunerations to the patients, 
investigator’s scientific biography and other documents at request. 
The list of IEC’s members and the statement of its organization and operations compliance 
with the standards of the Good Clinical Practice and regulatory requirements shall be submitted to 
the Sponsor. 
10.5.2. 
Ethical conduct of clinical study  
The procedures described in the Protocol of clinical studies related to its conduct, assessment 
and documentation of the findings have been designed to ensure that the Sponsor and the 
Investigator followed the requirements of the Good Clinical Practice guidance of International 
Conference on Harmonization (ICH GCP(E6 R2)) and the Eurasian Economic Union (EEU). This 
clinical study will also be conducted in accordance with applicable law and applicable regulatory 
requirements. This includes the possibility of conducting audits and inspections by representatives 
of the Sponsor and/or competent authorities. The Investigator should give their consent to 
monitoring, audits and inspections in study site and at any time on demand providing direct access 
to the study for the Sponsor and representatives thereof, Independent Ethics Committee and 
competent authorities 
10.5.3. 
Informed Consent  
Prior to the clinical study, the Investigator shall obtain IEC’s written approval of the patient’s 
information sheet and the informed consent form, as well as any other written information, which 
will be provided to the study subjects. IEC’s written approval and approved documents shall be 
filed with the Study Record.  


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The procedure for obtaining the informed consent shall comply with the requirements of 
International Conference on Harmonization Good Clinical Practice Guideline (ICH GCP(E6)) and 
Eurasian Economic Union (EAU), principles provided in Helsinki Declaration, as well as in 
accordance with the applicable legislation and regulations of the Russian Federation. The informed 
consent form shall be signed and dated by the patient before beginning of any study procedures. 
The process of obtaining the informed consent shall be described in detail in the primary 
documentation, including the fact of patient’s consent to take part in this clinical study and the 
date of signing; the version of the informed consent form should be specified 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 


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12. REFERENCES 
 
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Российской Федерациипо диагностике и лечению больных с синдромом раздраженного кишечника РЖГГК 
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ultrasound premedication]; Vergleichsuntersuchung zweier Dosierungsformen von flüssigem Dimeticon zur 
Sonographie-Prämedikation. Ultraschall Med 1990;11:95–99 
112 Abu-Yousef MM, El-Zein Y: Improved US visualization of the pancreatic tail with simethicone water and patient 
rotation. Radiology 2000;217:780–785 
113 Banerjee B, Parker J, Waits W, Davis B: Effectiveness of preprocedure simethicone drink in improving visibility 
during esophagogastroduodenoscopy a double-blind randomized study [letter]. J Clin Gastroenterol 1992;15:264–265 
114 Bertoni G, Gumina C, Conigliaro R, Ricci E, Staffetti J, Mortilla MG, Pacchione D: Randomized placebo-
controlled trial of oral liquid simethicone prior to upper gastrointestinal endoscopy. Endoscopy 1992;24:268–270. 
115 Albert J, Gobel CM, Lesske J, Lotterer E, Nietsch H, Fleig WE: Simethicone for small bowel preparation for 
capsule endoscopy a systematic, single-blinded, controlled study. Gastrointest Endosc 2004;59:487–491 
116 Ge ZZ, Chen HY, Gao YJ, Hu YB, Xiao SD. The role of Simethicone in small-bowel preparation for capsule 
endoscopy. Endoscopy. 2006; 38(8):836–840 
117 Shaver WA, Storms P, Peterson WL: Improvement of oral colonic lavage with supplemental simethicone. Dig 
Dis Sci 1988;33:185–188. 
118 McNally PR, Maydonovitch CL, Wong R: The effectiveness of simethicone in improving visibility during 
colonoscopy a double-blind randomized study. Gastrointest Endosc 1988;34:255–258 
119 Lazzaroni M, Petrillo M, Desideri S, Bianchi Porro G: Efficacy and tolerability of polyethylene glycol-electrolyte 
lavage solution with and without simethicone in the preparation of patients with inflammatory bowel disease for 
colonoscopy. Aliment Pharmacol Ther 1993;7:655–659 
120 Kark W, Krebs-Richter H, Hotz J: [Improving the effect of orthograde colonic lavage with golytely solution by 
adding dimethicone]; WCRFungsverbesserung der orthograden Dickdarm-lavage mit Golytelylösung durch 
zusatzliche Gabe von Dimeticon. Z Gastroenterol 1995;33:20–23 
121 Sudduth RH, DeAngelis S, Sherman KE, McNally PR: The effectiveness of simethicone in improving visibility 
during colonoscopy when given with a sodium phosphate solution a double-bind randomized study. Gastrointest 
Endosc 1995; 42:413–415 
122 de la Portilla F, Ynfante I, Fernandez A, Bejarano D, Carranza G: Improved quality of anorectal endoluminal 
ultrasonography using emulsion of dimethicone. Dis Colon Rectum 2003;46:1436–1437 
123 R. UrgesiRapaccini, I. Dе Vitis A randomized double-blind placebo-controlled clinical trial on efficacy and safety 
of association of simethicone and Bacillus coagulans (Colinox®) in patients with irritable bowel syndrome European 
Review for Medical and Pharmacological Sciences 2014; 18: 1344-1353 
124 Lacy BE: Irritable Bowel Syndrome A Primer on Management. Rev Gastroenterol Disord 2003; 3:32–42 
 


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125 Oswald WJ: Treatment of flatulence with methylpolysiloxane. Curr Ther Res 1961;3:443–446. 
126 Weiss J: Etiology and management of intestinal gas. Current Therapeutic Study 1974;16:909–920 
127 Hanauer SB, DuPont HL, Cooper KM, Laudadio C Randomized, double-blind, placebo-controlled clinical trial 
of loperamide plus simethicone versus loperamide alone and simethicone alone in the treatment of acute diarrhea with 
gas-related abdominal discomfort. Curr Med Res Opin 2007;23:1033–1043 
128 Ducrotte, J. C. Grimaud, M. Dapoigny, S. Personnic, V. O’Mahony, M. C. Andro-Delestrain. On-demand 
treatment with alverine citrate/simethicone compared with standard treatments for irritable bowel syndrome: results 
of a randomised pragmatic study Int J Clin Pract, February 2014, 68, 2, 245–254 
129 
 
 

SAP_001.pdf: 
ClinicalTrials.gov Identifier: 
NCT05175131 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ABBOTT 
 
Statistical Analysis Plan 
 
 
Module 1 
(Non-standard data and analyses) 
 
 
 
Version 3.0, Date 09JUL2021 
 
 
Study: MESI3001 
 
 
Multicenter, randomized, parallel-group, open-label, comparative clinical study to 
evaluate efficacy and safety of Mebeverine+Simethicone fixed-dose combination versus 
Duspatalin® (mebeverine) and versus Espumisan® (simethicone) in patients with 
functional bowel disorders with abdominal pain and excess gas formation 
 
 
 
 
 
  
 
  
 
 


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SIGNATURE PAGE 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
  
 
 


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TABLE OF CONTENTS 
SIGNATURE PAGE ........................................................................................................... 2 
1. 
ABBREVIATIONS ........................................................................................... 5 
2. 
INTRODUCTION ............................................................................................. 7 
3. 
SUMMARY OF THE PROTOCOL ................................................................ 8 
3.1 
Overall Study Plan ............................................................................................... 8 
3.2 
Study Flowchart .................................................................................................. 8 
3.3 
Study Objectives .................................................................................................. 8 
4. 
STATISTICAL ANALYSIS ........................................................................... 10 
4.1 
Subject samples ................................................................................................. 10 
4.2 
Efficacy analysis ................................................................................................ 10 
4.2.1 
Primary Efficacy Analysis ................................................................................. 10 
4.2.2 
Secondary efficacy analysis .............................................................................. 12 
4.3 
Safety analysis ................................................................................................... 14 
4.3.1 
Demographic Data and Other Baseline Characteristics .................................... 16 
4.3.2 
Medical History ................................................................................................. 17 
4.3.3 
Physical Examinations ...................................................................................... 17 
4.3.4 
Vital Signs, height and weight .......................................................................... 17 
4.3.5 
Visual Analogue Scales ..................................................................................... 18 
4.3.6 
Safety Laboratory Data ..................................................................................... 18 
4.3.7 
Adverse Events .................................................................................................. 18 
4.3.8 
Time of administration (patient diary) .............................................................. 19 
4.3.9 
Concomitant Medication ................................................................................... 19 
4.3.10 
Drug Accountability, Treatment Compliance and Exposure ............................ 19 
4.3.11 
Compliance with selection criteria assessments. ............................................... 20 
4.4 
Interim Analysis ................................................................................................ 20 
4.5 
Data Safety Monitoring Board .......................................................................... 20 
4.6 
Safety Management Team ................................................................................. 20 
5. 
DESCRIPTION OF NON-STANDARD DATA COLLECTED AND 
DERIVED VARIABLES ................................................................................ 21 
5.1 
Other Non-Standard Baseline Characteristics ................................................... 21 
5.2 
Non-Standard Disease History .......................................................................... 21 
5.3 
Efficacy data ...................................................................................................... 21 
5.4 
Non-standard Safety Data ................................................................................. 21 
5.5 
Drug Accountability and Exposure ................................................................... 21 
6. 
FURTHER SPECIFICATIONS TO THE STANDARD ANALYSES IN 
MODULE 2 ...................................................................................................... 22 
6.1 
Trial Design [2] ................................................................................................. 22 


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6.1.1 
Trial Periods ...................................................................................................... 22 
6.1.2 
Trial Elements ................................................................................................... 22 
6.1.3 
Trial Arms ......................................................................................................... 22 
6.1.4 
Unique Treatments ............................................................................................ 23 
6.1.5 
Visits and related definitions ............................................................................. 24 
6.2 
Further Specifications to the Standard Tables in Module 2 .............................. 31 
6.3 
Other Further Specifications ............................................................................. 31 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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1. 
ABBREVIATIONS  
Standard Abbreviations 
 
AE 
adverse event 
ANCOVA 
analysis of covariance 
ATC 
Anatomical Therapeutic Chemical (class) 
AUC 
area under the curve 
BDR 
blind data review 
BMI 
body mass index 
bpm 
beats per minute 
CRF 
case report form 
CRO 
contract research organization 
CV 
coefficient of variation 
DARIUS 
Document And Regulatory Information 
Universal System 
DBP 
diastolic blood pressure 
DDT 
data definition table 
DSMB 
data safety monitoring board 
ECG 
electrocardiogram 
FA 
Full Analysis 
FDA 
food and drug administration 
Geo. mean 
geometric mean 
GOP 
global standard operating procedure 
HLGT 
High Level Group Term 
HLT 
High Level Term 
IBSQOL 
Irritable bowel syndrome quality of life 
ICH 
International Conference on Harmonization 
LDA 
day number of the last day of drug 
administration 
LLOQ 
lower level of quantification 
LLT 
Lowest Level Term 
LOCF 
last observation carried forward 
max 
maximum 
MedDRA 
Medical Dictionary for Regulatory Activities 
min 
minimum 
N,n 
number of observations 
NA 
not applicable 
OC 
observed cases 
PD 
pharmacodynamic 


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PK 
pharmacokinetic 
PP 
Per Protocol 
PT 
Preferred Term 
QOL 
quality of life 
S.I. 
System International 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SBP 
systolic blood pressure 
SD 
standard deviation 
SOC 
System Organ Class 
SOP 
standard operating procedure 
TARC 
Therapeutic Area Review Committee 
TEAE 
treatment-emergent adverse event 
TESAE 
treatment-emergent serious adverse event 
TLF/T,L,F 
tables, listings and figures 
ULOQ 
upper limit of quantification 
URL 
upper reference limit 
WC 
windowing convention 
WHO-
DD(E) 
World Health Organization – Drug Dictionary 
(enhanced) 
 
 
 


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2. 
INTRODUCTION 
 
 
 
 
 
 
 
  
  
 
 
   
 
 
 
 


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3. 
SUMMARY OF THE PROTOCOL  
3.1 
Overall Study Plan 
An open-label, randomized, comparative Phase III clinical study. The study is performed to 
evaluate efficacy and safety of Mebeverine+Simethicone fixed-dose combination versus 
Duspatalin ® (mebeverin) and versus Espumisan ® (simethicone) after 4 weeks of treatment in 
patients with functional bowel disorders with abdominal pain and excess gas formation. 
3.2 
Study Flowchart  
The flowchart of the study can be found in Appendix 9.1. 
3.3 
Study Objectives 
Primary objectives: 
To assess the efficacy of Mebeverine+Simethicone fixed-dose combination versus Duspatalin® 
(mebeverin) and Espumisan® (simethicone) based on the change of abdominal pain and 
bloating/flatulence intensity, assessed with NRS-11 scales after 4 weeks of treatment in patients 
with functional bowel disorders with abdominal pain and bloating/flatulence. 
Secondary objectives: 
To evaluate the following efficacy and safety parameters of Mebeverine+Simethicone fixeddose 
combination versus Duspatalin® (mebeverin) and versus Espumisan® (simethicone) in patients 
with functional bowel disorders with abdominal pain and excess gas formation 
(bloating/flatulence: 
• Change from baseline of NRS-11 pain intensity after 4 weeks of treatment; 
• Proportion of patients with the NRS-11 pain intensity reduction of ≥30% versus baseline 
during at least 50% of treatment weeks over treatment period; 
• Proportion of patients with the NRS-11 pain intensity reduction of ≥ 50% versus baseline 
during at least 50% of treatment weeks over treatment period; 
• Proportion of patients with the abdominal pain assessed in the Patient Dairy completely 
resolved during at least 50% of treatment weeks over treatment period (NRS-11 0 
assessment); 
• Change from baseline of NRS-11 bloating/flatulence intensity after 4 weeks of treatment; 
• Proportion of patients with the NRS-11 bloating/flatulence intensity reduction of ≥30% 
versus baseline during at least 50% of treatment weeks over treatment period; 
• Proportion of patients with the NRS-11 bloating/flatulence intensity reduction of ≥ 50% 
versus baseline during at least 50% of treatment weeks over treatment period; 
• Proportion of patients with the bloating/flatulence assessed in the Patient Dairy 
completely resolved during at least 50% of treatment weeks over treatment period (NRS- 
11 0 assessment); 


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• Change in number of days per week during study treatment period when drotaverine was 
taken; 
• Change in quality-of-life evaluation using IBSQOL questionnaire versus baseline; 
• The incidence and severity of adverse events (AE) and serious adverse events (SAE), 
physical examination, vital signs and lab results. 


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4. 
STATISTICAL ANALYSIS  
4.1 
Subject samples  
There will be five subject samples.  
The All Subjects Consented subject sample will consist of all subjects who: 
- 
gave their informed consent. 
The All Subjects Allocated to Treatment subject sample will consist of all subjects who: 
- 
are in the All Subjects Consented sample; 
- 
were allocated to treatment (randomized). 
The Safety subject sample will consist of all subjects who: 
- 
are in the All Subjects Allocated to Treatment sample; 
- 
received at least one dose of the study product.  
The Full Analysis (FA) subject sample will consist of all subjects who: 
- 
are included in the Safety subject sample; 
- 
have at least one post-baseline assessment of the efficacy parameters. 
The Per Protocol (PP) subject sample will consist of all subjects who: 
- 
are included in the Full Analysis sample; 
- 
had no significant protocol violations (consideration about exclusion of patients from the PP 
sample will be performed at the Blind Data Review before the Data Base Lock). 
4.2 
Efficacy analysis  
The FA subject sample will be used for the analysis of the efficacy data. Additionally, primary 
efficacy results analysis will be conducted on the PP sample as the sensitivity analysis. 
Descriptive statistics will be presented by treatment arm for all planned efficacy endpoints. 
The PP subject sample analyses will be based on available data only and no missing data will be 
imputed. 
The FA subject sample analyses will be based how on available data only so and data following 
the last observation carried forward (LOCF) approach will be used.All parameters will be 
summarized using descriptive statistics and listed. 
4.2.1 
Primary Efficacy Analysis 
The primary efficacy endpoint is:  
- 
Change from baseline of sum of NRS-11 abdominal pain and bloating/flatulence intensity 
scores after 4 weeks of treatment. 


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The baseline abdominal pain and bloating/flatulence intensity will be determined as the average 
of the NRS-11 daily assessment during 7 days before randomization (weekly average of last week 
of screening and run-in period, in other words, the average of - 6 to 1 days). The Week 4 
assessment is the same (data from last 7 days of the corresponding week in the case duration of 
treatment 28 days: 23 to 29 days or data from the last 7 days before the last treatment day 
inclusively in the case duration of treatment did not equal 28 days. 
 
For the difference of changes in sum scores of NRS-11 pain and bloating/flatulence intensities 
after 4 weeks of treatment versus baseline between the groups Mebeverine+Simethicone versus 
Duspatalin® and Mebeverine+Simethicone versus Espumisan®, a two-sided 95% confidence 
interval (CI) will be constructed, which is equivalent to a 97.5% one-sided CI.  
The confidence interval will be constructed using ANCOVA, which will include treatment and 
site as fixed effect, and baseline parameter will be included in the model as covariate.  
ANCOVA analysis will be performed using SAS code for the analysis: 
ods output LSmeans=LSMeans; 
ods output Diffs=CL; 
proc mixed data= <dataset_name> ; 
 
  CLASS <treatment> <site>; 
 
  MODEL <change from bl> = <treatment> <site> <baseline>; 
  lsmeans <treatment> / pdiff cl; 
run; 
ods output close; 
To test the hypothesis of superiority of the FDC Mebeverine+Simethicone versus every 
comparator (Duspatalin® and Espumisan®), the upper confidence limit will be used. 
The null hypothesis (H0: no difference in change from baseline of sum of bloating/flatulence and 
pain scores between the FDC and corresponding comparator, will be rejected in favor of the 
alternative hypothesis (Ha: larger change from baseline of sum of bloating/flatulence and pain 
scores in the fixed-dose combination Mebeverine+Simethicone group) only if the upper limit of 
two-sided 95% CI does not contain the value 0.  
In addition, the study will be considered successful in case both superiority hypothesizes are 
proven, i. e. upper limit of two-sided 95% CI does not contain the value 0 for both constructed 
confidence intervals. In this case, a conclusion will be drawn on the fixed-dose combination of 
Mebeverine+Simethicone is superior versus Duspatalin® (mebeverin) and Espumisan® 
(simethicone) for the pooled decrease of pain and bloating/flatulence intensity. 
As a Sensitivity analysis # 1, PP subject sample will be used for analysis of the primary endpoint. 
Sensitivity analysis # 2, LOCF method - one the FA subject sample  will be used for analysis of 
the primary endpoint.  
ANCOVA analysis will be performed using SAS code for the sensitivity analyses # 1 and # 2: 
ods output LSmeans=LSMeans; 


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ods output Diffs=CL; 
proc mixed data= <dataset_name> ; 
 
  CLASS <treatment> <site>; 
 
  MODEL <change from bl> = <treatment> <site> <baseline>; 
  lsmeans <treatment> / pdiff cl; 
run; 
ods output close; 
Missing values will be imputed using: the nearest previous post-baseline non-missing value for 
treatment period, the EoT or the nearest previous follow-up non-missing value for follow-up 
period. If patient has a missing value after such an imputation applying, his/her ALT response 
will be considered as failure. 
Source: NST001, NSL010, NSL017. 
4.2.2 
Secondary efficacy analysis  
The secondary efficacy data are:  
• Change from baseline of NRS-11 pain intensity after 4 weeks of treatment 
• Proportion of patients with the NRS-11 pain intensity reduction of ≥30% versus baseline 
during at least 50% of treatment weeks over treatment period 
• Proportion of patients with the NRS-11 pain intensity reduction of ≥ 50% versus baseline 
during at least 50% of treatment weeks over treatment period.  
• Proportion of patients with the abdominal pain assessed in the Patient Dairy completely 
resolved during at least 50% of treatment days over treatment period (NRS-11 0 
assessment). 
• Change from baseline of NRS-11 bloating/flatulence intensity after 4 weeks of treatment 
• Proportion of patients with the NRS-11 bloating/flatulence intensity reduction of ≥30% 
versus baseline during at least 50% of treatment weeks over treatment period. 
• Proportion of patients with the NRS-11 bloating/flatulence intensity reduction of ≥ 50% 
versus baseline during at least 50% of treatment weeks over treatment period. 
• Proportion of patients with the bloating/flatulence assessed in the Patient Dairy 
completely resolved during at least 50% of treatment days over treatment period (NRS-
11 0 assessment). 
• Change in number of days per week during study treatment period when drotaverine was 
taken. 
• Change in quality-of-life evaluation using IBS-QOL questionnaire versus baseline. 
Secondary endpoints “Change from baseline of NRS-11 pain intensity after 4 weeks of 
treatment”, “Change from baseline of NRS-11 bloating/flatulence intensity after 4 weeks of 
treatment” and “Change in quality-of-life evaluation using IBS-QOL questionnaire versus 


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baseline” will be compared between the two treatment groups by means of analysis of covariance 
(ANCOVA), with treatment, site as fixed effects and baseline value (if available) as covariate. 
The same SAS code with MIXED procedure as for primary endpoint will be used for these 
endpoints.  
Secondary endpoint “Change in number of days per week during study treatment period when 
drotaverine was taken” will be compared between the two treatment groups by means of analysis 
of variance (ANOVA), with treatment, site as fixed effects. To achieve full conformity with 
ANCOVA in case of missing’s the ANOVA analysis will be performed using MIXED procedure 
as well: 
ods output LSmeans=LSMeans; 
ods output Diffs=CL; 
proc mixed data= <dataset_name> ; 
 
  CLASS <treatment> <site>; 
 
  MODEL < change in number of days > = <treatment> <site>; 
  lsmeans <treatment> / pdiff cl; 
run; 
ods output close; 
The baseline abdominal pain and bloating/flatulence intensity will be determined as the average 
of daily episodes NRS-11 assessment during 7 days before randomization (last week of screening 
and run-in period, in other words, the average of daily episodes from - 6 to 1 days). The data from 
the last week of screening and run-in period will be also used for baseline assessment of stool 
frequency and consistency and number of days of drotaverine intake. Week 1 (average of data 2 
– 8 days), Week 2 (average of data 9 – 15 days), Week 3 (average of data 16 – 22 days) and Week 
4 (average of data from the last 7 days of the corresponding week in the case duration of treatment 
28 days: 23 to 29 days or data from the last 7 days before the last treatment day inclusively in the 
case duration of treatment did not equal 28 days).  
The proportion of patients with the Scale reduction of ≥A% versus baseline during at least 50% 
of treatment weeks over treatment period must be calculated as: 
𝑛𝑇
𝑁𝑇
 
where 𝑁𝑇 is total number of patients in the treatment arm T, 𝑛𝑇 is number of patients in the 
treatment arm T who had reduction of ≥A% versus baseline (week 0) during at least 2 of treatment 
weeks over treatment period: week 1, week 2, week 3, week 4). Reduction of ≥A% must calculate 
as: 
𝑅𝑒𝑑𝑢𝑐𝑡𝑖𝑜𝑛𝑖 =
𝑆𝑐𝑎𝑙𝑒𝑊𝑒𝑒𝑘𝑖
̅̅̅̅̅̅̅̅̅̅̅̅̅̅ −𝑆𝑐𝑎𝑙𝑒𝑊𝑒𝑒𝑘0
̅̅̅̅̅̅̅̅̅̅̅̅̅̅
𝑆𝑐𝑎𝑙𝑒𝑊𝑒𝑒𝑘0
̅̅̅̅̅̅̅̅̅̅̅̅̅̅
 × 100 ≥𝐴% 
 
The transformation formula used for the IBS-QOL total and scale scores is:  




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Treatment Emergent Adverse Events 
An AE that starts during a unique treatment or that already exists before the start of that unique 
treatment but worsens during the treatment or post-treatment period (if no longer than 7 days 
after last dose of respective treatment) will be considered as treatment emergent for that unique 
treatment.  
The following unique treatments are distinguished: Mebeverine + Simethicone, 135 mg+80 mg, 
three times a day; Duspatalin 135 mg three times a day; Espumisan, 80 mg (2 capsules 40 mg) 
three times a day. AEs will be reported on a per-subject basis, i.e., counting subjects rather than 
events. This means that if a subject suffers the same AEs repeatedly during the applicable study 
or treatment period, the event will be counted only once for that period. Repeated events per 
subject will be summarized according to the following rule: if a subject suffered the same AE 
more than once, the event will be assigned the worst severity, the closest relationship to the 
study drug and the earliest starting date. Only treatment emergent AEs (TEAE) will be reported. 
In the listings, however, all occurrences of the AEs will be presented. 
For each unique treatment, TEAES will be summarized by MedDRA primary system organ 
class (SOC), high level term (HLT) within primary SOC and preferred term (PT) within HLT 
and primary SOC. Severity and drug-event relationship of adverse events are summarized 
separately. 
In the listings, all occurrences of AEs will be presented together with all relevant information 
from the eCRFs. In addition, TEAEs will be flagged. Start and end day of the AE and the day of 
last dose of study drug will be also presented, relative to the start day of the treatment under 
which is started or worsened and relative to start of any study drug. 
SAEs leading to death, non-fatal SAEs, TEAEs leading to study termination, TEAEs leading to 
discontinuation of study drug will be listed separately. 
Vital signs, body weight, waist circumference and body mass index (BMI) 
Vital signs include systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse 
rate.  
Vital signs, body weight, waist circumference and BMI including changes from baseline will be 
summarized with descriptive statistics per treatment group.  
Markedly abnormal values will be identified in accordance with pre-defined criteria, as 
presented in Table 5 in SAP Module 2.  
The number and percentage of subjects with any post-baseline markedly abnormal value under 
treatment will be presented by variable, treatment. Percentages will be based on the total 
number of subjects with a baseline and post-baseline measurement of the specified variable in 
the analysis sample. All markedly abnormal values will be listed. 
 
Safety will be assessed per treatment arm, based on the incidence and severity of AE and SAE, 
physical examination, vital signs and laboratory test results. 


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Laboratory data 
Hematology and biochemistry values will be reported and analyzed in SI units (International 
System of Units). 
Laboratory test results including changes from baseline will be summarized with descriptive 
statistics by treatment and cohort.  
Each observed hematology and biochemistry value will be categorized whether it is lying 
below, within, or above the laboratory's reference range. These categories (low, normal, high) 
plus a category for missing values will be cross-tabulated (shift table) for baseline versus all 
time points. Only subjects with a value at baseline and the respective time point will be included 
in the shift table. 
Markedly abnormal values will be identified in accordance with pre-defined criteria, as 
presented in Table 2 and 3 in SAP Module 2.  
Additionally, a value of INR > 1.5 will be defined as markedly abnormal value. 
The number and percentage of subjects with any post-baseline markedly abnormal value under 
treatment will be presented by laboratory test and treatment. Percentages will be based on the 
total number of subjects with a post-baseline measurement of the specified laboratory test in the 
analysis sample. 
All markedly abnormal and/or clinically significant values will be listed. 
 
Analysis of safety endpoints: 
Safety variables will be summarized descriptively per treatment. Quantitative variables will be 
described by n, arithmetic mean, SD, minimum and maximum. Qualitative variables will be 
described by frequency tables containing counts and percentages. 
For each unique treatment, treatment emergent AEs will be summarized per primary SOC, per 
HLT by primary SOC and per PT by HLT and primary SOC. Severity and drug-event relationship 
of treatment emergent AEs are summarized separately. 
Laboratory values, vital signs and their changes from baseline will be summarized by visit in 
tables of descriptive statistics. Abnormal values (according to the reference ranges) will be 
presented in frequency tables (low, normal and high values). 
4.3.1 
Demographic Data and Other Baseline Characteristics 
Source: DMT002, DML002, VST003, VSL003, NSL016 
Patient distribution, demographic and baseline characteristics will be presented using descriptive 
statistics. The number and percentage of patients receiving concomitant medications will be 
presented in frequency tables according to the ATC classification and the generic name. The 
number of patients with prior medical conditions will be presented. Information on dosage, 
including daily doses, exposure time and the total dose, will be presented using descriptive 


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statistics for each treatment group, additionally baseline characteristics will be presented for 
subgroups (patients with IBS and other functional bowel diseases, patients with constipation, 
diarrhea, both constipation and diarrhea, neither of them) 
All variables in this section will be reported on a by-subject data listing. 
Such continuous characteristics as: age, height, weight, body mass index (BMI), body 
temperature, respiration rate, systolic blood pressure (in sitting position) (SBP), diastolic blood 
pressure (in sitting position) (DBP), pulse rate will be reported on tables grouped by treatment 
with the number (n), arithmetic mean, standard deviation (SD), median, minimum (min) and 
maximum (max) of unique subjects who have at least one measurement of the demographic data 
or other baseline characteristics. 
For more detailed information about values calculations see Module 2 
4.3.2 
Medical History 
Source: MHT001, MHL001, MHL002, NSL001, NST006 
Medical history will be presented in tables grouped by treatment, SOCs, HLTs, PTs and sorted 
by descending order of total incidence. SOCs, HLTs, PTs will be coded by the Medical Dictionary 
for Regulatory Activities version 24.0 ENG (MedDRA 24.0 ENG). In addition to this, the 
information will be reported on a by-subject data listing, for more detailed information see 
Module 2. 
Additionally, the listing for disease information (index diagnosis and start date) and frequency 
table by index diagnosis will be presented. 
An intergroup comparison for two treatment groups is not planned. 
4.3.3 
Physical Examinations 
Source: NSL002 
Physical examinations will be reported on a by-subject data listing with the visits, visit dates of 
physical examinations. 
4.3.4 
Vital Signs, height and weight 
Source: VST001, VST002, VSL004, VSL005 
All variables in this section will be reported on a by-subject data listing. 
All characteristics will be reported on tables grouped by treatment with the number (n), mean, 
standard deviation (SD), median, minimum (min) and maximum (max) of unique subjects who 
have at least one measurement of the vital signs (other baseline characteristics). 


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Also, abnormal vital signs from the module 1 and markedly abnormal vital signs criteria will be 
reported on table grouped by treatment with the number (n) and percentage (%) of unique subjects 
with at least one type of measurement of the parameter.   
For more detailed information about norms, value calculation etc. see Module 2. 
4.3.5 
Visual Analogue Scales  
Source: NST002, NSL003, NSL014, NSL015 
The results of assessment by visual analogue scales (NRS-11) at screening/run-in and study 
treatment periods will be presented in by-subject data listing with the name of a scale, time of 
assessment, units and result of assessment and summarized by treatment group and scale. The 
number (n), mean, standard deviation (SD), median, minimum (min) and maximum (max) of 
unique subjects with at least one scale measurement will be presented in the table. 
4.3.6 
Safety Laboratory Data 
Source: LBT001, LBT002, LBT003, LBT004, LBT005, LBL002, LBL003, LBL007, LBL008 
All variables in this section will be reported on a by-subject data listings. 
Safety laboratory information will be collected as quantitative (hematology and biochemistry 
assessments only) and qualitative (all laboratory tests) data. The quantitative data will be reported 
on listings and tables with the following statistics: the number (n), arithmetic mean, standard 
deviation (SD), median, minimum (min) and maximum (max) of unique subjects who have at 
least one measurement of safety laboratory data. In contrast to this, the qualitative data will be 
reported on shift-tables with the following statistics: the number (n) and percentage (%) of unique 
subjects with safety laboratory measurement. There are will be presented such characteristics of 
values as “Low”, “Normal” and “High”.  
Each center uses its own safety laboratory norms for hematology and biochemistry assessments 
and normal values for urinalysis are not defined centrally. Investigators will choose the most 
appropriate answer (“Normal” or “Abnormal”) for a value. In case an investigator chooses the 
point “Abnormal” he/she has to define whether the deviation is clinically significant (“Yes” or 
“No”). 
For more detailed information see Module 2. 
4.3.7 
Adverse Events 
 
Source: AET001, AET002, AET003, AET005, AET006, AET007, AET008, AET009, 
AET010, AEL002, AEL008, AEL009, AEL010, AEL011, AEL012, AEL013 
Adverse Events will be presented in tables grouped by treatment, SOCs, HLTs, PTs and sorted 
by descending order of total incidence. SOCs, HLTs, PTs will be coded by the Medical Dictionary 
for Regulatory Activities version 23.1 ENG (MedDRA 23.1 ENG). In addition to this, the 
information will be reported on a by-subject data listing. 


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Adverse Events (TEAEs) started after the last administration of study drug but within the Gap 
Period after the last administration will also be attributed to the Treatment Period. For more 
detailed information see Module 2.  
An intergroup comparison for two treatment groups is not planned. 
4.3.8 
Time of administration (patient diary) 
Source: NSL004 
Time of administration collected in patient diary will be presented in a by-subject data listing with 
the date and treatment day of assessment and also time of each administration per day. 
4.3.9 
Concomitant Medication 
Source: CMT001, CML001, CML002 
Concomitant Medication will be presented in tables grouped by treatment, ATC 3rd level or ATC 
4th level, preferred name WHO DD and sorted by descending order of total incidence. All 
parameters except treatment group will be coded by the World Health Organization-Drug 
Dictionary (WHO-DD) of the latest version. In addition to this, the information will be reported 
on a by-subject data listing. 
Medications started after the last administration of study drug but within the Gap Period (7 days) 
after the last administration will also be assigned to the Treatment Period. For more detailed 
information see Module 2. 
An intergroup comparison for two treatment groups is not planned. 
4.3.10 
Drug Accountability, Treatment Compliance and Exposure 
Source: DAT001, DAL001, NST005, NSL04 
The patient should take the first study drug dose at the Visit 2 day (Week 0). During telephone 
contact (TC 1, Week 2, Day 0), the Investigator checks the patient’s treatment compliance and 
whether he/she follows the recommendations on the Patient’s Diary filling, and, if necessary, 
conducts an additional conversation with the patient about the proper drug administration and 
filling out the Patient’s Diary. At Visit 3 (Week 4, Day 29), the patient should return all used and 
unused study drug packagings. The Investigator will check compliance with the recommendations 
for study drug self-administration at Visit 3 (Week 4, Day 29) based on the results of accounting 
for the returned study drug and the patient’s diary. 
The study drug compliance will be calculated at Visit 3 using the formula: 
Compliance = (N dispensed. – N returned.) / N calc. * 100% 
where N dispensed. = number of tablets/capsules dispensed,  
N returned. = number of tablets/capsules returned,  


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N calc. = estimated number of tablets/capsules the volunteer was to receive since the 
previous visit. 
The calculated percentage compliance will be categorized as: 
- Too Low:  < 80% compliance. 
- Adequate:  ≥ 80% to ≤ 120% compliance. 
- Too High:  > 120% compliance. 
Sum dose of study drug (mg), duration of taken study drug (days) and average dose taken per day 
(mg) will be calculated for each subject. Data is collected in patient diaries. 
Duration of taken study drug (days) will be calculated as sum of days where at least one dose 
were taken by subject. 
Average dose taken per day (mg) will be calculated with the following formula: 
Average dose taken per day (mg) = 
𝐒𝐮𝐦 𝐝𝐨𝐬𝐞 𝐨𝐟 𝐬𝐭𝐮𝐝𝐲 𝐝𝐫𝐮𝐠 (𝐦𝐠)
𝐃𝐮𝐫𝐚𝐭𝐢𝐨𝐧 𝐨𝐟 𝐭𝐚𝐤𝐞𝐧 𝐬𝐭𝐮𝐝𝐲 𝐝𝐫𝐮𝐠 (𝐝𝐚𝐲𝐬) 
All data of drug accountability, treatment compliance and exposure will be presented in subject 
data listings and by-treatment group tables. 
4.3.11 
Compliance with selection criteria assessments. 
Source: NSL006, NSL007, NSL008, NSL009 
Pregnancy test, test for HIV, hepatitis B and C, feces analysis for fecal calprotectin and 
colonoscopy results will be listed only. 
4.4 
Interim Analysis  
Interim analysis was removed after amendment. The reason for this was a very steep increase of 
patients’ recruitment over last weeks before interim analysis. Therefore, even if the interim 
analysis resolution would have been to stop the study, all screened patients would have already 
completed the study per the protocol. So, conduct of the interim analysis would have been 
futile. 
4.5 
Data Safety Monitoring Board  
Not applicable. 
4.6 
Safety Management Team  
Not applicable. 
 


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5. 
DESCRIPTION OF NON-STANDARD DATA COLLECTED AND DERIVED 
VARIABLES  
5.1 
Other Non-Standard Baseline Characteristics 
Not applicable. 
5.2 
Non-Standard Disease History 
Not applicable. 
5.3 
Efficacy data 
The efficacy data collected are:  
Efficacy data collected in the study are: assessment of pain abdominal pain and 
bloating/flatulence intensity as measured by NRS-11 scale. 
5.4 
Non-standard Safety Data 
The following non-standard safety data are collected: Exposure. 
5.5 
Drug Accountability and Exposure   
Drug accountability and exposure variables collected in the study is: number of tablets per day. 
Drug accountability and exposure variables calculated during the analysis are: sum dose of study 
drug (mg), duration of taken study drug (days), average dose taken per day (mg), compliance. 


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6. 
FURTHER SPECIFICATIONS TO THE STANDARD ANALYSES IN 
MODULE 2 
6.1 
Trial Design [2] 
6.1.1 
Trial Periods 
 
 
Screening 
and run-in 
period 
Treatment Period 
Follow up 
Mebeverine + 
Simethicone 
Screening (Days -21 - 1) Investigational 
Treatment (Days 1-29) 
Follow up 
(Day 36) 
Duspatalin 
Screening (Days -21 - 1) Investigational 
Treatment (Days 1-29) 
Follow up 
(Day 36) 
Espumisan 
Screening (Days -21 - 1) Investigational 
Treatment (Days 1-29) 
Follow up 
(Day 36) 
 
6.1.2 
Trial Elements 
 
Trial Element 
Description of 
Element 
Rule for Start of 
Element   
Rule for End of 
Element 
Planned 
Duration of 
Element 
Screen 
Screening and 
Randomization 
Informed consent 
obtained 
First dose of 
treatment 
 
Treatment 
“Mebeverine+ 
Simethicone” 
Investigational 
Treatment of taken study 
drug “Mebeverine + 
Simethicone” 
First administration 
of “Mebeverine + 
Simethicone” 
6 days after first 
administration of 
“Mebeverine + 
Simethicone” 
7 days 
Treatment 
“Duspatalin” 
Investigational 
Treatment of taken study 
drug “Duspatalin” 
First administration 
of “Duspatalin” 
6 days after first 
administration of 
“Duspatalin” 
7 days 
Treatment 
“Espumisan” 
Investigational 
Treatment of taken study 
drug “Espumisan” 
First administration 
of “Espumisan” 
6 days after first 
administration of 
“Espumisan” 
7 days 
FOLLOW UP 
Follow-up period 
Date of last study 
drug administration 
Last Contact with 
Subject 
1 day 
 
 
6.1.3 
Trial Arms 
 


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Trial Arm 
Elements 
Screen 
Treatment 
“Mebeverine + 
Simethicone” 
Treatment 
“Duspatalin” 
Treatment 
“Espumisan” 
FOLLOW 
UP 
Mebeverine 
+ 
Simethicone 
Screening and 
Randomization  
Investigational 
Treatment of 
taken study drug 
“Mebeverine + 
Simethicone” 
– 
– 
Follow-
up period 
Duspatalin 
Screening and 
Randomization 
– 
Investigational 
Treatment of 
taken study drug 
“Duspatalin” 
– 
Follow-
up period 
Espumisan 
Screening and 
Randomization  
– 
– 
Investigational 
Treatment of 
taken study drug 
“Espumisan” 
Follow-
up period 
 
6.1.4 
Unique Treatments 
The trial arms for this study are made up of the following unique treatments: 
 
Unique treatment 
Arm 
Elements 
Description 
Label 
Screen 
Treatment 
“Mebeveri
ne + 
Simethicon
e” 
Treatment 
“Duspatali
n” 
Treatment 
“Espumisa
n” 
FOLLO
W UP 
Mebeverine + 
Simethicone, 
135 mg+80 mg, 
three times a 
day 
Mebeveri
ne + 
Simethico
ne 
Mebeveri
ne + 
Simethic
one 
Screening 
and 
Randomizat
ion  
Investigatio
nal 
Treatment 
of taken 
study drug 
“Mebeveri
ne + 
Simethicon
e” 
– 
– 
Follow-
up 
period 
DuspatalinDuspatal
in– 


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Duspatalin 135 
mg three times 
a day 
Duspata
lin 
Duspata
lin 
Screening 
and 
Randomizat
ion 
– 
Investigatio
nal 
Treatment 
of taken 
study drug 
“Duspatali
n” 
– 
Follow-
up 
period 
Espumisan, 80 
mg (2 capsules 
40 mg) three 
times a day 
Espumis
an  
Espumis
an  
Screening 
and 
Randomizat
ion  
– 
– 
Investigatio
nal 
Treatment 
of taken 
study drug 
“Espumisa
n” 
Follow-
up 
period 
 
6.1.5 
Visits and related definitions 
 
Test / 
Examination 
Visit name 
Visit Label 
Visit 
Number 
Reference Start 
Date/Time 
Relative 
Day 
Number 
Informed 
Consent Form, 
patient 
registration 
Screening 
Screening 
1 
Date of 
Informed 
consent 
obtained 
-21…-7 
Demography, 
medical history  
Screening 
Screening 
1 
Date of 
Informed 
consent 
obtained 
-21…-7 
Weight, Height 
(screening only), 
BMI  
Screening 
Screening 
1 
Date of 
Informed 
consent 
obtained 
-21…-7 
Visit 1 
Visit 1 (week 0) 
2 
Date of first 
Drug 
Adminitration 
1 
 
Visit 3 (End 
of Trial)  
Visit 3 End of 
Trial or Early 
Discantinuation 
visit 
4 
Date of last 
Drug 
Administration 
29 (+-1) 


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Test / 
Examination 
Visit name 
Visit Label 
Visit 
Number 
Reference Start 
Date/Time 
Relative 
Day 
Number 
Physical 
examination 
Screening 
Screening 
1 
Date of 
Informed 
consent 
obtained 
-21…-7 
Visit 3 (End 
of Trial)  
Visit 3 End of 
Trial or Early 
Discantinuation 
visit 
4 
Date of last 
Drug 
Administration 
29 (+-1) 
Vital signs 
Screening 
Screening 
1 
Date of 
Informed 
consent 
obtained 
-21…-7 
Visit  
Visit 1 (week 0) 
2 
Date of first 
Drug 
Adminitration 
1 
 
Visit 3 (End 
of Trial)  
Visit 3 End of 
Trial or Early 
Discantinuation 
visit 
4 
Date of last 
Drug 
Administration 
29 (+-1) 
Hematology 
Screening 
Screening 
1 
Date of 
Informed 
consent 
obtained 
-21…-7 
Visit 3 (End 
of Trial)  
Visit 3 End of 
Trial or Early 
Discantinuation 
visit 
4 
Date of last 
Drug 
Administration 
29 (+-1) 
Biochemistry 
Screening 
Screening 
1 
Date of 
Informed 
consent 
obtained 
-21…-7 
Visit 3 (End 
of Trial)  
Visit 3 End of 
Trial or Early 
Discantinuation 
visit 
4 
Date of last 
Drug 
Administration 
29 (+-1) 


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Test / 
Examination 
Visit name 
Visit Label 
Visit 
Number 
Reference Start 
Date/Time 
Relative 
Day 
Number 
Pregnancy test 
Screening 
Screening 
1 
Date of 
Informed 
consent 
obtained 
-21…-7 
Urinalysis 
Screening 
Screening 
1 
Date of 
Informed 
consent 
obtained 
-21…-7 
Visit 3 (End 
of Trial)  
Visit 3 End of 
Trial or Early 
Discantinuation 
visit 
4 
Date of last 
Drug 
Administration 
29 (+-1) 
Tests for HIV, 
hepatitis B and C  
Screening 
Screening 
1 
Date of 
Informed 
consent 
obtained 
-21…-7 
Feces analysis 
for fecal 
calprotectin  
Screening 
Screening 
1 
Date of 
Informed 
consent 
obtained 
-21…-7 
Colonoscopy  
Screening 
Screening 
1 
Date of 
Informed 
consent 
obtained 
-21…-7 
ECG  
Screening 
Screening 
1 
Date of 
Informed 
consent 
obtained 
-21…-7 
Randomization  
Visit 1 
Visit 1 (week 0) 
2 
Date of first 
Drug 
Administration 
1 
 
Abdominal pain 
intensity on the 
NRS-11 scale 
Screening 
Screening 
1 
Date of 
Informed 
consent 
obtained 
-21…-7 


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Test / 
Examination 
Visit name 
Visit Label 
Visit 
Number 
Reference Start 
Date/Time 
Relative 
Day 
Number 
Visit 1 
Visit 1 (week 0) 
2 
Date of first 
Drug 
Administration 
1 
 
Visit 2 
(Telephone 
Call) 
Visit 2 (Telephone 
Call) 
3 
Date of 
Telephone Call 
15 (+-1) 
Visit 3 (End 
of Trial)  
Visit 3 End of 
Trial or Early 
Discantinuation 
visit 
4 
Date of last 
Drug 
Administration 
29 (+-1) 
Flatulence 
intensity on the 
NRS-11 scale 
Screening 
Screening 
1 
Date of 
Informed 
consent 
obtained 
-21…-7 
Visit 1 
Visit 1 (week 0) 
2 
Date of first 
Drug 
Adminitration 
1 
 
Visit 2 
(Telephone 
Call) 
Visit 2 (Telephone 
Call) 
3 
Date of 
Telephone Call 
15 (+-1) 
Visit 3 (End 
of Trial)  
Visit 3 End of 
Trial or Early 
Discantinuation 
visit 
4 
Date of last 
Drug 
Administration 
29 (+-1) 
Stool frequency 
Screening 
Screening 
1 
Date of 
Informed 
consent 
obtained 
-21…-7 
Visit 1 
Visit 1 (week 0) 
2 
Date of first 
Drug 
Adminitration 
1 
 
Visit 2 
(Telephone 
Call) 
Visit 2 (Telephone 
Call) 
3 
Date of 
Telephone Call 
15 (+-1) 


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Test / 
Examination 
Visit name 
Visit Label 
Visit 
Number 
Reference Start 
Date/Time 
Relative 
Day 
Number 
Visit 3 (End 
of Trial)  
Visit 3 End of 
Trial or Early 
Discantinuation 
visit 
4 
Date of last 
Drug 
Administration 
29 (+-1) 
Bristol stool 
scale 
Screening 
Screening 
1 
Date of 
Informed 
consent 
obtained 
-21…-7 
Visit 1 
Visit 1 (week 0) 
2 
Date of first 
Drug 
Adminitration 
1 
 
Visit 2 
(Telephone 
Call) 
Visit 2 (Telephone 
Call) 
3 
Date of 
Telephone Call 
15 (+-1) 
Visit 3 (End 
of Trial)  
Visit 3 End of 
Trial or Early 
Discantinuation 
visit 
4 
Date of last 
Drug 
Administration 
29 (+-1) 
Patient diary 
distribution 
Screening 
Screening 
1 
Date of 
Informed 
consent 
obtained 
-21…-7 
Visit 1 
Visit 1 (week 0) 
2 
Date of first 
Drug 
Adminitration 
1 
 
Patient diary 
assessment 
Visit 1 
Visit 1 (week 0) 
2 
Date of first 
Drug 
Adminitration 
1 
 
Visit 2 
(Telephone 
Call) 
Visit 2 (Telephone 
Call) 
3 
Date of 
Telephone Call 
15 (+-1) 
Visit 3 (End 
of Trial)  
Visit 3 End of 
Trial or Early 
Discantinuation 
visit 
4 
Date of last 
Drug 
Administration 
29 (+-1) 


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Test / 
Examination 
Visit name 
Visit Label 
Visit 
Number 
Reference Start 
Date/Time 
Relative 
Day 
Number 
Evaluate the 
quality of life 
(IBSQOL 
questionnaire) 
Visit 1 
Visit 1 (week 0) 
2 
Date of first 
Drug 
Adminitration 
1 
 
Visit 3 (End 
of Trial)  
Visit 3 End of 
Trial or Early 
Discantinuation 
visit 
4 
Date of last 
Drug 
Administration 
29 (+-1) 
Study drug 
dispense 
Visit 1 
Visit 1 (week 0) 
2 
Date of first 
Drug 
Adminitration 
1 
 
Study drug 
accountability 
and compliance 
assessment 
Visit 3 (End 
of Trial)  
Visit 3 End of 
Trial or Early 
Discantinuation 
visit 
4 
Date of last 
Drug 
Administration 
29 (+-1) 
Study drug return  
Visit 3 (End 
of Trial)  
Visit 3 End of 
Trial or Early 
Discontinuation 
visit 
4 
Date of last 
Drug 
Administration 
29 (+-1) 
Adverse events 
Screening 
Screening 
1 
Date of 
Informed 
consent 
obtained 
-21…-7 
Visit 1 
Visit 1 (week 0) 
2 
Date of first 
Drug 
Adminitration 
1 
 
Visit 2 
(Telephone 
Call) 
Visit 2 (Telephone 
Call) 
3 
Date of 
Telephone Call 
15 (+-1) 
Visit 3 (End 
of Trial)  
Visit 3 End of 
Trial or Early 
Discantinuation 
visit 
4 
Date of last 
Drug 
Administration 
29 (+-1) 
Follow up 
Follow up 
5 
Date of Follow 
up 
36 (+1) 


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Test / 
Examination 
Visit name 
Visit Label 
Visit 
Number 
Reference Start 
Date/Time 
Relative 
Day 
Number 
Concomitant 
medications 
Screening 
Screening 
1 
Date of 
Informed 
consent 
obtained 
-21…-7 
Visit 1 
Visit 1 (week 0) 
2 
Date of first 
Drug 
Adminitration 
1 
 
Visit 2 
(Telephone 
Call) 
Visit 2 (Telephone 
Call) 
3 
Date of 
Telephone Call 
15 (+-1) 
Visit 3 (End 
of Trial)  
Visit 3 End of 
Trial or Early 
Discantinuation 
visit 
4 
Date of last 
Drug 
Administration 
29 (+-1) 
Follow up 
Follow up 
5 
Date of Follow 
up 
36 (+1) 
 
 
 


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6.2 
Further Specifications to the Standard Tables in Module 2 
Not applicable 
 
 
6.3 
Other Further Specifications 
Not applicable