Effect of STW5 (Iberogast ®) and STW5-II (Iberogast N®) on Transit and Tolerance of Intestinal Gas
Effect of STW5 (Iberogast ®) and STW5-II (Iberogast N®) on Transit and Tolerance of Intestinal Gas
Study to asess the effects of Iberogast® (STW5) and Iberogast® N (STW5-II) in intestinal gas
 transit and abdominal symptoms of patients suffering from irritable bowel syndrome or
 functional dyspepsia.
Every day great amounts of gas enter into the intestine from several sources, including air
 swallowed during meals and gas produced by colonic fermentation by intestinal bacteria.

 Recent studies have shown that gastric nutrients delay emptying of gastric gas in healthy
 subjects, and this effect is exacerbated in patients with functional dyspepsia, leading to a
 lower tolerance to gastric gas and greater gas-related epigastric symptoms. Likewise,
 patients with lower functional gut disorders, like irritable bowel syndrome or functional
 bloating, have an altered transit and evacuation of intestinal gas that is associated to
 abdominal symptoms. In addition, bloating and abdominal distension are gas-related abdominal
 symptoms that are common to both upper and lower functional gut disorders, and referred by a
 majority of patients, as their most bothersome symptoms.

 STW5 (Iberogast®) is a medicinal product composed by 9 herbal preparations that has been
 shown to promote changes in gastric tone, gastrointestinal motility, intestinal inflammation
 and visceral sensitivity.

 Iberogast® is approved in Spain for treatment of gastrointestinal disorders like dyspepsia
 and gastritis, as well as for symptomatic relief of associated symptoms as epigastric pain,
 bloating, flatulence, gastrointestinal colics, nausea and epigastric burning sensation
 (extract from Summary of product characteristics, SmPC) ).

 STW5-II (Iberogast N®) is an herbal medicinal preparation consisting of six herbal extracts
 (Iberis amara whole plant, caraway fruits, liquorice roots, peppermint leaves, lemon balm
 leaves, and chamomile flowers). It contains an extract combination of Iberis amara as an
 alcoholic fresh plant extract as well as plant extracts of caraway fruits, liquorice roots,
 peppermint leaves, lemon balm leaves, and chamomile flowers as alcoholic drug extracts. The
 preparation contains 31% ethanol.

 Iberogast N® was approved in Germany only on 07 Oct 2010 and is indicated for the treatment
 of functional gastrointestinal diseases like functional dyspepsia (FD) and irritable bowel
 syndrome (IBS) . It was marketed with only very few packs to keep the license. It is approved
 for adolescents and adults from the age of 12 years, as for patients below the age of 12 no
 data are available.

 Iberogast N was tested in five controlled clinical trials with a dosage scheme of 3 x 20
 drops/day over 4 to 12 weeks.

 Efficacy was proven in the indications FD (four studies) and IBS (one study). Approximately
 441 participants have been treated with Iberogast N in clinical studies. The analysis of AEs
 did not lead to any safety signal or concern and supports the favorable benefit risk profile
 of BAY98-7410 (STW 5-II).

 Three subjects from the overall safety population that participated in 6 interventional
 studies, experienced at least one SAE, including 1 subject of 139 (0.71%) treated with
 BAY98-7410 (STW 5-II) (female, 43 years old, hospitalized due circulatory problems, treatment
 was discontinued) and 2 subjects (1.5%) of 133 treated with placebo (1 male, 65 years old,
 hospitalized due psychiatric disorders triggered by stressful life events, treatment was
 discontinued; 1 female, 47 years old, diagnosed during hospitalization with anemia, treatment
 was discontinued). All SAEs were only reported for the interventional study STW5
 II/212-D-03-III-V and were assessed as not related to study treatment (Information from
 Investigator Brochure).

 In addition, laboratory investigations of the subjects during the clinical trials gave no
 evidence for clinically relevant changes caused by treatment with Iberogast N.

 Functional gut disorders comprise a large number of chronic medical conditions that may
 affect all the segments of the gastrointestinal tract, from the esophagus to the anus,
 characterized by a combination of disturbances including dysbiosis, altered permeability,
 altered immunological responses and microinflammation, motor and sensory dysfunction, and
 altered processing of the gut stimuli by the central nervous system. The most prevalent
 functional gastrointestinal disorders are functional dyspepsia and irritable bowel syndrome.
 Functional dyspepsia is characterized by symptoms (pain, burning, fullness and early satiety)
 referred to the epigastrium, whereas irritable bowel syndrome is characterized by abdominal
 pain and altered bowel habits. In both disorders gas-related abdominal symptoms, like
 abdominal bloating and distension, are among the most frequently referred symptoms. Treatment
 of these gas-related abdominal symptoms is often disappointing, and patients are often
 advised to follow very restrictive diets, like the low-FODMAP diet, to control these
 symptoms. However, these restrictive diets are not harmless, because they can lead to
 malnutrition, and to severe alterations of gut microbiota.

 Now-to-date, despite the prevalence of gas-related abdominal symptoms in patients with
 functional gut disorders, and the multitarget effects of the herbal preparation Iberogast,
 with several mechanisms of action like changes in motility and sensitivity that could act on
 bloating and gas retention, there are no studies exploring the effects of Iberogast on
 intestinal gas transit and tolerance in subjects with functional gut disorders. Hence, the
 aim of the present trial is to determine the effects of Iberogast, and the simplified formula
 Iberogast N, on intestinal transit and tolerance in subjects with functional dyspepsia and
 irritable bowel syndrome according to Rome IV criteria, using a methodology for the study of
 gas transit that has been largely used and validated by the investigation team.
Inclusion Criteria:

 1. Subject has read and signed the institutional review board-approved informed consent
 form before screening.

 2. ≥18 years old.

 3. Confirmed irritable bowel syndrome (ibs) or functional dyspepsia (fd) diagnosis per
 rome iv criteria.

 4. Has active symptoms of bloating.

 5. Subject must be willing to comply with the protocol.

 6. Female subjects who are capable of conceiving must use an acceptable form of
 contraception in order to participate in the study*. *women of childbearing potential
 must have a negative pregnancy test prior to randomization into the study and
 commitment to use at least one of these birth control methods: male or female condom
 with or without spermicide, cap, hormonal contraception, diaphragm or sponge with or
 without spermicide, intrauterine device, bilateral tubal occlusion, vasectomized
 partner, sexual abstinence during the study. based on ich, m3 (r2) 2009 a woman is
 considered of childbearing potential: fertile, following menarche and until becoming
 post-menopausal unless permanently sterile. permanent sterilization methods include
 tubal ligation, hysterectomy, bilateral oophorectomy.

 Exclusion Criteria:

 1. Presence of any organic gastrointestinal diseases.

 2. Subjects with known hypersensitivity to Iberogast or one of the active substances or
 excipients.

 3. One or more medical condition(s), including renal, hepatic, hematologic,
 endocrinological, neurologic, or immune disease that in the opinion of the
 Investigator would make the subject an inappropriate candidate for this study.

 4. Subjects with impaired liver function tests

 5. Malignant disease not in remission.

 6. Presence of any active infectious disease.

 7. Subjects not willing to stop medications that may interfere with gastrointestinal
 motility during 48 h previous to the gas infusion tests. These include: bulking
 agents, laxatives, linaclotide, prokinetics, antidiarrheal or opioids.

 8. Known alcohol or drug abuse.

 9. Female participants of childbearing potential with a positive pregnancy test, breast
 feeding, or female participants of childbearing potential without adequate
 contraception.

 10. Subject judged by the investigator or study staff to be unable or unlikely to comply
 with daily protocol requirements, or study visits.