The Role of Irritable Bowel Syndrome in Lactose Intolerance (LION)

Study Overview
=================
Brief Summary
-----------------
Irritable bowel syndrome (IBS) is a functional gastrointestinal disease. There is no well-defined pharmacological treatment. This clinical trial is a prospective, double-blind, two-armed randomized controlled, single-center trial. It is created to examine the role of IBS in patients with lactose intolerance. IBS patients undergo lactose H2 breath test (LHBT) and lactose tolerance test (LTT). Those with positive LTT and LHBT will be randomized into two groups: alverine-citrate + simethicone and lactase group (1) or alverin-citrate + simethicone with the placebo group (2). The goal of this study is to compare the lactase enzyme with placebo in IBS patients with lactose intolerance.

Detailed Description
-----------------
Irritable bowel syndrome (IBS) is one of the most frequently diagnosed gastroenterological disorders and can lead to significant deterioration of quality of life and an increase in health care and societal costs. Patients with lactose intolerance are unable to fully digest lactose caused by lactose malabsorption. The undigested lactose moves into the large intestine, fermented by bacteria, and causes bloating, gas, and diarrhea symptoms. The two, most frequently used diagnostic methods are the lactose H2 breath test (LHBT) and the lactose tolerance test (LTT). The restriction of lactose input or the replacement of the lactase enzyme can lead to the relief of the symptoms. Lactose intolerance is a common disorder among patients with IBS, it is more frequent than in the general population. There are no studies that assess the link between lactose intolerance and IBS. Our primary objective is the examination of the relationship between lactose intolerance and IBS with or without the replacement of lactase enzyme. Our secondary objectives are to compare the lactase/beta-galactosidase enzyme replacement with placebo with the evaluation of a TSS (Total symptom score), VAS (Visual Analog Scale), QoL (Quality of life) questionnaires. The other secondary outcomes are to compare the severity of baseline symptoms during and after lactose administration. Patients diagnosed with IBS according to the Rome IV criteria will test with LTT and LHBT. Who has positive LTT and LHBT will randomize into two groups: (1) alverine-citrate + simethicone and lactase; (2) alverin-citrate + simethicone with placebo.

Official Title
-----------------
The Role of Irritable Bowel Syndrome in Lactose Intolerance (LION Trial): Protocol of a Multicentre Randomized Controlled Clinical Trial

Conditions
-----------------
Irritable Bowel Syndrome, Lactose Intolerance, Lactose Malabsorption

Intervention / Treatment
-----------------
* Drug: alverine-citrate + simethicone and lactase
* Drug: alverin-citrate + simethicone with placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: age 18-80 years patients diagnosed with irritable bowel syndrome based on the ROME IV. criteria positive LHBT (lactose H2 breath test) and LTT (lactose tolerance test) results negative abdominal ultrasound/CAT scan/MRI results within one year signed the informed consent Exclusion Criteria: organic gastroenterological disorders which can explain symptoms (e.g. positive serological screening: anti-gliadin IgG / IgA, anti-tissue transglutaminase IgG / IgA, high level of fecal calprotectin tested by endoscopy or positive colonoscopy for IBD, currently active diverticulitis Alarm symptoms: fever (> 38 Co), anaemia (Hgb < 120 g/l), unintended weight loss (> 4.5 kg / 3 months), gastrointestinal bleeding (hematemesis, hematochesia, melena) cardiac failure (NYHA III-IV) liver cirrhosis (Child-Pugh C) active malignancy major abdominal surgery in the history pregnant or breastfeeding women any circumstances which can lead to false results of LHBT and LTT: cigarette smoking or physical exercise within 2 hours before the test, ingestion of dietary fibers on the evening before the test, recent use of antibiotics, lung disease, baseline H2 concentration in the exhaled air is higher than 20 ppm, not properly treated diabetes mellitus, following lactose restricted or another special diet within 1 week prior to study enrolment (ingestion of less than 12 g lactose - less than 250 ml milk - per day) small intestinal bacterial overgrowth (SIBO): if there is a rapid increase of H2 level in the exhaled air (≥20 ppm above baseline within 90 minutes), SIBO is suspected and antibiotic therapy will be started (peroral rifaximin for 5 days) after negative Helicobacter pylori serology. After this procedure, lactulose H2 breath test will be performed to exclude SIBO (≥20 ppm H2 rise only after 90 min). In case of negative lactulose H2 breath test, another LHBT will be carried out slow oro-cecal transit: clinical signs and typical findings on the tests (the LHBT is normal, but the increase of blood glucose level is less than 1.1 mmol/l and/or no H2 rise during lactulose H2 breath test) milk allergy (positive IgE test)

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: LION is a two-armed, randomized, double-blind, placebo-controlled, two-phase clinical trial. In the first phase, we will enroll 100 patients, the allocation ratio will be 1:1 (50 patinets in each arm). Then, an interim analysis will be performed to determine the appropriate sample size. During the interim analysis, if there is already significant difference (p<0.0294) between the arms, the recruitment will be considered completed; otherwise, recruitment will continue until the desired sample size is reached. If there is no hope for ascertaining significance, the study will be stopped.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: alverine-citrate + simethicone and lactase<br>Patients diagnosed with irritable bowel syndrome based on the ROME IV criteria will go through a lactase intolerance test (LTT) and (lactose H2 breath test) LHBT. Those who have positive LTT and LHBT will receive alverine-citrate + simethicone and lactase. | Drug: alverine-citrate + simethicone and lactase<br>* Patients who randomized in the first arm are treated with alverine-citrate + simethicone and lactase.<br>* Other names: lactase;|
| Placebo Comparator: alverin-citrate + simethicone with placebo<br>Patients diagnosed with irritable bowel syndrome based on the ROME IV criteria will go through a lactase intolerance test (LTT) and (lactose H2 breath test) LHBT. Those who have positive LTT and LHBT will receive alverine-citrate + simethicone with placebo. | Drug: alverin-citrate + simethicone with placebo<br>* Patients in the second arm receive alverin-citrate + simethicone with placebo without lactase.<br>* Other names: placebo;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| change of the symptoms measured by TSS (total symptom score) | The primary outcome is the number of enrolled patients with significant improvement in each treatment arm. Significant improvement is considered if there is >50% reduction in the TSS, compared to the baseline symptoms. | The one- and two-week total symptom score (TSS) change compared to baseline value. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| improvement in stool consistency | stool consistency score of <5, according to the Bristol stool chart | The two time points at which the measurement is assessed are the time of enrollment and after 2 weeks. | 
| the absence of a bowel movement | The absence of a bowel movement is accompanied by an improvement of ≥30 mm in the VAS (visual analogue scale) for the worst abdominal pain. | The three time points at which the measurement is assessed are the time of enrollment, after 1 and 2 weeks. | 
| relief of IBS-related bloating | The number of patients with acceptable relief of IBS-related bloating determined by a questionnaire, from the response (yes or no) compare to the baseline IBS-related bloating. | The three time points at which the measurement is assessed are the time of enrollment, after 1 and 2 weeks. | 
| Onset and duration of relief of bloating | Onset and duration of relief of bloating is measured by a questionnaire. | The three time points at which the measurement is assessed are the time of enrollment, after 1 and 2 weeks. | 
| incidence of Small intestinal bacterial overgrowth (SIBO) | Early (within 90 minutes), significant (≥20 ppm) H2 rise during LHBT or lactulose breath test compared to the baseline value. | At the time of patient enrollment and after two weeks of treatments this test will be carried out again. | 
| results of LHBT and LTT | Results of LHBT (lactose H2 breath test) and LTT (lactose tolerance test). | At the time of patient enrollment and after two weeks of treatments LHBT and LTT will be carried out again. | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
irritable bowel syndrome, lactose intolerance, lactose malabsorption, lactase, simethicone, alverine-citrate, placebo