Pain Relief In Irritable Bowel Syndrome

This is a phase IV, double- blind, randomized, placebo controlled, monocentric study.

Males and women over 18 y.o. with Irritable bowel syndrome (IBS) diagnosed applying Rome III criteria will be enrolled consecutively.

The study consist of 4 periods:

• A screening's period of 2 weeks starting from visit 1, useful to screen potentially eligible patients performing diagnostic investigations necessary to confirm diagnosis.
• A run- in's period, starting from visit 2 and lasting 2 weeks will represent a baseline without specific treatments in order to characterize the severity of symptomatology and evaluate patients' compliance relative to daily diaries
• A 2 weeks- treatment's period ( active/ placebo) starting from visit 3. The 1st day of the period of treatment, eligible patients will be randomized following a 1:1 ratio to receive Proklama ( 1 sachet/ day) or placebo. Treatments will be administered daily during the whole 2 weeks- treatment's period.
• A wash out's period lasting 2 weeks starting from visit 4, to be performed the day after the end of the 2 weeks- treatment's period.
• A 2 weeks- treatment's period ( placebo/ active) starting from visit 5, to be performed the last day of wash out's period. During this visit patients will receive the second treatment, following a crossover design.

Inclusion criteria

• patients over 18 y.o.
• clinical diagnosis of IBS following Rome III symptom- based criteria:

• abdominal pain or discomfort recurring for at least 3 days a month in the previous 3 months, associated with 2 of the following characteristics at least: improved with evacuation; onset associated with variation of stool frequency; onset associated with changes in stool consistency
• onset of symptomatology at least 6 months preceding diagnosis
• additional criterion: mean severity of abdominal pain higher than 3 in the 11-points NRS
• For patients over 50 y.o. or with positive familiarity for colorectal cancer: normal colonoscopy performed within 5 years from the beginning of the screening's period and after symptomatology's onset
• For patients over 65 y.o. : absence of ischemic / microscopic colitis, or other organic gastrointestinal disorders, as highlighted through colonoscopy with biopsy performed within 6 months from the beginning of the screening's period
• For fertile and sexually active women: use of effective contraception with failure rate of less than 1% for one year during the trial period and 30 days after its end.

Oral contraceptive are admitted as long as formulation didn't undergo changes during the 6 months preceeding the trial.

• Physical examination is negative during the period of screening
• Absence of significant alterations in 12- lead ECG during the period of screening.
• Normal haematochemical parameters during the period of screening
• Compliant patients towards procedures provided for the study, especially the use of daily diary
• Patients with mental integrity, able to express an informed before any procedure related to protocol, compliant toward clinical examinations provided for the protocol.
• Patients willing to avoid loperamide and laxatives use during the 3 days preceding run in and during the whole run in's period ( to be verified before randomization)
• Patients that during both the 2 run in's weeks reported an average daily intensity of abdominal pain for every week >3 on 0-10 (NRS)

Exclusion criteria

• Male gender
• Patient has a diagnosis of IBS with a subtype of constipation, mixed IBS, or unsubtyped IBS according to the Rome III criteria
• Patient has had surgery that meets any of the following criteria:

a) colonic or major abdominal surgery, i.e. bariatric surgery and stomach, small/ large bowel or large vessel abdominal surgery ( except appendicectomy, hysterectomy, cholecystectomy, caesarean section, or laparoscopic surgery).

• Patient has any elective major surgery planned or expected at any time during the study.
• Patient has a history of inflammation bowel diseases, complicated diverticulosis ( i.e. diverticulitis), ischaemic colitis, microscopic colitis.
• Patient has a history of organic abnormalities of the GI tract, intestinal obstruction, stricture, toxic megacolon, GI perforation, fecal impaction, gastric banding, adhesions or impaired intestinal circulation ( e.g., aortoiliac disease).
• Patient has a history of pancreatitis of any etiology, cholecystitis or of symptomatic gallbladder stone disease in the previous 6 months.
• Patient has an active biliary duct disease of a history of Sphincter of Oddi dysfunction.
• Patient has a history of gluten enteropathy.
• Patient has a history of lactose intolerance as assessed by response to diet.
• Patient has a current or previous diagnosis of neoplasia ( except non-GI) neoplasia in complete remission < or = 5 years, squamous and basal cell carcinomas and cervical carcinoma in situ).
• Patient has a history of ectopic endometriosis.
• Patient has a history of positive tests for ova or parasites, or clostridium difficile toxin or occult blood in the stool in the previous 6 months.
• Patient has a history of human immunodeficiency virus infection.
• Patient has a history of a cardiovascular event, including stroke, myocardial infarction, congestive heart failure ( NYHA class > 2), or transient ischemic attack in the previous 6 months.
• Patient has uncontrolled hypertension, defined as systolic blood pressure <180 mmHg or a diastolic blood pressure < 100 mmHg.
• Patient has insulin- dependent diabetes mellitus.
• Patient has a major pshychiatric or neurological disorders.
• Patient has an unstable medical condition which may compromise the efficacy and safety assessments as required in the study and/or require change in concomitant medication.
• Patient has a history of abnormal thyroid function. Patient is candidate for the study if thyroid hormone replacement therapy is stable from at least 2 months.
• Patient has evidence of clinically hepatic disease as defined by alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3 times rthe upper limit of normal or total bilirubin >3 mg/dl (>51.3 mmoL/L), with the exception of Gilbert's syndrome or albumin < 2.8 g/dL during the Screening period.
• Patient has a sever renal insufficiency ( Glomerular Filtration Rate [GFR] <30 mL/min/ 1.73 m^2 calculated by the Cockcroft. Gault formula adjusted for the body surface area [BSA]) during the Screening period
• Patient has evidence of anemia as confirmed by hemoglobin < 9 g/dL during the Screening period.
• Relevant changes in dietary habits, lifestyle or exercise regimen should be maintained for the duration of the study.
• Use of prohibited concurrent medication within the previous month, namely:

• Antibiotics ( 4 months in the case of rifaximin);
• 5- HT3 antagonists alosetron.
• Use of prohibited concurrent medication in the previous 7 days namely:

• Antimuscarinic drugs;
• Drug enhancing GI motility such as prokinetic agents and other stimulants of GI contractility drugs, laxatives, or anti- diarrhoeal agents ( except for loperamide, please refer to inclusion criterion No.12);
• Analgesic drugs ( opioids or non- steroidal anti- inflammatory drugs). NOTE: short term use of paracetamol is allowed for max 2 consecutive days;
• Fibre products and herbal preparations;
• Antidepressants. NOTE: the use of a single antidepressant is only allowed when the drug type and its dose regimen have not been changed in the previous 6 months;
• Benzodiazepines. NOTE: the use of a single benzodiazepine is only allowed when it is administered as sleep- inducer and the drug type and its dose regimen have not been changed in the previous 6 months.
• Pregnancy or breastfeeding.
• Hypersensitivity to the drug excipients.
• Patient is not able to understand or collaborate throughout the study.
• Patient is unable to swallow solid, oral dosage forms whole with the aid of liquid ( patients may not chew, divide, dissolve, or crush the study drug).
• Partecipation in other clinical studies in the previous 4 weeks or the patient is currently enrolled in a clinical study with another investigational drug.
• Patient has any condition that, in the opinion of the Investigator, would compromise the well- being of the patient or the requirements of the study.