E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Irritable bowel syndrome (IBS) is a heterogeneous gastrointestinal (GI) disorder characterized by frequent and debilitating symptoms (e.g. diarrhoea, bloating, abdominal pain, urgency to defecate, gas, faecal incontinence). A distinct feature of the disorder is the often cyclical waxing and waning of various symptoms. There remains a significant unmet need for effective and safe therapies, particularly for IBS with diarrhoea (IBS-D). |
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E.1.1.1 | Medical condition in easily understood language |
Irritable Bowel Syndrome with Diarrhoea |
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E.1.1.2 | Therapeutic area | Diseases [C] - Digestive System Diseases [C06] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 16.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10060849 |
E.1.2 | Term | Diarrhoea predominant irritable bowel syndrome |
E.1.2 | System Organ Class | 100000004856 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To evaluate the efficacy of repeat treatment with rifaximin 550mg TID in subjects with IBS-D who responded to initial treatment with rifaximin 550 mg TID. |
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E.2.2 | Secondary objectives of the trial |
To evaluate the safety of rifaximin 550 TID in subjects with IBS-D. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Subject is 18 years of age
2. Male or female
Females of childbearing (reproductive) potential must have a negative pregnancy test at Screening/Treatment 1 Phase and agree to use an acceptable method of contraception throughout their participation in the study. Acceptable methods of contraception include double barrier methods (condom with spermicidal jelly or a diaphragm with spermicide), hormonal methods (e. g. oral contraceptives, patches or medroxyprogesterone acetate), or an intrauterine device (IUD) with a documented failure rate of less than 1% per year.
Abstinence or partner(s) with a vasectomy may be considered an acceptable method of
contraception at the discretion of the investigator.
Females who have been surgically sterilized (e.g, hysterectomy or bilateral tubal ligation) or who are postmenopausal (total cessation of menses for > 1 year) will not be considered “females of childbearing potential”.
3. Subject has IBS confirmed by the Rome III diagnostic criteria3 (below):
Recurrent abdominal pain or discomfort** at least 3 days per month in the last 3 months, with symptom onset at least 6 months prior to diagnosis associated with 2 or more of the following:
Improvement with defecation;
Onset associated with a change in frequency of stool;
Onset associated with a change in form (appearance) of stool
**Discomfort means an uncomfortable sensation not described as pain.
4. During the Screening/Treatment 1 Phase (at least 7 and up to 13 days), the following
average daily symptom scores for IBS are required in all categories for entry into the study:
An average score of greater than or equal to 3 for abdominal pain
An average score of greater than or equal to 3 for bloating
At least 2 days in a week with stool consistency of 6 (Fluffy pieces with ragged edges, a mushy stool) or 7 (Watery stool, no solid pieces; entirely liquid) using the BSS
5. Subject may be included if they have had a documented colonoscopy within the past
10 years (preferably including biopsies) as part of a workup for IBS-D. Subjects with a
clinical diagnosis of IBS-D who are either (1) less than 50 years of age and have never had a colonoscopy or (2) whose last colonoscopy was greater than 10 years ago may be possible etiologies of the diarrhoea such as microscopic colitis and in the opinion of the investigator, the subject does not need a complete colonoscopy for other medical reasons.
6. Subject must maintain a stable diet; including dietary supplements, vitamins and other nutraceuticals. Subject should not introduce any major lifestyle changes for the duration of the study (eg.: initiation or discontinuation of a high fibre or low carbohydrate diet)
7. Subject is capable of understanding the requirements of the study, is willing to comply with all study procedures, understands the language of the informed consent form, and is capable and willing to sign the informed consent form. |
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E.4 | Principal exclusion criteria |
A subject will be eligible for inclusion in this study if he/she meets any of the following
criteria:
1. Presents with Type 1 = Separate hard lumps, like nuts (hard to pass) or Type 2 = Sausage-shaped but lumpy (on the BSS) during the Screening/Treatment 1 Phase (for entry into Treatment 2 Phase)
2. Subject has failed to record 7 days of the daily diary assessments during the
Screening/Treatment 1 Phase (for entry into Treatment 2 Phase)
3. Subject has current evidence of duodenal ulcer, gastric ulcer, diverticulitis, gastroesophageal reflux (GERD), or infectious gastroenteritis. Note: subjects with GERD controlled by stable (> 30 days) doses of medication or diet are eligible to participate in the study.
4. Subject has a history of inflammatory bowel disease (e.g., Crohn’s disease, ulcerative colitis, celiac disease), GI malignancy, GI obstruction, gastroparesis, carcinoid syndrome, pancreatitis, amyloidosis, ileus or cholelithiasis. The subject is eligible to participate if they have had cholelithiasis and had a cholecystectomy greater than 6 months prior to signing the ICF.
5. Subject has diabetes (Type 1 or Type 2)
6. Subject requires GI surgery, has a history of GI surgery, or has had a polypectomy (open surgical or endoscopic) for which the histology showed it to be malignant. Subjects are excluded if they have had a cholecystectomy and/or abdominal hernia repair less than 6 months prior to signing the ICF. The subject is eligible to participate if they have had: a routine endoscopic
polypectomy with benign histology, and/or an uncomplicated appendectomy with no
history of post operative obstruction or symptomatic adhesions for at least 5 years prior to signing the ICF.
7. Subject has lactose intolerance not controlled by a lactose free diet.
8. Subject presents with symptoms of enteric infections including but not limited to Yersinia enterocolitica, Campylobacter jejuni, Salmonella, Shigella, ovum and parasites, and/or Clostridium difficile.
9. Subject has history of a major psychiatric disorder (DSM-III-R or DSM-IV), including
major depression, psychoses, alcohol or substance abuse within the past 24 months prior to signing the informed consent
10. Subject has a history of seizure disorders
11. Subject is pregnant, planning to become pregnant, or is lactating
12. Subject has a history of human immunodeficiency virus (HIV) or hepatitis (B or C)
13. Subject has a history of abnormal thyroid function not controlled by thyroid medications
14. Subject has hepatic disease manifested by twice the upper limit of normal (ULN) for any of the following liver function tests: alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, or total bilirubin (except in isolated elevation of unconjugated bilirubin)
15. Subject has renal disease manifested by 1.5 times the ULN of serum creatinine or blood urea nitrogen levels
16. Exclusion criteria #16 removed during Amendment 2
17. Subject has unstable cardiovascular or pulmonary disease, categorized by a worsening in the disease condition that requires a change in treatment or medical care within 30 days of signing the ICF
18. Subject has any condition or circumstance that adversely affects the subject or could cause noncompliance with treatment or visits
19. Subject has an active malignancy within the last 5 years (exceptions: basal cell carcinomas of the skin, or if female, in situ cervical carcinoma that has been surgically excised)
20. Subject has participated in an investigational study within the 30 days prior to signing the ICF
21. Subject is taking any products specifically marketed as probiotics (standard food or yogurt products are allowed) after initiating diary assessments
22. Subject is taking products or foods containing sugar alcohols (including hydrogenated starch hydrolysates, isomalt, lactitol, maltitol, mannitol, sorbitol (e.g. sugar-free chewing gums or drinks) or xylitol (e.g. sugar-free hard candy, chewing gum, and many processed foods labelled “sugar-free”) after initiating diary assessments
23. Subject is taking/has started a course of:
Antidepressants (within 6 weeks of signing the ICF, or if a change in dose or
discontinuation of the drug during the course of the study is anticipated).
Anti-seizure and/or antipsychotic drugs (including those for bipolar disorder) within 4
weeks of signing the ICF.
24. Subject is currently taking and plans to continue taking antidiarrheals (e.g., loperamide and bismuth subsalicylate) after initiating diary assessments.
25. Subject is taking rifaximin within 60 days or any other antibiotic within 14 days prior to
signing the informed consent (ICF).
26. Subject is taking antispasmodics, narcotics, prokinetic drugs, warfarin, lubiprostone, or drugs indicated for IBS (e.g., alosetron) after initiating diary assessments.
27. Subject has biopsy proven diagnosis of microscopic colitis. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Efficacy Endpoint:
Proportion of subjects who are responders to repeat treatment in both IBS-related abdominal pain AND stool consistency during the 4 week treatment-free follow-up (or Primary Evaluation Period [PEP]) in the Double Blind Repeat (DBR) Treatment Phase.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Weeks 2 to 6 of the 4 week follow up of Treatment 2 Phase |
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E.5.2 | Secondary end point(s) |
Key Secondary Efficacy Endpoints:
Proportion of subjects who are responders to repeat treatment in stool consistency during PEP in the DBR
Treatment Phase.
Proportion of subjects who are responders to repeat treatment in IBS-related abdominal pain during PEP in the
DBR Treatment Phase.
Proportion of subjects who are responders to repeat treatment in both IBS-related abdominal pain AND stool consistency with at least 1 point improvement in weekly average daily IBS symptoms compared to baseline during
PEP in the DBR Treatment Phase.
Proportion of subjects who are responders to repeat treatment in IBS-related bloating during PEP in the DBR
Treatment Phase.
Safety Endpoints:
Incidence, intensity and type of adverse events (AEs)
Changes from baseline in laboratory parameters (haematology, clinical chemistry, urinalysis)
Changes from baseline in vital sign measurements
Changes from baseline in physical examination |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
4 Week follow-up phase (Primary Evaluation Period - PEP) of the Treatment 3 Phase (DBR Treatment Phase) |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 5 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Germany |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | |
E.8.9.1 | In the Member State concerned months | 11 |
E.8.9.1 | In the Member State concerned days | 23 |
E.8.9.2 | In all countries concerned by the trial months | 11 |
E.8.9.2 | In all countries concerned by the trial days | 23 |