Rifamycin SV-MMX® 600 mg Tablets Administered Three or Two Times Daily to Patients With IBS-D

A Phase II, Multicentre, Randomised, Double-blind, Placebo Controlled, Proof of Concept Study of Efficacy and Safety of Rifamycin SV-MMX® 600 mg Tablets Administered Three or Two Times Daily to Patients With Diarrhoea-predominant Irritable Bowel Syndrome (IBS-D)

The objective of this study is to evaluate the safety and efficacy Rifamycin SV-MMX® 600 mg tablets for patients with diarrhoea-predominant irritable bowel syndrome when administered two to three times daily.

Study Overview

• Status: Completed
• Conditions: Diarrhea-predominant Irritable Bowel Syndrome
• Intervention / Treatment: Drug: Rifamycin SV 600mg t.i.d.; Drug: Rifamycin SV b.i.d. + Placebo; Drug: Placebo t.i.d.

• Study Type: Interventional
• Enrollment (Actual): 279
• Phase: Phase 2

Contacts and Locations

Study Locations

• Belgium
  • Bruxelles, Belgium, 1200
    • Clinique universitaires Saint-Luc Gastroenterologie Route 606 Avenue Hippocrate, 10
  • Gent, Belgium, 9000
    • Maria Middelares, Digestief Centrum, Buitenring St-Denijs 30
  • Gent, Belgium, 9000
    • University Hospital Gent, Depintelaan 185
  • Herestraat 49
    • Leuven, Herestraat 49, Belgium, 3000
      • University Hospital Gasthuisberg, Department of Gastroenterology
  • Lucaslaan 29
    • Brugge, Lucaslaan 29, Belgium, 8310
      • St Lukas Ziekenhuis,
• Germany
  • Berlin, Germany, 10629
    • Emovis GmbH Wilmersdorfer Straße 79
  • Essen, Germany, 45359
    • Unterfrintroper Hausarztzentrum Lehrpraxis der Universität Essen
  • Gauting, Germany, 82131
    • Internistenzentrum Bahnhofstrasse 30
  • Hamburg, Germany, 22143
    • Clinical Research Hamburg GmbH, Rahlstedter Bahnhofstraße 33
  • Hannover, Germany, 30459
    • Gastroenterologie, Interventionelle Endoskopie, Diabetologie und Akutgeriatrie, KRH-Zentrumsgeschaftsfuhrer innere Medizin, KRK Klinikum Siloah-Oststadt-Heidehaus Stadionbrucke 4
  • Künzing, Germany, 94550
    • Gemeinschaftspraxis Dr. Klein & J. Minnich
  • Leipzig, Germany, 04107
    • AmBeNet GmbH, Wilhelm-Leuschner-Platz I2,
  • Magdeburg, Germany, 39120
    • Universitatsklinikum Magdeburg A.O.R. Klinik fur Gastroenterologie, Hepatologie und Infektiologie, Leipziger Str.44
  • Reinfeld, Germany, 23858
    • Ärztehaus Reinfeld Praxisgemeinschaft für Allgemeinmedizin Klosterstraße 7
  • Rodgau, Germany, 63110
    • Innomed Dr. med. Naudts Ludwig-Erhard-Platz 11
  • Weyhe, Germany, 28844
    • Internistische Praxisgemeinschaft, Bereich Gastroenterologie Hauptstraße. 51
• Italy
  • Cagliari, Italy, 09100
    • Azienda Ospedaliera G. Brotzu, U.O. di Gastroenterelogia, Via Peretti
  • Milano, Italy, 20089
    • Istituto Clinico Humanitas, Centro Malattie Infiammatorie Croniche Intestinali
  • Milano, Italy, 20122
    • Fonazione IRCCS Ospedale Maggiore
  • Pavia, Italy, 27100
    • Fondazione IRCCS Policlinico S. Matteo, Dip Area Medica: Medicina Generale 1, Viale Camillo Golgi, 19
  • Roma, Italy, 00168
    • Polo Scienze Gastroenterologiche ed
  • Roma, Italy, 21
    • Universita Campus Bio Medico, U.O.C di Gastroenterologia ed Endoscopia Digestiva
  • San Donato Milanese, Italy, 20097
    • IRCCS Policlinico San Donato, Medicina Generale III- Gastroenterologia
  • PN
    • Aviano, PN, Italy, 233081
      • S.O.C Gastroenterologia Oncologica
• Spain
  • Barcelona, Spain, 08035
    • Hospital Universitari vall d'Hebron, Servicio de Aparato Digestivo, Passeig Vall d'Hebron, 119-129
  • Madrid, Spain, 28040
    • Hospital Universitario Clinico San Carlos, Servicio de Aparato Digestivo, Calle del Prof Martin Lagos, s/n,
  • Barcelona
    • Badalona, Barcelona, Spain, 08916
      • Hospital Universitari Germans Trias i Pijol (Can Ruti). Servicio de Aparto Digestivo Carretera de Canyet, s/n
  • Madrid
    • Castellana, Madrid, Spain, 28046
      • Hospital Universitario La Paz, Servicio de Aparato Digestivo Po de la Castellana 261
    • Colmenar Viejo, Madrid, Spain, 28034
      • Hospital Universitario Ramon Y Cajal, Servicio de Gastroenterologia y Hepatologia Ctra. de colmenar Viejo, Km 9,100

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Informed Consent: signed written informed consent before inclusion in the study
2. Sex and Age: males/females, ≥18 year old
3. IBS Diagnosis: confirmed IBS-D diagnosis per Rome IV criteria

4. Symptoms: active symptoms of IBS at baseline (day 1) as measured by average daily scores for at least 7 days before baseline:

   1. abdominal pain score ≥3 using an 11-point numeric rating scale and
   2. bloating score: 2-4 inclusive and

   3. stool consistency: score 6 or 7 (measured by the Bristol stool form scale) for at least 2 days from day -7 to day -1

      and by a negative response to the global IBS symptom assessment question and to the IBS-related bloating assessment question both given weekly during the screening phase up to day 1 before randomisation:

   4. "In the past 7 days, have you had adequate relief of your IBS symptoms?" [No] and
   5. "In the past 7 days, have you had adequate relief of your IBS symptom of bloating?"[No]
5. Colonoscopy: performed within 5 years; if patient's age >50, colonoscopy performed within 2 years
6. Full comprehension: ability to comprehend the full nature and purpose of the study, including possible risks and side effects; ability to co-operate with the investigator and to comply with the requirements of the study
7. Literacy: sufficiently literate to comply with the study requirement of using electronic diaries and filling in electronic forms
8. Contraception and fertility: females of childbearing potential and fertile males must be using at least one reliable method of contraception.

Reliable methods of contraception for women include:

1. Hormonal oral, implantable, transdermal, or injectable contraceptives for at least 2 months before the screening visit

2. A non-hormonal intrauterine device [IUD] or female condom with spermicide or contraceptive sponge with spermicide or diaphragm with spermicide or cervical cap with spermicide for at least 2 months before the screening visit

   Reliable methods of contraception for men and male partners of female patients include:

3. Male condoms with spermicide

   Reliable methods of contraception for both women and men include:

4. A sterile sexual partner or sexual abstinence Women of non-childbearing potential or in post-menopausal status for at least 1 year and sterile or surgically sterilised men will be admitted.

For women of childbearing potential, serum pregnancy test result must be negative at screening

Exclusion Criteria:

1. IBS: symptoms of constipation at baseline:

   1. less than 3 bowel movements a week and
   2. stool consistency score ≤2 for ≥2 days in a week
2. Screening phase: failure to record the daily symptom assessments in the diary cards for at least 7 days before baseline
3. Gastroenteric: underlying gastrointestinal diseases including ulcerative colitis, Crohn's disease, pancreatitis, any active infectious, haemorrhagic or inflammatory disorder not related to IBS-D, gastrointestinal motility disorders such as ileus, gastroparesis or pseudoobstruction, gastroduodenal ulcer, gastrointestinal malignancy or potentially fatal diseases if not full in remission (5 years from diagnosis and without maintenance treatment), amyloidosis and cholelithiasis if cholecystectomy not performed
4. Intolerance: ascertained underlying lactose intolerance with response to diet or any other malabsorption syndrome with the exclusion of asymptomatic lactose malabsorption
5. Coeliac disease: ascertained or presumptive underlying coeliac disease
6. Bile: ascertained or presumptive bile acid malabsorption or bile acid induced diarrhoea
7. Diabetes: underlying diabetes type I or II
8. Thyroid: abnormal thyroid function not controlled by thyroid medications
9. Allergy: ascertained or presumptive hypersensitivity to the active principle and/or formulations' ingredients; history of anaphylaxis to drugs or allergic reactions in general, which the investigator considers may affect the outcome of the study
10. Renal function: ascertained or presumptive clinically significant renal insufficiency or creatinine above twice the upper limit of normal (ULN) of the performing laboratory reference range
11. Liver function: chronic liver disease or clinically significant liver enzyme abnormality as evidenced by elevated AST, ALT or total bilirubin >1.5 times ULN
12. AIDS/HIV: ascertained or presumptive acquired immunodeficiency (AIDS) or known infection with human immunodeficiency virus (HIV)
13. Diseases: significant history of medical or surgical conditions excluding hysterectomy, caesarean section, appendectomy, cholecystectomy, benign polypectomy and inguinal hernia and including renal, hepatic, cardiovascular, haematological, endocrine, immune, psychiatric or neurological diseases that in the investigator's opinion may interfere with the aim of the study; malignant diseases not in remission for at least 5 years
14. Medications: alosetron, eluxadoline, ondansetron, tegaserod, lubiprostone, warfarin, antipsychotic, antispasmodic, prokinetic, antidiarrhoeal, laxative, probiotic, narcotic or antibiotic agents within 14 days before the screening visit; antidepressant agents of the selective serotonin-reuptake inhibitor and tricyclic classes unless taken at a stable dose for at least 6 weeks before the screening visit
15. Investigational drugs: participation in the evaluation of any investigational product within 30 days before this study
16. Drug and alcohol: known history of drug or alcohol [>1 drink/day for females and >2 drinks/day for males, defined according to the USDA Dietary Guidelines 2015] abuse
17. Pregnancy (females only): pregnant or lactating women or wishing to become pregnant in the 3 months following this visit

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Treatment group 1: dose regimen 1; Rifamycin SV-MMX® 600 mg modified release tablets, three times daily (t.i.d.)	Drug: Rifamycin SV 600mg t.i.d.; Morning: one 600 mg tablet Afternoon: one 600 mg tablet Evening: one 600 mg tablet
Active Comparator: Treatment group 2: dose regimen 2; Rifamycin SV-MMX® 600 mg modified release tablets, two times daily (b.i.d.) + matching placebo daily (q.d.)	Drug: Rifamycin SV b.i.d. + Placebo; Morning. one 600 mg tablet Afternoon: one matching placebo tablet Evening: one 600 mg tablet
Placebo Comparator: Treatment group 3: matching placebo; Rifamycin SV-MMX® matching placebo tablets, t.i.d.	Drug: Placebo t.i.d.; Morning. one matching placebo tablet Afternoon: one matching placebo tablet Evening: one matching placebo tablet

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of subjects with relief from abdominal pain and improved stool consistency.	Proportion of weekly responders defined as subjects who weekly have relief of the composite of abdominal pain and stool consistency, on the basis of their daily assessments. Relief of abdominal pain is defined as a decrease in the weekly average of abdominal pain score of at least 30% compared with baseline and relief of stool consistency is defined as a 50% or greater reduction in the number of days per week with at least one stool that has a consistency of Type 6 or 7 compared with baseline. All participants will complete daily assessments of abdominal pain and stool consistency: Abdominal Pain: Scored between 0 (no pain) and 10 (as bad as it could be); Stool Consistency: Bristol Stool Scale (Scored 1-7)	88 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of subjects with relief of global IBS symptoms during weeks 3-12 [Efficacy]	Proportion of subjects with adequate relief of global IBS symptoms for at least 2 (consecutive or not) of the 10 weeks during the follow-up period (i.e., weeks 3 through 12). Adequate relief of global IBS symptoms is defined as a response of "yes" to the following question, which will be asked weekly (every 7 days): "In regard to all your symptoms of IBS, as compared to the way you felt before you started study medication, have you, in the past 7 days, had adequate relief of your IBS symptoms? [Yes/No]"	10 weeks
Proportion of subjects with monthly relief of global IBS symptoms [Efficacy]	Proportion of subjects with adequate relief of global IBS symptoms during at least 2 weeks (consecutive or not) per month ("monthly response") during month 1, during month 1 through 2 and during month 1 through 3 will be assessed to identify the onset and duration of the therapeutic effect.	88 days
Proportion of subjects with relief of IBS-related bloating during weeks 3-12 [Efficacy]	Proportion of subjects with adequate relief of IBS-related bloating for at least 2 (consecutive or not) of the 10 weeks during the follow-up period (i.e., weeks 3 through 12). Adequate relief of bloating is defined as a response of "yes" to the following question, which will be asked weekly (every 7 days): "In regard to your symptom of bloating, as compared to the way you felt before you started study medication, have you, in the past 7 days, had adequate relief of your IBS symptom of bloating? [Yes/No]."	10 weeks
Proportion of subjects with monthly relief of IBS-related bloating [Efficacy]	Proportion of subjects with adequate relief of bloating during at least 2 weeks (consecutive or not) per month ("monthly response") during month 1, during month 1 through 2 and during month 1 through 3 will be assessed to identify the onset and duration of the therapeutic effect.	88 days
Proportion of subjects with weekly relief of IBS symptoms, bloating and abdominal pain [Efficacy]	Proportion of subjects with relief (weekly responders) determined from the subjects' daily assessments of IBS symptoms, bloating, and abdominal pain; relief of IBS symptoms and bloating is defined as a score of either 0 (not at all) or 1 (hardly) for at least 50% of the days in a given week or a score of 0 (not at all), 1 (hardly), or 2 (somewhat) for 100% of the days in a given week for at least 2 (consecutive or not) of the 4 weeks during a given month. Relief of abdominal pain is defined as a decrease by ≥30% from baseline in weekly mean rating of IBS-related abdominal pain. All participants will complete daily assessments of IBS symptoms, bloating and abdominal pain: IBS Symptoms: Scored between 0 (Not bothersome at all) and 6 (a very great deal bothersome); Bloating: Scored between 0 (not at all bothersome) and 6 (a very great deal bothersome); Abdominal Pain: Scored between 0 (no pain) and 10 (as bad as it could be)	88 days
Number of weeks of IBS-symptom relief during follow-up [Efficacy]	Number of weeks (consecutive or not) subjects achieve adequate relief of IBS symptoms during the follow up period.	10 weeks
Number of weeks of bloating relief during follow-up [Efficacy]	Number of weeks (consecutive or not) subjects achieve adequate relief of bloating during the follow up period.	10 weeks
Change in IBS-symptoms, bloating and abdominal pain from baseline to 12 weeks - captured by a daily diary [Efficacy]	Change from baseline to week 12 in daily IBS symptoms, bloating and abdominal pain. This information will be captured in a daily diary by the participants. All participants will complete daily assessments of IBS symptoms, bloating and abdominal pain: IBS Symptoms: Scored between 0 (Not bothersome at all) and 6 (a very great deal bothersome); Bloating: Scored between 0 (not at all bothersome) and 6 (a very great deal bothersome)	12 weeks
Proportion of monthly responders for IBS-symptoms, bloating and abdominal pain [Efficacy]	Proportion of monthly responders during month 1, during month 1 through 2 and during month 1 through 3 determined from the subjects' daily assessments of IBS symptoms, bloating, and abdominal pain; relief of IBS symptoms and bloating is defined as a score of either 0 (not at all) or 1 (hardly) for at least 50% of the days in a given month or a score of 0 (not at all), 1 (hardly), or 2 (somewhat) for 100% of the days in a given month. Relief of abdominal pain is defined as a decrease by ≥30% from baseline in weekly mean rating of IBS-related abdominal pain. Relief of stool consistency is defined as a 50% or greater reduction in the number of days per month with at least one stool that has a consistency of Type 6 or 7 compared with baseline. Daily Assessments: IBS Symptoms: Scored between 0 (Not bothersome at all) and 6 (a very great deal bothersome); Bloating: Scored between 0 (not at all bothersome) and 6 (a very great deal bothersome)	3 months
Change from baseline to each week during follow up for IBS-symptoms bloating, abdominal pain, stool consistency, urgency - captured by a daily diary [Efficacy]	Change from baseline to each week during the 12 week follow up for daily IBS symptoms, bloating, abdominal pain, stool consistency and sense of urgency, asked as "Have you felt or experienced a sense of urgency today? [Yes/No]" and calculated as 100* (number of days with urgency/number of days with data), and daily number of stools. This information will be captured in a daily diary by the participants. All participants will complete daily assessments of IBS symptoms, bloating and abdominal pain: IBS Symptoms: Scored between 0 (Not bothersome at all) and 6 (a very great deal bothersome); Bloating: Scored between 0 (not at all bothersome) and 6 (a very great deal bothersome); Stool Consistency: Bristol Stool Scale (Scored 1-7); Urgency: Answered Yes or No	12 weeks
Change from baseline at weeks 4, 8 and 12 in quality of life assessment [Efficacy]	Change from baseline at weeks 4, 8 and 12 in quality of life inquired as IBS-QoL	12 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Treatment Emergent Adverse Events [Safety]	Monitoring of treatment emergent adverse events.	12 weeks
Change from Baseline in Physical Exam [Safety]	Changes from baseline in physical examination.	12 weeks
Change from Baseline in Vital Signs [Safety]	Changes from baseline in vital signs.	12 weeks
Change from Baseline in Lab Tests [Safety]	Changes from baseline in clinical laboratory tests.	12 weeks
Change from Baseline in ECG [Safety]	Changes from baseline in ECG.	12 weeks

Collaborators and Investigators

• Sponsor: Cosmo Technologies Ltd

Study record dates

Study Major Dates

• Study Start (Actual): December 18, 2017
• Primary Completion (Actual): September 11, 2020
• Study Completion (Actual): December 14, 2020

Study Registration Dates

• First Submitted: March 14, 2017
• First Submitted That Met QC Criteria: March 28, 2017
• First Posted (Actual): April 4, 2017

Study Record Updates

• Last Update Posted (Actual): January 8, 2021
• Last Update Submitted That Met QC Criteria: January 7, 2021
• Last Verified: January 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Disease; Signs and Symptoms, Digestive; Gastrointestinal Diseases; Colonic Diseases, Functional; Colonic Diseases; Intestinal Diseases; Syndrome; Irritable Bowel Syndrome; Diarrhea; Anti-Infective Agents; Antirheumatic Agents; Anti-Bacterial Agents; Rifamycins; Rifamycin SV
• Other Study ID Numbers: CB-01-11/28

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No
• IPD Plan Description: None. IPD not to be shared.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No