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    Summary
    EudraCT Number:2018-004626-28
    Sponsor's Protocol Code Number:SymSF2
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Restarted
    Date on which this record was first entered in the EudraCT database:2019-04-17
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedGermany - BfArM
    A.2EudraCT number2018-004626-28
    A.3Full title of the trial
    Randomized, double-blind, placebo-controlled, multi-centre trial to
    evaluate the efficacy, safety and tolerability of oral treatment with living
    bacteria of E. coli DSM 17252 (Symbioflor®2) in patients with
    diarrhoea-predominant irritable bowel syndrome (IBS-D)
    Randomisierte, doppelblinde, placebokontrollierte, multizentrische Studie zur Beurteilung der Wirksamkeit, Sicherheit und Verträglichkeit der oralen Behandlung mit Bakterienkonzetrat aus E. coli-Bakterien DSM 17252 (Symbioflor® 2) bei Patienten mit Reizdarmsyndrom assoziiert mit Durchfall (RDS-D)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    N/A
    A.4.1Sponsor's protocol code numberSymSF2
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorSymbioPharm GmbH
    B.1.3.4CountryGermany
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportSymbioPharm GmbH
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAMS Advanced Medical Services GmbH
    B.5.2Functional name of contact pointClinical Operations
    B.5.3 Address:
    B.5.3.1Street AddressAm Exerzierplatz 2
    B.5.3.2Town/ cityMannheim
    B.5.3.3Post code68167
    B.5.3.4CountryGermany
    B.5.4Telephone number+4962170095100
    B.5.5Fax number+4962170095140
    B.5.6E-mailregulatoryaffairsDE@ams-europe.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Symbioflor® 2
    D.2.1.1.2Name of the Marketing Authorisation holderSymbioPharm GmbH
    D.2.1.2Country which granted the Marketing AuthorisationGermany
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.4Pharmaceutical form Oral drops, suspension
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNEscherichia coli DSM 17252
    D.3.9.2Current sponsor codeEscherichia coli DSM 17252
    D.3.9.3Other descriptive nameEscherichia coli DSM 17252, cells and autolysate
    D.3.9.4EV Substance CodeSUB182786
    D.3.10 Strength
    D.3.10.1Concentration unit million organisms/ml million organisms/millilitre
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number15 to 45
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product Yes
    D.3.11.13.1Other medicinal product typeEscherichia coli, the active substance in Symbioflor® 2, is a living bacterium that is present in the healthy intestinal flora of humans.
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboOral drops, suspension
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Diarrhoea-predominant irritable bowel syndrome with recurrent abdominal pain according to Rome IV criteria
    E.1.1.1Medical condition in easily understood language
    Gastrointestinal disorders
    E.1.1.2Therapeutic area Diseases [C] - Digestive System Diseases [C06]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To investigate the effectiveness of oral treatment with Symbioflor®2 in patients with IBS-D compared to placebo in the improvement of the frequency and severity of IBS-D symptoms
    To determine the safety and tolerability of Symbioflor®2
    E.2.2Secondary objectives of the trial
    Not applicable
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    • Male or female outpatients aged ≥18 years
    • Diagnosis of irritable bowel syndrome according to Rome IV:
    1. Recurrent abdominal pain, on average, at least 1 day per week in the last 3 months associated with two or more of the following criteria:
    - Related to defecation
    - Associated with a change in frequency of stool
    - Associated with a change in form (appearance) of stool
    2. Criteria fulfilled for the last 3 months and
    3. IBS symptom onset ≥ 6 months
    4. IBS-D subtype with abnormal stools being usually diarrhoea
    • Colonoscopy with no clinically relevant findings (performed
    for all patients younger than 50 years and for patients ≥50 years of
    age within the last 5 years)
    • Female patients of childbearing potential must be either surgically sterilized or use a highly effective method of contraception with a negative pregnancy test at screening and baseline/day 0
    • Willingness to refrain from significant changes in diet, fibre intake, fluid intake, or physical activity during the study
    • Willingness to refrain from the use of other medications for IBS treatment, including probiotic medication
    • Ability to comply with treatment
    • Sufficient knowledge of German language to understand trial instructions and rating scales
    • Written informed consent prior to enrolment
    • Email account and internet access available
    The patients will only be randomised to either treatment or control group if they meet the following criteria:
    • Mean abdominal pain intensity ≥ 3 on the 11-point NRS scale during the last 14 days
    • Loose or watery stools ≥ 25% and hard or lumpy stools in < 25% of the bowel movements measured by Bristol Stool Scale (BSS) during the last 14 days
    • At least 4 days per week with at least one loose or watery stool (6 or 7 in the BSS)
    • IBS-Symptom Severity Scale (IBS-SSS) ≤ 300
    • Negative stool culture
    • Negative faecal occult blood test (iFOBT)
    • Stool test on calprotectin within normal range (values between 50-200 mg/kg are accepted if not clinically relevant as justified by the investigator) and bile acid below upper limit of normal
    • No significant changes in diet, fibre intake, fluid intake, or physical activity level during the run-in period
    • At least 70% compliance during the run-in period with diary entries (at least 10 out of 14 diary entries)
    • No missing diary entries for more than 3 consecutive days
    E.4Principal exclusion criteria
    • History of abdominal surgery within the 6 months prior to screening
    • Presence or suspected presence of unstable coronary artery disease, untreated organic gastrointestinal disease and uncontrolled metabolic diseases causing IBS-related symptoms, or collagen vascular disease within the 6 months prior to screening
    • Lactose or fructose intolerance explaining the symptoms (in doubtful cases, a diagnostic test has to be performed)
    • Coeliac disease (in doubtful cases, a diagnostic test has to be performed)
    • Confirmed bile acid malabsorption by SeHCAT-Test or successful treatment by bile acid sequestrant
    • Change of diet e.g. FODMAP, gluten-free within last 3 months
    • Abnormal endoscopy/ abdominal ultrasound requiring further investigation
    • Any alarm symptoms including uninvestigated anaemia, rectal bleeding, weight loss, or unresolved fever within the 6 months prior to screening
    • Participation in another clinical trial or use of any investigational drug within 30 days or 5 half-lives (whichever is longer) before dosing
    • Evidence of current or recent alcohol or drug abuse within 6 months prior to screening
    • History or evidence of current laxative abuse
    • Pregnancy or breast feeding
    • Any illness or condition that might impact the safety of study drug administration or evaluability of drug effect based on Investigator’s discretionNo consent to recording and processing of pseudonymised data according to legal requirements
    • Patients who are committed to a clinic or similar institution by official or judicial order
    • Hypersensitivity to active ingredient or any excipients of the medicinal product

    Patients will be excluded from randomization to a treatment group if they have/are:
    • Current intake of prohibited medications except for rescue purposes (refer to 10.3)
    • Serum potassium, magnesium, or calcium values outside the normal range at screening and clinically significant
    • Serum aspartate transaminase (AST), alanine transaminase (ALT), or gamma glutamyltransferase (GGT) ≥3 times the upper limit of the normal range at screening or baseline, or a bilirubin value ≥2 times the upper limit of the normal range at screening
    • Abnormal thyroid stimulating hormone (TSH) value at screening, unless the free T4 value is normal; (Note: Levothyroxine will be allowed, if on stable dose for at least 30 days prior to screening and no changes expected during study)
    • Any further laboratory value(s) outside the laboratory reference range at screening considered clinically significant by the Investigator
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint is a combined endpoint containing two co-primary components to assess efficacy, namely Bristol Stool Scale and Abdominal Pain Intensity. A statistically significant change must be found in the combined endpoint.
    An overall responder for the combined primary endpoint is defined as a patient, who is classified as a BSS responder as well as an Abdominal Pain Intensity responder.

    First component of the combined primary efficacy endpoint:
    Response rate measured by Bristol Stool Scale. BSS response is defined as at least 50% reduction in the number of days with at least one stool that has a consistency of 6 or 7 per week compared to baseline for a minimum of 13 of the 26 measurements (i.e. at least 50% improvement of stool consistency during treatment).

    Second component of the combined primary efficacy endpoint:
    Response rate measured by the 11-point numeric rating scale (NRS). Abdominal Pain Intensity response is defined as a decrease in the weekly average of worst abdominal pain of at least 30% compared to baseline for a minimum of 13 of the 26 measurements (i.e. at least 50% improvement of Abdominal Pain Intensity during treatment).
    E.5.1.1Timepoint(s) of evaluation of this end point
    after 26 weeks of treatment
    E.5.2Secondary end point(s)
    Efficacy (see 14.6.3.2):
    • Response rate measured by the 7-point IBS Global Assessment of Improvement Scale (IBS-GAI) during the 26 weeks of treatment. IBS-GAI response is defined as at least 50% moderate or substantial improvement during the 26 weeks of treatment
    • Response rate measured by the 11-point numeric rating scale during the 26 weeks of treatment. Response is defined as ≥30% improvement in Abdominal Pain Intensity weekly response compared to baseline for a minimum of 20 of the 26 measurements (i.e. 75% improvement of Abdominal Pain Intensity) or 50% improvement and no worsening during the last 4 weeks of treatment
    • Response rate measured by the 11-point numeric rating scale during the 26 weeks of treatment. Response is defined as ≥40% improvement in Abdominal Pain Intensity weekly response compared to baseline for a minimum of 13 of the 26 measurements
    • Change from baseline of Abdominal Pain Intensity mean score
    • IBS-GAI weekly mean score
    • Change from baseline in IBS severity with IBS-SSS.
    • Change from baseline of the IBS specific Quality of Life questionnaire (IBS-QOL)
    • Change from baseline of the EQ-5D questionnaire
    • Stool frequency / week
    • Number of days with imperative urge to defecate / week
    • Number of pain-free days / week

    Subgroup analyses
    • Effectiveness of Symbioflor®2 by gender (male/female)
    • Effectiveness by severity (mild, moderate)
    Safety:
    • Adverse events
    • Vital signs
    • Laboratory values
    E.5.2.1Timepoint(s) of evaluation of this end point
    after 26 weeks of treatment
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) Yes
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    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.8.4.1Number of sites anticipated in Member State concerned40
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Germany
    E.8.7Trial 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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years7
    E.8.9.1In the Member State concerned months8
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years7
    E.8.9.2In all countries concerned by the trial months8
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 338
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 84
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state350
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 350
    F.4.2.2In the whole clinical trial 422
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    The patient will continue to be under the care of his physician,
    treatment would be according to local practice and may include
    continued treatment with Symbioflor 2
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2019-07-18
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-05-28
    P. End of Trial
    P.End of Trial StatusRestarted
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