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    Summary
    EudraCT Number:2014-004108-31
    Sponsor's Protocol Code Number:RHB-104-03
    National Competent Authority:Czechia - SUKL
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2015-06-02
    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 ConcernedCzechia - SUKL
    A.2EudraCT number2014-004108-31
    A.3Full title of the trial
    A Phase III Randomized, Double Blind, Placebo-controlled, Multicenter, Parallel Group Study to Assess the Efficacy and Safety of Fixed-dose Combination RHB-104 in Subjects with Moderately Active Crohn’s Disease
    Randomizované, dvojitě zaslepené, multicentrické, placebem kontrolované klinické hodnocení fáze III s paralelními skupinami k vyhodnocení účinnosti a bezpečnosti pevné dávky kombinace RHB-104 u subjektů se středně aktivní Crohnovou nemocí
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study to evaluate whether a fixed-dose of RHB-104 is safe and effective in subjects suffering from moderate Crohn’s disease. Subjects will be separated in two groups that will be treated in parallel to receive study drug or placebo. Neither the treating physician nor the subject will be aware of the actual treatment received.
    A.3.2Name or abbreviated title of the trial where available
    MAP EU
    A.4.1Sponsor's protocol code numberRHB-104-03
    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 SponsorRedHill Biopharma Ltd.
    B.1.3.4CountryIsrael
    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 supportRedHill Biopharma Ltd.
    B.4.2CountryIsrael
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationRedHill Biopharma Ltd.
    B.5.2Functional name of contact pointIra Kalfus, Medical Director
    B.5.3 Address:
    B.5.3.1Street Address251 Central Park West, Suite 3A
    B.5.3.2Town/ cityNew York, NY
    B.5.3.3Post code10024
    B.5.3.4CountryUnited States
    B.5.4Telephone number+1917817 7517
    B.5.5Fax number+1888685 5218
    B.5.6E-mailira@redhillbio.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 No
    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.3.2Product code RHB-104
    D.3.4Pharmaceutical form Capsule
    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 INNClarithromycin
    D.3.9.1CAS number 81103-11-9
    D.3.9.3Other descriptive nameCLARITHROMYCIN
    D.3.9.4EV Substance CodeSUB06641MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number95
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNRifabutin
    D.3.9.1CAS number 72559-06-9
    D.3.9.3Other descriptive nameRIFABUTIN
    D.3.9.4EV Substance CodeSUB10304MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number45
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNClofazimine
    D.3.9.1CAS number 2030-63-9
    D.3.9.3Other descriptive nameCLOFAZIMINE
    D.3.9.4EV Substance CodeSUB06694MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    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 No
    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 placeboCapsule
    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
    Moderately Active Crohn's Disease
    E.1.1.1Medical condition in easily understood language
    Crohn's Disease
    E.1.1.2Therapeutic area Diseases [C] - Digestive System Diseases [C06]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 19.0
    E.1.2Level PT
    E.1.2Classification code 10011401
    E.1.2Term Crohn's disease
    E.1.2System Organ Class 10017947 - Gastrointestinal disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective is to assess whether subjects randomized to receive RHB-104 have a higher probability of being in a state of remission at the 26-week assessment as compared to subjects randomized to receive placebo.
    E.2.2Secondary objectives of the trial
    Assess whether subjects randomized to receive RHB-104 have a higher probability of being in a state of response at 26 weeks as compared to subjects randomized to receive placebo.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Title: Colonoscopy and Crohn’s Disease Endoscopic Index of Severity (CDEIS) Sub-Study
    Date: 30-Dec-2014
    Version: 1.0

    Objectives:
    - To compare sub-study arm-specific endoscopic 26-week changes using the CDEIS score in those subjects who consent to undergo colonoscopy.
    - To compare sub-study arm-specific 26-week change from baseline in the endoscopic index (∆CDEIS) and the clinical index (∆CDAI).
    E.3Principal inclusion criteria
    1. Males and females 18 to 75 years of age.
    2. Able to adequately communicate with the investigator or their respective designee and/or comply with the requirements of the entire study.
    3. Be willing to provide written informed consent (IC) as evidenced by signature on an informed consent document approved by an institutional review board (IRB) or independent ethics committee (IEC).
    4. Diagnosis of Crohn’s disease confirmed by endoscopy or radiography and/or histology at least 6 months prior to randomization into the study.
    5. CD involving the ileum and/or colon.
    6. Moderately active Crohn’s Disease Activity Index (CDAI) score of ≥220 and ≤450 at Visit 1.
    7. Treatment with at least one of the following therapies at screening:
    - Oral 5-acetyl salicylic acid (5-ASA) compounds: Dose must be stable for at least 4 weeks
    - Corticosteroid therapy: Dose must be stable for at least 2 weeks
    - Azathioprine or 6-mercaptopurine (6-MP) or methotrexate: Dose must be stable for at least 8 weeks
    - Infliximab or adalimumab: Dose must be stable for at least 8 weeks
    8. White blood cell count ≥ 3.5x10^9 at screening.
    9. Active Crohn’s disease, defined by at least one of the following: C-reactive protein > Upper Limit of Normal (ULN) at screening, fecal calprotectin > Upper Limit of Normal (ULN) at screening, OR radiographic (CTE or MRE) OR endoscopic with photographic confirmation of the presence of active CD within 4 weeks of screening visit. Upon approval of the medical monitor, screening colonoscopy and baseline visit may be performed up to 6 weeks after the screening visit.
    10. Subject agrees to use barrier contraceptive methods (i.e. diaphragm, cervical cap, contraceptive sponge or condom) with spermicidal foam/gel/cream/suppository, or IUD throughout the study and for at least 6 weeks after last study drug administration, unless subject is post-menopausal or otherwise incapable of becoming pregnant by reason of surgery or tubal ligation, or has had a vasectomy.
    E.4Principal exclusion criteria
    1. Crohn’s disease involvement isolated to the mouth, upper gastrointestinal tract, or anus.
    2. History of total colectomy with ileorectal anastomosis or a proctocolectomy.
    3. Subject has postoperative stoma, ostomy, or ileoanal pouch.
    4. Any fistulizing Crohn’s Disease other than asymptomatic internal fistulae, simple (non- draining) perianal fistulae without inflammation or healed fistula.
    5. Subject has short bowel syndrome.
    6. Subject is scheduled for surgical bowel resection or is anticipated to require surgical intervention for CD during the study.
    7. Subject has known symptomatic obstructive strictures or bowel perforation in the 6 months prior to screening.
    8. Change in dose or discontinuation of oral 5-acetyl salicylic acid (5-ASA) compounds less than 4 weeks prior to screening.
    9. Change in dose or discontinuation of corticosteroids less than 2 weeks prior to screening.
    10. Change in dose or discontinuation of azathioprine, 6-mercaptopurine (6-MP) or methotrexate less than 4 weeks prior to screening
    11. Treatment with vedolizumab < 120 days prior to screening or other biological therapies (infliximab, adalimumab are allowed at a stable dose for at least 8 weeks) < 60 days prior to screening.
    12. Treatment with any medication that causes QT prolongation or Torsades de Pointes within 7 days prior to initiation of study drug.
    13. Treatment with the outlined medications within 7 days prior to initiation of study drug. Please see the Protocol for the full list of the exclusion criterion.
    14. Previous treatment with amiodarone.
    15. Previous treatment with rifabutin and/or clofazimine.
    16. Oral or parenteral antibiotics in the 4 weeks prior to screening (topical antibiotics are permitted).
    17. Treatment with probiotics (excluding yogurt and yogurt-derived products) in the 4 weeks prior to screening.
    18. Concomitant use of cyclosporine administered within the previous 8 weeks prior to screening.
    19. Chronic use of oral or systemic corticosteroid therapy for other disease(s) e.g. pulmonary diseases. Stable inhaled corticosteroids are permitted.
    20. Adverse reaction or hypersensitivity to the study drug or any medications related to the study drug.
    21. Positive stool results for C. difficile, other pathogens including ova, or parasites.
    22. Positive serology for Hepatitis B, Hepatitis C, or HIV.
    • If positive history of previously treated Hepatitis C, but HCV PCR is undetectable off medications for at least 6 months prior to screening, and treating hepatologist or infectious disease specialist believes the subject is cured – subject may be enrolled
    23. History of:
    • Atypical mycobacterial infections (other than MAP)
    • Active tuberculosis requiring treatment in the past 3 years
    24. Positive or indeterminate QuantiFERON TB Gold test:
    • In the presence of clinical signs/symptoms of TB or high risk of TB infection
    25. Currently diagnosed or history of uveitis confirmed by either an ophthalmologist or optometrist.
    26. Evidence of any significant hematological, hepatic, renal, cardiac, pulmonary, metabolic, neurological, psychiatric or other disease that might interfere with subject’s ability to safely enter and or complete the study requirements.
    27. History of malignancy within the past five years prior to screening except for basal cell carcinoma of the skin or carcinoma in situ of the cervix that has been treated with no evidence of recurrence.
    28. Current treatment with total parenteral nutrition.
    29. Females who have a positive pregnancy test or are lactating.
    30. History of drug or alcohol abuse within one year of screening.
    31. Participation in any experimental drug protocol within the past 60 days.
    32. Clinically significant abnormalities of hematology or biochemistry as confirmed by repeat testing based on investigator’s discretion, including but not limited to, elevations greater than 2 times the upper limit of normal of Aspartate Aminotransferase (AST), Alanine Aminotransferase (ALT), or creatinine clearance less than 60 ml/min at screening via estimated Cockcroft-Gault formula:
    Creatinine Clearance = [140 - age in years] * weight (kg) / 72 * Serum Creatinine (mg/dl) [multiply estimated rate by 0.85 for women], using actual body weight.
    33. QTcF>440ms, bundle branch block, or major ST or T wave abnormalities that make the assessment of the QT impossible.
    34. History of unstable cardiac syndromes including unstable angina, CABG, MI or coronary stenting within 2 months prior to screening; NYHA Class 3-4 CHF; history of ventricular tachycardia, VF, Long QT syndrome, or Torsade de Pointes, family or personal history of sudden death; HR<50 BPM (Note: at the discretion of the investigator, out-of-range heart rate measurement may be repeated once, and the repeat measurement used in relation to this exclusion); having taken any Class 1 or Class 3 antiarrhythmic medications or medicines known to prolong the QT interval or be associated with Torsade de Pointes.
    E.5 End points
    E.5.1Primary end point(s)
    Remission (primary outcome measure) – Remission in a subject is defined as a CDAI score of <150.
    E.5.1.1Timepoint(s) of evaluation of this end point
    26 weeks and 52 weeks
    E.5.2Secondary end point(s)
    Response - A response in the individual subject is defined as reduction in CDAI score of ≥100 from Visit 1
    E.5.2.1Timepoint(s) of evaluation of this end point
    Visit 1, 26 weeks and 52 weeks
    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 No
    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 No
    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) Yes
    E.7.4Therapeutic use (Phase IV) No
    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 concerned8
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA100
    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
    Czech Republic
    Hungary
    Ireland
    Russian Federation
    Ukraine
    United Kingdom
    E.8.7Trial has a data monitoring committee Yes
    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
    Upon completion of clinical activities and safety follow-up at week 56.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years2
    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: 330
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 30
    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 state29
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 360
    F.4.2.2In the whole clinical trial 360
    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)
    Subjects will be treated for 52 weeks with the study drug. On the last day of the treatment, subjects will visit the clinic to perform a full study visit including physical examination, hematology and chemistry blood sampling for safety analysis and other study related assessments. Subjects will be followed up 4 weeks after the last dose of study drug with a clinic visit including a full physical examination, Hematology and Chemistry blood sampling for safety assessments.
    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 Decision2015-10-13
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-05-15
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
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