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    Summary
    EudraCT Number:2018-003242-16
    Sponsor's Protocol Code Number:MRx-4DP0004-I-001
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:GB - no longer in EU/EEA
    Date on which this record was first entered in the EudraCT database:2018-10-31
    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 ConcernedUK - MHRA
    A.2EudraCT number2018-003242-16
    A.3Full title of the trial
    A first in human, double-blind, placebo-controlled, multicentre Phase I/II study to evaluate the safety, tolerability and immune modulatory effects of MRx-4DP0004, (a lyophilised formulation of Bifidobacterium breve proprietary strain of 4D Pharma Research), in participants taking long-term control medication for their asthma
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study to test the safety and effectiveness of bacteria called Bifidobacterium breve in adults with asthma
    A.3.2Name or abbreviated title of the trial where available
    A first in human study to evaluate safety, tolerability and immune modulatory effects of MRx-4DP0004
    A.4.1Sponsor's protocol code numberMRx-4DP0004-I-001
    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 Sponsor4D pharma plc
    B.1.3.4CountryUnited Kingdom
    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 support4D pharma plc
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisation4D pharma plc
    B.5.2Functional name of contact pointClinical Trials Department
    B.5.3 Address:
    B.5.3.1Street Address9 Bond Court
    B.5.3.2Town/ cityLeeds
    B.5.3.3Post codeLS1 2JZ
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number+44113895 0130
    B.5.6E-mailclinicaltrials@4dpharmaplc.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 MRx-4DP0004
    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 INNBifidobacterium breve
    D.3.9.2Current sponsor codeMRx-4DP0004
    D.3.9.3Other descriptive nameB. breve
    D.3.10 Strength
    D.3.10.1Concentration unit Other
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number1E9 to 1E10
    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 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
    Asthma
    E.1.1.1Medical condition in easily understood language
    Asthma is a common long-term disease where the airways can become inflamed. This makes the airways narrower causing chest tightness and wheezing, and making it harder to breathe.
    E.1.1.2Therapeutic area Diseases [C] - Respiratory Tract Diseases [C08]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10003553
    E.1.2Term Asthma
    E.1.2System Organ Class 10038738 - Respiratory, thoracic and mediastinal 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 of the study is to determine safety and tolerability of 12 weeks of dosing with MRx-4DP0004 given in addition to long-term treatment with ICS with or without LABA in participants who have asthma.
    E.2.2Secondary objectives of the trial
    Secondary:
    • To demonstrate improvement in asthma in response to treatment as measured by ACQ-6 score, number of exacerbations and of hospitalisations due to exacerbations.
    • To assess change from baseline in respect of FEV1, PEF and FVC.
    • To assess changes in eosinophil and neutrophil counts, the use of SABAs and in the AQLQ(S).

    Exploratory:
    • To assess changes in faecal microbiota and urine metabolomics.
    • To identify possible surrogate biomarkers of efficacy of MRx-4DP0004 in participants with partially controlled asthma, for assessment in future studies.
    • To assess changes from baseline in T Cell function.
    • To assess changes in sera cytokine concentrations.

    Additional UK sample objectives:
    • To assess changes in induced sputum eosinophil and neutrophil counts.
    • To assess changes in sputum microbiota.
    • To assess changes in sputum cytokine profile.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Participants must be 18 to 65 years of age inclusive, at the time of signing the informed consent.
    2. Participants with a documented medical history and diagnosis of asthma at least 6 months prior to Visit 1.
    3. Participants who have stable current treatment as per GINA treatment steps 2 to 4 (ICS with or without LABA) for the past 2 months at least.
    4. Participants who have an ACQ-6 score ≥1.5 and ≤4 at screening (V0), ≥1.0 and ≤4 at baseline (V2).
    5. Participants who have FEV1 >50% of predicted normal.
    6. Male and female participants are eligible to enter provided the following criteria regarding contraception, pregnancy and breast feeding are met.
    Female participants:
    A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies:
    • Not a woman of childbearing potential (WOCBP)
    OR
    • A WOCBP who agrees to follow the contraceptive guidance during the intervention period and for at least 2 menstrual periods after the last dose. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception.
    E.4Principal exclusion criteria
    1. Are non-compliant with prescribed asthma maintenance therapy in the opinion of the Investigator.
    2. Are at significant risk of being exposed to a change in environmental sensitising substances during the duration of the study (e.g., start or end of pollen season, exposure to sensitising animals etc.) according to Investigator’s judgement.
    3. Co-morbidities that have not been optimally controlled for the last 3 months. Any significant disease or disorder (e.g., cardiovascular, pulmonary other than asthma, gastrointestinal, hepatic, renal, neurological, musculoskeletal, endocrine, metabolic, malignant, psychiatric, major physical impairment) which, in the opinion of the Investigator, may either put the participant at risk because of inclusion in the study, or may influence the results of the study, or the participant’s ability to enter the study.
    4. Have human immunodeficiency virus (HIV) or active hepatitis B or hepatitis C.
    5. Participants with known GI fistula, feeding tubes or inflammatory bowel disease.
    6. Participants with GI disease resulting in an inability to take oral medication, malabsorption syndrome, prior surgical procedures affecting absorption, uncontrolled inflammatory GI disease (e.g., Crohn’s, ulcerative colitis).
    7. Medical history of life-threatening asthma including intubation and intensive care unit admission.
    8. Participants who use systemic corticosteroids for any reason within 6 weeks of first dose of IMP.
    9. Participants who are allergic to all the following 3 antibiotics: ampicillin, clindamycin, imipenem.
    10. Participants using probiotic supplements (probiotic yoghurts are allowed).
    11. Participants who are immunosuppressed or receiving immunosuppressant medication.
    12. Participants using ICS - LABA combination as both Maintenance And Reliever Therapy (MART regimen).
    13. Current smokers or nicotine users in any form including e-cigarettes and nicotine patches or sprays or participants who have smoked/used nicotine in the 3 months prior to Screening.
    14. Former smokers with >15 pack years.
    15. Participants who have completed a course of systemic antibiotics in the 4 weeks prior to first dose of IMP.
    16. Participants with clinically significant abnormal, in the opinion of the Investigator, values for haematology and serum biochemistry results at Screening.
    17. Participants who have a known sensitivity to any of the constituents of the IMP.
    18. Diastolic blood pressure <45 or >90 mmHg, systolic blood pressure <95 or >155 mmHg, and/or a pulse rate <40 or >100 beats per minute (bpm) after resting for 5 minutes.
    19. Participants with clinically significantly abnormal ECGs or structural cardiac abnormalities e.g. structural or valvular heart defects, patent foramen ovale.
    20. Any condition that, in the opinion of the Investigator, might interfere with the primary study objective.
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint/outcomes are the number of participants experiencing AEs and SAEs in each treatment arm, clinically relevant adverse changes in laboratory, spirometry, vital signs, and ECG parameters.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Every study visit from Visit 0 (Day -13 to 0) up to and including Visit 7 (Day 127)
    E.5.2Secondary end point(s)
    Secondary endpoints/outcomes:
    • Mean change from baseline in ACQ-6 score at Day 99.
    • Participants who have an ACQ-6 score of <1.0 at Day 99.
    • Participants who experience an exacerbation of their asthma
    • Participants who are hospitalised due to an exacerbation of their asthma
    • Change from baseline in participants’ FEV1 at Day 99.
    • Change from baseline in participants’ PEF at Day 99.
    • Change from baseline in participants’ FVC at Day 99.
    • Change from baseline in eosinophil and neutrophil counts (percentage and absolute) at Day 99.
    • Change from baseline (7-day period before dosing) in participants’ use of SABA during the 7-day period before Day 99.
    • Change from baseline score of at least 0.5 in AQLQ(S) at Day 99.

    Exploratory endpoints/outcomes are:
    • Faecal microbiota and urine metabolomics.
    • Participants FeNO concentrations.
    • Change in participant’s serum IgE concentration.
    • Participants urinary Leukotriene E4 concentration.
    • Change from baseline in T Cell function at Day 99.
    • Change in concentrations of cytokines in participants’ sera.

    Additional UK sample endpoints/outcomes are:
    • Change from baseline in induced sputum eosinophil and neutrophil counts (percentage and absolute) at Day 99.
    • Participant sputum microbiota.
    • Participant sputum cytokine profile.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Secondary:
    • ACQ-6: every visit (Visits 0 to 7)
    • Asthma exacerbation: ongoing AE collection
    • FEV1, PEF & FVC: every visit (Visits 0 to 7)
    • Eosinophils & neutrophils: Visit 0 & Visits 2 to 7
    • Use of SABA: daily diary
    • AQLQ(S): Visits 0, 2, 4, 5, 6 & 7

    Exploratory:
    • Faecal microbiota & urine metabolomics: Visits 1, 4, 6 & 7
    • FeNO: Visits 1 to 7
    • Serum IgE: Visits 1, 4 & 6
    • Leukotriene E4: Visits 1, 2, 4 & 6
    • T cell function: Visits 1, 4, 5 & 6
    • Serum cytokines: Visits 1, 4 & 6

    Induced sputum (UK sample):
    • Eosinophil, neutrophils, microbiota & cytokines: Visits 1, 2, 4, 6 & 7

    Visit 0: Day -13 to 0
    Visit 1: Day 1
    Visit 2: Day 15
    Visit 3: Day 29
    Visit 4; Day 43
    Visit 5: Day 71
    Visit 6: Day 99
    Visit 7: Day 127
    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 No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) Yes
    E.7.1.1First administration to humans Yes
    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) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    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 concerned5
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA7
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    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 years1
    E.8.9.1In the Member State concerned months8
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months8
    E.8.9.2In all countries concerned by the trial days0
    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: 90
    F.1.3Elderly (>=65 years) No
    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 state60
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 90
    F.4.2.2In the whole clinical trial 90
    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)
    Routine clinical care will be provided in parallel with study participation. After completion of the study, care will continue for each subject as normal.
    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 Decision2018-12-20
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-04-09
    P. End of Trial
    P.End of Trial StatusGB - no longer in EU/EEA
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