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    Summary
    EudraCT Number:2020-005496-13
    Sponsor's Protocol Code Number:IST-06
    National Competent Authority:Poland - Office for Medicinal Products
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2022-05-05
    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 ConcernedPoland - Office for Medicinal Products
    A.2EudraCT number2020-005496-13
    A.3Full title of the trial
    A Randomised, Double-Blind, Placebo-Controlled, Dose-Ranging Phase 2b Study to Investigate the Efficacy and Safety of MBS2320 With Background Methotrexate (MTX) in Participants With Moderate to Severe Active Rheumatoid Arthritis (RA) Who Have Had an Inadequate Response to MTX Alone
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Study to Evaluate Safety and Efficacy of MBS2320 in Patients receiving therapy with Mehtotrexate (MTX) with moderate to severe Rheumatoid Arthritis, who have had an inadequate response to MTX alone
    A.4.1Sponsor's protocol code numberIST-06
    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 SponsorModern Biosciences Ltd.
    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 supportModern Biosciences Ltd.
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationModern Biosciences Ltd.
    B.5.2Functional name of contact pointKerry Highlands
    B.5.3 Address:
    B.5.3.1Street Address2nd Floor 3 Pancras Square (Kings Cross)
    B.5.3.2Town/ cityLondon
    B.5.3.3Post codeN1C 4AG
    B.5.3.4CountryUnited Kingdom
    B.5.6E-mailKerry@istesso.co.uk
    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 MBS2320
    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.3.9.1CAS number 1642602-54-7
    D.3.9.2Current sponsor codeMBS2320
    D.3.9.3Other descriptive nameMBS2320
    D.3.9.4EV Substance CodeSUB218387
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number5/20/40
    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
    Moderate to Severe Active Rheumatoid Arthritis (RA)
    E.1.1.1Medical condition in easily understood language
    Moderate to Severe Active Rheumatoid Arthritis (RA)
    E.1.1.2Therapeutic area Diseases [C] - Musculoskeletal Diseases [C05]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 23.1
    E.1.2Level PT
    E.1.2Classification code 10039073
    E.1.2Term Rheumatoid arthritis
    E.1.2System Organ Class 10028395 - Musculoskeletal and connective tissue disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate the efficacy of MBS2320 (5 mg once daily, 20 mg once daily, and 40 mg once daily) compared with placebo in participants with active RA on stable background MTX who have had an inadequate response to MTX alone, with confirmed intra-articular synovitis on baseline MRI.
    E.2.2Secondary objectives of the trial
    To evaluate the safety and tolerability of select MBS2320 doses (5 mg once daily, 20 mg once daily, and 40 mg once daily) compared with placebo in participants with active RA on stable background MTX who have had an inadequate response to MTX alone, with confirmed intra-articular synovitis on baseline MRI.

    To evaluate steady-state plasma concentrations of MBS2320 and MBS2473.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Each participant must meet all the following criteria to be enrolled in this study:
    1.Between 18 and 75 years of age, inclusive.
    2.Diagnosed with RA based on either the 1987-revised ACR classification criteria or the 2010 ACR/EULAR criteria for ≥3 months prior to screening.
    3.Has active RA as defined by the following minimum disease activity criteria:
    o≥6 swollen joints (based on 66 joint counts) at screening and baseline visits.
    o≥6 tender joints (based on 68 joint counts) at screening and baseline visits.
    ohsCRP > upper limit of normal reference range (ULN) at screening. On repeat assessment is acceptable for C-reactive protein per Investigator's discretion if all other eligability criteria are met.
    4.Considered to be inadequately responding to oral or parenteral MTX therapy for ≥3 months and <10 years prior to screening and to be tolerating a dose of 15 to 25 mg per week for at least 56 days prior to baseline visit. Participants should also be on a stable dose of folic acid (or equivalent) for at least 56 days prior to baseline visit. Participants should continue with their stable doses of MTX and folic acid throughout the study.
    5.Except for MTX, must have discontinued all oral DMARDs prior to baseline visit as specified below or for at least 5 half-lives of a drug, whichever is longer:
    o≥4 weeks prior to baseline visit for minocycline, D-penicillamine, sulfasalazine, hydroxychloroquine, chloroquine, azathioprine, oral or parenteral gold formulations.
    o≥8 weeks prior to baseline visit for leflunomide if no elimination procedure was followed or adhere to a washout procedure (i.e. 11 days washout with cholestyramine or 30 days washout with activated charcoal) and for oral cyclosporine.
    o≥24 weeks prior to the baseline visit for cyclophosphamide.
    6.Negative test for TB by QuantiFERON-TB Gold In-Tube test. Indeterminate results may be repeated and if negative or still indeterminate, participant may be included in the study if they have no clinical symptoms of TB, have had no known exposure to TB, and have had a negative chest X ray within previous 3 months.
    7.If participants are taking NSAIDs or acetaminophen for stable medical conditions, they should be receiving these medications at a stable dose for at least 4 weeks prior to baseline visit and the doses of the medications should be kept stable throughout the study. Non-steroidal anti-inflammatory drugs, acetaminophen, tramadol, codeine, hydrocodone, and propoxyphene on a need basis, these drugs should not be taken 24 hours prior to any study visit.
    8.If participants are taking oral corticosteroids (equivalent to prednisolone ≤10 mg), or inhaled corticosteroids, they should be receiving these medications at a stable dose for at least 4 weeks prior to baseline visit for stable medical conditions. The doses of the medications should be kept stable throughout the study. Oral and inhaled corticosteroids taken as needed are allowed but may not be taken 24 hours prior to any study visit.
    9.Willing to provide written informed consent to participate in the study and to abide by the study restrictions.
    E.4Principal exclusion criteria
    1.Abnormality in heart rate or blood pressure at screening that increases the risk of participating in the study.
    2.Abnormality in the 12-lead ECG at screening increases the risk of participating in the study.
    oSpecific exclusion criteria are participants with QTcF of >450 ms (males) or >460 ms (females) and participants with PR interval of >220 ms at screening (1 repeat assessment is allowed).
    3.Significant history of drug allergy, including to MBS2320 or excipients
    4.Allergic reaction, anaphylaxis, or other reactions to sulphonamides drugs.
    5.Any clinically significant neurological, GI, renal, hepatic, CV, psychiatric, respiratory, metabolic, endocrine, haematological, ophthalmic, or other major disorder which, in the opinion of the Investigator, would put the participant at risk by participating in the study (except for RA or disorders associated with RA that, in the Investigator’s opinion, do not constitute a risk when taking the IP and would not interfere with the study objectives).
    6.Any current malignancy or a history of malignancy within 5 y prior to screening, with the exception of adequately treated or excised non-metastatic basal cell or squamous cell cancer of the skin or cervical carcinoma in situ.
    7.Any other inflammatory or arthritic disease in addition to RA that may interfere with the study
    8.Active infection that is clinically significant, or requiring hospitalisation or treatment with i.v. antimicrobials ≤60 days of screening, or any infection requiring oral antimicrobial therapy ≤2 weeks of the baseline visit.
    9.Clinical significant features of arthroses that could interfere with study assessments and objectives.
    10.Prior exposure to any JAK inhibitor, investigational or approved
    11.Prior exposure to any biologic RA therapy, investigational or approved, or any approved or investigational monoclonal antibody or recombinant protein therapy
    12.Prosorba column treatment within 60 days prior to baseline visit.
    13.Current or expected need of other immunosuppressant medications including >10 mg oral prednisolone/day or equivalent corticosteroid therapy (see Inclusion Criterion 8). Use of MTX as described in Inclusion Criteria 4 is permitted.
    14.Any i.v, i.m., or intra-articular corticosteroids within 30 days prior to baseline visit or expected to require parenteral corticosteroid through the study.
    15.High potency opiates
    16.Oral bisphosphonates within 6 months prior to baseline visit or once-a-year i.v. bisphosphonates within 1 year prior to baseline visit.
    17.Any prior use of denosumab.
    18.Use of strong CYP3A4 inhibitors/inducers within 30 days or 5 half-lives, whichever is longer, prior to baseline visit.
    19.Use of B7 (UGT2B7) inhibitors within 30 days or 5 half-lives, whichever is longer, prior to baseline visit.
    20.Systemically administered CA inhibitors within 30 days or 5 half-lives, whichever is longer, prior to baseline visit.
    21. Any prior use of cytotoxic agents for indications other than RA
    22. Participation in another clinical study (including attending follow-up visits) or receipt of any investigational drug of chemical or biologic nature within a minimum of 90 days or 5 half-lives of the drug (whichever is longer) prior to baseline visit.
    23.Previously received MBS2320.
    24. Chest X-ray within 90 days prior to baseline visit that shows an abnormality suggestive of malignancy, current infection, or old inactive TB.
    25. Screening laboratory values meeting the following criteria: o Serum AST or alanine ALT >1.2 × ULN OR total bilirubin >1.5 × ULN;
    o Estimated GFR by simplified 4-variable Modification of Diet in Renal Disease formula ≤60 mL/min/1.73 m²;
    o Total white blood cell count <3,000/μL;
    o Absolute neutrophil count <1,500/μL;
    o Platelet count <100,000/μL;
    o Absolute lymphocyte count <800/ μL;
    o Haemoglobin <9 gm/dL.
    26. Positive serology results for HBsAg or HBcAb, HCV antibody with positive confirmatory test for HCV (eg PCR) , or human immunodeficiency virus (HIV) antibody at the screening visit.
    27. Non-sterillized female participant who: do not agree to use appropriate contraception with their partners of childbearing potential or partner sterilised by tubal ligation.

    E.5 End points
    E.5.1Primary end point(s)
    Composite clinical response (Success/Failure) at Week 12 defined as:
    •Achieving clinical response according to the criteria for ACR20:
    •≥20% improvement in 68-TJC;
    •≥20% improvement in 66-SJC; and
    •≥20% improvement in at least 3 of the 5 following parameters:
    -Physician’s global assessment of disease activity
    -Participant’s global assessment of disease activity
    -Participant’s assessment of arthritis pain
    -HAQ-DI
    -hsCRP
    •Not discontinuing treatment due to tolerability issues or lack of efficacy; and
    •Not requiring any increase in RA medications - either in background medication dose (MTX) or any further alternative RA treatment or procedure.
    E.5.1.1Timepoint(s) of evaluation of this end point
    The primary efficacy estimand is the absolute difference between each of the 3 different doses of MBS2320 and placebo in the percentage of participants who would achieve
    successful composite clinical response at Week 12 (which assumes failure for those who have any increase in RA medications or treatment discontinuation due to lack of efficacy or tolerability issues).
    E.5.2Secondary end point(s)
    a) Change in RAMRIS scores (synovitis, bone oedema, and bone erosion scores, measured with MRI) from baseline to Week 12.
    b) Change in DAS28-hsCRP from baseline to Weeks 4, 8, and 12.
    c) Successful composite clinical response (Yes/No) at Weeks 4 and 8 defined as achieving clinical response according to the criteria for ACR20.
    E.5.2.1Timepoint(s) of evaluation of this end point
    a)Difference in mean change from baseline in each RAMRIS score,in patients assessed after 12 weeks of treat. with MBS2320 compared to placebo:
    1 as though no increase in any RA medication and no treat. discontinuation or interruption for any reason
    2 irrespective of treat. discontinuation or interruption due to tolerability issues or lack of efficacy, and as though no increase in any other RA medication
    b) Change in DAS28-hsCRP as dependent variable from baseline will be measured at week 4, 8 and 12 using a mixed model for repeated measures
    c) Difference in % of patients with a previous inadequate resp. to MTX alone,with intra-articular synovitis on baseline MRI, who would have successful comp. clinical resp. after each of 4 and 8 weeks of treatment with MBS2320 compared to placebo
    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 Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic Yes
    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) 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 No
    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 trial4
    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 concerned9
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA13
    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
    Chile
    Peru
    Czechia
    Mexico
    Poland
    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
    The end of the study is defined as the date of the last participant’s last assessment (scheduled or unscheduled).
    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 months3
    E.8.9.1In the Member State concerned days13
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months7
    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: 180
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 44
    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 state44
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 62
    F.4.2.2In the whole clinical trial 224
    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)
    There is no treatment following the end of the study. The Investigator is advised to return participants to their primary physician.
    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 Decision2022-05-23
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2022-04-20
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2023-12-28
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