E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Musculoskeletal Diseases [C05] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 23.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10039073 |
E.1.2 | Term | Rheumatoid arthritis |
E.1.2 | System Organ Class | 10028395 - Musculoskeletal and connective tissue disorders |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objective of this study is to determine the safety and tolerability of daily oral dosing of MBS2320 over 12 weeks in patients with active RA. |
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E.2.2 | Secondary objectives of the trial |
• To investigate whether there is evidence of a clinical benefit of MBS2320 over 12 weeks in patients with active RA, as assessed by the American College of Rheumatology 20% response (ACR20) and Disease Activity Score 28-C-reactive protein (DAS28-CRP).
• To evaluate the plasma concentrations of MBS2320 over 12 weeks in patients with active RA. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Patients will be:
1.1. males or females (of childbearing or non-childbearing potential) with a diagnosis of RA by ACR/European League against Rheumatism (EULAR) 2010 criteria (or, for those patients diagnosed before 2010, ACR 1987 criteria) for ≥6 months.
1.2. between 18 and 75 years of age, inclusive.
2. Female patients of childbearing potential must not be pregnant, as documented by a negative serum pregnancy test at screening and negative urine pregnancy test at Day 1, and must not be intending to become pregnant before the end of the study.
3. Patients must have active RA, defined as ≥6 swollen and/or ≥6 tender joints on 66/68 joint counts at screening and Day 1 (baseline).
4. Patients must have a high sensitivity CRP (hsCRP) result ≥1.5 × upper limit of normal (ULN) (0.3 mg/dL) or erythrocyte sedimentation rate (ESR) value ≥ULN (patients ≤50 years: 15 mm/hour [male], 20 or 25 mm/hour depending on site [female], >50 years: 20 mm/hour [male], 30 mm/hour [female]) at screening.
5. Patients must have been treated with, and tolerated, oral, SC or intramuscular (IM) MTX for a minimum of 90 days prior to screening, and must have been on a stable MTX dose between 7.5 and 25 mg once weekly for a minimum of 56 days prior to Day 1. Patients receiving MTX doses below 15 mg per week must have previously failed to tolerate a dose of 15 mg per week or higher.
6. Patients must have been treated with, and tolerated, folic acid, at a minimum dose of 5 mg per week, or be able and willing to commence such treatment from the screening visit.
7. Patients will have given their written informed consent to participate in the study and to abide by the study restrictions. |
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E.4 | Principal exclusion criteria |
Medical conditions:
1. Patients who have an abnormality in heart rate or blood pressure at screening that in the opinion of the Investigator increases the risk of participating in the study.
2. Patients who have an abnormality in the 12-lead ECG at screening that in the opinion of the Investigator increases the risk of participating in the study.
2.1. Specific exclusion criteria are patients with QTc interval corrected for heart rate using Fridericia’s formula (QTcF) of >450 ms (males) or >460 ms (females) and patients with PR interval of >220 ms at screening (1 repeat allowed).
3. Patients who have a significant history of drug allergy, including to MBS2320 or excipients, as determined by the Investigator.
4. Patients who have, or who have a history of, any clinically significant neurological, gastrointestinal, renal, hepatic, cardiovascular, psychiatric, respiratory, metabolic, endocrine, haematological or other major disorder (except for RA, or disorders associated with RA that, in the Investigator’s opinion, do not constitute a risk when taking the study medication and would not interfere with the study objectives) as determined by the Investigator.
5. Patients with any current malignancy, or a history of malignancy within 5 years 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.
6. Patients who have, or who have a history of, any other inflammatory or arthritic disease in addition to RA that may interfere with the study (such as polymyalgia rheumatica, giant cell arteritis, reactive arthritis, systemic lupus erythematosus, psoriatic arthritis, ankylosing spondylitis).
7. Patients who have known history of alcoholic hepatitis or non-alcoholic steatohepatitis.
8. Patients who have known history of opportunistic, chronic or recurrent infections.
Prior/concomitant therapy:
9. Patients who have received:
9.1. a live virus vaccination within the 90 days prior to Day 1 (1 year for bacille Calmette-Guerin [BCG] vaccination) or intend to receive a live virus vaccination during the study or within 28 days after study completion.
9.2. approved or investigational non-biological DMARDs (except MTX, sulfasalazine, chloroquine or hydroxychloroquine) such as tofacitinib, D-penicillamine, oral or parenteral gold salts, leflunomide, azathioprine, cyclosporine, tacrolimus and
mycophenolate mofetil within 30 days or 5 half-lives prior to Day 1, whichever is longer (1 year for leflunomide; unless there has been a washout procedure using cholestyramine or activated charcoal).
9.3. oral bisphosphonates within 6 months prior to Day 1 or once-yearly intravenous (IV) bisphosphonates within 1 year prior to Day 1.
9.4. any prior use of denosumab.
9.5. any prior use of the biological DMARD rituximab.
9.6. any biological DMARD therapy with agents such as abatacept, anakinra, tocilizumab, any therapeutic agent targeted at reducing TNFα such as adalimumab, golimumab, infliximab (or biosimilars thereof), or any approved or investigational monoclonal antibody or recombinant protein therapy or Prosorba column treatment within 60 days prior to Day 1.
9.7. two or more biological DMARD therapy agents where no therapeutic benefit was observed.
9.8. any prior use of cytotoxic agents (including, but not limited to, chlorambucil, cyclophosphamide, nitrogen mustard, or other alkylating agents).
9.9. non-steroidal anti-inflammatory drug (NSAID) background therapy for RA as prescribed by a physician, unless the doses have been stable for at least 14 days prior to Day 1 and is expected to remain unchanged for the duration of the study.
9.10. oral corticosteroid background therapy for RA as prescribed by a physician, unless the doses have been stable for at least 30 days prior to Day 1, the daily dose does not exceed 10 mg prednisolone (or equivalent), and is expected to remain unchanged for the duration of the study.
9.11. sulfalazine, chloroquine or hydroxychloroquine background therapy for RA as prescribed by a physician, unless patient has taken and tolerated treatment for at least 90 days and the dose has been stable for at least 56 days prior to Day 1.
9.12. therapies for conditions other than RA as prescribed by a physician, unless the doses have been stable for at least 14 days prior to Day 1.
9.13. any IV, IM or intra-articular corticosteroids within 30 days prior to Day 1.
9.14. any prior use of the P-glycoprotein (P-gp) substrates talinolol or tolvaptan.
9.15. any medication or substance (except MTX, sulfasalazine, chloroquine or hydroxychloroquine) known to chronically alter drug absorption or elimination processes (including St John’s Wort and strong CYP3A4 inhibitors/inducers) within 30 days prior to the first dose administration.
9.16. P-gp substrates within 30 days or 5 half-lives prior to Day 1, whichever is longer.
Please refer to Protocol for continued list of the exclusion criteria
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E.5 End points |
E.5.1 | Primary end point(s) |
1.Safety outcome measures include adverse events (AEs), vital signs, electrocardiograms (ECGs), clinical laboratory evaluations, physical examinations.
2. The main efficacy outcome measures are ACR20 and DAS28-CRP. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Throughout the 12 week study. |
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E.5.2 | Secondary end point(s) |
1. Exploratory efficacy outcome measures include patient and clinician reported outcomes, MRI of worst affected hand and wrist, DAS28-erythrocyte sedimentation rate, ACR 50% and 70% response (ACR50 and ACR70, respectively), percentage improvement in ACR components and number of patients achieving DAS28-CRP low disease activity.
2. Exploratory PD outcome measures are biomarkers (e.g. high sensitivity CRP, inflammatory cytokines and biomarkers of bone turnover) and peripheral blood leucocyte phenotype.
3. The PK outcome measures are MBS2320 and MBS2473 plasma concentrations. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Throughout the 12 week study. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Romania |
Georgia |
Moldova, Republic of |
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E.8.7 | Trial 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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 3 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 3 |
E.8.9.2 | In all countries concerned by the trial days | 0 |