| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Moderate to Severe Active Rheumatoid Arthritis (RA) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Moderate to Severe Active Rheumatoid Arthritis (RA) |
|
| 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 |
|
| 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 |
| 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.2.2 | Secondary 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.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Between 18 and 75 years of age, inclusive.
2. Diagnosed with RA based on either the 1987-revised American College of Rheumatology (ACR) classification criteria or the 2010 ACR/ European League Against Rheumatism (EULAR) criteria for ≥3 months prior to screening.
3. Has active RA as defined by the following minimum disease activity criteria: ≥6 swollen joints (based on 66 joint counts) at screening and baseline visits.; ≥6 tender joints (based on 68 joint counts) at screening and baseline visits.; High-sensitivity C-reactive protein (hsCRP) > upper limit of normal reference range (ULN) at screening. One repeat assessment is acceptable for C-reactive protein per Investigator’s discretion if all other eligibility 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:
- ≥4 weeks prior to baseline visit for minocycline, D-penicillamine, sulfasalazine, hydroxychloroquine, chloroquine, azathioprine, oral or parenteral gold formulations.
- ≥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.
- ≥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. If participants are taking 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.4 | Principal exclusion criteria |
1.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.Abnormality in the ECG at screening that in the opinion of the Investigator increases the risk of participating in the study.: Specific exclusion criteria are participants with QT interval corrected for heart rate using Fridericia's formula (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, as determined by the Investigator.
4.Allergic reaction, anaphylaxis, or other reactions (eg, Stevens-Johnson syndrome, toxic epidermal necrolysis or leukopenia) to sulphonamides drugs.
5.Any clinically significant neurological, gastrointestinal (GI), renal, hepatic, cardiovascular, 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
6.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.
7.Any other inflammatory or arthritic disease in addition to RA that may interfere with the study (such as fibromyalgia, polymyalgia rheumatica, giant-cell arteritis, reactive arthritis, systemic lupus erythematosus, psoriatic arthritis, ankylosing spondylitis).
8.Active infection that is clinically significant, in the Investigator’s opinion, or any infection requiring hospitalisation or treatment with intravenous antimicrobials ≤60 days of screening, or any infection requiring oral antimicrobial therapy ≤2 weeks of the baseline visit.
9.Clinically significant features of arthroses that could interfere with study assessments and objectives.
10.Prior exposure to any JAK inhibitor, investigational or approved, (e.g. tofacitinib, baricitinib, upadacitinib, filgotinib).
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 intravenous, intramuscular, or intra-articular corticosteroids within 30 days prior to baseline visit or expected to require parenteral corticosteroid through the study.
15.High potency opiates including (but not limited to): oxycodone, oxymorphone, fentanyl, levorphanol, buprenorphine, methadone, hydromorphone, and morphine within 4 weeks prior to baseline visit.
16.Oral bisphosphonates within 6 months prior to baseline visit or once-a-year intravenous bisphosphonates within 1 year prior to baseline visit.
17.Any prior use of denosumab.
18.Use of strong cytochrome P450 3A4 inhibitors/inducers within 30 days or 5 half lives, whichever is longer, prior to baseline visit.
19.Use of uridine 5'-diphospho-glucuronosyltransferase family 2 member B7 inhibitors within 30 days or 5 half-lives, whichever is longer, prior to baseline visit.
20.Systemically administered carbonic anhydrase 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 (including, but not limited to, chlorambucil, nitrogen mustard, or other alkylating agents).
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: Serum aspartate aminotransferase or alanine aminotransferase >1.2 × ULN OR total bilirubin >1.5 × ULN; Estimated glomerular filtration rate by simplified 4-variable Modification of Diet in Renal Disease formula ≤60 mL/min/1.73 m²; Total white blood cell count <3,000/µL; Absolute neutrophil count <1,500/µL; Platelet count <100,000/µL; Absolute lymphocyte count <800/µL; 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-sterilized male participants who: do not agree to use appropriate contraception with their partners of childbearing potential or partners sterilised by tubal ligation. |
|
| E.5 End points |
| E.5.1 | Primary 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.5.1.1 | Timepoint(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
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.5.2 | Secondary 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.5.2.1 | Timepoint(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 treatment with MBS2320 compared to placebo:
a.1 as though no increase in any RA medication and no treatment discontinuation or interruption for any reason.
a.2 irrespective of treatment 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 from baseline will be measured at week 4, week 8 and week 12
c) Difference in percentage of patients with a previous inadequate response to MTX alone, with confirmed intra-articular synovitis on baseline MRI, who would have a successful composite clinical response after each of 4 and 8 weeks of treatment with MBS2320 compared to placebo |
|
| 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 | Yes |
| 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 | Yes |
| 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 | No |
| 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 | 4 |
| 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 | No |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 13 |
| 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 |
| Chile |
| Peru |
| Ukraine |
| Mexico |
| Russian Federation |
| Czechia |
| Poland |
|
| E.8.7 | Trial 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.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 7 |
| 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 | 7 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
Print
