E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
active rheumatoid arthritis |
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E.1.1.1 | Medical condition in easily understood language |
arthritis due to overactive immune system |
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E.1.1.2 | Therapeutic area | Diseases [C] - Musculoskeletal Diseases [C05] |
MedDRA Classification |
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 determine the optimal dose of MK-8457 + MTX as compared to placebo + MTX, as demonstrated the RA subjects who achieve ACR20 (American College of Rheumatology 20) response after 24 weeks of treatment. |
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E.2.2 | Secondary objectives of the trial |
To determine the effects of 24 weeks of treatment with MK-8457 100 mg BID + MTX compared to placebo (PBO) + MTX on the following endpoints: ACR50, ACR70, hybrid ACR response, ACR-N, change from baseline in individual ACR components, DAS28CRP, DAS28ESR (DAS28 response, DAS28 remission, and change from baseline) DAS-AUC, Simplified Disease Activity Index (SDAI), Erythrocyte Sedimentation Rate (ESR), C-Reactive Protein (CRP), Short Form Health Survey (SF-36), Health Assessment Questionnaire (HAQ), and Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), change from baseline in Hemoglobin; (2) To determine the effects of 24 weeks of treatment with all other doses of MK-8457 + MTX compared to placebo (PBO) + MTX on the following endpoints: ACR50, ACR70, hybrid ACR response, and change from baseline in individual ACR components, DAS28, SDAI, ESR, CRP, SF-36, HAQ, and FACIT-F. |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
MRI Sub-Study (optional): To determine the effects of 24 weeks of treatment with MK-8457 100 mg BID + MTX compared to placebo + MTX on bone erosions, periarticular bone edema, synovitis, and other articular parameters in Magnetic Resonance Imaging (MRI) studies of selected joints.
PK Sub-Study (optional): To evaluate the effect of extrinsic and intrinsic factors to support proposed dosing regimen and to conduct exposure-safety analysis. |
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E.3 | Principal inclusion criteria |
• Subject must be ≥18 years of age on the day of signing the informed consent.
RA diagnosis and disease activity:
• Subject has a diagnosis of RA for at least 6 months prior to screening.
• Subject has active RA as defined by the presence of 6 swollen joints (of 66 joint count) AND 6 tender joints (of 68 joint count) at screening (Visit 1) and baseline (Visit 2).
• Subject has a C-reactive protein (CRP) blood level > 0.9 mg/dL from the central reference laboratory at screening.
• Subject is anti-cyclic citrullinated antibody positive and/or rheumatoid factor positive at screening.
• Subject is ACR functional Class I, II, or III.
• Subjects has received MTX for a minimum of 3 months with a regionally appropriate stable weekly dose (15-25 mg/wk for regions outside of Asia, 6–25 mg/week for Asia) for at least 4 wks prior to entering study.
• Subject must meet all Tuberculosis (TB) screening criteria: No history of untreated latent or active TB prior to baseline; Has no signs or symptoms suggestive of active TB; Has had no recent close contact with a person with active TB (if there has been contact, patient will be evaluated and receive appropriate treatment for latent TB at least 4 weeks prior to first dose of study medication; Within 4 weeks prior to first administration of study medication, has negative diagnostic TB test result ; has a chest radiograph within two months prior to screening with no evidence of current or old inactive TB |
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E.4 | Principal exclusion criteria |
• Subject has inflammatory disease other than RA, including but not limited to psoriatic arthritis, ankylosing spondylitis, systemic lupus erythematosus, or Lyme disease.
• Previous exposure to fostamatinib or other splenic tyrosine kinase (SYK) inhibitors.
• Previous exposure to TNF-alpha targeted therapy or any biological agents for RA.
• Subject has received any treatment listed below more recently than the indicated washout period prior to Screening.
Prohibited Medications, Supplements, and Other Substances Washout Period Prior to Screening
Disease modifying anti-rheumatic drugs such as but not limited to (not including cytotoxic agents):
Leflunomide, cyclosporine, mycophenolate mofetil, azathioprine, corticosteroids (parenteral, intra-articular), sulfasalazine, hydroxychloroquine 30 days (8 weeks for leflunomide unless subject undergoes standard cholestyramine or activated charcoal washout)
Cytotoxic agents including chlorambucil, cyclophosphamide, nitrogen mustard, or other alkylating agents 3 months
Live vaccinations 1 month
Investigational medications 30 days or 5 half lives of the investigational agent whichever is longer
Bacille Calmette-Guerin (BCG) vaccination 1 month
• Subject has sustained uncontrolled hypertension or uncontrolled diabetes
• Subject has been hospitalised due to an acute cardiovascular event, CV illness or CV surgery within 6 months of screening
• Subject is taking concomitant doses of statins exceeding the following: atorvastatin 40mg/day; fluvastatin 40mg/day, pravastatin 40mg/day, rosuvastatin 20mg/day and simvastatin 20mg/day, pitavastatin 2mg/day (if lower doses of statins are approved in an individual country, subjects taking concomitant statins above half the maximum approved dose are excluded)
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E.5 End points |
E.5.1 | Primary end point(s) |
American College of Rheumatology 20 (ACR20) response at 24 weeks |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
Objective: To determine the effects of 24 weeks of treatment with MK-8457 100 mg BID + MTX compared to placebo (PBO) + MTX on the following endpoints: ACR50, ACR70, hybrid ACR response, ACR-N, change from baseline in individual ACR components, DAS28CRP, DAS28ESR (DAS28 response, DAS28 remission, and change from baseline) DAS-AUC, Simplified Disease Activity Index (SDAI), Erythrocyte Sedimentation Rate (ESR), C-Reactive Protein (CRP), Short Form Health Survey (SF-36), Health Assessment Questionnaire (HAQ), and Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), change from baseline in Hemoglobin
(2) Objective: To determine the effects of 24 weeks of treatment with all other doses of MK-8457 + MTX compared to placebo (PBO) + MTX on the following endpoints: ACR50, ACR70, hybrid ACR response, and change from baseline in individual ACR components, DAS28, SDAI, ESR, CRP, SF-36, HAQ, and FACIT-F.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | Yes |
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 | Yes |
E.8.1.7.1 | Other trial design description |
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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 | 6 |
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.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 7 |
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 |
Brazil |
Canada |
Chile |
Denmark |
Germany |
Hungary |
India |
Japan |
Korea, Democratic People's Republic of |
Lithuania |
Mexico |
Moldova, Republic of |
Peru |
Poland |
Russian Federation |
South Africa |
Taiwan |
United Kingdom |
United States |
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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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Last Subject Last Visit (Post-study visit). |
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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 | 4 |
E.8.9.1 | In the Member State concerned months | 2 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 5 |
E.8.9.2 | In all countries concerned by the trial days | 0 |