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 |
Rheumatoid Arthritis due to overactive immune system |
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E.1.1.2 | Therapeutic area | Diseases [C] - Musculoskeletal Diseases [C05] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 16.0 |
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 |
- To determine the effects of MK-8457 100 mg BID compared to placebo over 12 weeks of treatment as measured by ACR20 response.
To determine the safety and tolerability of MK-8457 100 mg BID compared to placebo over 12 weeks of treatment. |
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E.2.2 | Secondary objectives of the trial |
Key Secondary: To determine the effects of MK-8457 100 mg BID compared to placebo as measured by ACR20 at Week 24; DAS28CRP change from baseline at Week 12; and ACR50 at Week 12.
- Base Study: To determine the effects of MK-8457 100 mg BID compared to placebo as measured by
change from baseline in DAS28CRP at Week 24; ACR50 at Week 24; and HAQ change
from baseline at Weeks 12 and 24.
Safety Extension: To assess the safety and tolerability of MK-8457 during the safety extension period
through Week 100.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• 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.
• Subject must have received MTX for a minimum of 3 months prior to screening with a regionally appropriate stable weekly dose for at least 4 weeks prior to screening (15-25 mg/wk for regions outside of Asia, and 6-25 mg/week for Asia). The subject’s dose of weekly MTX must remain stable through week 24 of the study.
• Subject must have either failed treatment with 1 or 2 anti-TNFtherapies or was intolerant to anti-TNFtherapy prior to screening. For subjects who have failed therapy, the treatment with anti-TNF therapies must have been for at least 3 months.
Note: The inadequate response or intolerance to anti-TNF therapy will be defined by the Investigator’s assessment and will be recorded. Typically, an inadequate response is based on clinical reasons (e.g., no improvement or worsening of RA). Lack of access to the medication or financial reasons are not considered an inadequate response
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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 any biological agents other than anti-TNF therapeutic agents, including but not limited to abatacept, tocilizumab, rituximab or other biological agents used for the treatment of RA.
• Subject has received any treatment (listed in the table below) more recently than the indicated washout period prior to randomization.
Washout Period for Medications Prior to Randomization
Medications, Supplements, and Other Substances Washout Period Prior to Randomization
Anti-TNF-α Therapies:
Adalimumab
Certolizumab
Etanercept
Golimumab
Infliximab
8 weeks
8 weeks
4 weeks
8 weeks
8 weeks
Cyclosporine, corticosteroids¹ (parenteral, intra-articular), azathioprine, sulfasalazine, hydroxychloroquine 4 weeks
Leflunomide² 8 weeks unless subject undergoes standard cholestyramine or activated charcoal washout in which case 4 weeks washout is required.
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
1 Subjects will be allowed to take stable doses of oral corticosteroids as specified in inclusion criterion #10; i.e., subjects must be on a stable dose of ≤10 mg prednisone per day (or equivalent) for at least 2 weeks prior to first administration of study medications.
2 Subjects may be allowed to use leflunomide instead of methotrexate on or after Week 24 of study treatment.
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E.5 End points |
E.5.1 | Primary end point(s) |
• The primary efficacy endpoint is the proportion of subjects achieving ACR20 response at Week 12.
The primary safety endpoints are:
• Percentage of subjects with adverse experiences;
• Change from baseline in laboratory parameters;
• Change from baseline in vital signs parameters;
• Change in blood pressure from predose to 1 hour, 2 hours and 3 hours after the morning study drug dose at Week 2 and Week 12; and
• Average change in blood pressure from predose in the 3 hours time period after am study drug dose at Week 2 and Week 12
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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) |
The key secondary efficacy endpoints are:
• Proportion of subjects achieving ACR20 response at Week 24;
• Change from baseline in DAS28CRP at Week 12; and
• Proportion of subjects achieving ACR50 response at Week 12.
Other secondary efficacy endpoints that will be evaluated include:
• Change from baseline in DAS28CRP at Week 24;
• Proportion of subjects achieving ACR50 response at Week 24; and
• Change from baseline in HAQ at Weeks 12 and 24.
Safety endpoints will also be evaluated through Week 100 of the safety extension.
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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 | 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 | Yes |
E.8.2.3.1 | Comparator description |
All patients will take background methotrexate (MTX). |
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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
| 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 | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 23 |
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 |
Australia |
Brazil |
Colombia |
Denmark |
France |
Greece |
Hungary |
Italy |
New Zealand |
Peru |
Poland |
South Africa |
Spain |
Sweden |
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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LVLS (Post-Study Visit is the scheduled last visit for patients.) |
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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 | 2 |
E.8.9.1 | In the Member State concerned months | 10 |
E.8.9.1 | In the Member State concerned days | 18 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 2 |
E.8.9.2 | In all countries concerned by the trial days | 0 |