E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Moderately to Severely Active Rheumatoid Arthritis (RA) |
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E.1.1.1 | Medical condition in easily understood language |
Rheumatoid Arthritis (RA) |
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E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
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 |
Period 1 • To compare the efficacy of Upadacitinib QD versus placebo, and versus adalimumab (ADA) for the treatment of signs and symptoms of rheumatoid arthritis (RA) in subjects with moderately to severely active RA who are on a on a stable background of methotrexate (MTX) and who have an inadequate response to MTX (MTX-IR). • To compare the efficacy of Upadacitinib QD versus placebo for the prevention of structural progression in RA subjects with moderately to severely active RA who are on a on a stable background of MTX and who have an inadequate response to MTX (MTX-IR). • To compare the safety and tolerability of Upadacitinib QD versus placebo, and versus ADA in subjects with moderately to severely active RA subjects who are on a stable background of MTX and who have an inadequate response to MTX (MTX-IR). Period 2 • To evaluate the long-term safety, tolerability, and efficacy of Upadacitinib in subjects with RA who have completed Period 1. |
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E.2.2 | Secondary objectives of the trial |
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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 |
The objective of this optional sub-study is to assess the immunogenecity of the adjuvanted recombinant glycoprotein E (gE) herpes zoster (HZ) vaccine (recombinant zoster vaccine; RZV; Shingrix®) in rheumatoid arthritis (RA) patients receiving upadacitinib 15 mg QD with background MTX. |
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E.3 | Principal inclusion criteria |
• Adult male or female, at least 18 years old. • Diagnosis of RA for ≥ 3 months. • Subjects must have been on oral or parenteral MTX therapy ≥ 3 months prior to the first dose of study drug. • Subjects meeting both: ≥ 6 swollen joints and ≥ 6 tender joints at screening and baseline and hsCRP ≥ 5 mg/L at screening • At least one of the following at Screening: ≥ 3 bone erosions on x-ray OR ≥ 1 bone erosion and a positive rheumatoid factor OR ≥ 1 bone erosion and a positive anti-cyclic citrullinated peptide autoantibodies. • Subjects with prior exposure to at most one bDMARD (except ADA) may be enrolled (up to 20% of total study population) • Except for MTX, subject must have discontinued all conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs).
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E.4 | Principal exclusion criteria |
• Prior exposure to any Janus kinase (JAK) inhibitor (including but not limited to tofacitinib, baricitinib, and filgotinib). Subjects who are considered inadequate responders to bDMARD therapy • History of inflammatory joint disease other than RA. History of secondary Sjogren's Syndrome is permitted. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint is the proportion of subjects achieving ACR20 response at Week 12 / the proportion of subjects achieving clinical remission (CR) based on DAS28 (CRP) at 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) |
Ranked: 1. Change from baseline in modified Total Sharp Score (mTSS) at Week 26 2. Proportion of subjects achieving LDA at Week 12 3. Change from baseline in Disease Activity Score (DAS) 28(CRP) at Week 12 4. Change from baseline in Health Assessment Questionnaire (HAQ-DI) at Week 12 5. ACR20 response at Week 12 6. Proportion of subjects achieving LDA based on DAS28 (CRP) ≤ 3.2 at Week 12 (noninferiority of upadacitinib vs ADA) 7. Change from baseline in Short Form 36 (SF-36) PCS at Week 12 8. Proportion of subjects achieving LDA based on Clinical Disease Activity Index (CDAI) at Week 12 9. Change from baseline in morning stifness at Week 12 10. Change from baseline in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) at Week 12 11. Proportion of subjects with no radiographic progression at Week 26 Other: 1. ACR50 response at Week 12 2. ACR70 response at Week 12 |
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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 | 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 | Yes |
E.6.11 | Pharmacogenomic | No |
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) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
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) | Yes |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 3 |
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 | 7 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 115 |
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 |
Argentina |
Australia |
Belarus |
Bosnia and Herzegovina |
Brazil |
Canada |
Chile |
Colombia |
Egypt |
Hong Kong |
Israel |
Kazakhstan |
Korea, Republic of |
Malaysia |
Mexico |
New Zealand |
Puerto Rico |
Russian Federation |
Serbia |
Singapore |
South Africa |
Taiwan |
Turkey |
Ukraine |
United States |
European Union |
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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 or last follow up contact whichever is later |
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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 | 10 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 10 |