E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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] - Musculoskeletal Diseases [C05] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
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 objective of this study is to assess and compare 1) the proportion of subjects who achieve remission with active conventional therapy (ACT) versus three different biologic therapies; and 2) two alternative deescalation strategies in patients who respond to first-line therapy. |
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E.2.2 | Secondary objectives of the trial |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Subject is ≥18 years of age. 2. Subject has a diagnosis of RA as defined by the newly established ACR/EULAR criteria, 2010 (Appendix D). (Patients should also be classified according to the 1987-revised ACR-classification criteria, without this being an inclusion criteria) (Appendix C). 3. <24 months from arthritis symptom debut (symptom duration will be registered). 4. Subject must have DAS28 (CRP) > 3.2. 5. ≥ 2 s11. Subjects must be able and willing to self-administer s.c. injections or have a qualified person available to administer s.c. injections.wollen joints AND ≥ 2 tender joints. 6. Subject must fulfill one of the following three criteria: RF positive OR ACPA positive OR CRP >10 mg/L. 7. Female subject is either not of childbearing potential (postmenopausal, surgically sterile etc.), or is of childbearing potential and practicing a reliable method of birth control throughout the study and for 90 days after study completion. 8. Female subjects of childbearing potential must have a negative serum pregnancy test at the Screening visit. 9. Subject is judged to be in good general health as determined by the principal investigator based upon the results of medical history, laboratory profile, physical examination, chest X-ray (CXR), and 12-lead electrocardiogram (ECG) performed at Screening. 10. Subjects must be able and willing to provide written informed consent and comply with the requirements of this study protocol. 11. Subjects must be able and willing to self-administer s.c. injections or have a qualified person available to administer s.c. injections. |
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E.4 | Principal exclusion criteria |
1. Subject has been previously treated with disease modifying antirheumatic drugs (DMARDs) for rheumatic diseases. 2. Current active inflammatory joint disease other than RA. 3. Subject has been treated with intra-articular or parenteral administration of corticosteroids in the preceding 4 weeks. Inhaled corticosteroids for stable medical conditions are allowed. 4. Subject has undergone joint surgery within the preceding two months (at joints to be assessed within the study). 5. Subject has chronic arthritis diagnosed before age 17 years. 6. Subject has a history of an allergic reaction or significant sensitivity to constituents of study drugs. 7. Subject has been treated with any investigational drug within one month prior to screening visit. 8. Active infection of any kind (excluding fungal infections of nail beds), or any major episode of infection requiring hospitalization within 4 weeks of screening. 9. Subject has a poorly controlled medical condition, such as uncontrolled diabetes, unstable heart disease, congestive heart failure, recent cerebrovascular accidents and any other condition which, in the opinion of the investigator, would put the subject at risk by participation in the study. 10. Subject has a history of clinically significant hematologic (e.g., severe anemia, leukopenia, thrombocytopenia), renal or liver disease (e.g., fibrosis, cirrhosis, hepatitis). 11. Subject has history of neurologic symptoms suggestive of central nervous system (CNS) demyelinating disease and/or diagnosis of central demyelinating disease. 12. Subject has history of cancer or lymphoproliferative disease. Allowable exceptions: a. Successfully treated cutaneous squamous cell or basal cell carcinoma b. Localized carcinoma in situ of the cervix c. Curatively treated malignancy (treatment terminated) > 5 years prior to screening 13. Subject has a history of listeriosis, histoplasmosis, untreated TB, persistent chronic infections, or recent active infections requiring hospitalization or treatment with intravenous (iv) anti-infectives within 30 days or oral anti-infectives within 14 days prior to the BL visit. 14. Subjects will be evaluated for latent TB infection with a PPD or QuantiFERON test and X-ray. Subjects with evidence for latent TB will not be enrolled but first assessed according to local guidelines. 15. Subject is known to have immune deficiency, history of Human Immunodeficiency Virus (HIV) or is otherwise severely immunocompromised. 16. Female subject who is pregnant or breast-feeding or considering becoming pregnant during the study or for 90 days after the last dose of study medication. 17. Subject has a history of clinically significant drug or alcohol usage in the last year. 18. Subject has a chronic widespread pain syndrome. 19. Subject is considered by the investigator, for any reason, to be an unsuitable candidate for the study. 20. Subject is unwilling to comply with the study protocol. 21. Screening clinical laboratory analyses show any of the following abnormal laboratory results: a. Aspartate transaminase (AST) or alanine transaminase (ALT) > 1.75 times upper limit of normal (ULN). b. Positive serum human chorionic gonadotropin (hCG). c. Positive tests for hepatitis B surface antigen (HBsAg) or hepatitis C serology indicative of current infection. d. Creatinine levels > 2x the ULN. If creatinine 1-2 times ULN, check GFR. e. Hemoglobin < 90 g/L. f. Absolute neutrophil count (ANC) < 1.5x10^3/microL. g. Serum total bilirubin > 1.5 mg/dL (>26 micromol/L). |
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E.5 End points |
E.5.1 | Primary end point(s) |
A. Treatment Part 1: The primary efficacy outcome is the proportion of patients in remission at week 24 from baseline according to CDAI. B. Treatment Part 2: The primary efficacy outcome is the proportion of patients in remission according to CDAI, at the time point 24 weeks after the dose was first reduced. C. The primary efficacy outcome is the progression of total Sharp van der Heijde score after 56 weeks from baseline. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
A. 24 weeks from baseline B. 24 weeks after the dose was first reduced C. 56 weeks from baseline |
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E.5.2 | Secondary end point(s) |
Clinical outcomes 1. CDAI/SDAI/2010 ACR/EULAR remission at all time points 2. ACR20/ACR50/ACR70/ACR-hybrid 3. DAS28 (based on ESR) •values •DAS28-ESR based disease categories •EULAR responses 4. DAS28-CRP •values •DAS28-CRP based disease categories •EULAR responses 5. SDAI, CDAI values 6. Core set variables (66/68 joint count) 7. FACIT fatigue score and VAS fatigue 8. WPAI 9. EQ5D 10. HAQ 11. SF36 12. Patient VAS for general health and pain assessment 13. Physician VAS for general health assessment Radiographic outcomes Change in modified total Sharp score, modified Sharp erosion score, modified Sharp joint space narrowing score, the proportion of patients without radiographic progression (defined as change in total modified Sharp score <= 0) and the reduction of predicted progression according to the published "POPERA" model. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Clinical outcomes are relevant at all time points (vistits between 2-12 weeks of duration throughout the study)
Radiographic outcomes are relevant at all time points (vistits between 2-12 weeks of duration throughout the 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 | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
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) | No |
E.7.4 | Therapeutic use (Phase IV) | Yes |
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 | Yes |
E.8.1.4 | Double blind | No |
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 | No |
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
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 60 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
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 | 3 |
E.8.9.1 | In the Member State concerned months | 1 |
E.8.9.1 | In the Member State concerned days | |
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 | 1 |