E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Subjects with active rheumatoid arthritis incompletely controlled on stable MTX doses |
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E.1.1.1 | Medical condition in easily understood language |
Subjects with active rheumatoid arthritis incompletely controlled on stable MTX doses |
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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 | 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 |
To determine the efficacy and safety of three doses of tregalizumab administered
over 24 weeks, followed by a 24-week extension phase (active treatment only), in
combination with methotrexate (MTX), for the treatment of adult subjects with active
rheumatoid arthritis (RA) who have had an inadequate response to MTX alone
(MTX-IR). |
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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 demonstrates active RA according to the 1987 American College of Rheumatology (ACR) or 2010 ACR/European League Against Rheumatism (EULAR) classification criteria for RA with functional class I–III for ≥6 months.
2. Subject receives oral or parenteral MTX treatment for ≥12 weeks (overall), with
an unchanged mode of application and stable MTX dose of ≥15 mg per week (or ≥12.5 mg per week in case of MTX intolerance), but no more than the highest locally approved dose for RA, for ≥8 weeks prior to baseline. The dose of MTX is expected to remain stable throughout the study and may be adjusted only for
safety reasons. If applicable, the dose of folic acid must be unchanged for ≥8 weeks prior to baseline.
3. Subject meets the following two criteria at both screening and baseline:
− At least 6 swollen joints at 28-joint assessment.
− At least 6 tender joints at 28-joint assessment.
4. Subject has an erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP) above the upper limit of normal (ULN) at screening. These tests may be repeated once during the screening period at the discretion of the investigator.
5. Subject is ≥18 and ≤75 years of age.
6. Subject has a body mass index ≥18 and ≤35 kg/m².
7. Subject receives treatment with corticosteroids ≤10 mg prednisone equivalent,
stable for at least 4 weeks prior to baseline and during the study, if applicable.
8. Subject receives treatment with non-steroidal anti-inflammatory drugs (NSAIDs), stable for at least 2 weeks prior to baseline and during the study, if applicable.
9. Female subjects of childbearing potential: has both a negative serum pregnancy test at screening and a negative urine pregnancy test at baseline.
10. Subject is judged to be in good general health as determined by the investigator
based upon the results of medical history, laboratory profile, physical examination, chest X-ray (within 3 months before screening date is acceptable), and 12−lead electrocardiogram (ECG).
11. Subject has a cluster of differentiation 4 (CD4) cell count of >400/µL at screening.
12. Subject is willing and able to provide written informed consent.
13. Subject is willing and able to self administer SC injections or has a qualified person available to administer SC injections.
From week 24 onwards:
14. Subject has completed the main phase of the study (Visit V10 at 24 weeks)
15. Subjects who experienced a SAE or a medically significant laboratory or ECG abnormality in the main phase of the study who have not been previously discontinued must have completely recovered prior to entering the extension phase.
16. Subject must have a CD4 cell count of 400/µL at Week 16.
17. Subjects must have achieved a reduction in TJC and SJC of ≥20% at Week 24 |
|
E.4 | Principal exclusion criteria |
1. Subject has previous exposure to any systemic biologic therapy (details in protocol), to Janus kinase (JAK) or spleen tyrosine kinase (SYK) inhibitors, or to tregalizumab. Previous treatment with an anti-TNF agent is allowed only, if all of the following criteria apply:
− treatment was stopped for reasons other than lack of efficacy or adverse events (AEs)
− treatment was stopped at least 12 weeks or five half-lives of the compound prior to baseline (whichever is longer), and − the treatment period did not exceed 6 weeks.
2. Subject received treatment with conventional disease-modifying anti-rheumatic drugs (DMARDs) apart from MTX in the 12 weeks prior to baseline, and for DMARD leflunomide in the 24 weeks prior to baseline (exeptions in protocol).
3. Subject has been treated with intra-articular or parenteral administration of corticosteroids in the 4 weeks prior to baseline. Inhaled corticosteroids for stable medical conditions are allowed.
4. Subject has undergone joint surgery in the 12 weeks prior to baseline (at joints to be assessed within the study) or has undergone major surgery in the 8 weeks prior to baseline.
5. Subject has a history of acute inflammatory joint disease of an origin other than RA or subject has any other rheumatic disease other than RA . However, subjects may have secondary Sjögren's syndrome.
6. Vaccination with live vaccines in the 12 weeks prior to baseline or vaccination with killed vaccines in the 4 weeks prior to baseline.
7. Subject has a history of an allergic reaction or significant sensitivity to constituents of study drugs or a history of severe allergic or anaphylactic reaction to proteins of human origin.
8. Subject has participated in another clinical study in the 90 days prior to baseline or within 5 half lives of the investigated compound—whichever is longer—or plans to do so during the study.
9. Subject has a poorly controlled medical condition - detailed list in the protocol.
10. Subject has a history of clinically significant hematologic, renal, or liver disease , or gastroenteric ulcer or has, at screening, clinically relevant deviations in laboratory tests - detailed list in the protocol.
11. Subject has a presence or history of malignancy within the previous 5 years (exeptions in protocol).
12. Subject has a presence or history of lymphoproliferative disease.
13. Subject has a positive diagnosis for acute or chronic infections (list in protocol).
14. Subject has a history or presence of active or latent tuberculosis.
15. Subject has an acute or clinically symptomatic Epstein Barr virus (EBV) or cytomegalovirus (CMV) infection.
16. Subject has a serious local or systemic infection or recurrent chronic infections in the 6 weeks prior to the screening visit (Visit V1) or during the screening period.
17. Subject has any infection requiring antibiotic or antiviral therapy by any route of administration in the 2 weeks prior to baseline.
18. Subject currently uses or plans to use anti retroviral therapy at any time during the study.
19. Subject received an alkylating agent in the 6 months prior to baseline.
20. Subject has a history of clinically significant drug or alcohol abuse within the last 12 months.
21.Subject is a pregnant or nursing woman or is considering becoming pregnant during the study or in the 3 months after the last dose of study drug.
22.Subject is a woman of childbearing potential (unless surgically sterile or post menopausal >52 weeks) who is not using two independent effective contraceptive methods during the study and for at least 3 months after the last administration of study drug OR
Subject is a man and is not vasectomized or is not using two independent effective contraceptive methods or who is planning sperm donation during the study and for at least 3 months after the last administration of study drug.
For both women and men sexual abstinence is an acceptable method of contraception.
23. Blood donation between 56 days prior to baseline and study end.
24. Subject is an employee of any involved study investigator or any involved institution including the sponsor.
25. Subject is not able or is lacking motivation to adhere to the study requirements and to comply with the study schedule.
From Week 24 onwards
26. Subject has had a change in his/her preexisting medical condition or the onset of a new medical condition
27. Subject has, at Week 16, clinically relevant deviations in laboratory tests - details in protocol.
28. Subject has an acute or clinically symptomatic EBV or CMV infection.
29. Subject has a serious local or systemic infection or recurrent chronic infection at Week 24.
30. Subject is a pregnant or nursing woman or considering becoming pregnant during the study or within 3 months after the last dose of study medication. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The proportion of subjects who achieve an ACR20 at Week 12 following treatment with tregalizumab (25 mg, 100 mg or 200 mg) + MTX compared with subjects treated with placebo + MTX. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
E.5.2 | Secondary end point(s) |
Proportion of subjects with an ACR20 at Week 24,
Proportion of subjects with an ACR50 at Week 12,
Proportion of subjects with an ACR50 at Week 24
Proportion of subjects with an ACR70 at Week 12
Proportion of subjects with an ACR70 at Week 24
Proportion of subjects with a Disease Activity Score (DAS)28 ≤2.6 at Week 12
Proportion of subjects with a DAS28 ≤2.6 at Week 24
Proportion of subjects with low disease activity (DAS28 ≤3.2, Simplified Disease Activity Index [SDAI] ≤11, Clinical Disease Activity Index [CDAI] ≤10) at Week 12
Proportion of subjects with low disease activity (DAS28 ≤3.2, SDAI ≤11, CDAI ≤10) at Week 24
ACR score by visit
DAS28 by visit
EULAR response by visit
ACR and DAS28 score components by visit
-TJC (68 joint count, incl. 28 joint count)
- SJC (66 joint count, incl. 28 joint count)
-CRP
-ESR
- Patient's assessment of pain (Visual Analog Scale [VAS])
- Patient's Global Assessment of Disease Activity (VAS)
- Physician Global Assessment of Disease Activity (VAS)
- Health Assessment Questionnaire Disability Index (HAQ DI)
Morning stiffness by visit
SDAI by visit
CDAI by visit
Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue by visit
Short Form (36)® Health Survey, Version 2.0 (SF 36) by visit
Work Productivity and Activity Impairment Questionnaire: Rheumatoid Arthritis WPAI RA by visit
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Screening, Weeks 0, 1, 2, 4, 6, 8, 12, 16, 24, 28, 32, 40, 48 except FACIT-Fatigue, SF-36, WPAI-RA (Screening, Weeks 0, 2, 6, 12, 24, 32, 48) |
|
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 | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
|
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 | 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 | 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 | 51 |
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 |
Bulgaria |
Canada |
Estonia |
Germany |
Hungary |
Lithuania |
Mexico |
Poland |
Russian Federation |
Ukraine |
Czech Republic |
Serbia |
Slovakia |
Sweden |
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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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 | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
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 | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |