E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
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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 | 18.0 |
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 |
Main primary objectives
Induction phase
1. To investigate if an early US response at week 12 may be predictive of later clinical response (week 24 and week 48) and to identify a minimum set of joints to be monitored to adequately assess disease activity
2. To investigate the mean change from baseline PD, SH, JE scores and global scoring system (GLOSS) assessing the MCP (2-5 joints of both hands) and wrists [time frame: baseline to weeks 2, 4, 8, 12, 16, 24]
3. To define the earliest time point at which improvement in PD, SH, JE and GLOSS scores in MCP (2-5 joints of both hands) and wrists can be detected [time frame: weeks 2, 4, 8, 12, 16, 24]
4. To investigate the mean change from baseline to the end of the induction phase in PD, SH, JE and GLOSS scores for the whole 32-US joint set [time frame: baseline to week 2, 4, 8, 12, 16, 24]
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E.2.2 | Secondary objectives of the trial |
Main secondary objectives
1. To investigate the mean change from the beginning of maintenance phase to 54 weeks in PD, SH, JE and GLOSS scores for the whole 32-US joint set [time frame: baseline to week 2, 4, 8, 12, 16, 24]
2. To investigate the mean change from the beginning of maintenance phase to 54 weeks in PD, SH, JE, GLOSS scores assessing the MCP (2-5 joints of both hands) [time frame: week 24 to 32, 40, 54]
3. To assess if PD score at 12 weeks is predictive of clinical response at 24 and at 48 weeks
4. To assess the predictive value of PD findings in relation to radiologic outcome at 54 weeks.
5. ACR and EULAR core data set response during the induction and maintenance phase.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Inclusion criteria
1. Diagnosis of RA fulfilling the 2010 EULAR/ACR (European League Against Rheumatism/ American College of Rheumatology classification criteria)
2. Disease duration no longer than 12 months from the time of initial diagnosis
3. Age : 18-70 years
4. Disease activity defined by a disease activity score DAS28-CRP > 3.2 or all must be met: tender joint count (TJC) of ≥4 and swollen joint count (SJC) ≥4
5. US SH or PD synovitis scores >1 for at least 2 metacarpophalangeal (MCP) joints (2-5) and US SH or PD synovitis scores ≥1
6. Naïve to DMARD (methotrexate, leflunomide, sulphasalazine) and biologics (TNF-, IL6-, CD20-, IL1-blockers)
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E.4 | Principal exclusion criteria |
Exclusion criteria
1. History of other concomitant autoimmune disease such as lupus or psoriatic arthritis
2. Meeting diagnostic criteria for any other rheumatic disease than RA (e.g. gout, Lyme disease, seronegative spondyloarthropathy including reactive arthritis, psoriatic arthritis, arthropathy or inflammatory bowel disease)
3. Any previous treatment with :
a. Etanercept, infliximab, certolizumab, golimumab, abatacept or adalimumab, anakinra
b. Any cell-depleting therapies, including investigational agents or approved therapies, some examples are CAMPATH, anti-CD4, anti-CD5, anti- CD3, anti-CD19 and anti-CD20
c. Intravenous gamma globulin, plasmapheresis or Prosorba column within 6 months of baseline.
d. Alkylating agents such as chlorambucil, or with total lymphoid irradiation
4. Previous MCP arthroplasty or wrist arthrodesis. Participants who have undergone or are scheduled to undergo joint arthroplasties other than the MCP joints can be recruited in the study provided all other eligibility criteria are met.
5. Current liver disease requiring medication
6. Current symptoms of severe progressive or uncontrolled renal, hematologic, gastro-intestinal, pulmonary, cardiac, neurologic or cerebral disease whether or not related to rheumatoid arthritis, that would jeopardize inclusion in the protocol as judged by the clinician
7. History of malignancy or lymphoproliferative disease, within the last 5 years, with the exception of basal cell or squamous cell carcinoma of the skin or carcinoma in situ of cervix which that has been fully excised/cured with no evidence of recurrence
8. Concomitant diagnosis or history of diverticulitis, peptic ulcer disease, diverticulosis requiring antibiotic treatment or chronic ulcerative lower GI disease such as Crohn’s disease, ulcerative colitis or other symptomatic lower GI conditions that might predispose to perforations
9. Evidence of active or latent bacterial, viral, fungal (except for fungal infections of nail beds), mycobacterial or other opportunistic infections at the time of potential enrolment
10. Any major episode of infection requiring hospitalisation or treatment with IV antibiotics within 4 weeks or oral antibiotics within 2 weeks of screening’
11. Herpes zoster or cytomegalovirus infection that resolved less than 2 months before the informed consent was signed
12. Subjects at risk of tuberculosis (TB) are excluded if any of the following is present:
- A history of active TB within the last 3 years, even if treated
- Latent TB that was not successfully treated ≥ 4 weeks
- Current clinical radiographic, or laboratory evidence of active TB
13. Subjects who received live vaccines within 4 weeks of the anticipated first dose of study medication. Live and live attenuated vaccines should not be given concurrently
14. Subjects must agree not to take live attenuated vaccines (including seasonal nasal flu vaccine, varicella vaccine for shingles or chickenpox, MMR or MMRV, oral polio vaccine and vaccines for yellow fever, measles, mumps or rubella) thirty (30) days before the Screening Visit, throughout the duration of the trial and for sixty (60) days following the subject’s last dose of study drug
15. Subjects with positive test results for hepatitis B surface antigen or hepatitis C, or HIV detected with polymerase chain reaction or immunoblot assay
16. Subjects with primary or secondary immunodeficiency
17. History of severe allergic or anaphylactic reactions to human, humanized or murine monoclonal antibodies
18. Major surgery within 8 weeks
19. Patients with lack of peripheral venous access
20. Pregnancy or breast-feeding
21. Females of childbearing potential can only participate if using reliable contraception
22. Intra-articular steroid injection in the joints assessed by US less than four weeks before screening
23. Anticipated non-compliance with the protocol
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary end points
Induction phase
Area under the curve of the US parameters (SH, JE, PD, GLOSS) assessing the MCP joints
(2nd to 5th of both hands) and wrists from baseline through 24 weeks
Time to change in US parameters (SH, JE, PD, GLOSS) defined as US improvement (20%, 50%, 70%) of the sum scores of individual joints, from baseline through 24 weeks
US response at week 12 may be predictive of later clinical response at week 24 and week 48
Maintenance phase
4. Area under the curve of the US parameters (SH, JE, PD, GLOSS) assessing MCP joints (2nd to 5th of both hands) from 24 weeks to 54 weeks
5. Area under the curve in PD, SH, JE and GLOSS scores assessing the MCP joints (2nd to 5th of both hands) and wrists from baseline to weeks 54
6. Percentage of patients which have an US improvement (20%, 50%, 70%) in US parameters (SH, JE, PD, GLOSS) of the sum scores of individual joints, at 24 weeks and 48 weeks
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
To identify the minimum set of joint to be monitored to adequately assess disease activity by comparing the sensitivity to change of different reduced ultrasound joint counts. |
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E.5.2 | Secondary end point(s) |
Main secondary end points
1. Area under the curve of the US parameters (SH, JE, PD, GLOSS) for the whole 32-US joint set, from 24 weeks to 54 weeks
2. Area under the curve of the US parameters (SH, JE, PD, GLOSS) for the for the whole 32-US joint set, from baseline to 54 weeks
3. ACR and EULAR core data set response during the induction and maintenance phase.
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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.6.13.1 | Other scope of the trial description |
????????????
to be completed |
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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 | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
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) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
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 | No |
E.8.5 | The trial involves multiple Member States | No |
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 | 0 |
E.8.9.1 | In the Member State concerned days | 30 |
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 | 30 |