| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Earliest clinically perceptible phase of arthritis. Classification criteria to delineate this group of patients are not available. Therefore eligibility will be based on three important criteria: 1) the duration of arthritis-symptoms, as evaluated by the patient; and 2) the presence of arthritis, as documented by the rheumatologist; and 3) the persistence of arthritis, as documented by a rheumatologist.
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| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10003246 |
| E.1.2 | Term | Arthritis |
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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 primary objective of the study is to demonstrate that patients with very early arthritis have a higher probability of achieving a state of clinical remission at end of therapy if treated with infliximab plus MTX when compared to MTX monotherapy or supportive treatment only. |
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| E.2.2 | Secondary objectives of the trial |
In patients with very early arthritis, treatment with a combination of MTX and infliximab compared to MTX monotherapy or supportive therapy alone leads to less radiological progression at 30, 54 and 106 weeks.
In patients with very early arthritis, treatment with a combination of infliximab plus MTX for 22-54 weeks leads to better clinical outcomes in RA composite scores as well as in individual RA core set variables and socio-economic variables at week 106 compared to MTX monotherapy or supportive therapy.
Patients with very early arthritis have less frequent relapses until week 106 if treated with a combination of MTX and infliximab for 22 to 54 weeks compared to MTX monotherapy or supportive therapy alone.
In patients with very early arthritis, prediction markers, with respect to diagnosis and response to therapy will be validated or developed. This study will allow to validate or characterize such models.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
All patients to be included into this trial must meet the following inclusion criteria:
1) Men and women, ≥ 18 and ≤ 75 years of age, capable of understanding and signing an informed consent.
2) The presence of arthritis:
a) Must be established in a rheumatology center,
b) Must be present in at least 2 joints of the 66 joint count, of which at least one joint must be an MCP-, or a PIP- (IP-) or a wrist- or a MTP-joint. Two MTP-joints will not suffice. Any kind of polyarthritis (≥ 6 joints of any kind) will be sufficient.
c) Without any previous episodes of inflammatory joint disease
3) Duration of symptoms :
a) Must be assessed by the subject and should involve the inflamed joints described under 2.
b) Must be 2 weeks at least, according to the algorithm in Table 1 (subjects will not receive study treatment before 12 weeks of symptom duration according to the algorithm in Table 1)
c) Must be 16 weeks at most, as assessed by the subject, including the observation period of at least 2 weeks by the physician, according to the algorithm in Table 1.
4) Confirmation of persistent arthritis:
a) Duration must be 2 weeks at least, according to the algorithm in Table 1.
b) Duration must be 12 weeks at most, according to the algorithm in Table 1.
c) Must be documented by the same rheumatology center that established arthritis at the first visit
d) Must involve at least one of the same joints as were involved at the first visit
5) Men and women of childbearing potential must use adequate birth control measures (e.g., abstinence, oral contraceptives, intrauterine device, barrier method with spermicide, implantable or injectable contraceptives or surgical sterilization) for the duration of the study and should continue such precautions for 6 months after receiving the last medication.
6) Are considered eligible according to the tuberculosis (TB) eligibility assessment, screening, and early detection of reactivation rules defined in Section 7.14: Tuberculosis Eligibility Assessment, Screening, and Early Detection of Reactivation
7) Chest radiograph (which must not be older than three months at the visit 1/day 0 visit) must show no evidence of malignancy, infection, or fibrosis. The chest radiograph should also show no atypical scarring, cavitary lesions, or calcified granulomas, as evidence of past tuberculosis infections, without a documented history of adequate therapy.
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| E.4 | Principal exclusion criteria |
Patients must not
1) Have arthritis with a distinct diagnosis, made after a routine diagnostic work-up (examples are SLE, psoriatic arthritis, systemic sclerosis, gout, pseudogout, Lyme arthritis, reactive arthritis, Parvo viral arthritis)
2) Be incapacitated, largely or wholly bedridden, or confined to a wheelchair, or have little or no ability for self care.
3) Weigh more than 100 kg
4) Use glucocorticoids > 10 mg/day prednisone or equivalent
5) Have received Intramuscular or intra-articular injection of steroids in the previous month.
6) Have Screening laboratory test results as follows:
a) White blood cells (WBCs) < 3.0 x 109 cells/L
b) Platelets < 100 X 109 cells/L
c) Serum creatinine > 1.4 mg/dL
d) Serum transaminase levels exceeding 2 times the upper limit of normal for the site laboratory
7) Have had any previous treatment with monoclonal antibodies or antibody fragments.
8) Have a history of receiving human/murine recombinant products or a known allergy to murine products. A known allergy to murine product is definitely an exclusion criterion.
9) Have had prior treatment with MTX and/or other DMARDs (except hydroxychloroquine).
10) Have documentation of seropositivity for human immunodeficiency virus (HIV).
11) Have documentation of a positive test for hepatitis B surface antigen or hepatitis C-antibodies.
12) Have a history of alcohol or substance abuse within the preceding 6 months that, in the opinion of the investigator, may increase the risks associated with study participation or study agent administration, or may interfere with interpretation of results.
13) Have a known history of serious infections (such as, but not limited to hepatitis, pneumonia, or pyelonephritis) in the previous 3 months.
14) Have a known history of a demyelinating disease, such as multiple sclerosis
15) Have or have had an opportunistic infection (eg, herpes zoster [shingles], cytomegalovirus, Pneumocystis carinii, aspergillosis, histoplasmosis, or mycobacteria other than TB) within 12 months prior to screening.
16) Have undergone any joint replacement surgery.
17) Have a chronic or recurrent infectious disease, including but not limited to, chronic renal infection, chronic chest infection (eg. bronchiectasis), sinusitis, recurrent urinary tract infection, open, draining or infected skin wound or ulcer.
18) Be considered ineligible according to the TB eligibility assessment, screening, and early detection of reactivation rules defined in Section on: Tuberculosis Eligibility Assessment, Screening, and Early Detection of Reactivation Rules
19) Have a chest radiograph at screening that shows evidence of malignancy, infection, or any abnormalities suggestive of TB.
20) Have a history of lymphoproliferative disease, including lymphoma or signs suggestive of possible lymphoproliferative disease such as lymphadenopathy of unusual size or location (eg, nodes in the posterior triangle of the neck, infraclavicular, epitrochlear, or periaortic area), or splenomegaly.
21) Currently have any known malignancy other than the condition being treated or have a history of malignancy within the previous 5 years, with the exception of basal cell or squamous cell carcinoma of the skin that has been fully excised with no evidence of recurrence.
22) Have current signs or symptoms of severe, progressive or uncontrolled renal, hepatic, hematologic, gastrointestinal, endocrine, pulmonary, cardiac, neurologic, or cerebral disease.
23) Be unable or unwilling to undergo multiple venipunctures because of poor tolerability or lack of easy access.
24) Use any investigational drug within 3 months prior to screening or within 5 half-lives of the investigational agent, whichever is longer.
25) Have presence of a transplanted solid organ (with the exception of a corneal transplant > 3 months prior to screening).
26) Have a concomitant diagnosis or history of congestive heart failure (NYHA class III or IV).
27) Be women who are pregnant, nursing, or planning pregnancy within 6 months after the last infusion
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Comparison of presence of clinical remission between treatment with infliximab plus MTX versus MTX monotherapy and supportive treatment only at end of therapy, i.e. at at least 2 consecutive visits after month 3 during the first 54 weeks. |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | Yes |
| 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 | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | Yes |
| 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 | No |
| 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.8.3 |
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.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 20 |
| 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 | Information not present in EudraCT |
| 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 | 4 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
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