| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 8.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10039073 |
| E.1.2 | Term | Rheumatoid 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 objective of this study is to assess and compare the proportion of subjects who achieve low disease activity as defined by both a clinical response (DAS28<3.2) and no radiographic progression (∆mTSS<0.5) at week 78 (among those subjects who responded at Weeks 22 and 26, i.e., DAS28 <3.2) in subjects treated with adalimumab/MTX (combination therapy) for 78 weeks (Arm 2) and subjects treated with placebo/MTX (monotherapy) for 78 weeks (Arm 4). Subjects who did not achieve a clinical response (DAS <3.2) at Week 22 or 26 were not allowed to continue on their current treatment and were given open-label combination therapy (adalimumab and MTX) for the remeinder of the study under ethical consideration. This study is also designed to evaluate the maintenance of clinical response in a population of subjects initially treated with combination therapy but subsequently with methotrexate monotherapy by discontinuing adalimumab (HUMIRA®), the TNF antagonist). |
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| E.2.2 | Secondary objectives of the trial | |
| 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 |
High Field (1.5 Tesla) Magnetic Resonance Imaging (MRI) Substudy (11-Apr-07)
Objectives: The aim of this 78 week study of a cohort of patients with early RA is to investigate the ability of a high-field MRI, to detect changes in joint inflammation and destruction in wrist and finger joints (metacarpophalangeal [MCP] joints) to investigate the predictive value of early MRI findings for subsequent development of radiographic and MRI bone erosions under treatment conditions with adalimumab. Erosion, osteitis and synovitis will be evaluated and scored by two independent blinded readers according to RAMRIS (OMERACT).
Low Field (0.2 Tesla) Magnetic Resonance Imaging (MRI) Substudy
Objectives: The aim of this 26 week study of a cohort of patients with early RA is to investigate the ability of a low-field dedicated extremity MRI (E-MRI) system, to detect changes in joint inflammation and destruction in wrist and finger joints (metacarpophalangeal (MCP) joints) to investigate the predictive value of early E-MRI findings for subsequent development of radiographic and MRI bone erosions under treatment conditions with adalimumab. Active inflammatory lesions of the hand (wrist and MCP joints of the clinically dominant hand) and the therapeutic efficacy of the study drug will also be evaluated and scored by two independent readers according to a modification of the RAMRIS (OMERACT). |
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| E.3 | Principal inclusion criteria |
1. Subject is ≥ 18 years of age.
2. Subject has a diagnosis of RA as defined by the 1987-revised ACR-classification criteria and have a disease duration of less than 1 year from diagnosis.
3. Subject must meet the following three criteria: a. DAS28 (CRP) > 3.2. b. At least 6 swollen joints out of 66 assessed. c. At least 8 tender joints out of 68 assessed.
4. Subject must have an ESR ≥ 28 mm/1h (at the Screening and Baseline visits) or CRP ≥ 1.5 mg/dL (at the Screening visit only).
5. Subject must fulfill one of the following three criteria: a. Rheumatoid Factor (RF)positive. b. Have greater than 1 erosion. c. Anti- CCP Antibody positive.
6. Female subject is either not of childbearing potential, defined as postmenopausal (at least 1 year since last menses) or surgically sterile (bilateral tubal ligation, bilateral oophorectomy or hysterectomy), or is of childbearing potential and practicing one of the following methods of birth control throughout the study and for 150 days after study completion:
• Condoms, sponge, foams, jellies, diaphragm or intrauterine device (IUD)
• Contraceptives (oral, parenteral, patch) for three months prior to study drug administration)
• A vasectomized partner
7. Female subjects of childbearing potential must have a negative serum pregnancy test at the Screening visit and a negative urine pregnancy test at Baseline.
8. 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.
9. Subjects will be evaluated for latent TB infection with a purified protein derivative (PPD) test and chest X-ray. Chest X-ray will not be required if the subject had a previous chest-ray (and film with required report results available) 90 days prior to Screening. For this protocol, evidence of latent TB infection is defined as an induration (not erythema) of 5 mm or greater, 48-72 hrs after placement. Subjects who demonstrate evidence of latent TB infection, irrespective of Bacille Calmette − Guérin (BCG) vaccination status, and negative CXR findings for active TB and/or suspicious CXR findings will be allowed to participate in the study provided that one of the following conditions are satisfied;
• Prophylactic treatment is initiated at least two weeks prior to administration of study drug; however the course of prophylaxis need not be completed prior to the onset of study drug. Prophylactic treatment will be according to the United States Centers for Disease Control [CDC] recommended preventive therapy for TB) or per local guidelines. Prophylactic treatment should be captured on the concomitant medications page in the CRF and in the source documents. See Appendix D for Centers for Disease Control (CDC) recommended preventive therapy for TB.
• Subject has documented prophylactic treatment for TB and so need not repeat this treatment.
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 sc injections or have a qualified person available to administer sc injections.
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| E.4 | Principal exclusion criteria |
1. Subject has previous exposure to any systemic anti-TNF therapy (e.g., infliximab or etanercept) including adalimumab.
2. Subject has been previously treated with > 2 prior disease modifying antirheumatic drugs (DMARDs) or prior MTX treatment.
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 a history, or current, acute inflammatory joint disease of different origin (e.g., mixed connective tissue disease, seronegative spondyloarthropathy, psoriatic arthritis, Reiter´s syndrome, fibromyalgia, systtemic lupus erythematosus or any arthritide with onset prior to age 17 years)
6. Subject has a history of an allergic reaction or significant sensitivity to constituents of study drugs (adalimumab, MTX, or matching placebo).
7. Subject has been treated with any investigational drug of a "chemical" nature within one month prior to study entry (screening visit).
8. 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.
9. Subject has a history of clinically significant hematologic (e.g., severe anemia, leukopenia, thrombocytopenia), renal or liver disease (e.g., fibrosis, cirrhosis, hepatitis).
10. Subject has history of neurologic symptoms suggestive of central nervous system (CNS) demyelinating disease and/or diagnosis of central demyelinating disease.
11. Subject has history of cancer or lymphoproliferative disease other than a successfully treated non − metastatic cutaneous squamous cell or basal cell carcinoma and/or localized carcinoma in situ of the cervix.
12. 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 Baseline visit.
13. Subject currently uses or plans to use anti-retroviral therapy at any time during the study.
14. Subject is known to have immune deficiency, history of HIV or is immunocompromised.
15. Female subject who is pregnant or breast-feeding or considering becoming pregnant during the study or for 150 days after the last dose of study medication.
16. Subject has a history of clinically significant drug or alcohol usage in the last year or cannot maintain an alcohol intake of 30 g a day or less throughout the study. One standard drink is defined as 180 mL/6 oz (approx. 10 g) of wine, 360 mL/12 oz (approx. 15 g) of regular beer, or 45 mL/1.5 oz (approx. 10 g) of spirits.
17. Screening clinical laboratory analyses show any of the following abnormal laboratory results:
• Aspartate transaminase (AST) or alanine transaminase (ALT) >1.75x the upper limit of normal (ULN).
• Serum total bilirubin ≥ 1.5 mg/dL (≥ 26 micromol/L); or
• Creatinine > 1.5 mg/dL (133 micromol/L) in subjects < 65 years old and > upper limit of normal range in subjects ≥ 65.
• Positive Hepatitis B or C serology indicative of previous or current infection.
18. Subject is considered by the investigator, for any reason, to be an unsuitable candidate for the study. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary efficacy variable is the composite response at Week 78 defined by low disease activity (DAS28 < 3.2) and no radiographic progression from Basesine ((∆mTSS<0.5).
The primary efficacy variable will be compared between subjects treated with blinded, combination therapy (both adalimumab and MTX) for 78 weeks and subjects treated with blinded, MTX monotherapy for 78 weeks (Arm 2 versus Arm 4).
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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 | 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.8.3 |
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 | 11 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 85 |
| 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 | Information not present in EudraCT |
| 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 |
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| E.8.7 | Trial has a data monitoring committee | No |
| 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
| |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 7 |
| 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 | 5 |
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