| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Early Rheumatoid Arthritis in adults |
|
| 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 |
|
| 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 evaluate the efficacy of ACZ885 plus methotrexate (MTX) by assessing the response to treatment (ACR50) as compared to MTX alone in early rheumatoid arthritis patients after 6, 14 and 26 weeks of treatment |
|
| E.2.2 | Secondary objectives of the trial |
evaluate efficacy of ACZ885 plus MTX by assessing the response to treatment (ACR20, 70 and 90) compared to MTX alone in early RA patients after 6, 14 and 26 weeks of treatment
establish a biomarker profile including genomics, cytomics and biochemical markers of bone and cartilage turn over to dissect high-responders (≥ ACR50) versus non-responders (≤ ACR20) to ACZ885 plus MTX treatment after 6, 14 and 26 weeks of treatment.
To assess the overall safety and tolerability of ACZ885 plus MTX, and in particular the infection occurence, in early RA patients as compared to MTX alone and to evaluate the immunogenicity of ACZ885 in early RA patients
To evaluate the pharmacokinetics (PK) / pharmacodynamics (PD) of ACZ885 in early RA patients
for other secondary EPs see protocol |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male and female patients of 18 to 75 years of age (inclusive)
2. Patient has a recent definite diagnosis of RA (less than 3 years since diagnosis), classified by ARA 1987 revised criteria
3. Candidate for methotrexate or biologic due to erosive arthritis, with no contraindications to such therapy, including:
• Negative tuberculin skin test reaction (PPD 5 TU or as according to local standard practice) (< 5 mm induration) at 48 to 72 hours after administration at the screening visit or within 2 months prior to the screening visit, according to national guidelines. Patients who have a positive PPD skin test, but were previously treated with anti-tuberculosis drugs, or are known to have a negative chest X-ray (within the last year) can be included.
• Normal chest X-ray (within the last year) prior to possibility of receiving MTX (r/o lung fibrosis).
4. Functional status class I, II or III classified according to the ACR 1991 revised criteria.
5. Patient presents active disease at screening and baseline evaluation (same evaluator), defined as at least 6 swollen and 6 painful tender joints of 28 joint count, and at least one of the following: hsCRP > 1.0 mg/dL, and/or ESR > 28 mm/h.
6. At Screening, and Baseline, vital signs (systolic and diastolic blood pressure and pulse rate) will be assessed after the patient has rested for at least 3 minutes, and again when required after 3 minutes in the standing position. Vital signs should be within the following ranges:
• young subjects:
oral body temperature between 35.0-37.5 °C
systolic blood pressure, 90-140 mm Hg
diastolic blood pressure, 50-90 mm Hg
pulse rate, 40 - 90 bpm
• elderly subjects (60-75 years of age):
oral body temperature between 35.0-37.5 °C
systolic blood pressure, 100-160 mm Hg
diastolic blood pressure, 50-100 mm Hg
pulse rate, 50 - 100 bpm
7. Women of child-bearing potential may participate if they have a negative serum pregnancy test at screening and prior to dosing, and are willing to practice double-barrier contraception during the study, i.e. intra-uterine device plus condom, or spermicidal gel plus condom, from the date of screening and for at least 3 months following last study drug administration.
Postmenopausal women must have no regular menstrual bleeding for at least 1 year prior to inclusion. Menopause will be confirmed by a plasma FSH level of >40 IU/L.
Surgically sterilized women must have been sterilized at least 6 months prior to screening. Surgical sterilization procedures must be supported with clinical documentation made available to sponsor and noted in the Relevant Medical History / Current Medical Conditions section of the CRF.
Male patients must be using a double-barrier local contraception, i.e., spermicidal gel plus condom, for the entire duration of the study, up to Study Completion visit, and refrain from fathering a child in the 3 months following last study drug administration.
8. - 11. See Protocol |
|
| E.4 | Principal exclusion criteria |
1. Contraindication for MRI of wrist.
2. Patients with magnetizable metal parts/devices on and in the body that could interfere with the interpretation of the MRI
3. Patients with an unstable active medical condition likely to impair evaluation of safety and biomarker results.
4. Previous treatment with biological therapy or MTX.
5. limited kidney function (creatinin clearance < 60 ml/min)
6. Previous treatment with other disease-modifying anti-rheumatic drugs (DMARDS) such as sulfasalazine, hydroxychloroquine within 4 weeks of screening.
7. Intra-articular corticosteroids within 4 weeks prior to screening.
8. Participation in any clinical investigation within 4 weeks prior to dosing or longer if required by local regulations, and for any other limitation of participation based on local regulations.
9. Donation or loss of 400 mL or more of blood within 8 weeks prior to first dosing, or longer if required by local regulation.
10. Significant illness within two weeks prior to dosing.
11. A past medical history of clinically significant ECG abnormalities or a family history (grandparents, parents and siblings) of a prolonged QT-interval syndrome.
12. History of autonomic dysfunction (e.g. history of fainting, orthostatic hypotension, sinus arrhythmia).
13. History of clinically significant acute or chronic bronchospastic disease (including asthma and chronic obstructive pulmonary disease, treated or not treated).
14. History of clinically significant drug allergy or history of atopic allergy (asthma, urticaria, eczematous dermatitis). A known hypersensitivity to the study drug or drugs similar to the study drug.
15. History of disease of the blood building system
16. History of serious or active infections
17. History of gastric ulcers
18. Any surgical or medical condition which might significantly alter the absorption, distribution, metabolism or excretion of drugs or which may jeopardize the patient in case of participation in the study. The investigator should be guided by evidence of any of the following:
• history of inflammatory bowel syndrome, gastritis, ulcers, gastrointestinal or rectal bleeding;
• history of major GI tract surgery such as gastrectomy, gastroenterostomy, or bowel resection;
• history or clinical evidence of pancreatic injury or pancreatitis;
• clinical evidence of liver disease or liver injury as indicated by abnormal liver function tests such as AST, ALT, GGT, alkaline phosphatase, or serum bilirubin.
If the total bilirubin concentration is increased above 1.5 times the upper normal limit total bilirubin should be differentiated into the direct and indirect reacting bilirubin.
• history or presence of impaired renal function as indicated by clinically significantly abnormal creatinine clearance.
• evidence of urinary obstruction or difficulty in voiding at screening;
19. History of immunodeficiency diseases, including a positive HIV test result.
20. A positive Hepatitis B surface antigen (HBsAg) or Hepatitis C test result.
21. History of drug or alcohol abuse within the 12 months prior to dosing or evidence of such abuse as indicated by the laboratory assays conducted during the screening or baseline evaluations. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
|
| 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 | No |
| 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 | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| 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) | 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) | 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 | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 15 |
| 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 |
|
| 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 | 1 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
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