A Randomized, Placebo-controlled Phase II Clinical Trial to Evaluate the Safety and Efficacy of F8IL10 (Dekavil) in Patients With Active RA Receiving MTX

A multicenter, randomized, parallel assignment, double blind, placebo-controlled, safety/efficacy phase II study of two different dosages of subcutaneous F8IL10 in patients with active rheumatoid arthritis receiving MTX.

The study is designed to formally demonstrate the superiority of F8IL10 vs placebo and to further evaluate safety and efficacy of two different dosages of F8IL10 when administered to patients receiving MTX.

Patients will be enrolled and double-blind, parallel assigned (via automated randomization system) in a 1:1:1 fashion to one of three different arms:

* Arm 1: placebo + MTX
* Arm 2: F8IL10 30 µg/kg + MTX
* Arm 3: F8IL10 160 µg/kg + MTX

F8IL10 or placebo will be subcutaneously injected once a week for 8 weeks. Treatment will terminate at the earliest of the following: completion of the 8 weeks of therapy, withdrawal of informed consent, unacceptable toxicity/intolerability of the study drug or need to increase MTX, oral corticosteroids or NSAIDs dosages above baseline levels or need to introduce a new DMARD or biologic therapy to control rheumatoid arthritis activity. The study will be conducted in a double blind fashion.

Eligibility Criteria:
Inclusion Criteria

At the time of enrolment, patients must fulfil all of the following criteria:

1. Patients aged ≥18 and \< 75 years.
2. Diagnosis of RA according to ACR/EULAR classification criteria (2010) with a disease duration exceeding 6 months.
3. Active RA (DAS28 ≥ 3.2) for ≥ 3 months at time of signing informed consent despite MTX therapy (stable regimen of methotrexate 10-25 mg/week orally, subcutaneous or intramuscular injections: stable dosage from ≥ 8 weeks before screening).
4. ≥ 6 tender joints out of 68, ≥ 6 swollen joints out of 66 and serum CRP \> 0.5 mg/dl at screening.
5. History of inadequate clinical response to at least one anti-TNF drug (applied for at least 3 months).
6. Stable regimens of NSAIDs and/or oral corticosteroid (≤ 10 mg/day; prednisone equivalent) for a period ≥ 2 weeks prior to screening.
7. All acute toxic effects of any prior therapy must have returned to classification "mild" according to CTCAE v.4.03 (published on June 14, 2010).
8. Sufficient hematologic, liver and renal function:

   * Absolute neutrophil count (ANC) ≥ 1.5 x 109/L, platelets ≥100 x109/L, haemoglobin (Hb) ≥ 10.0 g/dL.
   * Alkaline phosphatase (AP), alanine aminotransferase (ALT) and or aspartate aminotransferase (AST) ≤ 3 x upper limit of normal range (ULN), and total bilirubin ≤ 2.0 mg/dl (34.2 µmol/L).
   * Creatinine ≤ 1.5 ULN or 24 h creatinine clearance ≥ 50 mL/min.
9. Documented negative test for HIV, HBV and HCV. For patients with serology documenting previous exposure to HBV (i.e., anti-HBs Ab with no history of vaccination and/or anti-HBc Ab), negative serum HBV DNA is required.
10. All female subjects must have negative pregnancy test results at the screening. Women of childbearing potential must be using simultaneously double-barrier or two acceptable methods of contraception (i.e. intra-uterine device plus condom, spermicidal gel plus condom, diaphragm plus condom, etc.) from the screening to three months following the last study drug administration. Pregnancy test will be repeated at the end of treatment visit.
11. Male patients must agree to use simultaneously two acceptable methods of contraception (i.e. spermicidal gel plus condom) from the screening to three months following the last study drug administration.
12. Signed and dated Ethics Committee-approved informed consent form indicating that the patient has been informed of all pertinent aspects of the study.
13. Willingness and ability to comply with the scheduled visits, treatment plan, laboratory tests and other study procedures.
14. Chest X rays performed (for other reasons than the present clinical trial) within a period of 3 months prior to the screening visit. However, in the case the patient performs the Quantiferon TB test during the screening visit, this period can be extended to 6 months.

Exclusion Criteria

Patients must not be enrolled into the study if, at the time of enrolment, they have any of the following:

1. Presence of active infections or other severe concurrent disease, which, in the opinion of the investigator, would place the patient at undue risk or would interfere with the study objectives or conduct.
2. Pregnancy, lactation or unwillingness to use adequate contraceptive methods.
3. Diagnosis of any other inflammatory arthritis or active autoimmune diseases other than RA.
4. Last treatment with monoclonal antibodies (i.e., adalimumab, infliximab, golimumab, tocilizumab, certolizumab pegol) less than 8 weeks prior to first administration of study drugs. Last treatment with rituximab less than 16 weeks prior to first administration of study drugs. Last treatment with fusion proteins (i.e., abatacept, etanercept) less than 4 weeks prior to first administration of study drugs.
5. Treatment with any immunosuppressant drug other than MTX and corticosteroids.
6. Active or latent tuberculosis (TB).
7. HIV infection.
8. Acute or chronic HBV or HCV infection, as assessed by serology or serum HBV DNA.
9. History or currently active primary or secondary immunodeficiency.
10. Concurrent malignancy or history of malignancy from which the patient has been disease-free for less than 5 years.
11. History within the last year of acute or subacute coronary syndromes including myocardial infarction, unstable or severe stable angina pectoris.
12. Treatment with warfarin or other coumarin derivatives.
13. Heart insufficiency (\> Grade II, NYHA criteria).
14. Irreversible cardiac arrhythmias requiring permanent medication.
15. Clinically significant (to clinical investigator's discretion) abnormalities in baseline ECG analysis.
16. Uncontrolled hypertension.
17. Ischemic peripheral vascular disease (Grade IIb-IV).
18. Severe diabetic retinopathy.
19. Major trauma including surgery within 4 weeks prior to administration of study treatment.
20. Known history of allergy or other intolerance to IL10, methotrexate, folic acid or other drugs based on human proteins/peptides/antibodies.
21. Treatment with any investigational agent within the 6 weeks before study treatment.
22. Immunization with a live/attenuated vaccine within 4 weeks prior to baseline or plan to receive vaccines during the study.
23. Treatment with growth factors or immunomodulatory agents, including Anakinra, within 7 days of the administration of study drugs.
24. Chronic pain disorders (not RA-related) that might interfere with pain evaluation.
25. Patients requiring stable doses of corticosteroids \> 10 mg/day (prednisone equivalent). Limited use of corticosteroids to treat or prevent acute hypersensitivity reactions is not considered an exclusion criterion.
26. Concurrent intra-articular corticosteroids treatment or patient who have received it within 2 weeks prior to randomization.
27. History of alcohol, drug or chemical substance abuse within the 6 months prior to screening.
28. Any condition that in the opinion of the investigator could hamper compliance with the study protocol.