Study redesigned and registered under NCT07245992 (Protocol n° PH-F8IL10INTRA-03/24)

This multicenter, prospective Phase I study is aimed at testing the safety of F8IL10 via i.a. administration once every 4 weeks over 8 weeks in patients with RA who, despite treatment with stable doses (at least 3 months) of DMARDs (conventional, biologic and/or targeted synthetic), present arthritis flare(s) suitable for i.a. injections.

Inclusion Criteria:

1. Patients aged ≥18 and ≤ 80 years.

2. Diagnosis of RA according to ACR/EULAR classification criteria (2010) with a disease duration exceeding 6 months.

3. Presence of at least an arthritis flare suitable for i.a. injection despite treatment with stable doses (for at least 3 months) of DMARDs (conventional, biologic and targeted synthetic) background therapy.

4. Stable regimens of NSAIDs and/or oral corticosteroid (≤ 10 mg/day; prednisone equivalent) for a period ≥ 2 weeks prior to screening.

5. All acute toxic effects of any prior therapy must have returned to classification "mild" according to CTCAE v.5.0 (published on November 27, 2017).

6. 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.

7. Documented negative TB test (e.g. Quantiferon or equivalent) and Chest X-ray. Results of tests carried out prior to the participation in the study may be accepted, if deemed as appropriate to exclude active TB by the study physician.

8. Documented negative test for HIV-HBV-HCV. For HBV serology, the determination of HBsAg and anti-HBcAg Ab is required. In 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. For HCV, HCV-RNA or HCV antibody test is required. Subjects with a positive test for HCV antibody but no detection of HCV-RNA indicating no ongoing infection are eligible. Results of tests carried out prior to the participation in the study may be accepted, if deemed as appropriate to exclude active infections by the study physician.

9. Sexually active male or female patients of childbearing potential are eligible providing that:

   Female:

   • Women of childbearing potential (WOCBP) have a negative pregnancy test performed within 14 days prior to treatment start.
   • WOCBP agree to use, from the screening to 6 months following the last study drug administration, effective method of birth control as applicable per local law that both results in a Pearl index < 1 and considered highly effective as defined by the "Recommendations for contraception and pregnancy testing in clinical trials" issued by the "Clinical Trial Facilitation Group" (e.g. combined estrogen and progestogen containing hormonal contraception, progestogen-only hormonal contraception, intrauterine device, intrauterine hormone-releasing system, vasectomized partner, total sexual abstinence or bilateral tubal occlusion).

   Male:

   - Agree to use two acceptable methods of contraception (e.g. condom with spermicidal gel) from the screening to 6 months following the last study drug administration. Females of childbearing potential that are partners of male study participants must observe the same birth control indications that apply to female participants.

10. Signed and dated Ethics Committee-approved informed consent form indicating that the patient has been informed of all pertinent aspects of the study.

11. Willingness and ability to comply with the scheduled visits, treatment plan, laboratory tests and other study procedures.

Exclusion Criteria:

Patients must not be enrolled into the study if, at the time of enrollment, 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. Received intra-articular administration of corticosteroids/DMARDs (for other reasons than the current study) within 4 weeks or 5 half-lives prior to the first dose of study drug, whichever is longer.
5. History or currently active primary or secondary immunodeficiency.
6. Concurrent malignancy or history of malignancy (except in situ melanoma) from which the patient has been disease-free for less than 2 years.
7. History within the last year of acute or subacute coronary syndromes including myocardial infarction, unstable or severe stable angina pectoris.
8. Treatment with warfarin or other coumarin derivatives.
9. Clinically significant cardiac arrhythmias or requiring permanent medication.
10. Abnormal LVEF or any other abnormalities observed during baseline ECG and echocardiogram investigations that are considered as clinically significant by the investigator; subjects with current or a history of QT/QTc prolongation.
11. Uncontrolled hypertension.
12. Known arterial aneurism at high risk of rupture.
13. Ischemic peripheral vascular disease (Grade IIb-IV according to Leriche-Fontaine classification).
14. Severe diabetic retinopathy.
15. Major trauma including surgery within 4 weeks prior to administration of study treatment.
16. Known history of allergy or other intolerance to IL10 or other drugs based on human proteins/peptides/antibodies.
17. Treatment with any investigational agent within 4 weeks or 5 half-lives prior to the first dose of study drug, whichever is longer.
18. Immunization with a live/attenuated vaccine within 4 weeks prior to baseline or plan to receive vaccines during the study.
19. Chronic pain disorders (not RA-related) that might interfere with pain evaluation.
20. 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.
21. History of alcohol, drug or chemical substance abuse within the 6 months prior to screening.
22. Any condition that in the opinion of the investigator could hamper compliance with the study protocol.