Efficacy and Safety Study Comparing CPL409116 to Placebo in Participants With Active Rheumatoid Arthritis

Exclusion Criteria

• •1. Has had a serious infection (e.g. sepsis, pneumonia, pyelonephritis or any other serious infection as per Investigator's judgement), or has been hospitalized or received intravenous antibiotics for an infection within 3 months prior to Day 1/ baseline;
• •2. Any active infection including localized infections within 2 weeks prior to baseline;
• •3. History of opportunistic or recurrent (3 or more of the same infection requiring anti-infective treatment in any rolling 12-month period) infection;
• •4. History of chronic infections requiring anti-infective treatment within 6 months prior to Screening;
• •5. Subjects with a high risk of infection in the Investigator's opinion (e.g. subjects with leg ulcers, indwelling urinary catheter);
• •6. History of infected joint prosthesis or other implanted device with the retention of prosthesis or device in situ;
• •7. Symptomatic herpes zoster within 3 months prior to Screening;
• •8. History of disseminated herpes simplex infection or disseminated/complicated herpes zoster;
• •9. Hereditary or acquired immunodeficiency disorder, including immunoglobulin deficiency;
• •10. Known infection with human immunodeficiency virus (HIV) or positive test at Screening;
• •11. Presence of any of the following laboratory abnormalities at Screening:
• •1. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels ≥1.5 x the upper limit of normal (ULN);
• •2. Absolute neutrophil count of \<1.5 x 10\^9/L (\<1500/mm\^3);
• •3. Absolute lymphocyte count of \<0.75 x 10\^9/L (\<750/mm\^3);
• •4. Absolute white blood cell (WBC) count of \< 3.0 x 10\^9 /L (\<3000/mm\^3);
• •5. Hemoglobin \<9.0 g/dL (90 g/L);
• •6. Thrombocytopenia, as defined by a platelet count \<100 x 10\^9/L (\< 100 000/mm\^3) at Screening;
• •7. Total bilirubin ≥1.5× the upper limit of normal (ULN).
• •12. Current or history of clinically significant (per Investigator's judgment) liver or biliary disease or significantly abnormal liver function test at screening (ALT or AST level ≥ 1.5 x ULN and/or total bilirubin ≥1,5× the upper limit of normal (ULN);
• •13. Current acute or chronic HCV and/or HBV infection:
• •1. Subjects who are seropositive for antibodies to hepatitis C virus (at Screening) may be allowed to participate in the study provided they have 2 negative HCV RNA test results 6 months apart after completing antiviral treatment and prior to Screening, and have a third negative HCV RNA test result at Screening.
• •2. HBV serology:
• •* a positive result for HBsAg will be exclusionary;
• •* a positive result for anti-HBc antibodies in subjects negative for HBsAg requires HBV DNA testing. A positive test result for HBV DNA will be exclusionary;
• •* For subjects who are negative for HBsAg and anti-HBc antibodies and has had a HBV vaccination a positive test result for anti-HBs antibodies is expected - such subjects may be enrolled without HBV DNA testing. In non-vaccinated patients positive for anti-HBs antibodies HBV DNA testing is required;
• •* a positive result for HBV DNA will be exclusionary.
• •NOTE: enrolled subjects positive for anti-HBc antibodies and/or anti-HBs antibodies (except for vaccinated subjects negative for anti-HBc antibodies and positive for anti-HBs antibodies) will have repeated HBV DNA testing at week 6 (or early termination visit) and last follow-up visit. A positive result for HBV DNA testing in these subjects will require immediate interruption of study drug and a hepatologist consultation.
• •14. Current or history of clinically significant renal disease (per investigation judgment) or eGFR\<60mL/min/1.73m\^2;
• •15. Breast cancer or other malignancy (including lymphoma, leukemia) within the past 5 years except for cervical carcinoma in situ that has been completely resected with no evidence of recurrence or metastatic disease for at least 12 months or cured basal cell carcinoma with no evidence of recurrence for at least 12 months;
• •16. History of major organ transplant (e.g. kidney, heart, liver, lung) or hematopoietic stem cell/bone marrow transplant;
• •17. History of lymphoproliferative disease or signs/ symptoms suggestive of possible lymphoproliferative disease, including splenomegaly of lymphadenopathy;
• •18. History or current moderate to severe congestive heart failure (New York Heart Association \[NYHA\] class III or IV), or within the last 6 months, a cerebrovascular accident, myocardial infarction, unstable angina, unstable arrhythmia or any other cardiovascular condition which, in the opinion of the investigator, would put the subject at risk by participation in the study;
• •19. History or presence of other significant concomitant illness that, according to the Investigator's judgment, would place the participant at unacceptable risk when taking investigational product or could interfere with the interpretation of data;
• •20. History of other (than RA) chronic inflammatory arthritis or systemic autoimmune disorder other than Sjögren's syndrome secondary to RA, that may confound the evaluation of the effect of the study intervention such as mixed connective tissue disease, psoriatic arthritis, juvenile chronic arthritis, spondyloarthritis, Felty's Syndrome, systemic lupus erythematosus, scleroderma, Crohn's disease, ulcerative colitis, or vasculitis;
• •21. Presence of fibromyalgia that, in the Investigator's opinion, would make it difficult to appropriately assess RA activity for the purposes of this study;
• •22. Undergone any major surgery within 8 weeks prior to study entry or will require major surgery during the study that, in the opinion of the Investigator would pose an unacceptable risk to the participant;
• •23. Current or previous active Mycobacterium tuberculosis (TB) regardless of treatment;
• •24. Evidence of latent TB (as documented by a positive QuantiFERON-TB test at Screening, no findings on medical history or clinical examination consistent with active TB, and a normal chest radiograph);
• •25. Previous household contact with a person with active tuberculosis (TB) and did not receive appropriate and documented prophylaxis for TB;
• •26. Clinically significant multiple or severe drug allergies or severe post-treatment hypersensitivity reactions (including, but not limited to erythema multiforme major, linear immunoglobulin A dermatosis, toxic epidermal necrolysis, and exfoliative dermatitis);
• •27. Inherited or acquired thrombophilia and/ or current or history of thromboembolic events/ disease;
• •28. Screening 12-lead ECG that demonstrates relevant abnormalities that, in the opinion of the Investigator, are clinically significant and indicate an unacceptable risk for the subject's participation in the study (eg, QTc \>450 msec or a QRS interval \>120 msec). If QTc exceeds 450 msec, or QRS exceeds 120 msec, the ECG should be repeated two more times and the average of the three QTc or QRS values should be used to determine the subject's eligibility;
• •29. Pregnancy or breast- feeding.
• •NOTE: Women of childbearing potential must have a negative pregnancy test at Screening, at randomization and at scheduled visits throughout the study.
• •30. Narcotic and alcohol addiction or abuse (more than 14 alcohol units per week: one unit = 150 mL wine, 360 mL beer, 45 mL 40 % spirits) (UK guidelines);
• •31. Positive drug screen or alcohol breath tests;
• •32. Blood donation within the last month before Day1/ baseline;
• •33. Current therapy with any disease-modifying antirheumatic drugs (DMARDs) other than MTX. All DMARDs (except for MTX) must be ceased before Day 1/ baseline, as follows:
• •* 1 month before: etanercept, sulfasalazine, chloroquine/ hydroksychloroquine;
• •* 3 months before: leflunomide (4 weeks in case of cholestyramine washout);
• •* 3 months before: adalimumab, golimumab, infliksimab, certolizumab, tocilizumab, gold, cyclosporine, penicillamine, azathioprine.
• •34. Previous use of (at any time):
• •1. cyclophosphamide
• •2. tacrolimus
• •35. Previous use of JAK inhibitors;
• •36. Previous use of biologic agent other than tocilizumab or TNF-alpha inhibitor. Previous use of one (and only one) biologic agent (tocilizumab or TNF-alpha inhibitor) is allowed if administered for less than 3 months or ceased because of other than lack of effectiveness causes;
• •37. Vaccinated with a live vaccine (i.e. containing live or attenuated pathogens) within 3 months before Day 1/ baseline or necessity to vaccinate during the clinical trial.
• •NOTE: Investigators should ensure that all study enrolment criteria have been met at Screening and on Day 1. If a patient status after Screening changes at baseline (Day 1) such that the study patient no longer meets all eligibility criteria, then the patient should be excluded from participation in the study (such patient is to be considered as screen failure). History or presence of any other medical or psychiatric condition, or laboratory abnormality that, in the opinion of the Investigator, may place the subject at unacceptable risk for study participation or may interfere with the study results should be considered as an exclusion criterion.