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

Inclusion Criteria:

1. Age ≥18 and ≤75 years at the time of signing informed consent;

2. Meets ACR/EULAR 2010 RA Classification Criteria with a duration of RA disease of ≥6months at time of screening and participant not diagnosed before 16 years of age;

3. Must have active disease at both screening and baseline, as defined by having allthree listed below:

4. ≥ 6/68 tender/painful joints (TJC);

5. ≥ 6/66 swollen joints (SJC);

6. DAS28> 3,2. NOTE: If surgical treatment of a joint has been performed, that joint cannot becounted in the TJC or SJC for enrolment purposes.

7. Must have a C-reactive protein (CRP) measurement ≥7 mg/L at screening;

8. Must meet Class I, II or III of the ACR 1991 Revised Criteria for Global FunctionalStatus in RA;

9. Must have inadequate response, despite currently taking Methotrexate (MTX): weekly 15-25 mg oral or injected (subcutaneous or intramuscular) for at least 12 weeksprior to Screening, and with no change in dosage and route of administration for atleast 8 weeks prior to Day 1/ baseline. A lower dose of ≥10 mg/week is acceptable ifreduced for reasons of side effects or intolerance to MTX, e.g. nausea/vomiting,hepatic or hematologic toxicity (there must be clear documentation in the medicalrecord);

10. If using oral GCS must be on stable dose (equivalent to ≤10mg/day of prednisone) forat least 4 weeks prior to Day 1/ baseline;

11. If using NSAIDs must be on stable dose for at least 4 weeks prior to Day 1/baseline;

12. A woman must be either:

13. Not of childbearing potential:

• postmenopausal (>45 years of age with amenorrhea for at least 12 months,without using exogenous hormonal contraception and with FSH ≥ 40 IU/L);
• permanently sterile (hysterectomy, bilateral salpingectomy; bilateraloophorectomy); or otherwise be incapable of pregnancy.NOTE: premenopausal women who have had a bilateral tubal ligation/occlusion areconsidered capable of becoming pregnant.

2. Of childbearing potential and using a double contraception including a barriermethod (condom or occlusive cap) and a highly effective method of birth control (listed below): NOTE: highly effective methods of contraception are defined as:

• established use (i.e. at least 8 weeks prior to Day 1) of combined (estrogenand progesterone) hormonal contraception associated with inhibition ofovulation (oral, intravaginal, transdermal, injectable) or progesterone-onlyhormone contraception associated with inhibition of ovulation (oral,injectable);

• intrauterine device (IUD) or intrauterine hormone-releasing system (IUS);

• bilateral tubal occlusion/ligation;

• vasectomized partner (vasectomized partner should be the sole partner for thatsubject and the absence of sperm should be confirmed). NOTE: sexual abstinence, defined as refraining from heterosexual intercoursethroughout the study and for 12 weeks after the last IMP dose, is acceptable as asole contraception method when this is in line with the preferred and usuallifestyle of the subject.

10. Participant (a man) who is sexually active with a woman of childbearing potentialmust agree to use a double contraception including a barrier method (male condom)and a highly effective method of contraception (highly effective method ofcontraception are listed above) during the study and 12 weeks after the last dose ofCPL409116/ placebo administration. NOTE: Male subjects are responsible for informing his partner(s) of the risk ofbecoming pregnant and for reporting any pregnancy to the study doctor. NOTE: Participants (males and females) are furthermore willing to use contraceptionmethods for 12 weeks after the last dose of CPL409116/ placebo administration. It iscrucial to maintain appropriate methods of contraception if it is planned tocontinue methotrexate administration after the end of the study.

11. A woman of childbearing potential must have a negative blood pregnancy test (β -human chorionic gonadotropin [β-hCG]) at screening and negative urine pregnancytest on Day1/ baseline;

12. Informed Consent Form signed and dated prior to Screening evaluations;

13. Ability and willingness to comply with the requirements of the study Protocol;

14. Negative result of the COVID-19 RT-PCR test (real-time reverse transcriptionpolymerase chain reaction) for the qualitative detection of nucleic acid coming fromSARS- CoV-2 before inclusion to the study (Screening- 72 h before Day1/ baseline).

Exclusion Criteria:

1. Has had a serious infection (e.g. sepsis, pneumonia, pyelonephritis or any otherserious infection as per Investigator's judgement), or has been hospitalized orreceived intravenous antibiotics for an infection within 3 months prior to Day 1/baseline;

2. Any active infection including localized infections within 2 weeks prior tobaseline;

3. History of opportunistic or recurrent (3 or more of the same infection requiringanti-infective treatment in any rolling 12-month period) infection;

4. History of chronic infections requiring anti-infective treatment within 6 monthsprior to Screening;

5. Subjects with a high risk of infection in the Investigator's opinion (e.g. subjectswith leg ulcers, indwelling urinary catheter);

6. History of infected joint prosthesis or other implanted device with the retention ofprosthesis or device in situ;

7. Symptomatic herpes zoster within 3 months prior to Screening;

8. History of disseminated herpes simplex infection or disseminated/complicated herpeszoster;

9. Hereditary or acquired immunodeficiency disorder, including immunoglobulindeficiency;

10. Known infection with human immunodeficiency virus (HIV) or positive test atScreening;

11. Presence of any of the following laboratory abnormalities at Screening:

12. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels ≥1.5x the upper limit of normal (ULN);

13. Absolute neutrophil count of <1.5 x 10^9/L (<1500/mm^3);

14. Absolute lymphocyte count of <0.75 x 10^9/L (<750/mm^3);

15. Absolute white blood cell (WBC) count of < 3.0 x 10^9 /L (<3000/mm^3);

16. Hemoglobin <9.0 g/dL (90 g/L);

17. Thrombocytopenia, as defined by a platelet count <100 x 10^9/L (< 100 000/mm^3)at Screening;

18. Total bilirubin ≥1.5× the upper limit of normal (ULN).

19. Current or history of clinically significant (per Investigator's judgment) liver orbiliary disease or significantly abnormal liver function test at screening (ALT orAST level ≥ 1.5 x ULN and/or total bilirubin ≥1,5× the upper limit of normal (ULN);

20. Current acute or chronic HCV and/or HBV infection:

21. Subjects who are seropositive for antibodies to hepatitis C virus (atScreening) may be allowed to participate in the study provided they have 2negative HCV RNA test results 6 months apart after completing antiviraltreatment and prior to Screening, and have a third negative HCV RNA test resultat Screening.

22. HBV serology:

• a positive result for HBsAg will be exclusionary;
• a positive result for anti-HBc antibodies in subjects negative for HBsAgrequires HBV DNA testing. A positive test result for HBV DNA will beexclusionary;
• For subjects who are negative for HBsAg and anti-HBc antibodies and hashad a HBV vaccination a positive test result for anti-HBs antibodies isexpected - such subjects may be enrolled without HBV DNA testing. Innon-vaccinated patients positive for anti-HBs antibodies HBV DNA testingis 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 foranti-HBs antibodies) will have repeated HBV DNA testing at week 6 (or earlytermination visit) and last follow-up visit. A positive result for HBV DNA testingin these subjects will require immediate interruption of study drug and ahepatologist consultation.

14. Current or history of clinically significant renal disease (per investigationjudgment) or eGFR<60mL/min/1.73m^2;

15. Breast cancer or other malignancy (including lymphoma, leukemia) within the past 5years except for cervical carcinoma in situ that has been completely resected withno evidence of recurrence or metastatic disease for at least 12 months or curedbasal 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 hematopoieticstem cell/bone marrow transplant;

17. History of lymphoproliferative disease or signs/ symptoms suggestive of possiblelymphoproliferative disease, including splenomegaly of lymphadenopathy;

18. History or current moderate to severe congestive heart failure (New York HeartAssociation [NYHA] class III or IV), or within the last 6 months, a cerebrovascularaccident, myocardial infarction, unstable angina, unstable arrhythmia or any othercardiovascular condition which, in the opinion of the investigator, would put thesubject at risk by participation in the study;

19. History or presence of other significant concomitant illness that, according to theInvestigator's judgment, would place the participant at unacceptable risk whentaking investigational product or could interfere with the interpretation of data;

20. History of other (than RA) chronic inflammatory arthritis or systemic autoimmunedisorder other than Sjögren's syndrome secondary to RA, that may confound theevaluation of the effect of the study intervention such as mixed connective tissuedisease, psoriatic arthritis, juvenile chronic arthritis, spondyloarthritis, Felty'sSyndrome, systemic lupus erythematosus, scleroderma, Crohn's disease, ulcerativecolitis, or vasculitis;

21. Presence of fibromyalgia that, in the Investigator's opinion, would make itdifficult 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 requiremajor surgery during the study that, in the opinion of the Investigator would posean 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 notreceive appropriate and documented prophylaxis for TB;

26. Clinically significant multiple or severe drug allergies or severe post-treatmenthypersensitivity reactions (including, but not limited to erythema multiforme major,linear immunoglobulin A dermatosis, toxic epidermal necrolysis, and exfoliativedermatitis);

27. Inherited or acquired thrombophilia and/ or current or history of thromboembolicevents/ disease;

28. Screening 12-lead ECG that demonstrates relevant abnormalities that, in the opinionof the Investigator, are clinically significant and indicate an unacceptable riskfor 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 berepeated two more times and the average of the three QTc or QRS values should beused to determine the subject's eligibility;

29. Pregnancy or breast- feeding. NOTE: Women of childbearing potential must have a negative pregnancy test atScreening, at randomization and at scheduled visits throughout the study.

30. Narcotic and alcohol addiction or abuse (more than 14 alcohol units per week: oneunit = 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 thanMTX. 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):

35. cyclophosphamide

36. tacrolimus

37. Previous use of JAK inhibitors;

38. Previous use of biologic agent other than tocilizumab or TNF-alpha inhibitor.Previous use of one (and only one) biologic agent (tocilizumab or TNF-alphainhibitor) is allowed if administered for less than 3 months or ceased because ofother than lack of effectiveness causes;

39. 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.