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

This is to be a 12-week, phase II, multicentre, randomised, double blind, efficacy and safety study of CPL409116 in participants with active rheumatoid arthritis who are taking methotrexate but have an inadequate response to this drug. Eligible subjects are to be randomised into one of the 4 treatment arms (60 mg BID, 120 mg BID, 240 mg BID of CPL409116 or palcebo) and approximately 100 male and female subjects are to be enrolled in the study (25 patients per arm). The study is to include the screening period, the treatment period and the follow-up period. In all treatment arms the investigated product/ placebo is to be administered orally for 12 weeks in a blinded fashion. In order to maintain the blind and minimize bias, all subjects will receive the same number and types of tablets each day of treatment. In the screening period, patients are to undergo screening assessments from Day -28 to Day 0. Rolling admission is to be employed in this study. Patients that fulfil all the inclusion criteria and none of the exclusion criteria will be considered eligible for this study. During the treatment period, patients are to be dosed with 60, 120, 240 mg CPL409116 administered twice a day or placebo administered twice a day for 85 consecutive days (Day 1 to Day 85). The MTX dosage which should be orally or parenterally administered by participants during the study and before the start of the study should be in the range of 15-25 mg/ week, which is typical of current clinical practice. MTX must be applied for at least 12 weeks prior to Screening, and with no change in dosage and route of administration for at least 8 weeks prior to Day 1/ baseline. Within the follow-up period patients are to undergo safety assessment for 4 weeks after the last dose of IMP.

Inclusion criteria

• Age ≥18 and ≤75 years at the time of signing informed consent;
• Meets ACR/EULAR 2010 RA Classification Criteria with a duration of RA disease of ≥6 months at time of screening and participant not diagnosed before 16 years of age;
• Must have active disease at both screening and baseline, as defined by having all three listed below:

• ≥ 6/68 tender/painful joints (TJC);
• ≥ 6/66 swollen joints (SJC);
• DAS28> 3,2.

NOTE: If surgical treatment of a joint has been performed, that joint cannot be counted in the TJC or SJC for enrolment purposes.

• Must have a C-reactive protein (CRP) measurement ≥7 mg/L at screening;
• Must meet Class I, II or III of the ACR 1991 Revised Criteria for Global Functional Status in RA;
• Must have inadequate response, despite currently taking Methotrexate (MTX): weekly 15-25 mg oral or injected (subcutaneous or intramuscular) for at least 12 weeks prior to Screening, and with no change in dosage and route of administration for at least 8 weeks prior to Day 1/ baseline. A lower dose of ≥10 mg/week is acceptable if reduced for reasons of side effects or intolerance to MTX, e.g. nausea/vomiting, hepatic or hematologic toxicity (there must be clear documentation in the medical record);
• If using oral GCS must be on stable dose (equivalent to ≤10mg/day of prednisone) for at least 4 weeks prior to Day 1/ baseline;
• If using NSAIDs must be on stable dose for at least 4 weeks prior to Day 1/ baseline;
• A woman must be either:

• 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; bilateral oophorectomy); or otherwise be incapable of pregnancy.

NOTE: premenopausal women who have had a bilateral tubal ligation/occlusion are considered capable of becoming pregnant.

• Of childbearing potential and using a double contraception including a barrier method (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 (estrogen and progesterone) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal, injectable) or progesterone-only hormone 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 that subject and the absence of sperm should be confirmed).

NOTE: sexual abstinence, defined as refraining from heterosexual intercourse throughout the study and for 12 weeks after the last IMP dose, is acceptable as a sole contraception method when this is in line with the preferred and usual lifestyle of the subject.

• Participant (a man) who is sexually active with a woman of childbearing potential must agree to use a double contraception including a barrier method (male condom) and a highly effective method of contraception (highly effective method of contraception are listed above) during the study and 12 weeks after the last dose of CPL409116/ placebo administration.

NOTE: Male subjects are responsible for informing his partner(s) of the risk of becoming pregnant and for reporting any pregnancy to the study doctor.

NOTE: Participants (males and females) are furthermore willing to use contraception methods for 12 weeks after the last dose of CPL409116/ placebo administration. It is crucial to maintain appropriate methods of contraception if it is planned to continue methotrexate administration after the end of the study.

• A woman of childbearing potential must have a negative blood pregnancy test (β -human chorionic gonadotropin [β-hCG]) at screening and negative urine pregnancy test on Day1/ baseline;
• Informed Consent Form signed and dated prior to Screening evaluations;
• Ability and willingness to comply with the requirements of the study Protocol;
• Negative result of the COVID-19 RT-PCR test (real-time reverse transcription polymerase chain reaction) for the qualitative detection of nucleic acid coming from SARS- CoV-2 before inclusion to the study (Screening- 72 h before Day1/ baseline).

Exclusion criteria

• 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;
• Any active infection including localized infections within 2 weeks prior to baseline;
• History of opportunistic or recurrent (3 or more of the same infection requiring anti-infective treatment in any rolling 12-month period) infection;
• History of chronic infections requiring anti-infective treatment within 6 months prior to Screening;
• Subjects with a high risk of infection in the Investigator's opinion (e.g. subjects with leg ulcers, indwelling urinary catheter);
• History of infected joint prosthesis or other implanted device with the retention of prosthesis or device in situ;
• Symptomatic herpes zoster within 3 months prior to Screening;
• History of disseminated herpes simplex infection or disseminated/complicated herpes zoster;
• Hereditary or acquired immunodeficiency disorder, including immunoglobulin deficiency;
• Known infection with human immunodeficiency virus (HIV) or positive test at Screening;
• Presence of any of the following laboratory abnormalities at Screening:

• Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels ≥1.5 x the upper limit of normal (ULN);
• Absolute neutrophil count of <1.5 x 10^9/L (<1500/mm^3);
• Absolute lymphocyte count of <0.75 x 10^9/L (<750/mm^3);
• Absolute white blood cell (WBC) count of < 3.0 x 10^9 /L (<3000/mm^3);
• Hemoglobin <9.0 g/dL (90 g/L);
• Thrombocytopenia, as defined by a platelet count <100 x 10^9/L (< 100 000/mm^3) at Screening;
• Total bilirubin ≥1.5× the upper limit of normal (ULN).
• 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);
• Current acute or chronic HCV and/or HBV infection:

• 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.
• 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.

• Current or history of clinically significant renal disease (per investigation judgment) or eGFR<60mL/min/1.73m^2;
• 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;
• History of major organ transplant (e.g. kidney, heart, liver, lung) or hematopoietic stem cell/bone marrow transplant;
• History of lymphoproliferative disease or signs/ symptoms suggestive of possible lymphoproliferative disease, including splenomegaly of lymphadenopathy;
• 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;
• 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;
• 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;
• Presence of fibromyalgia that, in the Investigator's opinion, would make it difficult to appropriately assess RA activity for the purposes of this study;
• 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;
• Current or previous active Mycobacterium tuberculosis (TB) regardless of treatment;
• 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);
• Previous household contact with a person with active tuberculosis (TB) and did not receive appropriate and documented prophylaxis for TB;
• 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);
• Inherited or acquired thrombophilia and/ or current or history of thromboembolic events/ disease;
• 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;
• 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.

• 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);
• Positive drug screen or alcohol breath tests;
• Blood donation within the last month before Day1/ baseline;
• 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.
• Previous use of (at any time):

• cyclophosphamide
• tacrolimus
• Previous use of JAK inhibitors;
• 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;
• 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.