Efficacy and safety study, comparing GSK3196165 (study drug) with placebo and with tofacitinib in combination with conventional synthetic antirheumatic drugs, in participants with moderately to severely active rheumatoid arthritis who have an inadequate response to conventional synthetic/biologic antirheumatic drugs

Phase 1

Conditions: Rheumatoid Arthritis
MedDRA version: 23.1Level: PTClassification code 10039073Term: Rheumatoid arthritisSystem Organ Class: 10028395 - Musculoskeletal and connective tissue disorders
Therapeutic area: Diseases [C] - Musculoskeletal Diseases [C05]

Registration Number: EUCTR2019-000867-26-BG

Lead Sponsor: GlaxoSmithKline Research & Development Limited

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: ot Recruiting

Sex: All

Target Recruitment: 1800

Inclusion Criteria

1. Age =18 years at the time of signing informed consent.
2. Meets ACR/EULAR 2010 RA Classification Criteria (see study reference manual [SRM]) with a duration of RA disease of =6 months 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 both:
a. =6/68 tender/painful joints (TJC), and
b. =6/66 swollen joints (SJC).
If surgical treatment of a joint has been performed, that joint cannot be counted in the TJC or SJC for enrolment purposes.
4. Must have a high sensitivity C-reactive protein (hsCRP) measurement =3 mg/L at screening.
5. Must meet Class I, II or III of the ACR 1991 Revised Criteria for Global Functional Status in RA (see SRM).
6. Must have at least 1 bone erosion present on hand/wrist or foot radiographs confirmed by central reading at screening.
7. Must have inadequate response, despite currently taking at least one and at most two concomitant csDMARDs for at least 12 weeks prior to Day 1, from the following:
a. Methotrexate (MTX): weekly 15-25 mg oral or injected, for at least 12 weeks at the maximum tolerated dose prior to Day 1, with no change in route of administration in this time. A lower dose of =7.5 mg/week is acceptable if reduced for reasons of intolerance to MTX, e.g. nausea/vomiting, hepatic or hematologic toxicity, or per local requirement (there must be clear documentation in the medical record). Exception: A lower dose of 6 mg/week is allowed if the minimum locally approved or recommended dose is lower than 7.5 mg/week.
b. Hydroxychloroquine up to 400 mg/day or chloroquine up to 250 mg/day.
c. Sulfasalazine up to 3000 mg/day.
d. Leflunomide up to 20 mg/day. Note: concomitant use of leflunomide and methotrexate is not allowed, for safety reasons.
e. Bucillamine up to 100 mg/day (or up to 300 mg/day if permitted per local requirements).
f. Iguratimod up to 50 mg/day.
The dose of csDMARD(s) must be stable and tolerated for at least 8 weeks prior to Day 1 and should remain stable throughout the study from screening to end of treatment period, except adjustment for safety reasons.
8. Body weight = 40 kg.
9. Male or female participants are eligible to participate so long as they meet and agree to abide by the contraceptive criteria detailed in Appendix 4 of protocol.
10. Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.
11. For participants on MTX: Must be willing to continue or initiate treatment with oral folic acid (at least 5 mg/week) or equivalent and be treated during the entire study (mandatory co-medication for MTX treatment).
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 1584
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 216

Exclusion Criteria

1. Active infections (including localised infections), or history of recurrent infections (excluding recurrent fungal infections of the nail bed), or has required management of acute or chronic infections, as described in the protocol
2. Symptomatic herpes zoster within 3 months prior to screening
3. Hereditary or acquired immunodeficiency disorder, including immunoglobulin deficiency
4. Known infection with human immunodeficiency virus (HIV) or positive test at screening
5. History of infected joint prosthesis at any time, with the prosthesis still in situ. History of chronic leg ulcers,permanent in-dwelling catheters,chronic sinusitis,recurrent chest infections or recurrent urinary tract infections
6. Any baseline symptomatology that in the investigator’s opinion would confound the early detection of pulmonary alveolar proteinosis based upon clinical features,such as persistent cough (CTC Grade =2) or persistent dyspnoea (dyspnoea scale Grade =2)
7. Current unstable liver or biliary disease per investigator assessment defined by the presence of ascites,encephalopathy,coagulopathy, hypoalbuminaemia, oesophageal or gastric varices, persistent jaundice,or cirrhosis
8. Current acute or chronic Hepatitis B and/or Hepatitis C
9. Current or history of renal disease or estimated glomerular filtration rate (eGFR) by Chronic Kidney Disease Epidemiology Collaboration equation (CKD-EPI) calculation <60 mL/min/1.73m2 at screening
10. Breast cancer within the past 10 years or lymphoma, leukaemia, or any other malignancy within the past 5 years except for cervical carcinoma in situ that has been resected with no evidence of recurrence or metastatic disease,or basal cell or squamous epithelial cancers of the skin that have been resected with no evidence of recurrence or metastatic disease for at least 3 years
11. History of any lymphoproliferative disorder, such as Epstein Barr Virus (EBV) related lymphoproliferative disorder,or signs and symptoms suggestive of current lymphatic disease
12. History or presence of significant other concomitant illness according to the Investigator judgment such as,but not limited to cardiovascular (including Stage III or IV cardiac failure according to New York Heart Association classification, myocardial infarction within 3 months, unstable angina pectoris, uncontrolled hypertension, uncontrolled hypercholesterolemia, uncontrolled diabetes mellitus, VTE requiring anticoagulation), neurological,endocrinological,gastrointestinal (including diverticulitis), hepatic disease,metabolic,lymphatic disease,or previous renal transplant that would adversely affect the participant’s participation in this study.
13. Any condition or contraindication as addressed in the local product information or local clinical practice for tofacitinib that would preclude the participant from participating in this protocol. For all participants, investigators should carefully review potential risk factors related to VTE, including deep vein thrombosis (DVT) and pulmonary embolism (PE) and review the risk of infection in participants older than 65 years of age. Refer to the risk table for tofacitinib in Section 2.3.1.
14. History of other inflammatory rheumatologic 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 Synd

Study & Design

Study Type: Interventional clinical trial of medicinal product

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method

Secondary Outcome Measures

Name	Time	Method

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