Efficacy and safety of GSK3196165 versus placebo and sarilumab in participants with moderately to severely active rheumatoid arthritis who have an inadequate response to biological DMARDs and/or Janus Kinase inhibitors.
- Conditions
- Rheumatoid ArthritisMedDRA version: 21.0Level: PTClassification code 10039073Term: Rheumatoid arthritisSystem Organ Class: 10028395 - Musculoskeletal and connective tissue disordersTherapeutic area: Diseases [C] - Musculoskeletal Diseases [C05]
- Registration Number
- EUCTR2019-000868-18-CZ
- Lead Sponsor
- GlaxoSmithKline Research & Development Limited
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- ot Recruiting
- Sex
- All
- Target Recruitment
- 550
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 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.
g. Tacrolimus up to 3 mg/day.
NOTE: 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.
7. Must have inadequate response to at least one biologic DMARD at an approved dose and/or at least one JAK inhibitor (JAKi) at an approved dose. In both cases this may be with or without combination with a csDMARD. Prior bDMARD or JAKi therapy must be discontinued before randomisation.
8. Body weight =40 kg
9. Male or female participants are eligible to participate so long as they meet the contraceptive eligibility criteria and agree to abide by the contraceptive requirements.
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 at screening, 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 528
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 72
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 <30 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 12 months, unstable angina pectoris, uncontrolled hypertension, uncontrolled hypercholesterolemia), neurological, endocrinological, gastrointestinal (including diverticulitis), hepatic disease, metabolic, lymphatic disease, or previous renal transplant that would adversely affect the participant’s participation
13. Any condition or contraindication as addressed in the local product information or local clinical practice for sarilumab that would preclude the participant from participating in this protocol.
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 investigational product 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.
15. Presence of fibromyalgia that, in the investigator’s opinion, would make it difficult to appropriately assess RA activity in this study.
16. Undergone any major surgery within 8 weeks prior to study entry or will require major surgery durin
Study & Design
- Study Type
- Interventional clinical trial of medicinal product
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method Main Objective: To compare the efficacy of GSK3196165 at doses of 90 mg and 150 mg weekly versus placebo, for the treatment of participants with moderately to severely active RA who are on a stable background of csDMARD(s) and who have had an inadequate response to biological DMARDs and/or JAK inhibitors.;Secondary Objective: To compare:<br>- Efficacy of GSK3196165 at doses of 90 mg and 150 mg weekly versus sarilumab, for the treatment of participants with moderately to severely active RA who are on a stable background of csDMARD(s) and who have had an inadequate response to biological DMARDs and/or JAK inhibitors.<br>- The effect of GSK3196165 on Patient Reported Outcomes (PROs) versus placebo and the active comparator sarilumab.<br>- Safety and tolerability of GSK3196165 versus placebo and the active comparator sarilumab<br><br>-To determine the immunogenic potential of GSK3196165;Primary end point(s): Proportion of participants achieving ACR20.;Timepoint(s) of evaluation of this end point: At Week 12.
- Secondary Outcome Measures
Name Time Method