| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
| Rheumatoid Arthritis (RA) is a chronic, systemic inflammatory autoimmune disease, characterised by a symmetrical polyarthritis that is associated with substantial disability and morbidity |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Musculoskeletal Diseases [C05] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 23.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10039073 |
| E.1.2 | Term | Rheumatoid arthritis |
| E.1.2 | System Organ Class | 10028395 - Musculoskeletal and connective tissue disorders |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
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. |
|
| E.2.2 | Secondary objectives of the trial |
To compare:
- 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.
- The effect of GSK3196165 on Patient Reported Outcomes (PROs)
versus placebo and the active comparator sarilumab.
- Safety and tolerability of GSK3196165 versus placebo and the active
comparator sarilumab
-To determine the immunogenic potential of GSK3196165 |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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 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 comedication
for MTX treatment). |
|
| E.4 | Principal 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 prosthesisstill 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 3 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 during the study that, in the opinion of the investigator in consultation with the medical monitor, would pose an unacceptable risk to the participant.
17. Current or previous active Mycobacterium tuberculosis (TB) regardless of treatment.
18. Evidence of latent TB (as documented by a positive QuantiFERON-TB Gold plus test or T-SPOT.TB test at screening, no findings on medical history or clinical examination consistent with active TB, and a normal chest radiograph) except for participants that either:
- Are willing to complete at least 4 weeks of anti-TB therapy as per WHO
or national guidelines prior to randomisation and agree to complete the
remainder of treatment while in the study OR
- Are documented as having evidence of satisfactory anti-TB treatment
as per WHO or national guidelines within the last 5 years following
review by a physician specialising in TB.
19. Previous close contact with a person with active TB and did not
receive satisfactory anti-tuberculosis treatment as per WHO or national
guidelines. 20. Significant allergies to humanised monoclonal antibodies or known hypersensitivity to sarilumab or any of its inactive ingredients.
21-34. Other exclusion criteria as mentioned in the protocol |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Proportion of participants achieving ACR20. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
1) Major Secondary Efficacy Endpoints
Change from baseline at Week 12 (versus placebo) in:
- HAQ-DI.
Change from baseline at Week 12 (versus sarilumab) in:
- CDAI total score.
- Arthritis pain VAS.
Other Secondary Efficacy Endpoints
Proportion of participants at Week 12 (vs. placebo and vs. sarilumab)
and Week 24 (vs. sarilumab) achieving:
- CDAI total score ≤10 (CDAI LDA).
- CDAI total score ≤2.8 (CDAI Remission).
- ACR20/50/70.
- DAS28-CRP ≤3.2 and DAS28(ESR) ≤3.2 (DAS28 LDA).
- DAS28(CRP) <2.6 and DAS28(ESR) <2.6 (DAS28 Remission).
- A good/moderate EULAR response
- ACR/EULAR Remission.
Change from baseline at Week 12 (vs. placebo and vs. sarilumab) and
Week 24 (vs. sarilumab) in:
- CDAI total score.
- DAS28(CRP)/DAS28(ESR).
2)Change from baseline at Week 12 (vs.placebo and vs. sarilumab) and
Week 24 (vs.sarilumab) in:
- HAQ-DI.
- Arthritis pain VAS.
- SF-36 physical and mental component scores, and domain scores.
- FACIT-Fatigue.
3)- Incidence of AEs, SAEs and AESIs.
- Change from baseline in key lab parameters at Weeks 12 and 24.
- Proportion of participants with NCICTCAE ≥Grade 3
haematology/clinical chemistry abnormalities.
4) Safety Biomarker Endpoints
- GM-CSF autoantibody concentrations.
- Immunogenicity. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| At various timepoint up to week 24 as defined in the protocol |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
- Immunogenicity
- Research on Biomarkers
- Optional Genetics research |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 6 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 8 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 62 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Canada |
| China |
| Japan |
| South Africa |
| United States |
| Belgium |
| Germany |
| Hungary |
| Italy |
| Lithuania |
| Poland |
| Spain |
| United Kingdom |
| Czechia |
| Argentina |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 2 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 2 |
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