E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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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 |
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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 | 19.0 |
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 |
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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 assess the efficacy of GSK3196165 |
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E.2.2 | Secondary objectives of the trial |
To assess
- Dose-efficacy response of GSK3196165
- Safety
- Population pharmacokinetics
- Pharmacodynamics
- Novel biomarkers:
- To examine the molecular profiles of blood samples to identify factors that may influence biological and clinical
responses to GSK3196165 and/or associated with the development or progression of RA or medically related
conditions |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Actigraphy substudy
To explore how actigraphy measurements of physical activity correlate to disease activity, the following measures will be explored as change over time and change from baseline:
- Inter- and intra-daily measures of physical activity including but not limited to:
- Time spent sedentary (sitting and lying), time spent active (walking and standing), total activity score (function of duration and intensity of activity), number and duration of continuous walking periods
- Duration of morning stiffness
- Measures of sleep quality including but not be limited to:
- Time lying, number of movement episodes, sleep efficiency (function of % of movement time and total % of lying time) and fragmentation index (function of movement time % andnumber of movement episodes)
- RA Symptom and Impact diary |
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E.3 | Principal inclusion criteria |
1. Age ≥18 years at the time of signing informed consent.
2. Meets ACR/EULAR 2010 RA Classification Criteria.
3. Functional class I, II or III defined by the 1992 ACR Classification of Functional Status in RA.
4. Disease duration of ≥12 weeks (time from onset of patient-reported symptoms of either pain or stiffness or swelling in hands, feet or wrists).
5. Swollen joint count of ≥4 (66-joint count) and tender joint count of ≥4 (68-joint count) at screening and at Day 1.
6. DAS28(CRP) ≥3.2 at screening and DAS28(ESR) ≥3.2 at Day 1.
7. C-Reactive Protein (CRP) ≥5.0 mg/L at screening.
8. Must have previously received MTX (15-25 mg weekly) for at least 12 weeks before screening, with no change in route of administration, with a stable and tolerated dose for ≥4 weeks prior to Day 1. A stable dose of MTX ≥7.5 mg/week is acceptable, if the MTX dose has been reduced for reasons of documented intolerance to MTX, e.g. hepatic or hematologic toxicity, or per local requirement.
9. Weight ≥45 kg.
10. Male or female subjects are eligible to participate so long as they meet and agree to abide by the contraceptive criteria detailed in Appendix 12.2.
11. Written informed consent prior to any of the screening procedures including discontinuation of prohibited medications.
12. 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).
13. Diffusing capacity of the lung for carbon monoxide (DLCO) ≥60% (a,b) predicted; forced expiratory volume in 1 second (FEV1) ≥70% predicted.
a. Screening and Day 1 values within 10% of each other (the test may be repeated twice within the screening period, i.e. subjects may undergo a total of three DLCO tests during the screening period).
b. For subjects with DLCO values >60% to <70%, a baseline chest HRCT must be performed during the screening period, and it is recommended that the subject be reviewed by a local pulmonologist to exclude significant preexisting respiratory disease.
14. No evidence of active or latent infection with Mycobacterium tuberculosis (TB), as defined by all of the following:
a. No history of active or latent TB infection irrespective of treatment status.
b. A negative diagnostic TB test within 28 days of baseline (Day 1) defined as:
i. A negative QuantiFERON Gold test or T-spot test (performed locally) (NB: 2 successive indeterminate QuantiFERON
tests will be considered as a positive result).
OR
ii. If QuantiFERON gold or T-spot test not approved or registered in country of participation, then a negative
tuberculin skin test (TST) reaction as per local guidelines is required (it is strongly recommended that subjects with
a history of BCG vaccination be tested with QuantiFERON gold test).
c. Chest X-ray within 12 weeks of Day 1, locally read by a radiologist, with no evidence of current or previous
pulmonary tuberculosis.
NB: If there has been recent close contact with persons who have active TB prior to study
enrolment the subject will be referred to a TB physician to undergo additional evaluation. |
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E.4 | Principal exclusion criteria |
1. Pregnant or lactating women.
2. History of other inflammatory rheumatological or autoimmune disorders, other than Sjögren’s syndrome secondary to RA.
3. History of any respiratory disease which (in the opinion of the investigator) would compromise subject safety or the ability of the subject to complete the study (e.g. significant interstitial lung disease, such as pulmonary fibrosis, chronic obstructive pulmonary disease (COPD), moderate-severe asthma, bronchiectasis, previous PAP).
4. Clinically-significant or unstable (in the opinion of the investigator) persistent cough or dyspnea that is unexplained.
5. QTc >450msec or QTc >480msec for subjects with bundle branch block.
The QTc is the QT interval corrected for heart rate according to Fridericia’s formula (QTcF).
6. Liver function tests: alanine aminotransferase (ALT) >1.5x upper limit of normal (ULN); aspartate transaminase (AST) >1.5 upper limit of normal; alkaline phosphatase and bilirubin ≥1.5xULN (isolated bilirubin >1.5xULN is acceptable if
bilirubin is fractionated and direct bilirubin <35%).
7. Current active liver or biliary disease (with the exception of Gilbert’s syndrome or asymptomatic gallstones or otherwise stable chronic liver disease per investigator assessment).
8. Significant unstable or uncontrolled acute or chronic disease (e.g., cardiovascular including uncompensated congestive cardiac failure NYHA III or IV, myocardial infarction within 12 months, unstable angina pectoris, uncontrolled hypertension, uncontrolled hypercholesterolemia) pulmonary, hematologic, gastrointestinal (including Crohn’s Disease or ulcerative colitis), hepatic, renal, neurological, psychiatric, malignancy, endocrinological or infectious diseases, which, in the opinion of the investigator, could confound the results of the study or put the subject at undue risk.
9. A history of malignant neoplasm within the last 10 years or breast cancer within the last 20 years, except for non-melanoma skin cancers that have been excised and cured or carcinoma in situ of the uterine cervix.
10. Kidney disease: Current or history of renal disease, or estimated creatinine clearance <60 mL/min/1.73m2 or serum creatinine >1.5xULN within 28 days of Day 1.
11. Hereditary or acquired immunodeficiency disorder, including immunoglobulin deficiency.
12. History of infected joint prosthesis at any time, with the prosthesis still in situ.
History of leg ulcers, catheters, chronic sinusitis or recurrent chest or urinary tract infections.
13. Active infections, or history of recurrent infections (excluding recurrent fungal infections of the nail bed), or have required management of acute or chronic infections, as follows:
a. Currently on any suppressive therapy for a chronic infection (such as tuberculosis, pneumocystis, cytomegalovirus,
herpes simplex virus, herpes zoster and atypical mycobacteria).
OR
b. Hospitalization for treatment of infection within 26 weeks of Day 1.
OR
c. Use of parenteral (IV or IM) antimicrobials (antibacterials, antivirals, antifungals, or antiparasitic agents) within 26
weeks of Day 1 or oral antimicrobials within 14 days of Day 1.
14. A vaccination (live or attenuated) within 30 days of Day 1 or BCG vaccination within 365 days of Day 1, or a live vaccination planned during the course of the study.
15. Any surgical procedure, including bone or joint surgery/synovectomy within 12 weeks prior to Day 1 or any planned surgery within the duration of the study or follow-up period.
16. For those subjects in the actigraphy substudy: wheelchair, walking aids, artificial limbs; history of severe skin allergy; active implantable device; pacemaker |
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E.5 End points |
E.5.1 | Primary end point(s) |
Proportion of subjects who achieve DAS28(CRP) remission (DAS28(CRP) <2.6) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
Major Secondary Efficacy Endpoints
- Change from baseline in DAS28(CRP) at Week 12 (to support dose response evaluation).
- Proportion of subject achieving DAS28(CRP) remission at all assessment timepoints.
- Change from baseline in DAS28(CRP) at all assessment timepoints.
- Time to first DAS28(CRP) remission.
- Proportion of subjects achieving categorical DAS28(CRP) response (moderate/good EULAR response) at all assessment
timepoints.
- ACR 20/50/70 response rates at all assessment timepoints.
- Index- and Boolean-based ACR/EULAR remission rates, and CDAI remission rate at all assessment timepoints.
- Change from baseline in SDAI and CDAI at all assessment timepoints.
- Change from baseline in HAQ-DI score at all assessment timepoints.
- Change from baseline in pain score at all assessment timepoints.
- Change from baseline in physical and mental component scores and in domain scores of SF-36 at all assessment timepoints.
- Change from baseline in FACIT-Fatigue at all assessment timepoints.
- Change from baseline in BFI Question 3 at all assessment timepoints.
Major Secondary Safety Endpoints
- Incidence of adverse events and serious adverse events.
- Incidence of infections.
- Incidence of pulmonary events. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Please refer to section E.5.2 |
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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 | No |
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 | Yes |
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 |
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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) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
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) | No |
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
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 46 |
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 |
Argentina |
Bulgaria |
Canada |
Czech Republic |
Estonia |
Germany |
Hungary |
Italy |
Mexico |
Poland |
Russian Federation |
South Africa |
Spain |
Ukraine |
United Kingdom |
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E.8.7 | Trial has a data monitoring committee | No |
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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 5 |
E.8.9.1 | In the Member State concerned days | 12 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 5 |
E.8.9.2 | In all countries concerned by the trial days | 12 |