| 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 |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
| 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 |
|
| 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 evaluate the effect of GS-9876 versus placebo for the treatment of signs and symptoms of RA in subjects with active RA as measured by change from baseline in DAS28 (CRP) at Week 12 |
|
| E.2.2 | Secondary objectives of the trial |
- To evaluate the safety and tolerability of GS-9876 in subjects with RA
- To explore the effect of GS-9876 on other disease-specific outcomes in RA |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1) Male or female subjects who are between 18 and 75 years of age, inclusive, on the day of signing informed consent
2) Have a diagnosis of RA as defined by the 2010 American College of Rheumatology - European League Against Rheumatism Collaborative Initiative Classification Criteria for Rheumatoid Arthritis (Appendix 6)
3) Active RA disease as defined by: a TJC of ≥ 6 (out of 68), an SJC of ≥ 6 (out of 66) at Screening and Day 1
4) Inadequate response to treatment with oral or parenteral MTX 7.5 to 25 mg/week continuously for at least 12 weeks, with at least 6 weeks at a stable dose (defined as no change in prescription) prior to the first dose of study drug
5) Subjects must be receiving a folic or folinic acid supplementation at a stable dose. Subjects who are not taking folic or folinic acid at Screening should be initiated on an adequate dose of folic acid (>5 mg/week total dose or as per local practice) or equivalent and maintained
throughout the study.
6) Use of oral corticosteroids of no more than 10 mg prednisone or its equivalent per day is allowed if the dose is stable (defined as no change in prescription) for at least 28 days prior to the first dose of study drug
7) NSAIDs or other analgesics (including aspirin ≤ 100 mg daily) are allowed if doses are stable (defined as no change in prescription) for at least 14 days prior to the first dose of study drug; PRN use for other indications is allowed.
8) No evidence of active or latent TB as demonstrated by a negative QuantiFERON® TB-Gold In-Tube test at Screening. Tests with inconclusive results may be repeated one time. If an inconclusive test is repeated and is returned with inconclusive results a second time, the subject will be excluded from the study. Any prior history of active or latent TB (regardless of treatment) is exclusionary.
9) Able and willing to sign the informed consent as approved by the IRB/IEC. Written consent must be provided before initiating any Screening evaluations. Subjects must have read and understood the informed consent form (ICF), must fully understand the requirements of the study, and must be willing to comply with all study visits and assessments.
10) A negative serum pregnancy test is required for female subjects of childbearing potential, as defined in Appendix 5
11) Lactating females must agree to discontinue nursing before the study drug is administered and for the duration of the study.
12) Male subjects and female subjects of childbearing potential who engage in heterosexual intercourse must agree to use protocol specified method(s) of contraception as described in Appendix 5.
13) Male subject agrees to refrain from sperm donation throughout the study period and for at least 90 days following their last dose of study drug.
14) Female subject agrees to refrain from egg donation/harvest throughout the study period and for at least 35 days after their last dose of study drug. |
|
| E.4 | Principal exclusion criteria |
1) Prior treatment with B-cell depleting agents, unless more than 6 months prior to the first dose of study drug and documented return of CD19+ cells at Screening
2) Prior treatment with any SYK inhibitor
3) Concurrent treatment at Screening with any other csDMARD other than MTX and/or HCQ
4) Concurrent treatment at Screening with any bDMARD
5) QT interval corrected for heart rate using the Fridericia formula (QTcF) > 450 msec determined by the average of values at the Screening visit
6) History of any major bleeding event defined as Grade 3 severity and above within the last year or personal or family history of bleeding disorder
OR
Current use of chronic anticoagulant, not including daily aspirin for cardiac prophylaxis
7) Treatment with moderate or strong CYP3A inducers or inhibitors within 2 weeks prior to the first dose of study drug
8) Joint injections within 4 weeks prior to the first dose of study drug
9) Known hypersensitivity or allergy to GS-9876, filgotinib or MTX, and their metabolites, or their formulation excipients
10) Administration of a live or attenuated vaccine within 30 days of Screening or planned for during the study.
11) Participation in any investigational drug/device clinical study within 4 weeks or 5 half-lives prior to Screening, whichever is longer. Exposure to investigational biologics should be discussed with the sponsor.
12) Have a diagnosis of any generalized musculoskeletal disorder that would interfere with study procedures or assessments per the discretion of the investigator.
13) History of or current moderate to severe congestive heart failure, or within the last 6 months prior to Screening: 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 participating in the study.
14) History of malignancy within the past 5 years prior to Screening.
15) History of lymphoproliferative disease or possible current lymphoproliferative disease
16) History of organ or bone marrow transplant.
17) Positive serology at Screening for human immunodeficiency virus 1 or 2, hepatitis B virus or hepatitis C virus or any history of infectious hepatitis from any cause with the exception of hepatitis A.
18) History of opportunistic infection or immunodeficiency syndrome which would put the subject at risk, as per investigator judgment.
19) Known active infection of any kind (excluding fungal infections of nail beds) or any major episode of infection requiring hospitalization or treatment with intravenous (IV) or oral anti-infectives within 4 weeks of Screening.
20) History of symptomatic herpes zoster or herpes simplex infection within 12 weeks prior to Screening or history of disseminated/complicated herpes zoster infection (multi-dermatomal involvement, ophthalmic zoster, central nervous system involvement or postherpetic neuralgia).
21) History of an infected joint prosthesis or other implanted device with the prosthesis or device still in situ.
22) History within the previous 2 years prior to Screening or current drug or alcohol abuse, or heavy tobacco use, per the investigator judgment.
23) Any condition or circumstances (such as fibromyalgia or others) which in the opinion of the investigator or sponsor may make a subject unlikely or unable to complete the study or comply with study procedures and requirements.
24) Have any chronic, uncontrolled medical condition, which would put the subject at increased risk during study participation, such as uncontrolled: diabetes, hypertension, morbid obesity, thyroid, adrenal, pulmonary, hepatic, renal, neurologic or psychiatric disease, or other disease of concern, as per investigator judgment
25) Significant blood loss (>450 mL) or transfusion of any blood product within 12 weeks prior to the first dose of study drug
26) Subject has donated blood within 56 days of the first dose of study drug or plasma within 7 days of the first dose of study drug or does not agree to refrain from blood donation throughout the study period and for at least 30 days following the last dose of study drug.
27) The results of the following laboratory tests performed at the central laboratory at Screening meet any of the criteria below (out of range lab values may be rechecked one time, per investigator judgment, before subject is considered a screen-failure):
a) Hemoglobin <8.0 g/dL
b) White blood cells <3.0 x 10^3 cells/mm3
c) Neutrophils <1.5 x 10^3 cells/mm^3
d) Lymphocytes <0.5 x 10^3 cells/mm^3
e) Platelets <100 x 10^3 cells/mm3
f) Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥1.5x ULN;
g) Total bilirubin level ≥ 2x ULN unless the subject has been diagnosed with Gilbert’s disease and this is clearly documented;
h) Creatinine clearance (estimated GFR) < 60 mL/min based on the Cockcroft-Gault (CG) formula |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Change from baseline in DAS28 (CRP) at Week 12 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
- The proportion of subjects who achieve ACR 20/50/70 at Week 12
- Change from baseline in HAQ-DI score at Week 12 |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| 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 | No |
| 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 | 4 |
| 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 | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 21 |
| 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 |
| Bulgaria |
| Czech Republic |
| Hungary |
| Poland |
| Serbia |
| Ukraine |
| United States |
|
| 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
|
|
| 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 | 4 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 | 4 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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