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 |
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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 |
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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 GS-5745 versus placebo as an add-on therapy to a TNF inhibitor and methotrexate in subjects with moderate to severe rheumatoid arthritis Rheumatoid Arthritis. |
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E.2.2 | Secondary objectives of the trial |
To assess the safety and tolerability of GS-5745 versus placebo as an add-on therapy with a TNF inhibitor and methotrexate in subjects with moderate to severe Rheumatoid Arthritis.
To assess the pharmacokinetics (PK) of GS-5745 as an add-on therapy with a TNF inhibitor and methotrexate in subjects with moderate to severe Rheumatoid Arthritis. |
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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 |
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E.3 | Principal inclusion criteria |
Subjects must meet all of the following inclusion criteria to be eligible for participation in this
study.
1) Must have the ability to understand and sign a written informed consent form, which must be obtained prior to initiation of the study procedures; subjects who need a representative/guardian to provide consent are not permitted in this study
2) Male or female subjects between 18 and 80 years of age inclusive, at time of signing initial informed consent
3) Diagnosis of RA according to the 2010 ACR/EULAR classification criteria (See Appendix 8), confirmed at Screening
4) Subjects must meet Class I, II, or III of the ACR 1991 Revised Criteria for Global Functional Status in RA (Appendix 6), at Screening
5) Must have taken oral or parenteral methotrexate (MTX) dosed from 7.5 to 25 mg/week continuously for at least 12 weeks and tolerated this medication, with at least 6 weeks of stable dose (defined as no change in prescription) prior to the first dose of study drug
6) Must have ≥ 12 weeks of ongoing treatment with an approved, SC formulation of TNF inhibitor (adalimumab, certolizumab, etanercept, or golimumab, or marketed biosimilar TNF inhibitor), with at least 6 weeks of stable dose (defined as no change in prescription) defined as:
7) Subjects who have previously received other biologic DMARDs for the treatment of RA are eligible, providing the following washout periods for these have been met:
- Rituximab – none for at least 6 months prior to Baseline and subject has a CD19+ B cell count in normal range (per central lab) at Screening
- Infliximab – none for at least 8 weeks prior to Baseline
- Tocilizumab – none for at least 8 weeks prior to Baseline
8) Non-steroidal anti-inflammatory drugs (NSAIDs) and/or oral corticosteroids (≤ 10 mg prednisone/day or equivalent) at a stable dose (defined as no change in prescription) for ≥ 4 weeks prior to Baseline are allowed and should be continued at the same stable dose throughout the blinded period of the study; PRN NSAIDs for indications other than RA are also allowed.
9) TB Screening: Subjects must meet either a. or b.:
a. A negative history of TB infection and a negative QuantiFERON® TB-Gold In-Tube test and chest x-ray results (see below). QuantiFERON® tests with inconclusive results may be repeated one time. If the repeat result is also is inconclusive, the subject will be excluded from the study.
OR,
b. Subjects with a history of latent TB treated with a full course of prophylaxis as per local guidelines, are allowed per investigator judgment.
10) A negative chest x-ray (views per local guidelines) for active TB or other lung disease at Screening; or a chest x-ray within 90 days of Screening if films or report are available for investigator review
11) A negative pregnancy test is required for female subjects of childbearing potential (as defined per protocol), at Screening and at Day 1, prior to dosing of study drug. Female subjects must agree not to become pregnant for 30 days after the last dose of GS-5745
12) Subjects of child-bearing potential (as defined in protocol) must agree to use protocol specified contraceptive measures throughout the study and for 30 days after their last dose of study drug. Female subjects must agree not to become pregnant for 30 days after the last dose of study drug. Male and female subjects taking methotrexate or other drugs should also follow contraception guidelines in the relevant product local label
13) Lactating females must agree to discontinue breastfeeding prior to dosing of study drug and for the duration of the study. |
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E.4 | Principal exclusion criteria |
1) Current treatment with any disease modifying anti-rheumatic drug (DMARD) other than MTX, chloroquine or hydroxychloroquine, or current treatment with other immune modulating/suppressive non-biologic and biologic medications
2) Intra-articular corticosteroid injection within 4 weeks of Baseline
3) Any infection requiring oral antimicrobial therapy within 2 weeks prior to Baseline.
4) Previous treatment with GS-5745; known hypersensitivity to GS-5745 or its formulation excipients.
5) Known hypersensitivity to the TNF inhibitor or its formulation excipients that the subject is receiving at Screening
6) Any live or attenuated vaccines within 4 weeks prior to the first dose of study drug or plan to be vaccinated with these vaccines at any time during the study or within 12 weeks after the last dose of study drug.
7) Current inflammatory joint disease, other than RA, such as gout, reactive arthritis, psoriatic arthritis, seronegative spondylarthritis, or Lyme disease, OR other current autoimmune diseases such as: systemic lupus erythematosus (SLE), inflammatory bowel disease, fibromyalgia, polymyalgia rheumatica, scleroderma, inflammatory myopathy, mixed connective tissue disease, or other overlap syndrome that would interfere with the evaluation of RA or require protocol prohibited medication; (subjects with Sjogren’s syndrome or controlled thyroiditis as defined by the investigator are not excluded)
8) Active systemic involvement secondary to RA such as vasculitis or Felty’s syndrome
9) History of any of the following within 12 months of Baseline:
a) infection requiring parenteral antibiotics or hospitalization,
b) any life-threatening infection,
c) sepsis
10) History of infected prosthetic joint at any time, with the prosthesis still in situ
11) Significant blood loss (>450 mL) or transfusion of blood product within 12 weeks prior to Day 1.
12) The results of the following laboratory tests (hemoglobin, white blood cells, neutrophils, lymphocytes, platelets, alanine aminotransferase (ALT) or aspartate aminotransferase (AST), total bilirubin level, estimated glomerular filtration rate, positive HIV serology, evidence of active Hepatitis B, evidence of active Hepatitis C, any uncontrolled clinically significant laboratory abnormality that would affect interpretation of study data or the subject’s participation in the study), performed at the central laboratory at Screening meet any of the protocol criteria)
13) Any uncontrolled clinically significant laboratory abnormality that would affect interpretation of study data or the subject’s participation in the study, per judgment of investigator
14) Current malignancy, or a history of malignancy or lymphoproliferative disorder within 10 years of Screening, except:
a) Carcinoma in situ of the cervix that has been successfully treated
b) Basal or squamous cell cancer or other localized non-melanoma skin cancer that has been successfully treated
15) Participation in another investigational drug study within 1 month of Screening (for a small molecule) or within 3 months or 5 drug half-lives prior to Screening, whichever is longer (for a biologic agent)
16) Male subjects who are unwilling to refrain from sperm donation during the study and for 90 days after their last dose of study drug
17) Female subjects who are unwilling to refrain from egg donation or egg harvesting (for the purpose of current or future fertilization) during the course of the study for 30 days after their last dose of study drug and
18) Presence of any condition that could, in the opinion of the investigator, compromise the subject’s ability to participate in the study, eg, substance abuse, alcoholism, or an unstable psychiatric condition.
19) Known hypersensitivity to rubber or latex
20) Have undergone surgical treatments for RA including synovectomy or arthroplasty within the last 12 weeks prior to Screening or planned such surgery during the study
21) History of or current moderate to severe congestive heart failure (New York Heart Association [NYHA] class III or IV), or within the last 6 months, a cerebrovascular accident, myocardial infarction, unstable angina, unstable arrhythmia, or a new or significant ECG finding at Screening, or any other cardiovascular condition which, in the opinion of the investigator, would put the subject at risk by participating in the study.
22) Any chronic, uncontrolled medical condition which would put the subject at increased risk during the study, such as uncontrolled: diabetes, hypertension, morbid obesity, thyroid, adrenal, pulmonary, hepatic, renal, neurologic or psychiatric disease, or other disease of concern, as per judgment of the investigator.
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint of this study includes:
- Change in DAS28(CRP) from Baseline to Week 12 |
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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) |
The secondary endpoints of this study include:
- Proportion of subjects that achieve DAS28(CRP) ≤ 3.2 at Week 12
- Proportion of subjects that achieve DAS28(CRP) < 2.6 at Week 12
- Assess plasma concentrations of GS-5745 |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | Yes |
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 | 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 | 3 |
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 | 9 |
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 |
Australia |
Belgium |
Germany |
Hungary |
Mexico |
Taiwan |
United States |
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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
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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 | 3 |
E.8.9.1 | In the Member State concerned days | 13 |
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 | 3 |
E.8.9.2 | In all countries concerned by the trial days | 13 |