Rheumatoid Arthritis
Conditions
Keywords
Rheumatoid Arthritis, Tumor Necrosis Factor Inhibitor, TNF-IR, Methotrexate
Brief summary
The primary objective of this study is to evaluate the efficacy of andecaliximab (GS-5745) versus placebo as an add-on therapy to a tumor necrosis factor (TNF) inhibitor and methotrexate in adults with moderate to severe rheumatoid arthritis (RA).
Interventions
DRUGAndecaliximab
Administered via subcutaneous injection once weekly
DRUGPlacebo
Administered via subcutaneous injection once weekly
DRUGMethotrexate
Administered orally weekly as part of the participant's current treatment regimen
DRUGTNF Inhibitor
An approved stable subcutaneous formulation of one of the following TNF inhibitors may include adalimumab, certolizumab, etanercept, or golimumab.
Sponsors
Gilead Sciences
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Diagnosis of RA (according to the 2010 American College of Rheumatology and European League Against Rheumatism (ACR/EULAR) classification criteria) confirmed at screening * 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 first dose of study drug * Individuals on MTX may also be on concurrent chloroquine or hydroxychloroquine at a stable dose (defined as no change in prescription) for at least 4 week prior to Baseline; if so, they should plan to continue this medication for the duration of the study * Must have an inadequate response to ≥ 12 weeks of ongoing treatment with an approved, stable subcutaneous (SC) formulation of TNF inhibitor (adalimumab, certolizumab pegol, etanercept, or golimumab), or marketed SC biosimilar TNF inhibitor with at least 6 weeks of stable dose (defined as no change in prescription), defined as: must have a DAS28(CRP) \> 3.2 at screening AND must have ≥ 3 swollen and ≥ 3 tender joints (using the DAS28 joint counts) at screening and at baseline (do not need to be the same joints) * 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 throughout the blinded period of the study. PRN NSAID for indications other than RA are also allowed. (PRN means pro re nata or when necessary) * Tuberculosis (TB) Screening: Must meet either a. or b.: 1. A negative history of TB infection and a negative QuantiFERON® TB-Gold In-Tube test and chest x-ray results. (QuantiFERON® tests with inconclusive results may be repeated one time. If the repeat result is also inconclusive, the individual will be excluded from the study). OR, 2. Individuals with a history of latent TB treated with a full course of prophylaxis as per local guidelines are allowed per investigator judgment. It is the responsibility of the investigator to verify the adequacy of previous treatment and to provide appropriate documentation. In these cases, no QuantiFERON® test need be obtained. In addition, these cases must be approved by the medical monitor prior to enrollment. (Any new diagnosis of latent TB or prior untreated /partially treated latent TB in NOT allowed (ie, individuals who require prophylactic therapy for TB during the study). Any prior history of active TB \[regardless of treatment\] is exclusionary). * 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 Key
Exclusion criteria
* Current treatment with any other 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 as described in the study protocol * Intraarticular corticosteroid injection of any joint within 4 weeks of baseline * Any infection requiring oral antimicrobial therapy within 2 weeks prior to baseline * 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 (individuals with Sjogren's syndrome or controlled thyroiditis as defined by the investigator are not excluded) * Active systemic involvement secondary to RA such as vasculitis or Felty's syndrome * History of any of the following within 12 months of baseline: * infection requiring parenteral antibiotics or hospitalization * any life-threatening infection * sepsis * The results of the following laboratory tests performed at the central laboratory at screening meet any of the criteria below: * Hemoglobin \< 8.0 g/dL (International System of Units (SI): \< 80 g/L) * White blood cells \< 3.0 x 10\^3 cells/mm\^3 (SI: \< 3.0 x 10\^9 cells/L) * Neutrophils \< 1.5 x 10\^3 cells/mm\^3 (SI: \< 1.5 x 10\^9 cells/L) * Lymphocytes \< 0.5 x 10\^3 cells/mm\^3 (SI: \< 0.5 x 10\^9 cells/L) * Platelets \< 100 x 10\^3 cells/mm\^3 (SI: \< 100 x 10\^9 cells/L) * Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥ 2 x upper limit of normal (ULN) * Total bilirubin level ≥ 2 x ULN unless the individual has been diagnosed with Gilbert's disease and this is clearly documented * Estimated glomerular filtration rate \< 40 mL/min/1.73 m\^2 based on the Modification of Diet in Renal Disease (MDRD) formula * Positive HIV serology during screening * Evidence of active Hepatitis B Virus (HBV) infection * Evidence of active Hepatitis C Virus (HCV) infection * Any uncontrolled clinically significant laboratory abnormality that would affect interpretation of study data or the individual's participation in the study * Malignancy or a history of malignancy or lymphoproliferative disorder within 10 years of screening with the following exceptions: * Carcinoma in situ of the cervix that has been successfully treated * Adequately treated basal or squamous cell cancer that has been successfully treated Note: Other protocol defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in DAS28(CRP) at Week 12 | Baseline; Week 12 | The DAS28 score is a measure of the participant's disease activity calculated using the tender joint counts (28 joints), swollen joint counts (28 joints), Patient's Global Assessment of Disease Activity (visual analog scale: 0 = no disease activity to 100 = maximum disease activity), and CRP for a total possible score of 1 to 9.4. Higher values indicate higher disease activity. A negative change from baseline indicates improvement. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants That Achieve DAS28(CRP) ≤ 3.2 at Week 12 | Week 12 | The DAS28 score is a measure of the participant's disease activity calculated using the tender joint counts (28 joints), swollen joint counts (28 joints), Patient's Global Assessment of Disease Activity (visual analog scale: 0 = no disease activity to 100 = maximum disease activity), and CRP for a total possible score of 1 to 9.4. Higher values indicate higher disease activity. A negative change from baseline indicates improvement. |
| Percentage of Participants That Achieve DAS28(CRP) < 2.6 at Week 12 | Week 12 | The DAS28 score is a measure of the participant's disease activity calculated using the tender joint counts (28 joints), swollen joint counts (28 joints), Patient's Global Assessment of Disease Activity (visual analog scale: 0 = no disease activity to 100 = maximum disease activity), and CRP for a total possible score of 1 to 9.4. Higher values indicate higher disease activity. A negative change from baseline indicates improvement. |
| Plasma Concentration of Andecaliximab | Day 4 or 6 (± 1 day) | The plasma concentrations of andecaliximab were not collected and were not analyzed. |
Countries
United States
Participant flow
Recruitment details
Participants were enrolled at study sites in the United States. The first participant was screened on 15 December 2016. The last study visit occurred on 07 August 2017.
Pre-assignment details
28 participants were screened.
Participants by arm
| Arm | Count |
|---|---|
| Andecaliximab 300 mg Double-Blind Period: Andecaliximab 300 mg administered via subcutaneous injection once weekly for 12 weeks, in addition to participant's current regimen of a TNF inhibitor and methotrexate
Open-Label Period: Andecaliximab 300 mg administered via subcutaneous injection once weekly for up to 52 weeks, in addition to participant's current regimen of a TNF inhibitor and methotrexate | 5 |
| Andecaliximab 150 mg Double-Blind Period: Andecaliximab 150 mg administered via subcutaneous injection + placebo once weekly for 12 weeks, in addition to participant's current regimen of a TNF inhibitor and methotrexate
Open-Label Period: Andecaliximab 300 mg administered via subcutaneous injection once weekly for up to 52 weeks, in addition to participant's current regimen of a TNF inhibitor and methotrexate | 5 |
| Placebo Double-Blind Period: Placebo administered via subcutaneous injection once weekly for 12 weeks, in addition to participant's current regimen of a TNF inhibitor and methotrexate
Open-Label Period: Andecaliximab 300 mg administered via subcutaneous injection once weekly for up to 52 weeks, in addition to participant's current regimen of a TNF inhibitor and methotrexate | 5 |
| Total | 15 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Double-Blind Treatment Period | Adverse Event | 0 | 1 | 0 |
| Double-Blind Treatment Period | Study Terminated by Sponsor | 3 | 1 | 4 |
| Open-Label Treatment Period | Study Terminated by Sponsor | 2 | 3 | 1 |
Baseline characteristics
| Characteristic | Andecaliximab 300 mg | Andecaliximab 150 mg | Placebo | Total |
|---|---|---|---|---|
| Age, Continuous | 54 years STANDARD_DEVIATION 16.3 | 57 years STANDARD_DEVIATION 9.3 | 58 years STANDARD_DEVIATION 5.6 | 56 years STANDARD_DEVIATION 10.6 |
| Disease Activity Score C-reactive Protein (DAS28(CRP)) | 5.79 units on a scale STANDARD_DEVIATION 0.814 | 5.90 units on a scale STANDARD_DEVIATION 0.752 | 5.69 units on a scale STANDARD_DEVIATION 0.887 | 5.79 units on a scale STANDARD_DEVIATION 0.764 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 2 Participants | 0 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 5 Participants | 3 Participants | 5 Participants | 13 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 0 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 3 Participants | 5 Participants | 4 Participants | 12 Participants |
| Sex: Female, Male Female | 3 Participants | 4 Participants | 4 Participants | 11 Participants |
| Sex: Female, Male Male | 2 Participants | 1 Participants | 1 Participants | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 5 | 0 / 5 | 0 / 5 | 0 / 6 |
| other Total, other adverse events | 3 / 5 | 2 / 5 | 2 / 5 | 2 / 6 |
| serious Total, serious adverse events | 0 / 5 | 0 / 5 | 0 / 5 | 1 / 6 |
Outcome results
Primary
Change From Baseline in DAS28(CRP) at Week 12
The DAS28 score is a measure of the participant's disease activity calculated using the tender joint counts (28 joints), swollen joint counts (28 joints), Patient's Global Assessment of Disease Activity (visual analog scale: 0 = no disease activity to 100 = maximum disease activity), and CRP for a total possible score of 1 to 9.4. Higher values indicate higher disease activity. A negative change from baseline indicates improvement.
Time frame: Baseline; Week 12
Population: Participants in the Full Analysis Set (all randomized participants who received at least 1 dose of study drug) with available data were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Andecaliximab 300 mg | Change From Baseline in DAS28(CRP) at Week 12 | 0.13 units on a scale | Standard Deviation 0.115 |
| Andecaliximab 150 mg | Change From Baseline in DAS28(CRP) at Week 12 | -1.51 units on a scale | Standard Deviation 0.67 |
| Placebo | Change From Baseline in DAS28(CRP) at Week 12 | -0.36 units on a scale | Standard Deviation 0.353 |
Secondary
Percentage of Participants That Achieve DAS28(CRP) < 2.6 at Week 12
The DAS28 score is a measure of the participant's disease activity calculated using the tender joint counts (28 joints), swollen joint counts (28 joints), Patient's Global Assessment of Disease Activity (visual analog scale: 0 = no disease activity to 100 = maximum disease activity), and CRP for a total possible score of 1 to 9.4. Higher values indicate higher disease activity. A negative change from baseline indicates improvement.
Time frame: Week 12
Population: Full Analysis Set: all randomized participants who received at least 1 dose of study drug
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Andecaliximab 300 mg | Percentage of Participants That Achieve DAS28(CRP) < 2.6 at Week 12 | 0 percentage of participants |
| Andecaliximab 150 mg | Percentage of Participants That Achieve DAS28(CRP) < 2.6 at Week 12 | 0 percentage of participants |
| Placebo | Percentage of Participants That Achieve DAS28(CRP) < 2.6 at Week 12 | 0 percentage of participants |
Secondary
Percentage of Participants That Achieve DAS28(CRP) ≤ 3.2 at Week 12
The DAS28 score is a measure of the participant's disease activity calculated using the tender joint counts (28 joints), swollen joint counts (28 joints), Patient's Global Assessment of Disease Activity (visual analog scale: 0 = no disease activity to 100 = maximum disease activity), and CRP for a total possible score of 1 to 9.4. Higher values indicate higher disease activity. A negative change from baseline indicates improvement.
Time frame: Week 12
Population: Full Analysis Set: all randomized participants who received at least 1 dose of study drug
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Andecaliximab 300 mg | Percentage of Participants That Achieve DAS28(CRP) ≤ 3.2 at Week 12 | 0 percentage of participants |
| Andecaliximab 150 mg | Percentage of Participants That Achieve DAS28(CRP) ≤ 3.2 at Week 12 | 0 percentage of participants |
| Placebo | Percentage of Participants That Achieve DAS28(CRP) ≤ 3.2 at Week 12 | 0 percentage of participants |
Secondary
Plasma Concentration of Andecaliximab
The plasma concentrations of andecaliximab were not collected and were not analyzed.
Time frame: Day 4 or 6 (± 1 day)