Systemic Lupus Erythematosus
Conditions
Brief summary
The main purpose of this study is to evaluate the efficacy and safety of the study drug known as baricitinib in participants with systemic lupus erythematosus.
Interventions
DRUGBaricitinib
Administered orally
DRUGPlacebo
Administered orally
Sponsors
Eli Lilly and Company
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Have received a diagnosis of SLE at least 24 weeks prior to screening, meeting the American College of Rheumatology (ACR) 1982 revised criteria OR the 2012 Systemic Lupus Erythematosus International Collaborating Clinics (SLICC) criteria. * Have a positive antinuclear antibody (ANA) (titer ≥1:80) and/or a positive anti-double-stranded deoxyribonucleic acid (dsDNA) as assessed by a central laboratory at screening. * Have a SLEDAI-2K score ≥4 based on clinical symptoms (not including lab values) at randomization. * Have active arthritis and/or active rash as defined by the SLEDAI-2K at randomization.
Exclusion criteria
* Have active severe lupus nephritis. * Have active severe central nervous system (CNS) lupus. * Have a history or presence of cardiovascular, respiratory, hepatic, gastrointestinal, endocrine, hematological, neurological, or neuropsychiatric disorders or any other serious and/or unstable illness that, in the opinion of the investigator, could constitute an unacceptable risk when taking investigational product or interfere with the interpretation of data. * Have a current or recent clinically serious viral, bacterial, fungal, or parasitic infection. * Are currently receiving oral corticosteroids at doses \>20-milligrams per day of prednisone (or equivalent) or have adjusted the dose of corticosteroids within 2 weeks of planned randomization. * Have started treatment with or adjusted the dose of nonsteroidal anti-inflammatory drugs (NSAIDs) (for which the NSAID use is intended for treatment of signs and symptoms of SLE) within 4 weeks of planned randomization. * Have started treatment with or adjusted the dose of an antimalarial within 12 weeks of planned randomization. * Have started treatment with or adjusted the dose of an immunosuppressant within 12 weeks of planned randomization. * Have received cyclophosphamide (or any other cytotoxic agent) within 12 weeks prior to screening.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Who Achieve Remission of Arthritis and/or Rash Defined by the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) | Week 24 | Participants were defined as responder as follows using SLEDAI-2K definitions of arthritis and rash. If only arthritis is present at baseline, then arthritis must be absent at Week 24 to meet the primary endpoint. If only rash is present at baseline, then rash must be absent at Week 24 to meet the primary endpoint. If both arthritis and rash are present at baseline, then the primary endpoint is met if either arthritis, or rash, or both arthritis and rash are absent at Week 24. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Who Achieve SLE Responder Index 4 (SRI-4) Response | Week 24 | SRI-4 response is defined as: 1) Reduction of ≥4 points from baseline in Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) score; 2) no new British Isles Lupus Assessment Group (BILAG) A or no more than 1 new BILAG B disease activity scores; and 3) no worsening (defined as an increase of ≥0.3 points \[10 mm\] from baseline) in Physician's Global Assessment of Disease Activity. The SRI-4 is a composite index used to assess disease activity in SLE. SLEDAI-2K assessment consists of 24 items with total score of 0 to 105, with higher scores representing increased disease activity. BILAG Index: assessing clinical signs, symptoms, or laboratory parameters related to SLE, divided into 9 organ systems. For each organ system: A=severe disease, B=moderate disease, C=mild stable disease, D=inactive, but previously active, E=inactive and never affected. PGA is a visual analog scale scored from 0 to 3 (0=none, 1=mild, 2=moderate, 3=severe). |
| Change From Baseline in SLEDAI-2K Score | Baseline, Week 24 | SLE Disease Activity Index 2000 (SLEDAI-2K) score is a weighted, cumulative index of lupus disease activity. SLEDAI-2K is calculated from 24 individual descriptors across 9 organ systems; 0 indicates inactive disease and the maximum theoretical score is 105. Least Squares (LS) mean was determined by mixed-model repeated measures (MMRM) model with baseline of response, region, baseline disease activity (SLEDAI-2K \<10, \>=10), baseline anti-dsDNA status (positive, negative), treatment, time, treatment\*time (type III sum of squares). |
| Change From Baseline in Patient's Global Assessment of Disease Activity | Baseline, Week 24 | The Patient's Global Assessment of Disease Activity is a single-item, patient reported scale developed for the assessment of the patient's overall rating of their disease activity due to SLE. The scale measures disease activity through a 5 point Likert scale ranging from 0 (No disease activity) to 4 (Severe disease activity) at its worst over the past 7 days. LS mean was determined by MMRM model with baseline of response, region, baseline disease activity (SLEDAI-2K \<10, \>=10), baseline anti-dsDNA status (positive, negative), treatment, time, treatment\*time (type III sum of squares). |
| Population Pharmacokinetics (PK): Area Under the Concentration-Time Curve of Baricitinib at Steady State (AUCτ, ss) | Week (Wk) 0: 15-30 minutes (min) postdose; Wk 4: Predose, 1.5 - 4 hour (hr) postdose; Wk 8: 1 - 3 hr postdose; Wk 16: Predose | Plasma samples for pharmacokinetic (PK) analysis were obtained in week 0, week 4, week 8, week 16 and 24. AUC takes all time points post dose into account and one value is reported. |
| Population Pharmacokinetics (PK): Maximum Observed Drug Concentration at Steady State (Cmax,ss) | Week (Wk) 0: 15-30 minutes (min) postdose; Wk 4: Predose, 1.5 - 4 hour (hr) postdose; Wk 8: 1 - 3 hr postdose; Wk 16: Predose | Plasma samples for pharmacokinetic (PK) analysis were obtained in week 0, week 4, week 8, week 16 and 24. Cmax takes all time points post dose into account and one value is reported. |
Countries
Argentina, Austria, France, Japan, Mexico, Poland, Puerto Rico, Romania, South Korea, Spain, Taiwan, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants received Placebo orally once daily (QD) for 24 weeks. | 105 |
| 2 mg Baricitinib Participants received 2 mg of Baricitinib tablet orally once a day for 24 weeks. | 105 |
| 4 mg Baricitinib Participants received 4 mg of Baricitinib tablet orally once a day for 24 weeks. | 104 |
| Total | 314 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 4 | 10 | 11 |
| Overall Study | Lack of Efficacy | 9 | 3 | 0 |
| Overall Study | Lost to Follow-up | 2 | 0 | 0 |
| Overall Study | Physician Decision | 2 | 3 | 2 |
| Overall Study | Protocol Violation | 0 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 5 | 3 | 4 |
Baseline characteristics
| Characteristic | Placebo | Total | 4 mg Baricitinib | 2 mg Baricitinib |
|---|---|---|---|---|
| Age, Continuous | 44.9 Years STANDARD_DEVIATION 12.8 | 44.3 Years STANDARD_DEVIATION 12.1 | 45.0 Years STANDARD_DEVIATION 12.4 | 43.2 Years STANDARD_DEVIATION 11 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 38 Participants | 102 Participants | 32 Participants | 32 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 52 Participants | 174 Participants | 60 Participants | 62 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 15 Participants | 38 Participants | 12 Participants | 11 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 9 Participants | 25 Participants | 10 Participants | 6 Participants |
| Race (NIH/OMB) Asian | 20 Participants | 60 Participants | 20 Participants | 20 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants | 21 Participants | 7 Participants | 9 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 2 Participants | 1 Participants | 1 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 | 2 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) White | 71 Participants | 204 Participants | 65 Participants | 68 Participants |
| Region of Enrollment Argentina | 9 Participants | 28 Participants | 7 Participants | 12 Participants |
| Region of Enrollment Austria | 3 Participants | 8 Participants | 3 Participants | 2 Participants |
| Region of Enrollment France | 2 Participants | 16 Participants | 7 Participants | 7 Participants |
| Region of Enrollment Japan | 13 Participants | 33 Participants | 10 Participants | 10 Participants |
| Region of Enrollment Mexico | 11 Participants | 33 Participants | 14 Participants | 8 Participants |
| Region of Enrollment Poland | 13 Participants | 32 Participants | 9 Participants | 10 Participants |
| Region of Enrollment Puerto Rico | 6 Participants | 17 Participants | 6 Participants | 5 Participants |
| Region of Enrollment Romania | 4 Participants | 13 Participants | 7 Participants | 2 Participants |
| Region of Enrollment South Korea | 1 Participants | 6 Participants | 3 Participants | 2 Participants |
| Region of Enrollment Spain | 6 Participants | 15 Participants | 3 Participants | 6 Participants |
| Region of Enrollment Taiwan | 6 Participants | 18 Participants | 5 Participants | 7 Participants |
| Region of Enrollment United States | 31 Participants | 95 Participants | 30 Participants | 34 Participants |
| Sex: Female, Male Female | 99 Participants | 294 Participants | 99 Participants | 96 Participants |
| Sex: Female, Male Male | 6 Participants | 20 Participants | 5 Participants | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 105 | 0 / 105 | 0 / 104 |
| other Total, other adverse events | 27 / 105 | 36 / 105 | 32 / 104 |
| serious Total, serious adverse events | 5 / 105 | 11 / 105 | 10 / 104 |
Outcome results
Primary
Percentage of Participants Who Achieve Remission of Arthritis and/or Rash Defined by the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K)
Participants were defined as responder as follows using SLEDAI-2K definitions of arthritis and rash. If only arthritis is present at baseline, then arthritis must be absent at Week 24 to meet the primary endpoint. If only rash is present at baseline, then rash must be absent at Week 24 to meet the primary endpoint. If both arthritis and rash are present at baseline, then the primary endpoint is met if either arthritis, or rash, or both arthritis and rash are absent at Week 24.
Time frame: Week 24
Population: All randomized participants who received at least 1 dose of study drug with baseline and post-baseline values at the specified time point for remission of arthritis and/or rash.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants Who Achieve Remission of Arthritis and/or Rash Defined by the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) | 53.3 Percentage of Participants |
| 2 mg Baricitinib | Percentage of Participants Who Achieve Remission of Arthritis and/or Rash Defined by the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) | 58.1 Percentage of Participants |
| 4 mg Baricitinib | Percentage of Participants Who Achieve Remission of Arthritis and/or Rash Defined by the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) | 67.3 Percentage of Participants |
p-value: 0.39295% CI: [0.73, 2.27]Regression, Logistic
p-value: 0.04195% CI: [1.02, 3.29]Regression, Logistic
Secondary
Change From Baseline in Patient's Global Assessment of Disease Activity
The Patient's Global Assessment of Disease Activity is a single-item, patient reported scale developed for the assessment of the patient's overall rating of their disease activity due to SLE. The scale measures disease activity through a 5 point Likert scale ranging from 0 (No disease activity) to 4 (Severe disease activity) at its worst over the past 7 days. LS mean was determined by MMRM model with baseline of response, region, baseline disease activity (SLEDAI-2K \<10, \>=10), baseline anti-dsDNA status (positive, negative), treatment, time, treatment\*time (type III sum of squares).
Time frame: Baseline, Week 24
Population: All randomized participants who received at least 1 dose of study drug with baseline and post-baseline values at the specified time point for Patient's Global Assessment of Disease Activity.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Patient's Global Assessment of Disease Activity | -0.67 Units on a scale | Standard Error 0.105 |
| 2 mg Baricitinib | Change From Baseline in Patient's Global Assessment of Disease Activity | -0.83 Units on a scale | Standard Error 0.107 |
| 4 mg Baricitinib | Change From Baseline in Patient's Global Assessment of Disease Activity | -1.00 Units on a scale | Standard Error 0.105 |
p-value: 0.28595% CI: [-0.45, 0.13]Mixed Models Analysis
p-value: 0.02695% CI: [-0.62, -0.04]Mixed Models Analysis
Secondary
Change From Baseline in SLEDAI-2K Score
SLE Disease Activity Index 2000 (SLEDAI-2K) score is a weighted, cumulative index of lupus disease activity. SLEDAI-2K is calculated from 24 individual descriptors across 9 organ systems; 0 indicates inactive disease and the maximum theoretical score is 105. Least Squares (LS) mean was determined by mixed-model repeated measures (MMRM) model with baseline of response, region, baseline disease activity (SLEDAI-2K \<10, \>=10), baseline anti-dsDNA status (positive, negative), treatment, time, treatment\*time (type III sum of squares).
Time frame: Baseline, Week 24
Population: All randomized participants who received at least 1 dose of study drug with baseline and post-baseline values at the specified time point for SLEDAI-2K.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in SLEDAI-2K Score | -3.82 Units on a scale | Standard Error 0.352 |
| 2 mg Baricitinib | Change From Baseline in SLEDAI-2K Score | -4.07 Units on a scale | Standard Error 0.356 |
| 4 mg Baricitinib | Change From Baseline in SLEDAI-2K Score | -4.39 Units on a scale | Standard Error 0.353 |
p-value: 0.695% CI: [-1.23, 0.71]Mixed Models Analysis
p-value: 0.24395% CI: [-1.55, 0.39]Mixed Models Analysis
Secondary
Percentage of Participants Who Achieve SLE Responder Index 4 (SRI-4) Response
SRI-4 response is defined as: 1) Reduction of ≥4 points from baseline in Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) score; 2) no new British Isles Lupus Assessment Group (BILAG) A or no more than 1 new BILAG B disease activity scores; and 3) no worsening (defined as an increase of ≥0.3 points \[10 mm\] from baseline) in Physician's Global Assessment of Disease Activity. The SRI-4 is a composite index used to assess disease activity in SLE. SLEDAI-2K assessment consists of 24 items with total score of 0 to 105, with higher scores representing increased disease activity. BILAG Index: assessing clinical signs, symptoms, or laboratory parameters related to SLE, divided into 9 organ systems. For each organ system: A=severe disease, B=moderate disease, C=mild stable disease, D=inactive, but previously active, E=inactive and never affected. PGA is a visual analog scale scored from 0 to 3 (0=none, 1=mild, 2=moderate, 3=severe).
Time frame: Week 24
Population: All randomized participants who received at least 1 dose of study drug with baseline and post-baseline values at the specified time point for SRI-4 response.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants Who Achieve SLE Responder Index 4 (SRI-4) Response | 47.6 Percentage of Participants |
| 2 mg Baricitinib | Percentage of Participants Who Achieve SLE Responder Index 4 (SRI-4) Response | 51.4 Percentage of Participants |
| 4 mg Baricitinib | Percentage of Participants Who Achieve SLE Responder Index 4 (SRI-4) Response | 64.4 Percentage of Participants |
p-value: 0.4495% CI: [0.71, 2.19]Regression, Logistic
p-value: 0.01595% CI: [1.15, 3.62]Regression, Logistic
Secondary
Population Pharmacokinetics (PK): Area Under the Concentration-Time Curve of Baricitinib at Steady State (AUCτ, ss)
Plasma samples for pharmacokinetic (PK) analysis were obtained in week 0, week 4, week 8, week 16 and 24. AUC takes all time points post dose into account and one value is reported.
Time frame: Week (Wk) 0: 15-30 minutes (min) postdose; Wk 4: Predose, 1.5 - 4 hour (hr) postdose; Wk 8: 1 - 3 hr postdose; Wk 16: Predose
Population: All randomized participants who received at least one dose of study drug and had evaluable PK (pharmacokinetics) data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Population Pharmacokinetics (PK): Area Under the Concentration-Time Curve of Baricitinib at Steady State (AUCτ, ss) | 265 nanogram*hour per milliliter (ng*h/mL) | Geometric Coefficient of Variation 55 |
| 2 mg Baricitinib | Population Pharmacokinetics (PK): Area Under the Concentration-Time Curve of Baricitinib at Steady State (AUCτ, ss) | 569 nanogram*hour per milliliter (ng*h/mL) | Geometric Coefficient of Variation 50 |
Secondary
Population Pharmacokinetics (PK): Maximum Observed Drug Concentration at Steady State (Cmax,ss)
Plasma samples for pharmacokinetic (PK) analysis were obtained in week 0, week 4, week 8, week 16 and 24. Cmax takes all time points post dose into account and one value is reported.
Time frame: Week (Wk) 0: 15-30 minutes (min) postdose; Wk 4: Predose, 1.5 - 4 hour (hr) postdose; Wk 8: 1 - 3 hr postdose; Wk 16: Predose
Population: All randomized participants who received at least one dose of study drug and had evaluable PK (pharmacokinetics) data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Population Pharmacokinetics (PK): Maximum Observed Drug Concentration at Steady State (Cmax,ss) | 29.0 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 30 |
| 2 mg Baricitinib | Population Pharmacokinetics (PK): Maximum Observed Drug Concentration at Steady State (Cmax,ss) | 59.2 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 24 |