A Study of Baricitinib (LY3009104) in Participants With Systemic Lupus Erythematosus

Study Overview
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Brief Summary
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The reason for this study is to see how effective and safe the study drug known as baricitinib is in participants with systemic lupus erythematosus (SLE).

Official Title
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A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Phase 3 Study of Baricitinib in Patients With Systemic Lupus Erythematosus

Conditions
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Systemic Lupus Erythematosus

Intervention / Treatment
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* Drug: Baricitinib
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Have a clinical diagnosis of SLE at least 24 weeks prior to screening. Have documentation of having met at least 4 of 11 Revised Criteria for Classification of Systemic Lupus Erythematosus according to the 1997 Update of the 1982 American College of Rheumatology (ACR) criteria for classification of SLE prior to randomization. Have a positive antinuclear antibody (ANA) (titer ≥1:80) and/or a positive anti-double-stranded deoxyribonucleic acid (dsDNA), and/or a positive anti-Smith (anti-Sm) as assessed by a central laboratory during screening. Have a total Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) score ≥6 during screening. Have a clinical SLEDAI-2K score ≥4 at randomization. Have at least 1 British Isles Lupus Assessment Group (BILAG) A score or 2 BILAG B scores during screening. Are receiving at least one of the following standard of care medications for SLE: A single antimalarial at a stable dose for at least 8 weeks prior to screening A single immunosuppressant at a stable dose for at least 8 weeks prior to screening An oral corticosteroid, initiated at least 4 weeks prior to screening, at a stable dose ≤40 milligrams/day prednisone (or equivalent) for at least 2 weeks prior to screening. If the participant is not receiving an antimalarial or immunosuppressant, the dose of corticosteroid must be ≥7.5 milligrams/day prednisone (or equivalent) Exclusion Criteria: Have severe active lupus nephritis. Have active 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. Have received cyclophosphamide (or any other cytotoxic agent) within 12 weeks prior to screening.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Participants received two placebo tablets: one matching baricitinib 4 milligram (mg) and one matching baricitinib 2 mg administered orally every day (QD) for 52 weeks. | Drug: Placebo<br>* Administered orally.<br>|
| Experimental: 2 mg Baricitinib<br>Participants received one Baricitinib 2 mg tablet and one placebo tablet matching Baricitinib 4 mg administered QD for 52 weeks. | Drug: Baricitinib<br>* Administered orally.<br>* Other names: LY3009104;Drug: Placebo<br>* Administered orally.<br>|
| Experimental: 4 mg Baricitinib<br>Participants received one Baricitinib 4 mg tablet and one placebo tablet matching baricitinib 2 mg administered orally every day (QD) for 52 weeks. | Drug: Baricitinib<br>* Administered orally.<br>* Other names: LY3009104;Drug: Placebo<br>* Administered orally.<br>|
| Placebo Comparator: Placebo Maximum Extended Enrollment (MEE)<br>Participants received two placebo tablets: one matching baricitinib 4 mg and one matching baricitinib 2 mg administered orally QD for 52 weeks. | Drug: Placebo<br>* Administered orally.<br>|
| Experimental: 2 mg Baricitinib (MEE)<br>Participants received one Baricitinib 2 mg tablet and 1 placebo tablet matching Baricitinib 4 mg administered QD for 52 weeks. | Drug: Baricitinib<br>* Administered orally.<br>* Other names: LY3009104;Drug: Placebo<br>* Administered orally.<br>|
| Experimental: 4 mg Baricitinib (MEE)<br>Participants received one Baricitinib 4 mg tablet and one placebo tablet matching baricitinib 2 mg administered orally every day (QD) for 52 weeks. | Drug: Baricitinib<br>* Administered orally.<br>* Other names: LY3009104;Drug: Placebo<br>* Administered orally.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Achieving a Systemic Lupus Erythematosus Responder Index 4 (SRI-4) Response (4 mg Baricitinib) | SRI-4 response defined as 1)greater than or equal to (>=) 4-point reduction in Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) total score 2)no new British Isles Lupus Assessment Group (BILAG) A and no more than 1 new BILAG B domain score and 3)no worsening in Physician Global Assessment (PGA) of Disease Activity (worsening defined as an increase of >=0.3 from baseline on a 0-3 visual analogue scale). SLEDAI-2K assessment consists of 24 items with total score of 0(no symptoms) to 105 (presence of all defined symptoms) with higher scores representing increased disease activity. BILAG Index: assessing clinical signs, symptoms,or laboratory parameters related to Systemic Lupus Erythematosus (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 assess disease activity on a visual analogue scale from 0 to 3 (1=mild, 2=moderate, 3=severe). | Week 52 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Achieving SRI-4 Response - 2 mg Baricitinib | SRI-4 response defined as 1)greater than or equal to (>=) 4-point reduction in Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) total score 2)no new British Isles Lupus Assessment Group (BILAG) A and no more than 1 new BILAG B domain score and 3)no worsening in Physician Global Assessment (PGA) of Disease Activity (worsening defined as an increase of >=0.3 from baseline on a 0-3 visual analogue scale). SLEDAI-2K assessment consists of 24 items with total score of 0(no symptoms) to 105 (presence of all defined symptoms) with higher scores representing increased disease activity. BILAG Index: assessing clinical signs, symptoms,or laboratory parameters related to Systemic Lupus Erythematosus (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 assess disease activity on a visual analogue scale from 0 to 3 (1=mild, 2=moderate, 3=severe). | Week 52 | 
| Percentage of Participants Achieving a Lupus Low Disease Activity State (LLDAS) | The LLDAS is a composite measure designed to identify patients achieving a state of low disease activity. The LLDAS response criteria were: (1) SLEDAI-2K <=4, with no activity in major organ systems (CNS, vascular, renal, cardiorespiratory and constitutional); where no activity is defined as all items of SLEDAI-2K within these major organ systems equal to 0. (2) no new features of lupus disease activity compared to previous occurred visit, where the new feature is defined as any of the SLEDAI-2K 24 items changed from 0 to greater than 0; (3) PGA (scale 0-3), <=1; (4) current prednisolone (or equivalent) dose <=7.5 mg daily. | Week 52 | 
| Time to First Severe Flare | Time to first severe flare was analyzed using a Cox proportional hazards model with treatment group, baseline disease activity (Systemic Lupus Erythematosus Disease Activity Index 2000 [SLEDAI-2K ] <10; SLEDAI-2K ≥10), baseline corticosteroid dose (<10 mg/day; ≥10 mg/day prednisone or equivalent), and region fitted as explanatory variables. Participants who did not have severe flare during the flare exposure time period were censored at the end of the flare exposure time. | Baseline to Week 52 | 
| Percentage of Participants Whose Average Prednisone Dose Had Been Reduced by >=25% From Baseline to <=7.5 mg/Day During Weeks 40 Through 52 in Participants Receiving Greater Than 7.5 mg/Day at Baseline | For the analysis of steroid use, steroid dosages were converted to a prednisone equivalent in mg. A responder was defined as having a prednisone reduction by >=25% from Baseline to <=7.5 mg/day during Weeks 40 through 52. | Baseline, Week 40 through Week 52 | 
| Change From Baseline in Worst Pain Numeric Rating Scale (NRS) | Participants assessed their worst pain in the last 24 hours on an 11-point numeric rating scale (NRS) ranging from 0 (no pain) to 10 (pain as bad as you can imagine). The average worst daily pain score was calculated as the mean of the scores over the last 7 days prior to each assessment time point. Higher score indicated severe pain. Least Squares (LS) mean was calculated using Mixed Model Repeated Measures (MMRM) analysis with treatment, baseline disease activity (total SLEDAI-2K <10; >=10), baseline corticosteroid dose (<10 mg/day; >= 10 mg/day prednisone or equivalent), region (North America, Central/South, America/Mexico, Europe, Asia Rest of World), visit (as categorical variable), baseline value, treatment-by-visit interaction, and baseline value-by-visit interaction. | Baseline, Week 52 | 
| Change From Baseline in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) Total Score | FACIT-Fatigue score calculated according to a 13-item questionnaire that assess self reported fatigue and its impact upon daily activities and function. It uses a 5-point Likert-type scale (0 = not at all; 1 = a little bit; 2 = somewhat; 3 = quite a bit; 4 = very much). The sum of all responses resulted in the FACIT-Fatigue score for a total possible score of 0 (worse possible score) to 52 (best score). A higher score reflected an improvement in the participant's health status. Least Squares (LS) mean was calculated using Mixed Model Repeated Measures (MMRM) analysis with treatment, baseline disease activity (total SLEDAI-2K <10; >=10), baseline corticosteroid dose (<10 mg/day; >= 10 mg/day prednisone or equivalent), region (North America, Central/South, America/Mexico, Europe, Asia Rest of World), visit (as categorical variable), baseline value, treatment-by-visit interaction, and baseline value-by-visit interaction. | Baseline, Week 52 | 
| Percentage of Participants With Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) Total Activity Score ≥10 at Baseline With ≥50% Reduction in CLASI Total Activity Score | The CLASI is a single-page tool that separately quantifies disease activity and damage. For the activity score, points are given for the presence of erythema, scale, mucous membrane lesions, recent hair loss, and inflammatory alopecia. The total score represents the sum of the individual scores and ranges from 0 to 70. Higher scores are awarded for more severe manifestations. | Week 52 | 
| Change From Baseline in Tender Joints Count | The number of tender and painful joints is determined by examination of 28 joints (14 on each side) which include: the 2 shoulders, the 2 elbows, the 2 wrists, the 10 metacarpophalangeal joints, the 2 interphalangeal joints of the thumb, the 8 proximal interphalangeal joints, and the 2 knees. The joints are assessed and classified as tender or not tender. LS mean was calculated using Mixed Model Repeated Measures (MMRM) analysis with treatment, baseline disease activity (total SLEDAI-2K <10; >=10), baseline corticosteroid dose (<10 mg/day; >=10 mg/day prednisone or equivalent), region (North America, Central/South America/Mexico, Europe, Asia and Rest of World), visit (as categorical variable), baseline value, treatment-by-visit interaction, and baseline value-by-visit interaction. | Baseline, Week 52 | 
| Change From Baseline in Swollen Joint Count | The number of swollen joints is determined by examination of 28 joints (14 on each side) which include: the 2 shoulders, the 2 elbows, the 2 wrists, the 10 metacarpophalangeal joints, the 2 interphalangeal joints of the thumb, the 8 proximal interphalangeal joints, and the 2 knees. The joints are assessed and classified as swollen or not swollen. LS mean was calculated using MMRM analysis with treatment, baseline disease activity (total SLEDAI-2K <10; >=10), baseline corticosteroid dose (<10 mg/day; >=10 mg/day prednisone or equivalent), region (North America, Central/South America/Mexico, Europe, Asia and Rest of World), visit (as categorical variable), baseline value, treatment-by-visit interaction, and baseline value-by-visit interaction. | Baseline, Week 52 | 
| Population Pharmacokinetics (PK): Area Under the Concentration-Time Curve of Baricitinib at Steady State (AUCτ, ss) | PK: Area Under the Concentration-Time Curve of Baricitinib at Steady State (AUCτ, ss) was evaluated using population PK approach. | Week 0 (Baseline): 15 minutes (min) and 60 min postdose; Week 4: 2 to 4 hours (hr) postdose; Week 8: 4 to 6 hr postdose; Week 12 and Week 16 predose | 
| Population PK: Maximum Observed Drug Concentration at Steady State (Cmax,ss) | Population PK: Maximum Observed Drug Concentration at Steady State (Cmax,ss) was evaluated using population PK approach. | Week 0 (Baseline): 15 minutes (min) and 60 min postdose; Week 4: 2 to 4 hours (hr) postdose; Week 8: 4 to 6 hr postdose; Week 12 and Week 16 predose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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SLE