A Study to Evaluate the Efficacy and Safety of BIIB059 (Litifilimab) in Adult Participants With Active Systemic Lupus Erythematosus Receiving Background Nonbiologic Lupus Standard of Care

Study Overview
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Brief Summary
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The primary objective of this study is to demonstrate efficacy of BIIB059 (litifilimab) compared with placebo in participants with active systemic lupus erythematosus (SLE), who are receiving background lupus standard of care (SOC) therapy in reducing disease activity. Secondary objectives of this study are to demonstrate early onset of efficacy of BIIB059 compared with placebo in participants with active SLE, who are receiving background lupus SOC therapy in reducing disease activity; to demonstrate organ-specific efficacy of BIIB059 compared with placebo in participants with active SLE, who are receiving background lupus SOC therapy in reducing joint disease activity; to demonstrate effect of BIIB059 compared with placebo in reducing oral corticosteroid (OCS) use; to demonstrate organ-specific efficacy of BIIB059 compared with placebo in participants with active SLE, who are receiving background lupus SOC therapy in reducing skin disease activity; to demonstrate efficacy of BIIB059 compared with placebo in participants with active SLE, who are receiving background lupus SOC therapy in reducing occurrence of flare up to Week 52; to evaluate additional efficacy of BIIB059 compared with placebo in reducing disease activity with additional disease activity measures; to evaluate the effect of BIIB059 compared with placebo in reducing OCS use; to assess the difference between BIIB059 and placebo on participant-reported health-related quality of life (HRQoL), symptoms, and impacts of SLE; to evaluate the safety and tolerability of BIIB059 in participants with active SLE; and to evaluate immunogenicity of BIIB059 in participants with active SLE.

Official Title
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A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study to Evaluate the Efficacy and Safety of BIIB059 in Adult Participants With Active Systemic Lupus Erythematosus Receiving Background Nonbiologic Lupus Standard of Care

Conditions
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Lupus Erythematosus, Systemic

Intervention / Treatment
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* Drug: BIIB059 (litifilimab)
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Participant must be diagnosed with systemic lupus erythematosus (SLE) at least 24 weeks prior to screening and must meet the 2019 European League Against Rheumatism (EULAR) / American College of Rheumatology (ACR) classification criteria for SLE at screening by a qualified physician. Participant has a modified Systemic Lupus Erythematosus Disease Activity Index-2000 (SLEDAI-2K) score ≥ 6 (excluding alopecia, fever, lupus-related headache, and organic brain syndrome) at screening (adjudicated). Participant has a modified clinical SLEDAI-2K score ≥ 4 (excluding anti-dsDNA, low complement component 3 (C3) and/or complement component 4 (C4), alopecia, fever, lupus-related headache, and organic brain syndrome) at Screening (adjudicated) and randomization. Participant has BILAG-2004 grade A in ≥ 1 organ system or BILAG-2004 grade B in ≥ 2 organ systems at Screening (adjudicated) and randomization. Participant must be treated with one of the following background nonbiologic lupus SOC therapies, initiated ≥ 12 weeks prior to Screening and at stable dose ≥ 4 weeks prior to randomization: Antimalarials as stand-alone treatment Antimalarial treatment in combination with OCS and/or a single immunosuppressant Treatment with OCS and/or a single immunosuppressant Key Exclusion Criteria: History of or positive test result for human immunodeficiency virus (HIV). Current hepatitis C infection (defined as positive hepatitis C virus (HCV) antibody and detectable HCV ribonucleic acid [RNA]). Current hepatitis B infection (defined as positive for hepatitis B surface antigen (HBsAg) and/or total hepatitis B core antibody [anti-HBc]). History of severe herpes infection. Presence of uncontrolled or New York Heart Association class III or IV congestive heart failure. Active severe lupus nephritis where, in the opinion of the Investigator, protocol-specified SOC is insufficient and use of a more aggressive therapeutic approach is indicated, such as adding IV cyclophosphamide and/or high-dose IV pulse corticosteroid therapy or other treatments not permitted in the protocol is indicated; or urine protein-creatinine ratio > 2.0 or severe chronic kidney disease (estimated glomerular filtration rate < 30 milliliters per minute per 1.73 meter square [mL/min/1.73 m^2]) calculated using the abbreviated modification of diet in renal disease equation. Any active skin conditions other than cutaneous lupus erythematosus (CLE) that may interfere with the study assessment of CLE such as but not limited to psoriasis, dermatomyositis, systemic sclerosis, non-LE skin lupus manifestation or drug-induced lupus. History or current diagnosis of a clinically significant non-SLE-related vasculitis syndrome. Active neuropsychiatric SLE. Use of oral prednisone (or equivalent) above 20 mg/day. Note: Other protocol defined Inclusion/Exclusion criteria may apply.

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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BIIB059 High Dose<br>Participants who are receiving background nonbiologic lupus SOC therapy will receive high dose of BIIB059, subcutaneously (SC) every 4 weeks (Q4W), up to Week 48 with an additional dose at Week 2. | Drug: BIIB059 (litifilimab)<br>* Administered as specified in the treatment arm.<br>* Other names: litifilimab;|
| Experimental: BIIB059 Low Dose<br>Participants who are receiving background nonbiologic lupus SOC therapy will receive low dose of BIIB059, SC Q4W, up to Week 48 with an additional dose at Week 2. | Drug: BIIB059 (litifilimab)<br>* Administered as specified in the treatment arm.<br>* Other names: litifilimab;|
| Placebo Comparator: Placebo<br>Participants who are receiving background nonbiologic lupus SOC therapy will receive BIIB059 matching placebo, SC Q4W, up to Week 48 with an additional dose at Week 2. | Drug: Placebo<br>* Administered as specified in the treatment arm.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Who Achieved a Systemic Lupus Erythematosus Responder Index of 4 (SRI-4) Response at Week 52 | SRI-4 response is a composite endpoint defined by the following criteria: Reduction from baseline of ≥4 points in systemic lupus erythematosus disease activity index 2000 (SLEDAI-2K). No new organ system affected, as defined by no new organ system with British isles lupus assessment group-2004 (BILAG-2004) grade A and no more than 1 new organ system with BILAG-2004 grade B compared with Baseline. No worsening from baseline in lupus disease activity as defined by <0.3-point increase on 3-point Physician's Global Assessment (PGA) - Visual Analog Scale (VAS). No violation to protocol-specified medication rules. | Week 52 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Who Achieved an SRI-4 Response at Week 24 | SRI-4 response is a composite endpoint defined by the following criteria: Reduction from baseline of ≥4 points in SLEDAI-2K. No new organ system affected, as defined by no new organ system with British isles lupus assessment group-2004 (BILAG-2004) grade A and no more than 1 new organ system with BILAG-2004 grade B compared with Baseline. No worsening from baseline in lupus disease activity as defined by <0.3-point increase on 3-point PGA -VAS. No violation to protocol-specified medication rules. | Week 24 | 
| Percentage of Participants With at Least 4 Joints (Both Swollen and Tender) at Baseline Who Achieved a Joint-50 Response at Week 52 | Joint-50 response is 50% reduction in total active joint count from baseline. An active joint is defined as a joint with pain and signs of inflammation (e.g., tenderness, swelling or effusion). A 28-joint assessment will be performed to determine the active joint count, which is defined as the sum of tender and swollen joint counts. | Week 52 | 
| Percentage of Participants with OCS ≥10 milligrams per day (mg/day) at Baseline Who Have OCS Reduction to ≤7.5 mg/day at Week 40, Which Is Sustained Through Week 52 with No Disease Worsening from Week 40 to Week 52 | No worsening of the disease is defined as no new BILAG-2004 grade A or less than 2 new BILAG-2004 grade B since the last visit during the Week 40 to Week 52. | Week 40 to Week 52 | 
| Percentage of Participants with a CLASI-A score ≥10 at Baseline Who Achieved a 50% Improvement From Baseline in Cutaneous Lupus Erythematosus Disease Area and Severity Index Activity Score (CLASI-50) Response at Week 16 | Cutaneous Lupus Erythematosus Disease Area and Severity Index - Activity (CLASI-A) score is used to evaluate lupus skin manifestations. CLASI-A scores of 0 to 9, 10 to 20, and 21 to 70 represent disease severity of mild, moderate, and severe, respectively. CLASI-50 is 50% of improvement from baseline in CLASI-A. | Week 16 | 
| Annualized Flare Rate Through Week 52 | Annualized flare rate will be calculated as the total number of flares divided by the flare exposure time in days, and the ratio multiplied by 365.25. | Up to Week 52 | 
| Change from Baseline in Physician's Global Assessment (PGA) Visual Analog Scale (VAS) Score by Visit | The PGA is an Investigator-administered assessment used to quantify disease activity and is measured using an anchored VAS. The PGA asks the Investigator to assess the participant's current disease activity from a score of 0 (none) to 3 (severe), with the assessment made relative to the most severe state of SLE. | Up to Week 52 | 
| Percentage of Participants Who Achieved a British Isles Lupus Activity Group (BILAG)-Based Combined Lupus Assessment (BICLA) Response by Visit | The BILAG disease activity index evaluates SLE activity in number of organ systems, using a separate alphabetic score (A to E) assigned to each organ system defined as follows, BILAG A: severe disease activity; BILAG B: moderate disease activity; BILAG C: Stable mild disease; BILAG D: System previously affected but now inactive; BILAG E: System never involved. BICLA is a composite endpoint defined as BILAG-2004 improvement, defined as all BILAG-2004 grade A at Baseline improved to grade B, C, or D, and all BILAG-2004 grade B at baseline improved to grade C or D, no BILAG-2004 worsening in other BILAG-2004 organ systems such that there are no new BILAG-2004 grade A or greater than 1 new BILAG-2004 grade B, no worsening in the SLEDAI-2K total score compared with Baseline, no worsening from Baseline in lupus disease activity defined by < 0.3-point increase on 3-point PGA-VAS and no violation to protocol-specified medication rules. | Up to Week 52 | 
| Time to Onset of SRI-4 Response Sustained Through Week 52 | SRI-4 response is a composite endpoint defined by the following criteria: Reduction from baseline of ≥4 points in SLEDAI-2K. No new organ system affected, as defined by no new organ system with British isles lupus assessment group-2004 (BILAG-2004) grade A and no more than 1 new organ system with BILAG-2004 grade B compared with Baseline. No worsening from baseline in lupus disease activity as defined by <0.3-point increase on 3-point PGA -VAS. No violation to protocol-specified medication rules. | Up to Week 52 | 
| Percentage of Participants Who Achieved SRI-4, -5, or -6 Response by Visit | SRI-4 response is a composite endpoint defined by the following criteria: Reduction from baseline of ≥4 points in SLEDAI-2K. No new organ system affected, as defined by no new organ system with British isles lupus assessment group-2004 (BILAG-2004) grade A and no more than 1 new organ system with BILAG-2004 grade B compared with Baseline. No worsening from baseline in lupus disease activity as defined by <0.3-point increase on 3-point PGA -VAS. No violation to protocol-specified medication rules. The SRI-5 and SRI-6 are computed with a minimal five-point or six-point improvement in SLEDAI-2K being required, respectively. | Up to Week 52 | 
| Percentage of Participants with Joint-50 Response by Visit | Joint-50 response is 50% reduction in total active joint count from baseline. An active joint is defined as a joint with pain and signs of inflammation (e.g., tenderness, swelling or effusion). A 28-joint assessment will be performed to determine the active joint count, which is defined as the sum of tender and swollen joint counts. | Up to Week 52 | 
| Percentage of Participants with Baseline CLASI-A Score ≥10 Who Achieved a CLASI-20, -50, -70, or -90 Response by Visit | Cutaneous Lupus Erythematosus Disease Area and Severity Index - Activity (CLASI-A) score is used to evaluate lupus skin manifestations. CLASI-A scores of 0 to 9, 10 to 20, and 21 to 70 represent disease severity of mild, moderate, and severe, respectively. CLASI-20, -50, -70 and -90 represent 20%, 50%, 70% or 90% improvement from baseline in CLASI-A score, respectively. | Up to Week 52 | 
| Percentage of Participants with Baseline CLASI-A Score ≥10 Who Achieved a CLASI-A Score of ≤ 1 by Visit | Cutaneous Lupus Erythematosus Disease Area and Severity Index - Activity (CLASI-A) score is used to evaluate lupus skin manifestations. CLASI-A scores of 0 to 9, 10 to 20, and 21 to 70 represent disease severity of mild, moderate, and severe, respectively. CLASI-A ≤1 represent the absolute score ≤1 in CLASI-A by visit. | Up to Week 52 | 
| Time to First British Isles Lupus Activity Group-2004 (BILAG-2004) Severe Flare by Visit | BILAG-2004 severe flare is defined as an A score for items recorded as worse or new. BILAG-2004 is evaluated by scoring each item of a list of signs and symptoms given as 4 = new; 3 = worse; 2 = same; 1 = improving; 0 = not present; and ND = not done. | Up to Week 52 | 
| Time to First Severe Flare as defined by the Safety of Estrogens in Systemic Lupus Erythematosus National Assessment - Systemic Lupus Erythematosus Disease Activity Index Flare Index (SFI) | SFI severe flare is defined any of the following: change in SLEDAI instrument score to >12; or new or worse: central nervous system SLE; vasculitis; nephritis; myositis; platelets <60,000 per milliliter (/mL); or hemolytic anemia with hemoglobin <7 grams per deciliter (g/dL) or decrease in hemoglobin >3 g/dL and requiring: doubling prednisone dose; or increase to >0.5 milligrams per kilogram per day (mg/kg/day) or hospitalization; or increase in prednisone dose to >0.5 mg/kg/day; or new requirement for cyclophosphamide, azathioprine, methotrexate, or mycophenolate for SLE activity; or hospitalization for SLE activity; or increase in PGA score to >2.5. | Up to Week 52 | 
| Percentage of Time Spent in Lupus Low Disease Activity State (LLDAS) | LLDAS is a composite endpoint defined as: SLEDAI-2K score ≤ 4, with no activity in a major organ system (renal, central nervous system, cardiopulmonary, vasculitis, fever); and No new features of lupus disease activity compared with the previous assessment; and Safety of Estrogens in Lupus Erythematosus National Assessment - Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) PGA ≤ 1; and Current prednisone (or equivalent) dose ≤ 7.5 mg/day; and Standard maintenance doses of immunosuppressive drugs and approved biological agents. | Up to Week 52 | 
| Percentage of Participants With Sustained LLDAS as Defined by the Number of Participants With ≥ 3, ≥ 5, and ≥ 7 Consecutive Visits in LLDAS up to and Including Week 52 | LLDAS is a composite endpoint defined as: SLEDAI-2K score ≤ 4, with no activity in a major organ system (renal, central nervous system, cardiopulmonary, vasculitis, fever); and No new features of lupus disease activity compared with the previous assessment; and SELENA-SLEDAI PGA ≤ 1; and Current prednisone (or equivalent) dose ≤ 7.5 mg/day; and Standard maintenance doses of immunosuppressive drugs and approved biological agents. | Up to Week 52 | 
| Percentage of Participants who Achieved LLDAS at Week 52 | LLDAS is a composite endpoint defined as: SLEDAI-2K score ≤ 4, with no activity in a major organ system (renal, central nervous system, cardiopulmonary, vasculitis, fever); and No new features of lupus disease activity compared with the previous assessment; and SELENA-SLEDAI PGA ≤ 1; and Current prednisone (or equivalent) dose ≤ 7.5 mg/day; and Standard maintenance doses of immunosuppressive drugs and approved biological agents. | Week 52 | 
| Percentage of Participants With Baseline OCS ≥10 mg/day Who Achieved ≤7.5 mg/day at Week 52 |  | Week 52 | 
| Change from Baseline in Lupus-Specific Health-Related Quality-of-Life Questionnaire (LupusQoL) Score | The LupusQoL is a participant-reported, lupus-specific, Health-Related Quality-of-Life Questionnaire (HRQoL) consisting of 34 items grouped in 8 domains: physical health, pain, planning, intimate relationships, burden to others, emotional health, body image and fatigue. Participants indicate their responses on a 5-point Likert response format, where 4 = never, 3 = occasionally, 2 = a good bit of the time, 1 = most of the time, and 0 = all the time. A LupusQoL score for each domain will be reported on a 0 to 100 scale, with greater values indicating better HRQoL. | Up to Week 52 | 
| Change From Baseline in Short Form Health Survey-36 (SF-36) Score | The SF-36 determines participant's overall quality of life by assessing 1) limitations in physical functioning due to health problems; 2) limitations in usual role because of physical health problems; 3) bodily pain; 4) general health perceptions; 5) vitality; 6) limitations in social functioning because of physical or emotional problems; 7) limitations in usual role due to emotional problems; and 8) general mental health. Items 1-4 primarily contribute to the physical component summary (PCS) score of the SF-36. Items 5-8 primarily contribute to the mental component summary (MCS) score of the SF-36. Scores on each item are summed and averaged (range: 0=worst to 100=best). Increases from baseline indicate improvement. | Up to Week 52 | 
| Change From Baseline in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) Score | The FACIT-Fatigue is a participant-administered HRQoL questionnaire that evaluates participant's fatigue in the 5 broad categories: physical well-being, social/family well-being, emotional well-being, functional well-being and additional concerns. The level of fatigue is measured by questions assessed on a 5-point scale (0 = not at all; 1 = a little bit; 2 = somewhat; 3 = quite a bit; 4 = very much). The responses for each item are added to obtain a total score which ranges from 0 to 52, with a higher score indicating less fatigue. | Up to Week 52 | 
| Change From Baseline in Patient Health Questionnaire-9 (PHQ-9) Score | The PHQ-9 is a participant-administered HRQoL questionnaire to screen for the presence and severity of depression. The PHQ-9 is a participant-reported outcome (PRO) that is used to measure depression in adults. It contains 9 questions. The PHQ-9 yields an overall severity score that can range from 0 to 27 with the following severity scores: 0-4 = none; 5-9 = mild; 10-14 = moderate; 15-19 = moderate-to-severe; and 20-27 = severe. | Up to Week 52 | 
| Change From Baseline in Work Productivity and Activity Impairment (WPAI): Lupus Score | WPAI questionnaire is a validated instrument to measure impairments in work and activities. The WPAI yields four types of scores: 1. Absenteeism (work time missed) 2. Presenteesism (impairment at work / reduced on-the-job effectiveness) 3. Work productivity loss (overall work impairment / absenteeism plus presenteeism) 4. Activity Impairment. Each score ranges from 0 to 100, with higher numbers indicating greater impairment and less productivity | Up to Week 52 | 
| Number of Participants with Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | An adverse event (AE) is any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. A TEAE is an AE that started or worsened in severity after the first dose of study treatment through 28 days after the last dose of study treatment or end of study (EOS) date, whichever comes earlier. An SAE is any untoward medical occurrence that at any dose results in death (a life-threatening event), in the view of the investigator, places the participant at immediate risk of death, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, results in a birth defect, or is a medically important event. | Up to Week 52 | 
| Number of Participants with Antibodies to BIIB059 |  | Up to Week 52 | 

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