Phase 3 Study to Evaluate BIIB059 in Active SLE (TOPAZ-II Study)

JRCT ID: jRCT2071210089

Registered date:01/11/2021

Basic Information

• Recruitment status: Recruiting
• Health condition(s) or Problem(s) studied: Systemic Lupus Erythematosus
• Date of first enrollment: 28/02/2022
• Target sample size: 540
• Countries of recruitment: United States,Japan,Canada,Japan,Colombia,Japan,Puerto Rico,Japan,Argentina,Japan,United Kingdom,Japan,Israel,Japan,Italy,Japan,Netherlands,Japan,Serbia,Japan,Czech,Japan,Germany,Japan,Hungary,Japan,Belgium,Japan,Romania,Japan,China,Japan
• Study type: Interventional

Intervention(s)

This is a multicenter, randomized, double-blind, placebo-controlled, Phase 3 study designed to evaluate the efficacy and safety of BIIB059 in participants >= 18 years of age with active SLE, including joint and/or skin manifestations, who are receiving background nonbiologic lupus SOC therapy. The study will be conducted at approximately 135 sites globally. Approximately 540 participants will be randomized 1:1:1 to receive BIIB059 450 mg, BIIB059 225 mg, or placebo SC Q4W, with an additional dose at Week 2, as add-on to background nonbiologic lupus SOC therapy.
The study includes a screening period of up to 4 weeks; a double-blind, placebo-controlled treatment period of 52 weeks; and an SFU period (off-treatment) of 24 weeks.

Outcome(s)

Primary Outcome

Proportion of participants who achieved an SRI-4 response at Week 52.
The composite endpoint SRI-4 is defined by the following criteria:
-A reduction from Baseline of >= 4 points in SLEDAI-2K

-No new organ system affected, as defined by no new organ system with 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 changes to protocol-specified medication rules.

Secondary Outcome

-Proportion of participants who achieved an SRI-4 response at Week 24.

-Proportion of participants with at least 4 joints (both swollen and tender) at Baseline who achieved a Joint-50 response at Week 52. A joint is defined as a joint that is both swollen and tender. Joint-50 is defined as at least 50% reduction in total active joint count from Baseline based on the 28-joint count assessment.

-Proportion of participants with OCS >= 10 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.

-Proportion of participants with a CLASI-A score >= 10 at Baseline who achieved a CLASI-50 response at Week 16. CLASI-A scores of 0 to 9, 10 to 20, and 21 to 70 represent disease severity of mild, moderate, and severe, respectively.

-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.

-Change from Baseline in PGA-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.

-Proportion of participants who achieved a BICLA response by visit.
The BILAG Disease Activity Index is an instrument that evaluates SLE activity in a number of organ systems, a separate alphabetic score is assigned to each organ system, the following definitions:
-BILAG-2004 grade A: severe disease activity
-BILAG-2004 grade B: moderate disease activity
-BILAG-2004 grade C: mild disease.
-BILAG-2004 grade D: system previously affected but now inactive.
-BILAG-2004 grade E: system never involved.
BICLA is a composite endpoint defined as follows: 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 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; No change to protocol-specified medication rules.

-Time to onset of SRI-4 response sustained through Week 52.

-Proportion of participants who achieved SRI-4, -5, or -6 response by visit.

-Proportion of participants with Joint-50 response by visit.

-Proportion of participants with baseline CLASI-A score >= 10 who achieved a CLASI-20, -50, -70, or -90 response by visit.

-Proportion of participants with baseline CLASI-A score >= 10 who achieved a CLASI-A score of <= 1 by visit.

-Time to first BILAG-2004 severe flare, where severe flare is defined using BILAG definition.

-The 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.

-Time to first severe SFI flare during the double-blind, placebo-controlled treatment period, where severe flare is defined using the SFI definition. A severe flare is defined as any of the following:
-Change in SLEDAI instrument score to > 12
-New or worse: central nervous system SLE; vasculitis; nephritis; myositis; platelets < 60,000/mL; or hemolytic anemia with hemoglobin < 7 g/dL or decrease in hemoglobin > 3 g/dL AND requiring: doubling prednisone dose, increase to > 0.5 mg/kg/day or hospitalization
-Increase in prednisone dose to > 0.5 mg/kg/day
-New requirement for cyclophosphamide, azathioprine, methotrexate, or mycophenolate for SLE activity
-Hospitalization for SLE activity
-Increase in PGA score to < 2.5

-Proportion of participants with baseline OCS >= 10 mg/day who achieved <= 7.5 mg/day at Week 52.

-To assess the difference between BIIB059 and placebo in HRQoL, symptoms, and impacts on SLE by LupusQOL, SF-36, FACIT-fatigue, PHQ-9 and WAPAI.
-The LupusQoL is a participant-reported, lupus-specific, HRQoL questionnaire consisting of 34 items grouped in 8 domains: 1. physical health 2. pain 3. planning 4. intimate relationships 5. burden to others 6. emotional health 7. body image 8. 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.
-The SF-36 is a participant-administered 36-item scale constructed to survey HRQoL in 8 domains:
1. Limitations in physical activities due to health problems 2. Limitations in social activities due to physical or emotional problems 3. Limitations in usual role activities due to physical health problems 4. Bodily pain
5. General mental health 6. Limitations in usual role activities due to emotional problems 7. Vitality 8. General health perceptions
The interval level scoring for all 8 scales ranges from 0 (for worse health) to 100 (best possible health as measured by the questionnaire)
-The FACIT-Fatigue is a participant-administered HRQoL questionnaire that evaluates participant's fatigue in the 5 broad categories: 1. physical well-being 2. social/family well-being 3. emotional well-being 4. functional well-being 5. 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 PHQ-9 is a participant-administered HRQoL questionnaire to screen for the presence and severity of depression. The PHQ-9 is a PRO that is used to measure depression in adults. Itcontains 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.
-The WPAI questionnaire is a PRO that is used to measure lost productivity, including work productivity. Higher scores indicate greater impairment and less productivity.

-Incidence of TEAEs and SAEs.
An 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 EOS date, whichever comes earlier. An SAE is any untoward medical occurrence that at any dose:
-Results in death.
-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.
-Is a medically important event.

-Incidence of antibodies to BIIB059.

Key inclusion & exclusion criteria

• Age minimum: >= 18age old
• Age maximum: Not applicable
• Gender: Both

Include criteria

-Participant must be diagnosed with SLE at least 24 weeks prior to screening and must meet the 2019 EULAR/ACR classification criteria for SLE, at screening by a qualified physician.

-Participant has a modified 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 C3 and/or 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.

-Participants 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 immunosuppressant
-Treatment with OCS and/or immunosuppressants

Exclude criteria

-History of or positive test result for HIV.

-Current hepatitis C infection (defined as positive HCV antibody and detectable HCV RNA).

-Current hepatitis B infection (defined as positive for HBsAg and/or total 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, 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 mL/min/1.73 m^2) calculated using the abbreviated Modification of Diet in Renal Disease equation.

-Any active skin conditions other than 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.

-Use of oral prednisone (or equivalent) above 20 mg/day.

Related Information

• Primary Sponsor: Cho Kyo
• Secondary ID(s): NCT04961567