A Placebo-controlled, Patient and Investigator Blinded, Randomized Parallel Cohort Study to Assess Pharmacodynamics, Pharmacokinetics, Safety, Tolerability and Preliminary Clinical Efficacy of VAY736 and CFZ533 in Patients With Systemic Lupus Erythematosus (SLE)
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 107
- 试验地点
- 32
- 主要终点
- Percentage of Participants With SLE Responder Index (SRI)-4 Response Status at Week 29 With Reduced Steroid Dose Maintained Between Weeks 17 and 29
研究概览
简要总结
This study is designed to evaluate the safety, tolerability, pharmacokinetics and therapeutic efficacy of treatment with either VAY736 (ianalumab) or CFZ533 (iscalimab) in patients with systemic lupus erythematosus (SLE) to enable further development of these compounds as treatment in this disease population
详细描述
The study consisted of a 28-day screening period, a blinded treatment period of 28 weeks where randomized patients received treatment with investigational drug (ianalumab or iscalimab) or placebo. At the end of Week 29 visit, the patients entered the open-label treatment phase where patients in active treatment group continued to receive active treatment and patients in placebo group started active treatment with ianalumab/iscalimab until Week 49. After completion of the open-label treatment period, all patients entered a Follow-Up period in order to monitor safety and efficacy up to Week 69. The Week 69 visit was the End of Study (EoS) visit for patients in Cohort 2 (CFZ533). Study duration for patients in Cohort 2 was approximately 18 months. For Cohort 1 (VAY736), patients who did not achieve B-cell recovery by Week 69 Visit entered into a Secondary Follow-Up period until achieving B cell recovery criteria (B-cell count was at >= 50 cells/µl or at least 80% of baseline levels). Safety follow-up visits were scheduled as deemed appropriate until the patient achieved the B-cell recovery criteria, followed by an EoS 4 weeks later.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Triple (Participant, Investigator, Outcomes Assessor)
盲法说明
Patients, investigator staff, persons performing the assessments, and the clinical trial team (CTT) remained blind to the identity of the treatment within each cohort from the time of randomization until end of the Week 29 visit.
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Written informed consent must be obtained before any assessment is performed
- •Fulfill ≥4 of the 11 American College of Rheumatology 1997 classification criteria for SLE
- •Patient diagnosed with SLE for at least 6 months prior to screening
- •Elevated serum titers at screening of ANA (≥1:80) of a pattern consistent with an SLE diagnosis, including at a minimum either anti-double stranded DNA (anti-ds DNA) or anti-Ro (SSA) or anti-La (SSB) or anti-nuclear ribonucleoprotein (anti-RNP) or anti-Smith (anti-Sm)
- •Currently receiving corticosteroids and/or anti-malarial and/or thalidomide treatment and/or another DMARD on a stable dose according to protocol requirements
- •SLEDAI-2K score of ≥6 at screening
- •BILAG 2004 score of one "A" score either in the mucocutaneous or in the musculoskeletal domain or one "B" score in either the mucocutaneous or musculoskeletal domain and at least one "A" or "B" score in a second domain at screening
- •Weigh at least 40 kg at screening
排除标准
- •Cohort 2 (CFZ533/Placebo) only:
- •Patients who are at significant risk for thromboembolic events based on the following:
- •History of either thrombosis or 3 or more spontaneous abortions
- •Presence of lupus anticoagulant or significantly prolonged activated partial thromboplastin time (aPTT) consistent with co-existent anti-phospholipid syndrome and without concurrent prophylactic treatment with aspirin or anticoagulants as per local standard of care
- •All Cohorts:
- •History of receiving prior to screening:
- •Within 12 weeks: i.v. corticosteroids, calcineurin inhibitors or other oral DMARD
- •Within 24 weeks: cyclophosphamide or biologics such as intravenous Ig, plasmapheresis, anti-TNF-a mAb, CTLA4-Fc Ig (abatacept) or BAFF targeting agents (e.g., belimumab)
- •Any B-cell depleting therapies (e.g., anti-CD20 mAb, anti-CD22 mAb, anti-CD52 mAb) or TACI-Ig (atacicept) administered within 52 weeks prior to screening, and a B-cell count <50 cells/μ at the time of screening
- •Evidence of past exposure to tuberculosis as assessed by Quantiferon testing at screening
- •Presence of human immunodeficiency virus (HIV) infection at screening
- •Severe organ dysfunction or life threatening disease; ECOG performance status > 1 at screening
- •Presence of WHO Class III-IV renal involvement with proliferative disease Presence of severe lupus kidney disease as defined by proteinuria above 6 g/day or equivalent using spot urine protein creatinine ratio, or serum creatinine greater than 2.5 mg/dL (221.05 μmol/L), or requiring immune suppressive induction or maintenance treatment exceeding protocol defined limits
- •Active viral, bacterial or other infections at the time of screening or enrollment
- •Receipt of live/attenuated vaccine within a 2-month period before first dosing
- •Uncontrolled, co-existing serious disease, e.g., uncontrolled hypertension, heart failure, type I diabetes, thyroid disease within 3 months prior to first dosing, or significant, unresolved illness within 2 weeks prior to first dosing
- •History of hypersensitivity to drugs of similar chemical class
- •Chronic infection with hepatitis B (HBV) or hepatitis C (HCV). Subjects who are HBsAg negative and HBcAb positive are excluded unless negative for HBV DNA. Once past screening and enrolled into study, requirements for monitoring and antiviral treatment are enacted.
- •Subjects with a positive HCV antibody test should have HCV RNA levels measured. Subjects with positive (detectable) HCV RNA should be excluded.
研究组 & 干预措施
Cohort 1 VAY736
Blinded treatment phase:
VAY736 administered subcutaneously (s.c.) every 4 weeks as multiple doses of VAY736 150 mg (total dose being VAY736 300 mg) until Week 25 + Standard of Care (SoC) for systemic lupus erythematosus (SLE).
Open-label treatment phase:
VAY736 administered subcutaneously (s.c.) every 4 weeks as multiple doses of VAY736 150 mg (total dose being VAY736 300 mg) until Week 49.
干预措施: VAY736 (Drug)
Cohort 1 VAY736 Placebo
Blinded treatment phase:
VAY736 matching placebo administered subcutaneously (s.c.) every 4 weeks as multiple doses of placebo 0 mg until Week 25 + Standard of Care (SoC) for systemic lupus erythematosus (SLE).
Open-label treatment phase:
VAY736 administered subcutaneously (s.c.) every 4 weeks as multiple doses of VAY736 150 mg (total dose being VAY736 300 mg) until Week 49.
干预措施: VAY736 Placebo (Drug)
Cohort 2 CFZ533 Placebo
Blinded treatment phase:
CFZ533 matching placebo administered intravenously (i.v) every 4 weeks as multiple doses of placebo 0 mg, based on body weight (BW) of the patients (10 mg/kg (>= 50 kg BW) and 13 mg/kg (< 50 kg BW)) until Week 25 + Standard of Care (SoC) for systemic lupus erythematosus (SLE).
Open-label phase:
CFZ533 administered intravenously (i.v) every 4 weeks as multiple doses of CFZ533 150 mg, based on body weight (BW) of the patients (10 mg/kg (>= 50 kg BW) and 13 mg/kg (< 50 kg BW)) until Week 49.
干预措施: CFZ533 Placebo (Drug)
Cohort 1 VAY736 Placebo
Blinded treatment phase:
VAY736 matching placebo administered subcutaneously (s.c.) every 4 weeks as multiple doses of placebo 0 mg until Week 25 + Standard of Care (SoC) for systemic lupus erythematosus (SLE).
Open-label treatment phase:
VAY736 administered subcutaneously (s.c.) every 4 weeks as multiple doses of VAY736 150 mg (total dose being VAY736 300 mg) until Week 49.
干预措施: VAY736 (Drug)
Cohort 2 CFZ533
Blinded treatment phase:
CFZ533 administered intravenously (i.v) every 4 weeks as multiple doses of CFZ533 150 mg, based on body weight (BW) of the patients (10 mg/kg (>= 50 kg BW) and 13 mg/kg (< 50 kg BW)) until Week 25 + Standard of Care (SoC) for systemic lupus erythematosus (SLE).
Open-label phase:
CFZ533 administered intravenously (i.v) every 4 weeks as multiple doses of CFZ533 150 mg, based on body weight (BW) of the patients (10 mg/kg (>= 50 kg BW) and 13 mg/kg (< 50 kg BW)) until Week 49.
干预措施: CFZ533 (Drug)
Cohort 2 CFZ533 Placebo
Blinded treatment phase:
CFZ533 matching placebo administered intravenously (i.v) every 4 weeks as multiple doses of placebo 0 mg, based on body weight (BW) of the patients (10 mg/kg (>= 50 kg BW) and 13 mg/kg (< 50 kg BW)) until Week 25 + Standard of Care (SoC) for systemic lupus erythematosus (SLE).
Open-label phase:
CFZ533 administered intravenously (i.v) every 4 weeks as multiple doses of CFZ533 150 mg, based on body weight (BW) of the patients (10 mg/kg (>= 50 kg BW) and 13 mg/kg (< 50 kg BW)) until Week 49.
干预措施: CFZ533 (Drug)
结局指标
主要结局
Percentage of Participants With SLE Responder Index (SRI)-4 Response Status at Week 29 With Reduced Steroid Dose Maintained Between Weeks 17 and 29
时间窗: Baseline, Week 17 to Week 29
The primary endpoint was a composite of SRI-4 response at Week 29 with sustained reduction in oral corticosteroid from Week 17 through Week 29. Patients taking other rescue medication or prohibited medication or drop out before Week 29 were considered non-responders. SRI-4 response is defined as below: * having \>= 4 points reduction from baseline in Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) score (score is 0 to 105; a higher score indicating more severe disease) AND * no new British Isles Lupus Activity Group (BILAG)-2004 A organ domain score and no more than one new BILAG-2004 B organ domain scores compared with baseline AND * \<10 mm point increase from baseline with scale 0 to 100 mm in the physician's global assessment from baseline Sustained reduction in oral corticosteroid is defined as below: * =\< 5 mg/day or less than or equal to baseline dose, whichever was lower at Week 17 AND * no increase of that dose from Week 17 through Week 29
次要结局
- Flare Rate and Time to First Flare(18 months)
- PK Cohort 2 - Cmax,ss(18 months)
- Time to First Flare(18 months)
- PK Cohort 1 - Ctrough,ss(18+ months)
- Changes Between Baseline and Week 29 in the Physicians' Global Assessment (PhGA) Visual Analog Scale (VAS) Assessing Patient's Overall Disease Activity(Baseline, Week 5, Week 9, Week 13, Week 17, Week 21, Week 25, Week 29)
- PK Cohort 1 - Cmax,ss(18+ months)
- Changes Between Baseline and Week 29 in the Patient's Global Assessment (PGA) Visual Analog Scale (VAS) Assessing Patient's Global Disease Activity(Baseline, Week 5, Week 9, Week 13, Week 17, Week 21, Week 25, Week 29)
- PD Cohort 2 (CFZ533): Total Soluble CD40(18 months)
- PK Cohort 2 - Ctrough,ss(18 months)