CTRI/2023/11/059398招募中3 期
A Phase 2b/3, Multi-part, Randomized, Double-Blinded, Placebo-Controlled Study to Evaluate the Efficacy and Safety of Atacicept in Subjects with IgA Nephropathy (IgAN)
试验速览
- 阶段
- 3 期
- 状态
- 招募中
- 入组人数
- 376
- 试验地点
- 21
- 主要终点
- Evaluate the effect of atacicept compared to placebo on change in proteinuria in adult subjects with IgAN
研究概览
简要总结
This Phase 3 study will evaluate the efficacy and safety of the planned commercial dose of atacicept (150 mg) compared to placebo in reducing proteinuria in subjects with IgAN and persistent proteinuria despite being on a maximally tolerated dose (MTD) of a RASi. High risk of progression in IgAN is currently defined as proteinuria >0.75-1 g/d despite optimized supportive care (International Society of Nephrology 2021).
Atacicept is capable of binding to all known conformations of BLyS and APRIL and is thus expected to inhibit the maturation, differentiation, and effector function of B cells. These mechanisms are consistent with the known pharmacological effects of atacicept, which include depletion of peripheral B cell subsets, naïve follicular, marginal zone and long lived plasma cell B cell subsets, impeded germinal center reaction, and reduced immunoglobulins, while leaving immature B cells and memory B cells intact (Dillon 2006, Dillon 2010, Gross 2001, Moore 1999, Schneider 1999, Schneider 2005). These effects are predicted to reduce the production and subsequent deposition of Gd-IgA1-containing immune complexes in kidney glomeruli, and thus reduce the extent of kidney injury in IgAN patients.
This is a multi-part study comprising of the original Phase 2b study and the addition of a separate Phase 3 study. A Phase 3 study (i.e., Parts C and D) has been added as a separate component of the existing study to obtain study operational efficiency by keeping the original sites activated and modifying existing study systems and plans. The results from the Phase 2b parts have been used to determine the dose selection and sample size for the Phase 3 study design.
The Phase 3 study is a multicenter, randomized, double-blind, placebo-controlled trial. In Part C, subjects will be randomized 1:1 to atacicept 150 mg or placebo for 104 weeks:
• Atacicept 150 mg once weekly subcutaneous (SC) injections (N=188)
• Placebo once weekly subcutaneous (SC) injections (N=188)
Followed by a 52-week open-label extension (Part D) in which subjects will be given 150 mg atacicept once weekly subcutaneous (SC) injections.
研究设计
- 研究类型
- Interventional
- 分配方式
- Stratified block randomization
- 盲法
- Double Blind Double Dummy
入排标准
- 年龄范围
- 18.00 Year(s) 至 99.00 Year(s)（—）
- 性别
- All
入选标准
- •Must have the ability to understand and sign a written informed consent form, which must be obtained prior to initiation of study assessments.
- •Adult male or female of ≥18 years of age and ≤70 years, or as per country specific legally or nationally recognized adult age, who provide written informed consent prior to performing any study assessments.
- •Diagnosis of IgAN as demonstrated by renal biopsy conducted within 10 years of the Screening Visit.
- •Total urine protein excretion ≥1.0 g per 24-hour or urine protein to creatinine ratio (UPCR) ≥1.0 mg/mg based on a 24-hour urine sample during the Screening Period
- •eGFR ≥30 mL/min/1.73 m2 at screening, as per the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation.
- •On a stable prescribed regimen of RASi (ACEi or ARB) for at least 12 weeks that is at the maximum labeled or tolerated dose at screening and from screening to study Day
- •a.The subject is eligible if they do not tolerate RASi, provided their management of IgAN is standard of care (SoThe subject is eligible if they do not tolerate RASi, provided their management of IgAN is standard of care (SoC) per local practice.
- •This intolerance must be documented by the Investigator and discussed with the medical monitor.
- •Systolic blood pressure ≤150 mmHg and diastolic blood pressure ≤90 mmHg at screening
- •A female is eligible if she is not pregnant (i.e., after a confirmed menstrual period, a negative serum pregnancy test at screening and negative urine pregnancy test at Day 1), not breastfeeding (for at least 3 months prior to screening), and at least one of the following conditions applies: a.
- •Is not a woman of childbearing potential (WOCBP) b.
- •Is a WOCBP who agrees to use a highly effective contraceptive method (i.e., has a failure rate of less than 1% per year), at least 7 days prior to randomization, through 175 days after the last dose of study drug.
排除标准
- •Participation in the Phase 2b (Parts A and B) study or any previous treatment with atacicept
- •IgAN secondary to another condition (e.g., liver cirrhosis), or other causes of mesangial IgA deposition including IgA vasculitis (i.e., Henoch-Schonlein purpura), systemic lupus erythematosus (SLE), dermatitis herpetiformis, ankylosing spondylitis
- •Evidence of rapidly progressive glomerulonephritis (loss of ≥ 50% of eGFR within 3 months of screening)
- •Evidence of nephrotic syndrome within 6 months of screening (serum albumin <30g/L in association with UPCR >3.5 mg/mg)
- •Renal or other organ transplantation prior to, or expected during, the study, with the exception of corneal transplants.
- •Concomitant chronic renal disease in addition to IgAN (e.g., diabetic nephropathy, primary focal segmental glomerulosclerosis (FSGS), membranous nephropathy, C3 glomerulopathy, lupus nephritis)
- •Uncontrolled diabetes, defined as hemoglobin-A1c (HbA1c) >7.5% at screening
- •History of tuberculosis (TB), untreated latent TB infection (LTBI), or evidence of active TB determined by a positive Quantiferon test at the Screening Visit.
- •If the subject is undergoing current treatment for LTBI, they must have received at least 4 continuous weeks of an appropriate LTBI treatment prior to the Screening Visit without evidence of re-exposure to be eligible for this study.
- •If on LTBI treatment at the Screening Visit, the subject will be expected to complete an appropriate LTBI treatment regimen to remain in the trial.
- •Subjects with current household contacts with active TB will be excluded unless prophylaxis treatment has been completed, and evidence that household contacts have completed treatment is provided.
- •Indeterminate Quantiferon tests may be repeated once by the same test and will be considered positive if retest results are positive or indeterminate.
- •Prohibited medications: Use of systemic corticosteroids (including oral budesonide) for the treatment of IgAN within 6 months prior to screening, from screening to Day 1 or expected use during the study.
- •â€¢ For glucocorticosteroids (GCS), “Systemic†is defined as oral, rectal or injectable (intravenous or intramuscular) routes of administration.
- •Other routes of administration are allowed, including intra-articular, inhaled, topical, ophthalmic, otic and intranasal.For non-IgAN indications (e.g., gout flare, exacerbation of asthma, severe rash, etc.): − Within 12 weeks prior to randomization: Use of systemic corticosteroids or immunosuppressive medications for >1 week or average dose >0.5 mg/kg/day prednisolone or equivalent • Immunosuppressive medications (e.g., MMF, azathioprine, cyclophosphamide, hydroxychloroquine) for the treatment of IgAN within 12 weeks prior to screening, from screening to Day1 or expected use during the study.
- •â€¢ Use of traditional Chinese medications and/or Ayurvedic medications within 12 weeks prior to screening or from screening to Day 1 • Use of B-cell–directed biologic therapies including but not limited to belimumab, rituximab, ocrelizumab for any period of time • Use of other biologics (e.g., anti-TNF, abatacept, anti-IL-6) and investigational biologics for any period of time • Use of endothelin receptor antagonists (ERAs) for any period of time
- •Clinically significant or predefined abnormalities per central laboratory tests, at the Screening Visit, meeting any of the criteria below: • serum IgG below 7 g/L • aspartate aminotransferase, alanine aminotransferase or alkaline phosphatase level >2.5 × upper limit of normal (ULN) or total bilirubin >1.5 x ULN.
- •If subject has a known history of Gilberts (history of isolated increase in total bilirubin without increase in liver transaminases), contact the Medical Monitor for further discussion.
- •â€¢ hemoglobin <10 g/100 mL in men and hemoglobin <9 g/100 mL in women • platelets <100,000/L mm3
- •Administration of live and live-attenuated vaccinations within 30 days prior to randomization
- •History or current diagnosis of any demyelinating disease such as, but not restricted to, multiple sclerosis (MS) or optic neuritis (ON)
- •Patients with history of unstable angina, Class III and IV congestive heart failure and/or clinically significant arrhythmia, as judged by the Investigator.
- •Any condition, including any uncontrolled disease state other than IgAN, that in the opinion of the Investigator or the Sponsor/designee constitutes an inappropriate risk or a contraindication for participation in the study or that could interfere with the study objectives, conduct or evaluation
- •Active clinically significant viral, bacterial or fungal infection, or any major episode of infection requiring hospitalization or treatment with parenteral anti-infectives within 4 weeks prior to, or during the Screening Visit, or completion of oral anti-infectives within 2 weeks prior to, or during the Screening Visit or a history of recurrent infections (i.e., 3 or more of the same type of infection in a 12-month rolling period).
- •Vaginal candidiasis, onychomycosis and genital or oral herpes simplex virus considered by the Investigator to be sufficiently controlled are not exclusionary.
- •â€¢ Subjects with positive hepatitis B surface antigen (HBsAg) are excluded • Subjects who are HBsAg negative, hepatitis B core antibody (HBcAb) positive, hepatitis B surface antibody (HBsAb) positive with no detectable hepatitis B virus (HBV) DNA are eligible but will require monthly HBV DNA monitoring through safety follow-up
- •History of splenectomy
- •History of malignancy (hematologic or solid tumor) within 5 years prior to Screening Visit, except adequately treated basal cell or squamous cell carcinomas of the skin (no more than 3 lesions requiring treatment in lifetime) or carcinoma in situ/cervical intraepithelial neoplasia of the uterine cervix.
- •Known hypersensitivity to atacicept or any component of the formulated atacicept
- •Major surgery within 6 weeks prior to the Screening Visit or planned/expected major surgery during the study period (including the Safety Follow-up Period) • Major surgery often involves opening one of the major body cavities (abdomen, chest, and skull) and/or use of general anesthesia.
- •Types of surgery that have the highest risk include heart or lung, liver, abdomen, or major operations on the bones and joints (for example, hip replacement)
- •Clinically significant history of alcohol or drug abuse in the 1 year prior to the Screening Visit as per Investigator opinion
- •Unwillingness or lack of capacity to follow all study procedures
- •Treatment with other investigational agents within the last 4 weeks or 5 half-lives, whichever is longer, prior to the Screening Visit.
结局指标
主要结局
Evaluate the effect of atacicept compared to placebo on change in proteinuria in adult subjects with IgAN
时间窗: 36 weeks
次要结局
- Evaluate the effect of atacicept on annualized rate of change in estimated glomerular filtration rate (eGFR)(Through Week 104)
研究者
研究点 (21)
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