2023-503772-24-00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
- 216
- 试验地点
- 57
- 主要终点
- Phase 2b_01. Urine protein to creatinine ratio (UPCR) week 24. Phase 3_01. Urine protein to creatinine ratio (UPCR) week 36
研究概览
简要总结
Phase 2b and Phase 3: Evaluate the effect of atacicept compared to placebo on change in proteinuria in adult subjects with IgAN
入排标准
- 年龄范围
- 18 years 至 65+ years（65+ Years, 18-64 Years）
- 接受健康志愿者
- 是
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, 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 1 • The 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: • Is not a woman of childbearing potential (WOCBP). OR • Is a WOCBP who agrees to use a highly effective contraceptive method (i.e., has a failure rate of less than 1% per year), as listed in Appendix 2, at least 7 days prior to randomization through 175 days after the last dose of study drug. See Appendix 2 for further details.
- •Adult male or female of ≥18 years of age, or as per country specific legally or nationally recognized adult age, who provide written informed consent prior to performing any study assessments. For the Czech Republic an age limit of ≤70 also applies
- •Diagnosis of IgAN as demonstrated by renal biopsy conducted within 10 years of the Screening Visit
- •Total urine protein excretion > 0.75g per 24-hour or UPCR > 0.75 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 RAASi for at least 12 weeks that is at the maximum labeled or tolerated dose at screening. • The subject is eligible if they do not tolerate RAASi, provided their management of IgAN is SoC according to local guidelines. This must be documented by the Investigator.
- •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: • Is not a woman of childbearing potential (WOCBP). OR • Is a WOCBP who agrees to use a highly effective contraceptive method (i.e., has a failure rate of less than 1% per year), as listed in Appendix 2, at least 7 days prior to randomization through 175 days after the last dose of study drug. See Appendix 2 for further details.
- •Must have the ability to understand and sign a written informed consent form, which must be obtained prior to initiation of study assessments
排除标准
- •IgAN secondary to another condition (e.g., liver cirrhosis), or other causes of mesangial IgA deposition including IgA vasculitis (i.e., Henoch-Schonlein purpura), SLE, dermatitis herpetiformis, ankylosing spondylitis
- •Total urine protein excretion ≥ 5g per 24-hour or urine protein to creatinine ratio (UPCR) ≥ 5 mg/mg based on a 24-hour urine sample during Screening
- •Renal or other organ transplantation prior to, or expected during, the study with the exception of corneal transplants
- •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. i. 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. • For The Czech Republic only, the following criteria also apply: - hemoglobin <10 g/100 mL in men and hemoglobin <9 g/100 mL in women - platelets <100,000/mm3
- •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.
- •Prohibited medications: • Use of systemic corticosteroids or immunosuppressive medications (e.g., MMF, azathioprine, cyclophosphamide, hydroxychloroquine) for the treatment of IgAN within 3 months prior to screening or expected use during the study. • For non-IgAN indications (e.g., gout flare, exacerbation of asthma, severe rash, etc): • Within 3 months prior to randomization: Use of systemic corticosteroids or immunosuppressive medications for > 1 week or 0.5 mg/kg/day prednisolone or equivalent • Use of B-cell–directed biologic therapies including blisibimod, belimumab, rituximab, ocrelizumab for any period of time • Use of other biologics (e.g., anti-TNF, abatacept, anti-IL-6) and investigational biologics
- •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)
- •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. *For Germany only the following criteria apply: History of malignancy within the past 5 years prior to Screening (except for adequately treated basal cell carcinoma or non-metastatic squamous cell carcinoma of the skin or cervical carcinoma in situ, with no evidence of recurrence).
- •Total urine protein excretion ≥5g per 24-hour or urine protein to creatinine ratio (UPCR) ≥5 mg/mg based on a 24-hour urine sample during the Screening Period
- •Evidence of nephrotic syndrome within 6 months of screening (serum albumin <3.0 g/dL 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
- •Administration of live and live-attenuated vaccinations within 30 days prior to randomization
- •Concomitant chronic renal disease in addition to IgAN (e.g., diabetic nephropathy, primary focal segmental glomerulosclerosis (FSGS), membranous nephropathy, C3 glomerulopathy, lupus nephritis)
- •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. *For Germany only, the following criteria also apply: Specifically for COVID-19: Evidence of positive test for SARS-CoV-2, by PCR, at the Screening Visit; Subjects with a previous COVID-19 infection may be included provided the PCR test is negative for SARS-CoV-2 and they do not have chronic symptoms as a result of COVID-
- •COVID-19 testing may be performed at local lab, per site/local guidelines.
- •History of acute or chronic infection with human immunodeficiency virus, hepatitis C virus, or hepatitis B virus. Positive hepatitis B surface antigen (HBsAg): Subjects who are HBsAg negative and hepatitis B core antibody (HBcAb) positive with no detectable hepatitis B virus (HBV) DNA are eligible but will require monthly HBV DNA monitoring through safety follow-up.
- •Known hypersensitivity to atacicept or any component of the formulated atacicept
- •History of splenectomy
- •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. - 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 Day 1 or expected use during the study. • Use of traditional Chinese medications and/or Ayurvedic medications for IgAN within 12 weeks prior to screening, from screening to Day 1, or during the study period. - Including but not limited to: Lei Gong Teng, Tripterygium Wilfordii Hook F, Caulis sinomenii, and Sinomenium acutum. Any other medications used to treat IgAN that are not listed should be discussed with the Medical Monitor. • 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 • Use of complement inhibitors including but not limited to iptacopan 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. i. 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. • hemoglobin <10 g/100 mL in men and hemoglobin <9 g/100 mL in women • platelets <100 10^9/L
- •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. Specifically for COVID-19: Evidence of positive test for SARS-CoV-2, by PCR, at the Screening Visit; Subjects with a previous COVID-19 infection may be included provided the PCR test is negative for SARS-CoV-2 and they do not have chronic symptoms as a result of COVID-
- •COVID-19 testing may be performed at local lab, per site/local guidelines.
- •Evidence of rapidly progressive glomerulonephritis (loss of ≥ 50% of eGFR within 3 months of screening
- •History of acute or chronic infection with human immunodeficiency virus, or hepatitis B virus. • 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, and with no detectable hepatitis B virus (HBV) DNA are eligible but will require monthly HBV DNA monitoring through safety follow-up
- •Subjects with positive hepatitis C (HCV) RNA are excluded, however, subjects who are HCV antibody positive with no detectable HCV RNA at least 24 weeks after completion of antiviral therapy are eligible.
- •History of splenectomy
- •History of malignancy within the past 5 years prior to Screening (except for adequately treated basal cell carcinoma or non-metastatic squamous cell carcinoma of the skin or cervical carcinoma in situ, with no evidence of recurrence).
- •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 FU 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.
- •Major surgery within 6 weeks prior to the Screening Visit or planned/expected major surgery during the study period
- •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.
- •Evidence of nephrotic syndrome within 6 months of screening (serum albumin < 30g/L in association with UPCR >3.5 mg/mg
结局指标
主要结局
Phase 2b_01. Urine protein to creatinine ratio (UPCR) week 24. Phase 3_01. Urine protein to creatinine ratio (UPCR) week 36
Phase 2b_01. Urine protein to creatinine ratio (UPCR) week 24. Phase 3_01. Urine protein to creatinine ratio (UPCR) week 36
Phase 3_01. Urine protein to creatinine ratio (UPCR) week 36
Phase 3_01. Urine protein to creatinine ratio (UPCR) week 36
次要结局
- Phase 2b_01. Urine protein to creatinine ratio (UPCR) week 36. Phase 3_01. Annualized Rate of change in eGFR (ie., annualized eGFR total slope) week 104
- Phase 3_01. Annualized Rate of change in eGFR (ie., annualized eGFR total slope) week 104
研究者
Regulatory
Scientific
Vera Therapeutics Inc.
研究点 (57)
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