A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Safety, Efficacy, Pharmacodynamics, and Pharmacokinetics of Lademirsen (SAR339375) for Subcutaneous Injection Administered Every Week in Patients With Alport Syndrome
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 发起方
- 入组人数
- 43
- 试验地点
- 23
- 主要终点
- Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)
研究概览
简要总结
Primary Objectives:
- To assess the efficacy of lademirsen (SAR339375) in reducing the decline in renal function.
- To assess the safety and tolerability of lademirsen (SAR339375) in participants with Alport syndrome.
Secondary Objectives:
- To assess plasma pharmacokinetic (PK) parameters of the parent compound and its active major metabolite.
- To assess the potential formation of anti-drug antibodies (ADAs) following administration of lademirsen (SAR339375).
- To assess the pharmacodynamic effect of lademirsen (SAR339375) on miR-21 and on changes in renal injury and function biomarkers.
详细描述
The planned length of participation in the study for each participant was up to approximately 110 weeks (from screening through completion of follow-up). This included:
- Screening/baseline period of up to 4 weeks
- Double-blind, placebo-controlled treatment period of 48 weeks
- Open-label extension treatment period of 48 weeks (all participant to enter a 48-week open label extension period and receive active treatment with lademirsen [SAR339375]).
- Post-treatment follow-up period of 10 weeks.
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, Care Provider, Investigator)
入排标准
- 年龄范围
- 18 Years 至 55 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- 未提供
排除标准
- 未提供
研究组 & 干预措施
Placebo/Lademirsen
Participants received subcutaneous (SC) doses of placebo (matched to lademirsen) every week (QW) during the 48 weeks of double blind (DB) treatment period. Participants who received placebo and completed DB treatment period entered in open-label extension (OLE) treatment period and received lademirsen at a dose of 110 milligrams (mg) QW for an additional 48 weeks (i.e., up to Week 96).
干预措施: lademirsen (SAR339375) (Drug)
Lademirsen/Lademirsen
Participants received SC doses of lademirsen 110 mg QW during the 48 weeks of DB treatment period. Participants who completed DB treatment period entered in OLE treatment period and continued the same lademirsen treatment in OLE period for an additional 48 weeks (i.e., up to Week 96).
干预措施: Placebo (Drug)
结局指标
主要结局
Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)
时间窗: DB: from 1st dose of IMP upto 1st dose of IMP in OLE for participant who entered OLE (Week 48); up to 7 days post last dose for participant not continuing to OLE (Week 49); OLE:1st dose of IMP (at Week 48) in OLE upto 10 weeks post last dose (Week 106)
Adverse event (AE): any untoward medical occurrence in a participant who received study drug and did not necessarily had to have a causal relationship with the treatment. Serious adverse event (SAE) was any untoward medical occurrence that at any dose: resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect, was a medically important event. TEAEs: AEs with onset after the first dose of investigational medicinal product (IMP) or existing AEs that worsened during TEAE Period (for DB Period: from first IMP administration up to first administration in OLE period for participant who entered OLE period; and up to 7 days post last IMP administration for participant not continuing OLE period; for open-label: time from 1st IMP administration in open-label to last IMP administration+ 10 weeks).
DB Period: Annualized Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) at Week 48
时间窗: Baseline, Week 48
Annualized change in eGFR was calculated using Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) Creatinine Equation (for participants with age greater than 16 years) as: eGFR=142\*min(Scr/K, 1)α\*max(Scr/K, 1)\^-1.200\*0.9938\^Age\*1.012 \[if female\], where Scr = serum creatinine in milligrams per deciliter (mg/dL), K = 0.7 for females (F) and 0.9 for males (M), α = -0.241(F) and -0.302(M); age=years, calculated at time of creatinine measurement. eGFR measurements collected from baseline to Week 48 were the response variable and included fixed effects of treatment (lademirsen or placebo), screening eGFR stratification factor (less than \[\<\]60 versus greater than or equal to \[\>=\]60 milliliters per minute per 1.73 meters squared \[mL/min/1.73 m\^2\]), time, and treatment-by-time interaction. Least square (LS) mean and standard error (SE) estimated by linear mixed effect model.
次要结局
- DB Period: Pharmacokinetics (PK): Plasma Concentration of Lademirsen, Its Metabolite (RG0005) and SUM (Lademirsen+RG0005)(Post-dose (4 hours) on Day 1, Weeks 24 and 48)
- DB Period: Pharmacokinetics: Trough Plasma Concentrations (Ctrough) of SUM (Lademirsen+RG0005)(Pre-dose (up to 4 hours before study drug administration) on Weeks 4, 12, 24, 36 and 48)
- DB Period: Absolute Change From Baseline in eGFR Values at Week 24 and 48(Baseline, Weeks 24 and 48)
- DB Period: Number of Participants With Potentially Clinically Significant Laboratory Abnormalities (PCSA): Hematological Parameters(From Baseline up to Week 48)
- DB Period: Number of Participants With Potentially Clinically Significant Abnormalities in Vital Signs(From Baseline up to Week 48)
- DB Period: Number of Participants With Potentially Clinically Significant Abnormalities in 12-lead Electrocardiogram (ECG) Findings(From Baseline up to Week 48)
- DB Period: Change From Baseline in Blood Urea Nitrogen (BUN) Values at Weeks 24 and 48(Baseline, Weeks 24 and 48)
- DB Period: Change From Baseline in Urine Creatinine Values at Weeks 24 and 48(Baseline, Weeks 24 and 48)
- DB Period: Percent Change From Baseline in eGFR Values at Week 24 and 48(Baseline, Weeks 24 and 48)
- DB Period: Number of Participants With a Reduction From Baseline in eGFR of <10%, <20%, <30%, or <40% at Weeks 24 and 48(At Weeks 24 and 48)
- DB Period: Number of Participants Who Developed End Stage Renal Disease (ESRD)(From Baseline up to Week 48)
- DB Period: Number of Participants With Potentially Clinically Significant Laboratory Abnormalities: Renal Function Parameters(From Baseline up to Week 48)
- DB Period: Change From Baseline in Circulating MicroRNA-21 at Weeks 24 and 48(Baseline, Weeks 24 and 48)
- DB Period: Change From Baseline in Urine Albumin/Creatinine Ratio at Weeks 24 and 48(Baseline, Weeks 24 and 48)
- DB Period: Change From Baseline in Urine Epidermal Growth Factor (EGF)/Creatinine Ratio at Weeks 24 and 48(Baseline, Weeks 24 and 48)
- DB Period: Number of Participants With Potentially Clinically Significant Laboratory Abnormalities: Liver Function Parameters(From Baseline up to Week 48)
- DB Period: Change From Baseline in Blood Creatinine Values at Weeks 24 and 48(Baseline, Weeks 24 and 48)
- DB Period: Change From Baseline in Blood Cystatine C Values at Weeks 24 and 48(Baseline, Weeks 24 and 48)
- DB Period: Change From Baseline in Urine Transforming Growth Factor Beta 1/Creatinine Ratio at Week 24 and 48(Baseline, Weeks 24 and 48)
- DB Period: Change From Baseline in Blood Lipocalin-2 Values at Weeks 24 and 48(Baseline, Weeks 24 and 48)
- DB Period: Number of Participants With Treatment-emergent Anti-drug Antibodies (ADAs) Response(From first IMP administration (Day 1) up to first administration in OLE period for participant who entered OLE period (i.e., up to W48) & up to 7 days post last IMP administration for participant not continuing OLE period (i.e., up to W49))
- DB Period: Change From Baseline in Urine Protein/Creatinine Ratio at Weeks 24 and 48(Baseline, Weeks 24 and 48)
- DB Period: Change From Baseline in Blood Transforming Growth Factor Beta 1 Values at Week 24 and 48(Baseline, Weeks 24 and 48)
- DB Period: Number of Participants With Treatment-emergent Adverse Events (TEAEs) Associated With Anti-drug Antibody (ADA) Responses(From first IMP administration (Day 1) up to first administration in OLE period for participant who entered OLE period (i.e., up to W48) & up to 7 days post last IMP administration for participant not continuing OLE period (i.e., up to W49))
- DB Period: Change From Baseline in Urine Cystatin C/Creatinine Ratio at Weeks 24 and 48(Baseline, Weeks 24 and 48)
- DB Period: Change From Baseline in Urine Lipocalin-2/Creatinine Ratio at Weeks 24 and 48(Baseline, Weeks 24 and 48)