A Phase 2/3 Randomized, Double-Blind, Placebo-Controlled Study to Assess the Efficacy and Safety of ISIS 420915 in Patients With Familial Amyloid Polyneuropathy (NEURO-TTR Study)
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 173
- 试验地点
- 24
- 主要终点
- Change From Baseline In The Modified Neuropathy Impairment Score (mNIS) +7 Composite Score at Week 66
研究概览
简要总结
The purpose of this study is to evaluate the efficacy and safety of inotersen given for 65 weeks in participants with Familial Amyloid Polyneuropathy (FAP).
详细描述
FAP is a rare, hereditary disease caused by mutations in the transthyretin (TTR) protein. TTR is made by the liver and secreted into the blood. TTR mutations cause it to misfold and deposit in multiple organs causing FAP.
Inotersen (also known as ISIS 420915) is an antisense drug that was designed to decrease the amount of mutant and normal TTR made by the liver. It is predicted that decreasing the amount of TTR protein would result in a decrease in the formation of TTR deposits, and thus slow or stop disease progression.
The purpose of this study is to determine if inotersen can slow or stop the nerve damage caused by TTR deposits. This study will enroll late Stage 1 and early Stage 2 FAP participants. Participants will receive either inotersen or placebo for 65 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
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 82 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Stage 1 and Stage 2 FAP participants with the following:
- •NIS score within protocol criteria
- •Documented transthyretin variant by genotyping
- •Documented amyloid deposit by biopsy
- •Females of child-bearing potential must use appropriate contraception and be non-pregnant and non-lactating. Males engaging in relations of child-bearing potential are to use appropriate contraception
排除标准
- •Low Retinol level at screen
- •Karnofsky performance status ≤50
- •Poor Renal function
- •Known type 1 or type 2 diabetes mellitus
- •Other causes of sensorimotor or autonomic neuropathy (for example, autoimmune disease)
- •If previously treated with Vyndaqel®, will need to have discontinued treatment for 2 weeks prior to Study Day
- •If previously treated with Diflunisal, will need to have discontinued treatment for 3 days prior to Study Day 1
- •Previous treatment with any oligonucleotide or siRNA within 12 months of screening
- •Prior liver transplant or anticipated liver transplant within 1 year of screening
- •New York Heart Association (NYHA) functional classification of ≥3
- •Acute Coronary Syndrome or major surgery within 3 months of screening
- •Known Primary or Leptomeningeal Amyloidosis
- •Anticipated survival less than 2 years
- •Any other conditions in the opinion of the investigator which interfere with the participant participating in or completing the study
研究组 & 干预措施
Inotersen
300 mg inotersen administered subcutaneously (SC) 3 times on alternate days in the first week and then once-weekly for 64 weeks
干预措施: Inotersen (Drug)
Placebo
Placebo administered SC 3 times on alternate days in the first week and then once-weekly for 64 weeks
干预措施: Placebo (Drug)
结局指标
主要结局
Change From Baseline In The Modified Neuropathy Impairment Score (mNIS) +7 Composite Score at Week 66
时间窗: Baseline and Week 66
The mNIS+7 composite score is a measure of neurologic impairment that evaluates muscle weakness, sensation, reflexes, nerve conduction, and autonomic function. The mNIS+7 Composite Score has a range of -22.32 to 346.32 and a higher mNIS+7 composite score indicates lower function.
Change From Baseline In The Norfolk Quality Of Life Diabetic Neuropathy (QoL-DN) Questionnaire at Week 66
时间窗: Baseline and Week 66
The Norfolk QoL-DN score is a measure of physical function/large fiber neuropathy, symptoms, activities of daily living, small fiber neuropathy, and autonomic neuropathy. The Norfolk QoL-DN total score has a range of -4 to 136, and a higher Norfolk QoL-DN score indicates poorer QoL.
次要结局
- Change From Baseline In The Norfolk QoL-DN Questionnaire Symptoms Domain Score at Week 66(Baseline and Week 66)
- Change From Baseline In The Norfolk QoL-DN Questionnaire Physical Functioning/Large Fiber Neuropathy Domain Score at Week 66(Baseline and Week 66)
- Change From Baseline In Modified Body Mass Index (mBMI) at Week 65(Baseline and Week 65)
- Change From Baseline In Body Mass Index (BMI) at Week 65(Baseline and Week 65)
- Change From Baseline in Neuropathy Impairment Score (NIS) at Week 66(Baseline and Week 66)
- Change From Baseline in Modified +7 at Week 66(Baseline and Week 66)
- Change From Baseline in NIS+7 at Week 66(Baseline and Week 66)
- Change From Baseline in Global Longitudinal Strain (GLS) by Echocardiogram (ECHO) at Week 65 in the CM-ECHO Set(Baseline and Week 65)
- Change From Baseline in Global Longitudinal Strain (GLS) by Echocardiogram ECHO at Week 65 in the ECHO Subgroup(Baseline and Week 65)
- Change From Baseline in Transthyretin (TTR) Level at Week 65(Baseline and Week 65)
- Change From Baseline in Retinol Binding Protein 4 (RBP4) Level at Week 65(Baseline and Week 65)
- Maximum Measured Plasma Concentration (Cmax) Of Inotersen At Week 65(Week 65)
- Time To The Maximum Plasma Concentration (Tmax) Of Inotersen At Week 65(Week 65)
- Area Under The Plasma Concentration-time Curve From 0 To 24 Hours (AUC[0-24hr]) Of Inotersen At Week 65(Week 65)
- Area Under The Plasma Concentration-time Curve From 0 To 168 Hours (AUC[0-168hr]) Of Inotersen At Week 65(Week 65)
- Plasma Clearance From 0 To 24 Hours (CL[0-24hr]/F) Of Inotersen At Week 65(Week 65)
- Inotersen Plasma Clearance At Steady State (CLss/F) At Week 65(Week 65)