An Open-Label Extension Study to Assess the Long-Term Safety and Efficacy of ISIS 420915 in Patients With Familial Amyloid Polyneuropathy (FAP)
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 135
- 试验地点
- 22
- 主要终点
- Percentage of Participants With Change From Baseline in Weight
研究概览
简要总结
This study evaluates the safety and tolerability of extended dosing with IONIS-TTR Rx in patients with Familial Amyloid Polyneuropathy.
详细描述
Familial Amyloid Polyneuropathy (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.
IONIS-TTR Rx is an antisense drug that is designed to decrease the amount of mutant and normal TTR made by the liver. It is predicted that decreasing the amount of TTR protein will result in a decrease in the formation of TTR deposits, and thus slow or stop disease progression.
This study evaluates the safety and tolerability of extended dosing with IONIS-TTR Rx in patients with Familial Amyloid Polyneuropathy.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Satisfactory completion of dosing & efficacy assessments in ISIS 420915-CS2
排除标准
- •Any new condition or worsening of existing condition that could make the patient unsuitable for participation, or interfere with the patient participating in and/or completing the study
研究组 & 干预措施
Previous Placebo-Inotersen 300 mg
Participants received subcutaneous (SC) doses of 300 milligrams (mg) inotersen once weekly for up to 260 weeks. Participants who received inotersen-matching placebo in the previous study- ISIS 420915-CS2 (NCT01737398) were included in this group.
干预措施: Inotersen (Drug)
Previous Inotersen-Inotersen 300 mg
Participants received SC doses of 300 mg inotersen once weekly for up to 260 weeks. Participants who received inotersen in the previous study- ISIS 420915-CS2 were included in this group.
干预措施: Inotersen (Drug)
结局指标
主要结局
Percentage of Participants With Change From Baseline in Weight
时间窗: From first dose of study drug up to 3 months post treatment period of 260 weeks (Up to approximately 272 weeks)
As prespecified in the protocol, percentage of participants with change from baseline in weight is reported in 2 categories, decrease of ≥7% from Baseline and increase of ≥7% from Baseline.
Percentage of Participants With Change From Baseline in Vital Signs
时间窗: From first dose of study drug up to 3 months post treatment period of 260 weeks (Up to approximately 272 weeks)
Vital signs included blood pressure, heart rate, respiratory rate, and temperature. Only categories with at least one participant with event are reported.
Percentage of Participants With Change From Baseline in QT Interval Corrected Using Fridericia's Formula (QTcF) as Determined by Electrocardiogram (ECG)
时间窗: From first dose of study drug up to 3 months post treatment period of 260 weeks (Up to approximately 272 weeks)
Normal QTcF at Baseline is defined as ≤450 milliseconds (ms) for males or ≤470 ms for females. Percentage of participants with QT interval outside of normal range are reported.
Percentage of Participants Using Concomitant Medication for Nervous and Cardiovascular System Disorders
时间窗: From first dose of study drug up to 3 months post treatment period of 260 weeks (Up to approximately 272 weeks)
A concomitant therapy was any non-protocol-specified drug or substance (including over-the counter medications, herbal medications, and vitamin supplements) administered between signing of informed consent and the final post-treatment visit for treating nervous and cardiovascular system disorders.
Percentage of Participants With Change From Baseline in Ophthalmic Examination as Assessed by Visual Acuity Changes
时间窗: From first dose of study drug up to 3 months post treatment period of 260 weeks (Up to approximately 272 weeks)
Percentage of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, and TEAEs Related to Study Drug
时间窗: From first dose of study drug up to 3 months post treatment period of 260 weeks (Up to approximately 272 weeks)
An adverse event (AE) is any unfavorable and unintended sign (including a clinically significant abnormal laboratory finding, for example), symptom, or disease temporally associated with the study or use of investigational drug product, whether or not the AE is considered related to the investigational drug product. A TEAE is defined as an adverse event with an onset that occurs after receiving study drug. An SAE is any untoward medical occurrence that at any dose that results in death, is life threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, leads to a congenital anomaly/birth defect, or is an important medical event. TEAEs considered related to the study drug as assessed by the Investigator are reported.
Percentage of Participants With Clinically Significant Change From Baseline in Laboratory Test Values
时间窗: From first dose of study drug up to 3 months post treatment period of 260 weeks (Up to approximately 272 weeks)
Clinical laboratory tests included the analysis of chemistry, haematology, and urinalysis. Any value outside the normal range will be flagged for the attention of the investigator who will assess whether or not a flagged value is of clinical significance. Only those categories with at least one participant with event are reported. Normal range of creatinine clearance is 110 to 150 mL/min in males and 100 to 130 mL/min in females. Normal urine protein to creatinine (P/C) ratio= \<0.2. Normal range for Alanine Aminotransferase (ALT) is 4 to 36 units per liter (U/L). Platelets normal range=140×10\^9/L to 400×10\^9/L.
Percentage of Participants With Change From Baseline in Light Detection Ability Measured by Electroretinography
时间窗: Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Weeks 78 and 156
次要结局
- Ctrough: Trough Plasma Concentration of ISIS 420915(Pre-dose on Days 1, 43, 85, 120, 176, 267, 358, 449, 540, 631, 722, 813, 904, 995, 1086, 1268; Days 1359 and 1450 of Year 4; Days 1632, 1723 and 1814 of Year 5)
- Change From Baseline in the mNIS +7 Component: Heart Rate to Deep Breathing Score at Weeks 78 and 156(Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Weeks 78 and 156)
- Change From Baseline in the Modified Neuropathy Impairment Score (mNIS)+7 Composite Score at Weeks 78 and 156(Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Weeks 78 and 156)
- Change From Baseline in the mNIS +7 Component: Touch-Pressure Sensory Score at Weeks 78 and 156(Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Weeks 78 and 156)
- Change From Baseline in the NIS Component: Muscle Weakness Score at Week 52 of Years 4 and 5(Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Week 52 of Years 4 and 5)
- Change From Baseline in the Body Mass Index (BMI) at Weeks 78 and 156(Baseline, Weeks 78 and 156)
- Percentage of Participants With Change From Baseline in the Polyneuropathy Disability (PND) Score(Baseline, Weeks 78 and 156 and at the end of each subsequent treatment year (Week 52 of each year))
- Change From Baseline in the mNIS +7 Component: Nerve Conduction Score at Weeks 78 and 156(Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Weeks 78 and 156)
- Change From Baseline in the mNIS +7 Component: Heat-Pain Sensory Score at Weeks 78 and 156(Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Weeks 78 and 156)
- Change From Baseline in the NIS Component: Reflexes Score at Week 52 of Years 4 and 5(Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Week 52 of Years 4 and 5)
- Change From Baseline in Retinol Binding Protein 4 (RBP4) Level(Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Weeks 78 and 156, and at the end of each subsequent treatment year (Week 52 of Years 4 and 5))
- Change From Baseline in the Neuropathy Impairment (NIS) Composite Score at Week 52 of Years 4 and 5(Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Week 52 of Years 4 and 5)
- Change From Baseline in the NIS Component: Sensory Score at Week 52 of Years 4 and 5(Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Week 52 of Years 4 and 5)
- Change From Baseline in the NIS Component: Cranial Nerves Score at Week 52 of Years 4 and 5(Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Week 52 of Years 4 and 5)
- Change From Baseline in the Norfolk Quality of Life-Diabetic Neuropathy (QOL-DN) Questionnaire Total Score at Weeks 78 and 156(Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Weeks 78 and 156 and at the end of each subsequent treatment year (Week 52 of Years 4 and 5))
- Change From Baseline in the Norfolk QoL-DN Physical Functioning/Large Fiber Neuropathy Domain Score(Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Weeks 78 and 156 and at the Week 52 of Year 4)
- Change From Baseline in the Modified Body Mass Index (mBMI) at Weeks 78 and 156(Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Weeks 78 and 156)
- Percent Change From Baseline in Global Longitudinal Strain (GLS) by Echocardiogram (ECHO) in the Cardiomyopathy-ECHO (CM-ECHO) Set(Baseline, Weeks 78 and 156)
- Percent Change From Baseline in GLS by ECHO in the CS3 ECHO Subgroup(Weeks 78 and 156)
- Change From Baseline in Transthyretin (TTR) Level(Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Weeks 78 and 156)