A Phase 2, Single-Center, Double-Blind, Placebo-Controlled, Randomized Study to Investigate the Effect of Ledipasvir/Sofosbuvir Fixed-Dose Combination on Cerebral Metabolism and Neurocognition in Treatment-Naive and Treatment-Experienced Subjects With Chronic Genotype 1 HCV Infection
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 40
- 主要终点
- Change From Baseline in MRS Metabolic Ratio at 4 Weeks After Discontinuation of Therapy: Myoinositol
研究概览
简要总结
The primary objectives of this study are to evaluate the effect of sustained virologic response (SVR) on cerebral metabolism as determined by magnetic resonance spectroscopy (MRS) and on neurocognition as measured by neurocognitive tests. This study will also evaluate the antiviral efficacy, safety, and tolerability of ledipasvir/sofosbuvir (LDV/SOF) fixed-dose combination (FDC) for 12 weeks in treatment-naive or treatment-experienced adults.
During the blinded treatment phase, participants will be randomized 2:1 to receive LDV/SOF FDC or placebo for 12 weeks. After the unblinding at the Posttreatment Week 4 visit, participants in the placebo group will be offered open-label treatment of LDV/SOF FDC for 12 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
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 18 Years 至 60 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Chronic HCV infection (≥ 6 months) documented by prior medical history or liver biopsy
- •Chronic genotype 1 HCV infection
- •Screening laboratory values within defined thresholds
- •Use of protocol-specified method(s) of contraception if female of childbearing potential or sexually active male
排除标准
- •Clinically-significant illness (other than HCV) or any other major medical disorder that may interfere with treatment, assessment, or compliance with the protocol. Current or prior history of any of the following:
- •Hepatic decompensation
- •Solid organ transplantation
- •Significant pulmonary or cardiac disease
- •Chronic liver disease of a non-HCV etiology
- •Hepatocellular carcinoma (HCC)
- •Infection with hepatitis B virus (HBV)
- •Infection with human immunodeficiency virus (HIV)
- •History of recent epilepsy (within 2 years of screening) or cerebral vascular accident (CVA)
- •Structural brain damage
- •Presence of cirrhosis
- •Contraindication to MRI
- •Pregnant or nursing female
- •Prior treatment NS5A directly-acting antiviral agent. Any interferon (IFN)-containing regimen within 8 weeks of Screening
研究组 & 干预措施
LDV/SOF
Participants will receive LDV/SOF FDC for 12 weeks.
干预措施: LDV/SOF (Drug)
Placebo
Participants will receive LDV/SOF placebo for 12 weeks.
干预措施: Placebo (Drug)
Open-Label Treatment Phase
Following Posttreatment Week 4, participants in the placebo group will be offered open-label treatment with LDV/SOF FDC for 12 weeks.
干预措施: LDV/SOF (Drug)
结局指标
主要结局
Change From Baseline in MRS Metabolic Ratio at 4 Weeks After Discontinuation of Therapy: Myoinositol
时间窗: Baseline; Posttreatment Week 4
MRS was analyzed in the LCmodel program and measured in 3 specific areas of brain (basal ganglia, frontal cortex, and dorsolateral prefrontal cortex). The cerebral metabolic signal myoinositol was analyzed. Spectroscopy results are expressed as metabolic ratio with creatine used as the control metabolite, so there are no units of measure.
Change From Baseline in Neurocognitive Function at 4 Weeks After Discontinuation of Therapy: Attention Scaled Score
时间窗: Baseline; Posttreatment Week 4
Neurocognitive function tests were administered by a licensed clinician. The sum of following neurocognitive test scores was used to determine the Attention Scaled Score: forward digit span scaled score (FSCORESS), backward digit span scaled score (BSCORESS), and symbol span total scaled score (SYMSPSS). For this analysis, Attention Scaled Score (total) ranged from 3 to 57, with higher scores indicating better working memory capacity and control.
Change From Baseline in Neurocognitive Function at 4 Weeks After Discontinuation of Therapy: Executive 1 Processing Speed
时间窗: Baseline; Posttreatment Week 4
Neurocognitive function tests were administered by a licensed clinician. The sum of following neurocognitive test scores was used to determine the Executive 1 Processing Speed score: symbol search total scaled score (SSSS) and trails A total raw score (TrailARS). For this analysis, Executive 1 Processing Speed score (total) ranged from 1 to 108, with lower scores indicating better executive control.
Change From Baseline in Neurocognitive Function at 4 Weeks After Discontinuation of Therapy: Motor
时间窗: Baseline; Posttreatment Week 4
Neurocognitive function tests were administered by a licensed clinician. The sum of following neurocognitive test scores was used to determine the Motor score: dominant hand fine motor speed (time) (DomHtot) and non-dominant hand fine motor speed (time) (nonDOMHtot). For this analysis, Motor score (total) ranged from 20 to 600, with lower scores indicating better fine motor speed.
Change From Baseline in Neurocognitive Function at 4 Weeks After Discontinuation of Therapy: Memory T Score
时间窗: Baseline; Posttreatment Week 4
Neurocognitive function tests were administered by a licensed clinician. The sum of following neurocognitive test scores was used to determine the Memory T Score: visuospatial memory immediate total T score (BVMTTTs), visuospatial memory delayed T score (BVMTTDTS), verbal memory total T score (HVLTTTS), and verbal memory delayed T score (HVLTDTS). For this analysis, Memory T Score (total) ranged from 80 to 320, with higher scores indicating better memory.
Change From Baseline in Neurocognitive Function at 4 Weeks After Discontinuation of Therapy: Executive 2 Conceptual Shift and Initiation
时间窗: Baseline; Posttreatment Week 4
Neurocognitive function tests were administered by a licensed clinician. The sum of following neurocognitive test scores was used to determine the Executive 2 Conceptual Shift and Initiation score: trails B raw score (TrailBRS), age \& education adjusted raw score (FASadj), color word interference score (time) (CWTrial3), and color word interference/shifting score (time) (CWTrial4). For this analysis, Executive 2 Conceptual Shift and Initiation score (total) ranged from 1 to 570, with lower scores indicating better executive control.
Change From Baseline in Magnetic Resonance Spectroscopy (MRS) Metabolic Ratio at 4 Weeks After Discontinuation of Therapy: NAA + NAAG
时间窗: Baseline; Posttreatment Week 4
MRS was analyzed in the LCmodel program and measured in 3 specific areas of brain (basal ganglia, frontal cortex, and dorsolateral prefrontal cortex). The cerebral metabolic signal N-acetylaspartate (NAA) + N-acetylaspartylglutamate (NAAG) was analyzed. Spectroscopy results are expressed as metabolic ratio with creatine used as the control metabolite, so there are no units of measure.
Change From Baseline in MRS Metabolic Ratio at 4 Weeks After Discontinuation of Therapy: Choline
时间窗: Baseline; Posttreatment Week 4
MRS was analyzed in the LCmodel program and measured in 3 specific areas of brain (basal ganglia, frontal cortex, and dorsolateral prefrontal cortex). The cerebral metabolic signal choline was analyzed. Spectroscopy results are expressed as metabolic ratio with creatine used as the control metabolite, so there are no units of measure.
次要结局
- Percentage of Participants With Sustained Virologic Response (SVR) at 4, 12, and 24 Weeks After Discontinuation of Therapy (SVR4, SVR12, and SVR24)(Posttreatment Weeks 4, 12, and 24)
- Change From Baseline in Neurocognitive Function at 24 Weeks After Discontinuation of Therapy: Attention Scaled Score(Baseline; Posttreatment Week 24)
- Change From Baseline in Neurocognitive Function at 24 Weeks After Discontinuation of Therapy: Executive 2 Conceptual Shift and Initiation(Baseline; Posttreatment Week 24)
- Change From Baseline in Health-Related Quality of Life at 4 and 24 Weeks After Discontinuation of Therapy as Assessed by SF-36 Health Survey Scale - Mental Component Score(Baseline; Posttreatment (PT) Weeks 4 and 24)
- Change From Baseline in Health-Related Quality of Life at 4 and 24 Weeks After Discontinuation of Therapy as Assessed by Chronic Liver Disease Questionnaire - HCV (CLDQ-HCV)(Baseline; Posttreatment Weeks 4 and 24)
- Change From Baseline in Health-Related Quality of Life at 4 and 24 Weeks After Discontinuation of Therapy as Assessed by Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F)(Baseline; Posttreatment Weeks 4 and 24)
- Change From Baseline in Health-Related Quality of Life at 4 and 24 Weeks After Discontinuation of Therapy as Assessed by WPAI: Hepatitis C - Activity Impairment(Baseline; Posttreatment Weeks 4 and 24)
- Change From Baseline in Neurocognitive Function at 24 Weeks After Discontinuation of Therapy: Memory T Score(Baseline; Posttreatment Week 24)
- Change From Baseline in Neurocognitive Function at 24 Weeks After Discontinuation of Therapy: Executive 1 Processing Speed(Baseline; Posttreatment Week 24)
- Change From Baseline in Health-Related Quality of Life at 4 and 24 Weeks After Discontinuation of Therapy as Assessed by Short Form 36 (SF-36) Health Survey Scale - Physical Component Score(Baseline; Posttreatment Weeks 4 and 24)
- Change From Baseline in Neurocognitive Function at 24 Weeks After Discontinuation of Therapy: Motor(Baseline; Posttreatment Week 24)
- Change From Baseline in Health-Related Quality of Life at 4 and 24 Weeks After Discontinuation of Therapy as Assessed by Work Productivity and Activity Impairment Questionnaire, Hepatitis C (WPAI: Hepatitis C) - Overall Work Impairment(Baseline; Posttreatment Weeks 4 and 24)
- Change From Pre-treatment Assessment in Mood Related Assessment at 4 and 24 Weeks After Discontinuation of Therapy as Assessed by Beck Depression Inventory-II (BDI-II)(Baseline; Posttreatment Weeks 4 and 24)
- Change From Pre-treatment Assessment in Mood Related Assessment at 4 and 24 Weeks After Discontinuation of Therapy as Assessed by Beck Hopelessness Scale (BHS)(Baseline; Posttreatment Weeks 4 and 24)