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Ledipasvir/Sofosbuvir Fixed-Dose Combination on Cerebral Metabolism and Neurocognition in Treatment-Naive and Treatment-Experienced Participants With Chronic Genotype 1 HCV Infection

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ClinicalTrials.gov Identifier: NCT02219685
Recruitment Status : Completed
First Posted : August 19, 2014
Results First Posted : November 30, 2016
Last Update Posted : November 16, 2018
Sponsor:
Information provided by (Responsible Party):
Gilead Sciences

Tracking Information
First Submitted Date  ICMJE August 15, 2014
First Posted Date  ICMJE August 19, 2014
Results First Submitted Date  ICMJE August 2, 2016
Results First Posted Date  ICMJE November 30, 2016
Last Update Posted Date November 16, 2018
Study Start Date  ICMJE August 2014
Actual Primary Completion Date August 2015   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 7, 2016)
  • Change From Baseline in Magnetic Resonance Spectroscopy (MRS) Metabolic Ratio at 4 Weeks After Discontinuation of Therapy: NAA + NAAG [ Time Frame: 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 [ Time Frame: 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.
  • Change From Baseline in MRS Metabolic Ratio at 4 Weeks After Discontinuation of Therapy: Myoinositol [ Time Frame: 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: Memory T Score [ Time Frame: 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: Attention Scaled Score [ Time Frame: 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 [ Time Frame: 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: Executive 2 Conceptual Shift and Initiation [ Time Frame: 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 Neurocognitive Function at 4 Weeks After Discontinuation of Therapy: Motor [ Time Frame: 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.
Original Primary Outcome Measures  ICMJE
 (submitted: August 15, 2014)
  • Change from pretreatment assessment in MRS metabolic ratios at 4 weeks after discontinuation of therapy [ Time Frame: Baseline; Posttreatment Week 4 ]
  • Change from pretreatment assessment in neurocognitive function at 4 weeks after discontinuation of therapy [ Time Frame: Baseline; Posttreatment Week 4 ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: October 7, 2016)
  • Percentage of Participants With Sustained Virologic Response (SVR) at 4, 12, and 24 Weeks After Discontinuation of Therapy (SVR4, SVR12, and SVR24) [ Time Frame: Posttreatment Weeks 4, 12, and 24 ]
    SVR4, SVR12, and SVR24 were defined as HCV RNA < the lower limit of quantitation (LLOQ; ie, 15 IU/mL) at 4, 12, and 24 weeks after stopping study treatment with LDV/SOF, respectively.
  • Change From Baseline in Neurocognitive Function at 24 Weeks After Discontinuation of Therapy: Memory T Score [ Time Frame: Baseline; Posttreatment Week 24 ]
    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 24 Weeks After Discontinuation of Therapy: Attention Scaled Score [ Time Frame: Baseline; Posttreatment Week 24 ]
    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 24 Weeks After Discontinuation of Therapy: Executive 1 Processing Speed [ Time Frame: Baseline; Posttreatment Week 24 ]
    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 24 Weeks After Discontinuation of Therapy: Executive 2 Conceptual Shift and Initiation [ Time Frame: Baseline; Posttreatment Week 24 ]
    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 Neurocognitive Function at 24 Weeks After Discontinuation of Therapy: Motor [ Time Frame: Baseline; Posttreatment Week 24 ]
    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 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 [ Time Frame: Baseline; Posttreatment Weeks 4 and 24 ]
    The SF-36 Health Survey is a self-reporting, multi-item scale measuring 8 health concepts: 1) physical functioning, 2) role limitations due to physical health problems, 3) bodily pain, 4) general health, 5) vitality (energy/fatigue), 6) social functioning, 7) role limitations due to emotional problems and 8) mental health (psychological distress and psychological well-being). The first 6 concepts constitute the physical component summary. The total score is an average of the individual question scores, which are scaled 0-100 with lower scores representing more disability and higher scores representing less disability.
  • 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 [ Time Frame: Baseline; Posttreatment (PT) Weeks 4 and 24 ]
    The SF-36 Health Survey is a self-reporting, multi-item scale measuring 8 health concepts: 1) physical functioning, 2) role limitations due to physical health problems, 3) bodily pain, 4) general health, 5) vitality (energy/fatigue), 6) social functioning, 7) role limitations due to emotional problems and 8) mental health (psychological distress and psychological well-being). The last 5 concepts constitute the mental component summary. The total score is an average of the individual question scores, which are scaled 0-100 with lower score representing more disability and higher scores representing less disability.
  • 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) [ Time Frame: Baseline; Posttreatment Weeks 4 and 24 ]
    The CLDQ-HCV is a disease-specific questionnaire measuring health-related quality of life. CLDQ-HCV scores are calculated using participant responses to 29 questions divided into 4 domains: Activity/Energy, Emotion, Worry, and Systemic. An overall CLDQ-HCV score is calculated by taking the mean of all domain scores. Overall CLDQ-HCV scores range between 1 and 7, with higher scores representing better quality of life.
  • 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) [ Time Frame: Baseline; Posttreatment Weeks 4 and 24 ]
    The FACIT-Fatigue score was measured using a 40-item questionnaire that assesses self-reported fatigue and its impact upon daily activities and function. Participants scored each item on a 5-point scale from 0 (Not at all) to 4 (Very much). The FACIT-F total score was calculated by taking the sum of all 40 individual scores and ranged from 0-160, with higher scores indicating better quality of life.
  • 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 [ Time Frame: Baseline; Posttreatment Weeks 4 and 24 ]
    Impairment in overall work productivity was measured using the WPAI: Hepatitis C questionnaire completed by participants during study visits throughout the study. This questionnaire measured the effect of hepatitis C on the ability to work and perform regular activities. Overall work impairment is expressed as a percentage and ranges from 0% (no effect) to 100% (completely prevented from working).
  • 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 [ Time Frame: Baseline; Posttreatment Weeks 4 and 24 ]
    Activity impairment was measured using the WPAI: Hepatitis C questionnaire completed by participants during study visits throughout the study. This questionnaire measured the effect of hepatitis C on the ability to work and perform regular activities. Overall activity impairment is expressed as a percentage and ranges from 0% (no effect) to 100% (completely prevented from performing regular activities).
  • 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) [ Time Frame: Baseline; Posttreatment Weeks 4 and 24 ]
    The BDI-II is a 21-item self-report instrument for measuring the severity of depression. Each item is rated on a 4-point scale ranging from 0 to 3. The item scores are summed to yield a derived total score that can range from 0 to 63 with lower values indicating less depression.
  • 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) [ Time Frame: Baseline; Posttreatment Weeks 4 and 24 ]
    The BHS is a 20-item scale for measuring the extent of negative attitudes about the future (pessimism) as perceived by adolescents and adults. The BHS consists of 20 true-false statements. Each of the 20 statements is scored 1 or 0. Of the 20 true-false statements, 9 are keyed FALSE, and 11 are keyed TRUE to indicate endorsement of pessimism about the future. The item scores are summed to yield a total score that can range from 0 to 20 with higher scores indicating greater hopelessness.
Original Secondary Outcome Measures  ICMJE
 (submitted: August 15, 2014)
  • Proportion of participants with sustained virologic response (SVR) at 4, 12, and 24 weeks after discontinuation of therapy (SVR4, SVR12, and SVR24) [ Time Frame: Posttreatment Weeks 4, 12, and 24 ]
    SVR4, SVR12, and SVR24 are defined as HCV RNA < the lower limit of quantitation (LLOQ) 4, 12, and 24 weeks following the last dose of study drug.
  • Change from pretreatment assessment in neurocognitive function at 24 weeks after discontinuation of therapy [ Time Frame: Baseline; Posttreatment Week 24 ]
  • Change from pretreatment assessment in health-related quality of life at 4 and 24 weeks after discontinuation of therapy [ Time Frame: Baseline; Posttreatment Week 4; Posttreatment Week 24 ]
  • Change from pretreatment assessment in mood-related assessment at 4 and 24 weeks after discontinuation of therapy [ Time Frame: Baseline; Posttreatment Week 4; Posttreatment Week 24 ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Ledipasvir/Sofosbuvir Fixed-Dose Combination on Cerebral Metabolism and Neurocognition in Treatment-Naive and Treatment-Experienced Participants With Chronic Genotype 1 HCV Infection
Official Title  ICMJE 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
Brief Summary

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.

Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Condition  ICMJE Hepatitis C Virus Infection
Intervention  ICMJE
  • Drug: LDV/SOF
    90/400 mg FDC tablet administered orally once daily
    Other Names:
    • Harvoni®
    • GS-5885/GS-7977
  • Drug: Placebo
    Tablet administered orally once daily
Study Arms  ICMJE
  • Experimental: LDV/SOF
    Participants will receive LDV/SOF FDC for 12 weeks.
    Intervention: Drug: LDV/SOF
  • Placebo Comparator: Placebo
    Participants will receive LDV/SOF placebo for 12 weeks.
    Intervention: Drug: Placebo
  • Experimental: 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.
    Intervention: Drug: LDV/SOF
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: August 15, 2014)
40
Original Estimated Enrollment  ICMJE Same as current
Actual Study Completion Date  ICMJE April 2016
Actual Primary Completion Date August 2015   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • 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

Exclusion Criteria:

  • 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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 60 Years   (Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02219685
Other Study ID Numbers  ICMJE GS-US-337-1445
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: Qualified external researchers may request IPD for this study after study completion. For more information, please visit our website at http://www.gilead.com/research/disclosure-and-transparency.
Supporting Materials: Study Protocol
Supporting Materials: Statistical Analysis Plan (SAP)
Time Frame: 18 months after study completion
Access Criteria: A secured external environment with username, password, and RSA code.
URL: http://www.gilead.com/research/disclosure-and-transparency
Responsible Party Gilead Sciences
Study Sponsor  ICMJE Gilead Sciences
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Benedetta Massetto, MD Gilead Sciences
PRS Account Gilead Sciences
Verification Date October 2016

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP