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

Eksperimentel: LDV/SOF

Deltagerne modtager LDV/SOF FDC i 12 uger.

Medicin: LDV/SOF

90/400 mg FDC tablet indgivet oralt én gang dagligt

Andre navne:

• Harvoni®
• GS-5885/GS-7977

Placebo komparator: Placebo

Participants will receive LDV/SOF placebo for 12 weeks.

Medicin: Placebo

Tablet indgivet oralt én gang dagligt

Eksperimentel: 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.

Medicin: LDV/SOF

90/400 mg FDC tablet indgivet oralt én gang dagligt

Andre navne:

• Harvoni®
• GS-5885/GS-7977

Change From Baseline in Magnetic Resonance Spectroscopy (MRS) Metabolic Ratio at 4 Weeks After Discontinuation of Therapy: NAA + NAAG

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

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

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

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

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

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

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

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.

Percentage of Participants With Sustained Virologic Response (SVR) at 4, 12, and 24 Weeks After Discontinuation of Therapy (SVR4, SVR12, and SVR24)

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

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

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

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

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

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

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

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)

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)

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

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

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)

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)

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.