Back to resultsA Study to Investigate the Pharmacokinetic Interactions Between Simeprevir and Ledipasvir in a Treatment Regimen Consisting of Simeprevir, Sofosbuvir, and Ledipasvir in Treatment-naive Participants With Chronic Hepatitis C Virus Genotype 1 Infection
Primary Purpose
Hepatitis C, Chronic
Status
Completed
Phase
Phase 2
Locations
Belgium
Study Type
Interventional
Intervention
Simeprevir (SMV)
Ledipasvir (LDV)
Sofosbuvir (SOF)
Sponsored by
About this trial
This is an interventional other trial for Hepatitis C, Chronic focused on measuring Hepatitis C, Chronic, Simeprevir, Ledipasvir, Sofosbuvir
Eligibility Criteria
Inclusion Criteria:
- Participants with Body Mass Index (weight in kilogram [kg] divided by the square of height in meters) of 18.0 to 35.0 kilogram per square meter kg/m^2, extremes included
- Participants must be treatment-naive (that is, have not received prior treatment with any approved or investigational drug)
- Participants with HCV ribonucleic acid (RNA) plasma levels greater than (>) 10,000 international unit per milliliter (IU/ml) and lower than 6,000,000 international unit per milliliter (IU/ml) at screening
- Participants with absence of cirrhosis confirmed by FibroTest/Fibrosure score less or equal to 0.75 and an aspartate aminotransferase to platelet ration index less or equal to 2 or a Fibroscan less or equal to 14.6 kilopascale (kPA), performed within 6 months prior or during the screening period
- Participants with documented chronic HCV infection: diagnosis of HCV infection >6 months prior to screening, either by detectable HCV RNA, an HCV positive antibody test or presence of histological changes consistent with chronic hepatitis in a liver biopsy
Exclusion Criteria:
- Participant has infection/co-infection with HCV of a genotype other than genotype 1, human immunodeficiency virus (HIV) type 1 or 2
- Participant has any evidence of liver disease of non-HCV etiology. This includes, but is not limited to acute hepatitis A, active hepatitis B, drug- or alcohol-related liver disease, autoimmune hepatitis, hemochromatosis, Wilson's disease, alpha-1 antitrypsin deficiency, non-alcoholic steatohepatitis, primary biliary cirrhosis, or any other non-HC liver disease considered clinically significant by the investigator
- Participant with significant co-morbidities, conditions or clinical significant findings during screening assessments that in the opinion of the investigator could compromise the participants' safety or could interfere with the Participant participating in and completing the study
- Participant received an organ transplant (other than cornea or hair transplant or skin graft)
- Participants have key protocol defined laboratory abnormalities
Sites / Locations
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Experimental
Arm Label
Panel 1
Panel 2
Arm Description
Participants will receive Simeprevir (SMV) 150 milligram (mg) capsule (Treatment A) along with Sofosbuvir (SOF) 400 mg tablet, orally, once daily (Treatment C) from Day 1 until Day 14 followed by SMV 150 mg capsule (Treatment A) along with fixed dose combination (FDC) tablet of 90 mg Ledipasvir (LDV)/400 mg SOF (Treatment B), orally, once daily from Day 15 until Day 70.
Participants will receive FDC tablet of 90 mg LDV/400 mg SOF (Treatment B), orally, once daily from Day 1 until Day 14 followed by SMV 150 mg capsule (Treatment A) along with FDC tablet of 90 mg LDV/400 mg SOF (Treatment B), orally, once daily from Day 15 until Day 56.
Outcomes
Primary Outcome Measures
Minimum Plasma Concentration (Cmin) of Simeprevir (SMV)
The Cmin is the minimum observed plasma concentration.
Maximum Plasma Concentration (Cmax) of Simeprevir
The Cmax is the maximum observed plasma concentration.
Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) of Simeprevir
The AUCtau is the measure of the plasma drug concentration from time zero to end of dosing interval. It is used to characterize drug absorption.
Minimum Plasma Concentration (Cmin) of Ledipasvir (LDV)
The Cmin is the minimum observed plasma concentration.
Maximum Plasma Concentration (Cmax) of Ledipasvir
The Cmax is the maximum observed plasma concentration.
Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) of Ledipasvir
AUCtau is defined as area under the analyte concentration versus time curve during dosing interval tau, calculated by linear-linear trapezoidal summation.
Secondary Outcome Measures
Trough Plasma Concentration (Ctrough) of Simeprevir
The (Ctrough) is the plasma concentration before dosing or at the end of the dosing interval of any dose other than the first dose in a multiple dosing regimen.
Time to Reach Maximum Plasma Concentration (Tmax) of Simeprevir
The Tmax is defined as actual sampling time to reach maximum observed analyte concentration.
Average Plasma Concentration at Steady State (Cavg,ss) of Simeprevir
The Cavg,ss is calculated as area under the plasma concentration-time curve during a dosing Interval (AUC[tau]) divided by the dosing interval (tau).
Fluctuation Index (FI) of Simeprevir
Fluctuation index is defined as percentage fluctuation (variation between maximum and minimum concentration at steady state), calculated as: 100*([Cmax Cmin]/Cavg).
Trough Plasma Concentration (Ctrough) of Ledipasvir
The (Ctrough) is the plasma concentration before dosing or at the end of the dosing interval of any dose other than the first dose in a multiple dosing regimen.
Time to Reach Maximum Plasma Concentration (Tmax) of Ledipasvir
The Tmax is defined as actual sampling time to reach maximum observed analyte concentration.
Average Plasma Concentration at Steady State (Cavg,ss) of Ledipasvir
The Cavg,ss is calculated as area under the plasma concentration-time curve during a dosing Interval (AUC[tau]) divided by the dosing interval (tau).
Fluctuation Index (FI) of Ledipasvir
Fluctuation index is defined as percentage fluctuation (variation between maximum and minimum concentration at steady state), calculated as: 100*([Cmax Cmin]/Cavg).
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
An AE is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An SAE is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly.
Percentage of Participants With On-treatment Virologic Response
On-treatment virologic response was determined by hepatitis C virus (HCV) ribonucleic acid (RNA) results satisfying a specified threshold.
The following thresholds were considered at any time point: less than (<) lower limit of quantification (LLOQ) undetectable, <LLOQ detectable and <LLOQ undetectable/detectable.
Percentage of Participants With Sustained Virologic Response (SVR) 4 Weeks After the Actual EOT (SVR4) and 12 Weeks After the Actual EOT (SVR12)
SVR4 or SVR12 is defined as sustained virologic response 4 or 12 weeks after the actual EOT the participant has HCV RNA <LLOQ detectable or undetectable.
Percentage of Participants With On-treatment Failure
On-treatment failure is defined as participants who did not achieve SVR12 and with confirmed detectable HCV RNA at the actual end of treatment. This was to include participants with: 1) Viral breakthrough, defined as a confirmed increase of greater than (>)1 log10 in HCV RNA from nadir, or confirmed HCV RNA of >100 IU/mL in participants whose HCV RNA had previously been <LLOQ while on treatment; 2) Other with confirmed detectable HCV RNA at the actual end of treatment (example, completed, discontinued due to AEs, withdrawal of consent).
Percentage of Participants With Viral Relapse
Participants who did not achieve SVR12, with undetectable HCV RNA at the actual end of study drug treatment and confirmed HCV RNA greater than or equal to (>=) LLOQ during follow-up.
Number of Participants Not Achieving Sustained Virologic Response (SVR) Showing Emerging Mutation in HCV Nonstructural Protein 3/4A (NS3/4A), Nonstructural Protein 5A (NS5A), and Nonstructural Protein 5B (NS5B) Sequence
Full Information
NCT ID
NCT02421211
First Posted
April 15, 2015
Last Updated
March 27, 2019
Sponsor
Janssen Sciences Ireland UC
1. Study Identification
Unique Protocol Identification Number
NCT02421211
Brief Title
A Study to Investigate the Pharmacokinetic Interactions Between Simeprevir and Ledipasvir in a Treatment Regimen Consisting of Simeprevir, Sofosbuvir, and Ledipasvir in Treatment-naive Participants With Chronic Hepatitis C Virus Genotype 1 Infection
Official Title
A Phase 2, 2-panel, Open-label Randomized Study in Hepatitis C Virus Infected Subjects to Investigate the Pharmacokinetic Interactions Between Simeprevir and Ledipasvir in a Treatment Regimen Consisting of Simeprevir, Sofosbuvir and Ledipasvir in Treatment-naive Participants.
Study Type
Interventional
2. Study Status
Record Verification Date
March 2019
Overall Recruitment Status
Completed
Study Start Date
May 19, 2015 (Actual)
Primary Completion Date
November 10, 2015 (Actual)
Study Completion Date
January 27, 2016 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Janssen Sciences Ireland UC
4. Oversight
Data Monitoring Committee
No
5. Study Description
Brief Summary
The purpose of this study is to evaluate the pharmacokinetic interactions between simeprevir and ledipasvir in a treatment regimen consisting of simeprevir (SMV), sofosbuvir (SOF), and ledipasvir (LDV) in treatment-naive participants with chronic hepatitis C virus (HCV) genotype 1 infection.
Detailed Description
This is an open-label (all people know the identity of the intervention), 2-panel, Phase 2, randomized (study medication assigned to participants by chance) study. The study will consist of 3 study phases: Screening Phase (5 weeks), an Open-label Treatment Phase (70 days for Panel 1 and 56 days for Panel 2), a Post-treatment Follow-up Phase (12 weeks after the actual end of treatment). Participants will receive a combination of the following treatments: Treatment A: SMV 150 milligram (mg) once daily; Treatment B: LDV 90 mg along with SOF 400 mg once daily; Treatment C: SOF 400 mg once daily. Participants will be randomly assigned to Panel 1 (Treatment AC followed by Treatment AB) and Panel 2 (Treatment B followed by Treatment AB). The total study duration will be approximately 27 weeks for participants in Panel 1 and 25 weeks for participants in Panel 2. Participants will be primarily accessed for pharmacokinetic parameters. Participants' safety will be monitored throughout the study.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hepatitis C, Chronic
Keywords
Hepatitis C, Chronic, Simeprevir, Ledipasvir, Sofosbuvir
7. Study Design
Primary Purpose
Other
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
41 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Panel 1
Arm Type
Experimental
Arm Description
Participants will receive Simeprevir (SMV) 150 milligram (mg) capsule (Treatment A) along with Sofosbuvir (SOF) 400 mg tablet, orally, once daily (Treatment C) from Day 1 until Day 14 followed by SMV 150 mg capsule (Treatment A) along with fixed dose combination (FDC) tablet of 90 mg Ledipasvir (LDV)/400 mg SOF (Treatment B), orally, once daily from Day 15 until Day 70.
Arm Title
Panel 2
Arm Type
Experimental
Arm Description
Participants will receive FDC tablet of 90 mg LDV/400 mg SOF (Treatment B), orally, once daily from Day 1 until Day 14 followed by SMV 150 mg capsule (Treatment A) along with FDC tablet of 90 mg LDV/400 mg SOF (Treatment B), orally, once daily from Day 15 until Day 56.
Intervention Type
Drug
Intervention Name(s)
Simeprevir (SMV)
Intervention Description
Participants will receive 150 milligram (mg) of SMV (Treatment A) once daily in Panel 1 and Panel 2.
Intervention Type
Drug
Intervention Name(s)
Ledipasvir (LDV)
Intervention Description
Participants will receive 90 mg of LDV once daily as FDC tablet with SOF (Treatment B) in Panel 1 and Panel 2.
Intervention Type
Drug
Intervention Name(s)
Sofosbuvir (SOF)
Intervention Description
Participants will receive 400 mg of SOF alone (Treatment C) in Panel 1 and as FDC tablet with LDV (Treatment B) once daily in Panel 2.
Primary Outcome Measure Information:
Title
Minimum Plasma Concentration (Cmin) of Simeprevir (SMV)
Description
The Cmin is the minimum observed plasma concentration.
Time Frame
Pre-dose, 0.5, 1, 2, 4, 6, 8, 10, 12, 18, and 24 hours post-dose on Day 14 and Day 28
Title
Maximum Plasma Concentration (Cmax) of Simeprevir
Description
The Cmax is the maximum observed plasma concentration.
Time Frame
Pre-dose, 0.5, 1, 2, 4, 6, 8, 10, 12, 18, and 24 hours post-dose on Day 14 and Day 28
Title
Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) of Simeprevir
Description
The AUCtau is the measure of the plasma drug concentration from time zero to end of dosing interval. It is used to characterize drug absorption.
Time Frame
Pre-dose, 0.5, 1, 2, 4, 6, 8, 10, 12, 18, and 24 hours post-dose on Day 14 and Day 28
Title
Minimum Plasma Concentration (Cmin) of Ledipasvir (LDV)
Description
The Cmin is the minimum observed plasma concentration.
Time Frame
Pre-dose, 0.5, 1, 2, 4, 6, 8, 10, 12, 18, and 24 hours post-dose on Day 14 and Day 28
Title
Maximum Plasma Concentration (Cmax) of Ledipasvir
Description
The Cmax is the maximum observed plasma concentration.
Time Frame
Pre-dose, 0.5, 1, 2, 4, 6, 8, 10, 12, 18, and 24 hours post-dose on Day 14 and Day 28
Title
Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) of Ledipasvir
Description
AUCtau is defined as area under the analyte concentration versus time curve during dosing interval tau, calculated by linear-linear trapezoidal summation.
Time Frame
Pre-dose, 0.5, 1, 2, 4, 6, 8, 10, 12, 18, and 24 hours post-dose on Day 14 and Day 28
Secondary Outcome Measure Information:
Title
Trough Plasma Concentration (Ctrough) of Simeprevir
Description
The (Ctrough) is the plasma concentration before dosing or at the end of the dosing interval of any dose other than the first dose in a multiple dosing regimen.
Time Frame
Pre-dose on Day 14 and Day 28
Title
Time to Reach Maximum Plasma Concentration (Tmax) of Simeprevir
Description
The Tmax is defined as actual sampling time to reach maximum observed analyte concentration.
Time Frame
Pre-dose, 0.5, 1, 2, 4, 6, 8, 10, 12, 18, and 24 hours post-dose on Day 14 and Day 28
Title
Average Plasma Concentration at Steady State (Cavg,ss) of Simeprevir
Description
The Cavg,ss is calculated as area under the plasma concentration-time curve during a dosing Interval (AUC[tau]) divided by the dosing interval (tau).
Time Frame
Pre-dose, 0.5, 1, 2, 4, 6, 8, 10, 12, 18, and 24 hours post-dose on Day 14 and Day 28
Title
Fluctuation Index (FI) of Simeprevir
Description
Fluctuation index is defined as percentage fluctuation (variation between maximum and minimum concentration at steady state), calculated as: 100*([Cmax Cmin]/Cavg).
Time Frame
Pre-dose, 0.5, 1, 2, 4, 6, 8, 10, 12, 18, and 24 hours post-dose on Day 14 and Day 28
Title
Trough Plasma Concentration (Ctrough) of Ledipasvir
Description
The (Ctrough) is the plasma concentration before dosing or at the end of the dosing interval of any dose other than the first dose in a multiple dosing regimen.
Time Frame
Pre-dose on Day 14 and Day 28
Title
Time to Reach Maximum Plasma Concentration (Tmax) of Ledipasvir
Description
The Tmax is defined as actual sampling time to reach maximum observed analyte concentration.
Time Frame
Pre-dose, 0.5, 1, 2, 4, 6, 8, 10, 12, 18, and 24 hours post-dose on Day 14 and Day 28
Title
Average Plasma Concentration at Steady State (Cavg,ss) of Ledipasvir
Description
The Cavg,ss is calculated as area under the plasma concentration-time curve during a dosing Interval (AUC[tau]) divided by the dosing interval (tau).
Time Frame
Pre-dose, 0.5, 1, 2, 4, 6, 8, 10, 12, 18, and 24 hours post-dose on Day 14 and Day 28
Title
Fluctuation Index (FI) of Ledipasvir
Description
Fluctuation index is defined as percentage fluctuation (variation between maximum and minimum concentration at steady state), calculated as: 100*([Cmax Cmin]/Cavg).
Time Frame
Pre-dose, 0.5, 1, 2, 4, 6, 8, 10, 12, 18, and 24 hours post-dose on Day 14 and Day 28
Title
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
Description
An AE is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An SAE is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly.
Time Frame
Up to 10 Weeks for Panel 1 and 8 Weeks for Panel 2
Title
Percentage of Participants With On-treatment Virologic Response
Description
On-treatment virologic response was determined by hepatitis C virus (HCV) ribonucleic acid (RNA) results satisfying a specified threshold.
The following thresholds were considered at any time point: less than (<) lower limit of quantification (LLOQ) undetectable, <LLOQ detectable and <LLOQ undetectable/detectable.
Time Frame
Week 1, up to EOT (Week 10 in Panel 1 and Week 8 in Panel 2)
Title
Percentage of Participants With Sustained Virologic Response (SVR) 4 Weeks After the Actual EOT (SVR4) and 12 Weeks After the Actual EOT (SVR12)
Description
SVR4 or SVR12 is defined as sustained virologic response 4 or 12 weeks after the actual EOT the participant has HCV RNA <LLOQ detectable or undetectable.
Time Frame
4 weeks after EOT (Week 4 of follow-up phase in Panel 1 and Panel 2) and 12 weeks after EOT (Week 12 of follow-up phase in Panel 1 and Panel 2)
Title
Percentage of Participants With On-treatment Failure
Description
On-treatment failure is defined as participants who did not achieve SVR12 and with confirmed detectable HCV RNA at the actual end of treatment. This was to include participants with: 1) Viral breakthrough, defined as a confirmed increase of greater than (>)1 log10 in HCV RNA from nadir, or confirmed HCV RNA of >100 IU/mL in participants whose HCV RNA had previously been <LLOQ while on treatment; 2) Other with confirmed detectable HCV RNA at the actual end of treatment (example, completed, discontinued due to AEs, withdrawal of consent).
Time Frame
Day 70 in Panel 1 and Day 56 in Panel 2
Title
Percentage of Participants With Viral Relapse
Description
Participants who did not achieve SVR12, with undetectable HCV RNA at the actual end of study drug treatment and confirmed HCV RNA greater than or equal to (>=) LLOQ during follow-up.
Time Frame
Up to Week 12 follow-up phase after EOT
Title
Number of Participants Not Achieving Sustained Virologic Response (SVR) Showing Emerging Mutation in HCV Nonstructural Protein 3/4A (NS3/4A), Nonstructural Protein 5A (NS5A), and Nonstructural Protein 5B (NS5B) Sequence
Time Frame
Up to end of follow-up phase (Week 12 of follow-up phase) in Panel 1 and Panel 2
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
70 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Participants with Body Mass Index (weight in kilogram [kg] divided by the square of height in meters) of 18.0 to 35.0 kilogram per square meter kg/m^2, extremes included
Participants must be treatment-naive (that is, have not received prior treatment with any approved or investigational drug)
Participants with HCV ribonucleic acid (RNA) plasma levels greater than (>) 10,000 international unit per milliliter (IU/ml) and lower than 6,000,000 international unit per milliliter (IU/ml) at screening
Participants with absence of cirrhosis confirmed by FibroTest/Fibrosure score less or equal to 0.75 and an aspartate aminotransferase to platelet ration index less or equal to 2 or a Fibroscan less or equal to 14.6 kilopascale (kPA), performed within 6 months prior or during the screening period
Participants with documented chronic HCV infection: diagnosis of HCV infection >6 months prior to screening, either by detectable HCV RNA, an HCV positive antibody test or presence of histological changes consistent with chronic hepatitis in a liver biopsy
Exclusion Criteria:
Participant has infection/co-infection with HCV of a genotype other than genotype 1, human immunodeficiency virus (HIV) type 1 or 2
Participant has any evidence of liver disease of non-HCV etiology. This includes, but is not limited to acute hepatitis A, active hepatitis B, drug- or alcohol-related liver disease, autoimmune hepatitis, hemochromatosis, Wilson's disease, alpha-1 antitrypsin deficiency, non-alcoholic steatohepatitis, primary biliary cirrhosis, or any other non-HC liver disease considered clinically significant by the investigator
Participant with significant co-morbidities, conditions or clinical significant findings during screening assessments that in the opinion of the investigator could compromise the participants' safety or could interfere with the Participant participating in and completing the study
Participant received an organ transplant (other than cornea or hair transplant or skin graft)
Participants have key protocol defined laboratory abnormalities
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Janssen Sciences Ireland UC Clinical Trial
Organizational Affiliation
Janssen Sciences Ireland UC
Official's Role
Study Director
Facility Information:
City
Antwerpen
Country
Belgium
City
Brussel
Country
Belgium
City
Gent
Country
Belgium
City
Leuven
Country
Belgium
12. IPD Sharing Statement
Citations:
PubMed Identifier
28971875
Citation
Bourgeois S, Horsmans Y, Nevens F, van Vlierberghe H, Moreno C, Beumont M, Vijgen L, van Eygen V, Luo D, Hillewaert V, Van Remoortere P, van de Logt J, Ouwerkerk-Mahadevan S. Pharmacokinetic Interactions between Simeprevir and Ledipasvir in Treatment-Naive Hepatitis C Virus Genotype 1-Infected Patients without Cirrhosis Treated with a Simeprevir-Sofosbuvir-Ledipasvir Regimen. Antimicrob Agents Chemother. 2017 Nov 22;61(12):e01217-17. doi: 10.1128/AAC.01217-17. Print 2017 Dec.
Results Reference
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A Study to Investigate the Pharmacokinetic Interactions Between Simeprevir and Ledipasvir in a Treatment Regimen Consisting of Simeprevir, Sofosbuvir, and Ledipasvir in Treatment-naive Participants With Chronic Hepatitis C Virus Genotype 1 Infection
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