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Trial record 16 of 20 for:    Genotype 1 | BI 201335 OR faldaprevir

Drug Drug Interaction Study Between BI 201335 and BI 207127 in Chronic Hepatitis C Infected Patients

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ClinicalTrials.gov Identifier: NCT01525628
Recruitment Status : Completed
First Posted : February 3, 2012
Results First Posted : June 10, 2016
Last Update Posted : June 10, 2016
Sponsor:
Information provided by (Responsible Party):
Boehringer Ingelheim

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Hepatitis C, Chronic
Interventions Drug: midazolam
Drug: BI 201335
Drug: tenofovir
Drug: caffeine
Drug: tolbutamide
Drug: pegylated interferon
Drug: BI 207127
Drug: ribavirin
Enrollment 72
Recruitment Details 72 patients were treated and analysed.
Pre-assignment Details This was randomised (Groups A and B only), controlled, open-label, parallel-group (Groups A to E), multi-centre trial in treatment-naive patients and patients with prior treatment relapse or partial responders with Genotype 1 (GT1) chronic Hepatitis C infection.
Arm/Group Title Group A Group B Group C Group D Group E
Hide Arm/Group Description 600mg deleobuvir(DBV) tablet taken orally 3 times a day plus 120mg faldaprevir(FDV) capsule taken orally once daily plus ribavirin(RBV) tablet taken orally twice daily for 24 weeks along with pegylated interferon α-2a(PegIFN) injection and probe drugs(200 mg caffeine tablet, 500 mg tolbutamide tablet, and 2 mg midazolam syrup administered orally on days 1, 9, 17, and 66). In group A the effect of DBV on FDV, the effect of FDV, dual oral direct acting antiviral (DAAs) and their metabolites on caffeine, tolbutamide and midazolam were determined. 600mg deleobuvir(DBV) tablet taken orally 3 times a day plus 120mg faldaprevir(FDV) capsule taken orally once daily plus ribavirin(RBV) tablet taken orally twice daily for 24 weeks along with pegylated interferon α-2a (PegIFN) injection and probe drugs(200 mg caffeine tablet, 500 mg tolbutamide tablet, and 2 mg midazolam syrup administered orally on days 1, 9, 17, and 66). In group B the effect of FDV on DBV, the effect of DBV, dual oral direct acting antiviral (DAAs) and their metabolites on caffeine, tolbutamide and midazolam were determined. 600mg deleobuvir(DBV) tablet taken twice a day plus 120mg faldaprevir(FDV) capsule taken orally once daily plus ribavirin(RBV) tablet taken orally twice daily for 24 weeks with tenofovir tablet 300mg daily on days 1-17. 600mg deleobuvir(DBV) tablet taken twice a day plus 120mg faldaprevir(FDV) capsule taken orally once daily plus ribavirin(RBV) tablet taken orally twice daily with probe drugs(200 mg caffeine tablet, 500 mg tolbutamide tablet, and 2 mg midazolam syrup administered orally on days 1, 9, 17, and 66). 600mg deleobuvir(DBV) tablet taken twice a day plus 120mg faldaprevir(FDV) capsule taken orally once daily plus ribavirin(RBV) tablet taken orally twice daily for 24 weeks with raltegravir tablet 400mg twice daily on days 1-17.
Period Title: Overall Study
Started 16 19 16 14 7
Completed 14 14 11 10 4
Not Completed 2 5 5 4 3
Reason Not Completed
Adverse Event             1             1             2             0             1
Lack of Efficacy             0             2             2             1             2
Protocol Violation             0             0             1             0             0
Lost to Follow-up             1             1             0             0             0
Withdrawal by Subject             0             1             0             0             0
Other reason not defined above             0             0             0             3             0
Arm/Group Title Group A Group B Group C Group D Group E Total
Hide Arm/Group Description 600mg deleobuvir(DBV) tablet taken orally 3 times a day plus 120mg faldaprevir(FDV) capsule taken orally once daily plus ribavirin(RBV) tablet taken orally twice daily for 24 weeks along with pegylated interferon α-2a(PegIFN) injection and probe drugs(200 mg caffeine tablet, 500 mg tolbutamide tablet, and 2 mg midazolam syrup administered orally on days 1, 9, 17, and 66). In group A the effect of DBV on FDV, the effect of FDV, dual oral direct acting antiviral (DAAs) and their metabolites on caffeine, tolbutamide and midazolam were determined. 600mg deleobuvir(DBV) tablet taken orally 3 times a day plus 120mg faldaprevir(FDV) capsule taken orally once daily plus ribavirin(RBV) tablet taken orally twice daily for 24 weeks along with pegylated interferon α-2a (PegIFN) injection and probe drugs(200 mg caffeine tablet, 500 mg tolbutamide tablet, and 2 mg midazolam syrup administered orally on days 1, 9, 17, and 66). In group B the effect of FDV on DBV, the effect of DBV, dual oral direct acting antiviral (DAAs) and their metabolites on caffeine, tolbutamide and midazolam were determined. 600mg deleobuvir(DBV) tablet taken twice a day plus 120mg faldaprevir(FDV) capsule taken orally once daily plus ribavirin(RBV) tablet taken orally twice daily for 24 weeks with tenofovir tablet 300mg daily on days 1-17. 600mg deleobuvir(DBV) tablet taken twice a day plus 120mg faldaprevir(FDV) capsule taken orally once daily plus ribavirin(RBV) tablet taken orally twice daily with probe drugs(200 mg caffeine tablet, 500 mg tolbutamide tablet, and 2 mg midazolam syrup administered orally on days 1, 9, 17, and 66). 600mg deleobuvir(DBV) tablet taken twice a day plus 120mg faldaprevir(FDV) capsule taken orally once daily plus ribavirin(RBV) tablet taken orally twice daily for 24 weeks with raltegravir tablet 400mg twice daily on days 1-17. Total of all reporting groups
Overall Number of Baseline Participants 16 19 16 14 7 72
Hide Baseline Analysis Population Description
The treated set (TRT) included all patients who were dispensed trial medication and were documented to have taken at least one dose of trial drug.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 16 participants 19 participants 16 participants 14 participants 7 participants 72 participants
48.2  (12.3) 53.6  (9.3) 53.1  (9.5) 48.4  (12.7) 52.1  (10.4) 51.1  (10.9)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 16 participants 19 participants 16 participants 14 participants 7 participants 72 participants
Female
7
  43.8%
8
  42.1%
5
  31.3%
7
  50.0%
1
  14.3%
28
  38.9%
Male
9
  56.3%
11
  57.9%
11
  68.8%
7
  50.0%
6
  85.7%
44
  61.1%
1.Primary Outcome
Title Cmax of Faldaprevir (BI 201335)
Hide Description Maximum concentration of an analyte in plasma
Time Frame PK plasma samples were taken at: 5 minutes before drug administration and 1 hour (h), 2h, 3h, 4h, 5h, 5:55h, 8h, 10h, 11:55h, 15h, 23:55h after first drug administration on days 9, 17 and 66.
Hide Outcome Measure Data
Hide Analysis Population Description
The pharmacokinetic set (PKS): included all patients in the treated set who provided at least one observation for at least one primary (PK) endpoint without important protocol violations relevant to the evaluation of PK. This endpoint was not planned to be analysed for groups C, D and E.
Arm/Group Title Group A Group B
Hide Arm/Group Description:
600mg deleobuvir(DBV) tablet taken orally 3 times a day plus 120mg faldaprevir(FDV) capsule taken orally once daily plus ribavirin(RBV) tablet taken orally twice daily for 24 weeks along with pegylated interferon α-2a(PegIFN) injection and probe drugs(200 mg caffeine tablet, 500 mg tolbutamide tablet, and 2 mg midazolam syrup administered orally on days 1, 9, 17, and 66). In group A the effect of DBV on FDV, the effect of FDV, dual oral direct acting antiviral (DAAs) and their metabolites on caffeine, tolbutamide and midazolam were determined.
600mg deleobuvir(DBV) tablet taken orally 3 times a day plus 120mg faldaprevir(FDV) capsule taken orally once daily plus ribavirin(RBV) tablet taken orally twice daily for 24 weeks along with pegylated interferon α-2a (PegIFN) injection and probe drugs(200 mg caffeine tablet, 500 mg tolbutamide tablet, and 2 mg midazolam syrup administered orally on days 1, 9, 17, and 66). In group B the effect of FDV on DBV, the effect of DBV, dual oral direct acting antiviral (DAAs) and their metabolites on caffeine, tolbutamide and midazolam were determined.
Overall Number of Participants Analyzed 16 19
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ng/mL
Day 9 (N=15,0)
3520
(54.8%)
NA [1] 
(NA%)
Day 17 (N=14,14)
8780
(47.5%)
9950
(51.0%)
Day 66 (N=13,15)
4410
(48.7%)
6690
(78.8%)
[1]
Not calculated as this timepoint was not planned to be analysed for group B.
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Group A
Comments Day 17 vs. Day 9
Type of Statistical Test Non-Inferiority or Equivalence
Comments p-value for ratio outside 80% to 125%
Statistical Test of Hypothesis P-Value 1.0000
Comments [Not Specified]
Method ANOVA
Comments

ANOVA (analysis of variance) model on the logarithm scale was used with

‘subject’ as random, whereas the ‘treatment’ as fixed effect.

Method of Estimation Estimation Parameter Ratio of gmeans Day 17 vs. Day 9 (%)
Estimated Value 251.37
Confidence Interval (2-Sided) 90%
205.54 to 307.43
Parameter Dispersion
Type: Standard Deviation
Value: 31.0
Estimation Comments Relative bioavailability of BI 201335 at Day 17 vs. Day 9 −was estimated by the ratios of the adjusted geometric means (gMean). Standard deviation is actually Intra individual geometric coefficient variation (gCV).
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Group A
Comments Day 66 vs. Day 9
Type of Statistical Test Non-Inferiority or Equivalence
Comments p-value for ratio outside 80% to 125%
Statistical Test of Hypothesis P-Value 0.6514
Comments [Not Specified]
Method ANOVA
Comments

ANOVA (analysis of variance) model on the logarithm scale was used with

‘subject’ as random, whereas the ‘treatment’ as fixed effect.

Method of Estimation Estimation Parameter Ratio of gmeans Day 66 vs. Day 9 (%)
Estimated Value 131.30
Confidence Interval (2-Sided) 90%
105.40 to 163.57
Parameter Dispersion
Type: Standard Deviation
Value: 32.5
Estimation Comments Relative bioavailability of BI 201335 at Day 66 vs. Day 9 −was estimated by the ratios of the adjusted geometric means (gMean). Standard deviation is actually Intra individual geometric coefficient variation (gCV).
2.Primary Outcome
Title C24hr of Faldaprevir (BI 201335)
Hide Description Concentration of an analyte in plasma at 24 hours
Time Frame PK plasma samples were taken at: 5 minutes before drug administration and 1 hour (h), 2h, 3h, 4h, 5h, 5:55h, 8h, 10h, 11:55h, 15h, 23:55h after first drug administration on days 9, 17 and 66.
Hide Outcome Measure Data
Hide Analysis Population Description
The pharmacokinetic set (PKS): included all patients in the treated set who provided at least one observation for at least one primary (PK) endpoint without important protocol violations relevant to the evaluation of PK. This endpoint was not planned to be analysed for groups C, D and E.
Arm/Group Title Group A Group B
Hide Arm/Group Description:
600mg deleobuvir(DBV) tablet taken orally 3 times a day plus 120mg faldaprevir(FDV) capsule taken orally once daily plus ribavirin(RBV) tablet taken orally twice daily for 24 weeks along with pegylated interferon α-2a(PegIFN) injection and probe drugs(200 mg caffeine tablet, 500 mg tolbutamide tablet, and 2 mg midazolam syrup administered orally on days 1, 9, 17, and 66). In group A the effect of DBV on FDV, the effect of FDV, dual oral direct acting antiviral (DAAs) and their metabolites on caffeine, tolbutamide and midazolam were determined.
600mg deleobuvir(DBV) tablet taken orally 3 times a day plus 120mg faldaprevir(FDV) capsule taken orally once daily plus ribavirin(RBV) tablet taken orally twice daily for 24 weeks along with pegylated interferon α-2a (PegIFN) injection and probe drugs(200 mg caffeine tablet, 500 mg tolbutamide tablet, and 2 mg midazolam syrup administered orally on days 1, 9, 17, and 66). In group B the effect of FDV on DBV, the effect of DBV, dual oral direct acting antiviral (DAAs) and their metabolites on caffeine, tolbutamide and midazolam were determined.
Overall Number of Participants Analyzed 16 19
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ng/mL
Day 9 (N=15,0)
983
(65.5%)
NA [1] 
(NA%)
Day 17 (N=14,19)
3670
(90.4%)
5410
(91.6%)
Day 66 (N=13,14)
1140
(107%)
2580
(135%)
[1]
Not calculated as this timepoint was not planned to be analysed for group B.
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Group A
Comments Day 17 vs. Day 9
Type of Statistical Test Non-Inferiority or Equivalence
Comments p-value for ratio outside 80% to 125%
Statistical Test of Hypothesis P-Value 1.0000
Comments [Not Specified]
Method ANOVA
Comments

ANOVA (analysis of variance) model on the logarithm scale was used with

‘subject’ as random, whereas the ‘treatment’ as fixed effect.

Method of Estimation Estimation Parameter Ratio of gmeans Day 17 vs. Day 9 (%)
Estimated Value 381.11
Confidence Interval (2-Sided) 90%
317.01 to 458.19
Parameter Dispersion
Type: Standard Deviation
Value: 28.1
Estimation Comments Relative bioavailability of BI 201335 at Day 17 vs. Day 9 −was estimated by the ratios of the adjusted geometric means (gMean). Standard deviation is actually Intra individual geometric coefficient variation (gCV).
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Group A
Comments Day 66 vs. Day 9
Type of Statistical Test Non-Inferiority or Equivalence
Comments p-value for ratio outside 80% to 125%
Statistical Test of Hypothesis P-Value 0.4718
Comments [Not Specified]
Method ANOVA
Comments

ANOVA (analysis of variance) model on the logarithm scale was used with

‘subject’ as random, whereas the ‘treatment’ as fixed effect.

Method of Estimation Estimation Parameter Ratio of gmeans Day 66 vs. Day 9 (%)
Estimated Value 123.65
Confidence Interval (2-Sided) 90%
94.66 to 161.51
Parameter Dispersion
Type: Standard Deviation
Value: 40.0
Estimation Comments Relative bioavailability of BI 201335 at Day 66 vs. Day 9 −was estimated by the ratios of the adjusted geometric means (gMean). Standard deviation is actually Intra individual geometric coefficient variation (gCV).
3.Primary Outcome
Title Area Under the Concentration-time Curve (AUC) of Faldaprevir (BI 201335) From 0 to 24 Hours
Hide Description Area under the concentration-time curve of the analyte in plasma over the time interval from 0 to 24 hours
Time Frame PK plasma samples were taken at: 5 minutes before drug administration and 1 hour (h), 2h, 3h, 4h, 5h, 5:55h, 8h, 10h, 11:55h, 15h, 23:55h after first drug administration on days 9, 17 and 66.
Hide Outcome Measure Data
Hide Analysis Population Description
The pharmacokinetic set (PKS): included all patients in the treated set who provided at least one observation for at least one primary (PK) endpoint without important protocol violations relevant to the evaluation of PK. This endpoint was not planned to be analysed for groups C, D and E.
Arm/Group Title Group A Group B
Hide Arm/Group Description:
600mg deleobuvir(DBV) tablet taken orally 3 times a day plus 120mg faldaprevir(FDV) capsule taken orally once daily plus ribavirin(RBV) tablet taken orally twice daily for 24 weeks along with pegylated interferon α-2a(PegIFN) injection and probe drugs(200 mg caffeine tablet, 500 mg tolbutamide tablet, and 2 mg midazolam syrup administered orally on days 1, 9, 17, and 66). In group A the effect of DBV on FDV, the effect of FDV, dual oral direct acting antiviral (DAAs) and their metabolites on caffeine, tolbutamide and midazolam were determined.
600mg deleobuvir(DBV) tablet taken orally 3 times a day plus 120mg faldaprevir(FDV) capsule taken orally once daily plus ribavirin(RBV) tablet taken orally twice daily for 24 weeks along with pegylated interferon α-2a (PegIFN) injection and probe drugs(200 mg caffeine tablet, 500 mg tolbutamide tablet, and 2 mg midazolam syrup administered orally on days 1, 9, 17, and 66). In group B the effect of FDV on DBV, the effect of DBV, dual oral direct acting antiviral (DAAs) and their metabolites on caffeine, tolbutamide and midazolam were determined.
Overall Number of Participants Analyzed 16 19
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ng*h/mL
Day 9 (N=15,0)
45600
(54.5%)
NA [1] 
(NA%)
Day 17 (N=14,19)
138000
(62.1%)
173000
(60.8%)
Day 66 (N=13,15)
56200
(58.2%)
97300
(114%)
[1]
Not calculated as this timepoint was not planned to be analysed for group B.
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Group A
Comments Day 17 vs. Day 9
Type of Statistical Test Non-Inferiority or Equivalence
Comments p-value for ratio outside 80% to 125%
Statistical Test of Hypothesis P-Value 1.0000
Comments [Not Specified]
Method ANOVA
Comments

ANOVA (analysis of variance) model on the logarithm scale was used with

‘subject’ as random, whereas the ‘treatment’ as fixed effect.

Method of Estimation Estimation Parameter Ratio of gmeans Day 17 vs. Day 9 (%)
Estimated Value 306.45
Confidence Interval (2-Sided) 90%
250.93 to 374.26
Parameter Dispersion
Type: Standard Deviation
Value: 30.7
Estimation Comments Relative bioavailability of BI 201335 at Day 17 vs. Day 9 −was estimated by the ratios of the adjusted geometric means (gMean). Standard deviation is actually Intra individual geometric coefficient variation (gCV).
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Group A
Comments Day 66 vs. Day 9
Type of Statistical Test Non-Inferiority or Equivalence
Comments p-value for ratio outside 80% to 125%
Statistical Test of Hypothesis P-Value 0.6185
Comments [Not Specified]
Method ANOVA
Comments

ANOVA (analysis of variance) model on the logarithm scale was used with

‘subject’ as random, whereas the ‘treatment’ as fixed effect.

Method of Estimation Estimation Parameter Ratio of gmeans Day 66 vs. Day 9 (%)
Estimated Value 129.85
Confidence Interval (2-Sided) 90%
104.26 to 161.71
Parameter Dispersion
Type: Standard Deviation
Value: 32.5
Estimation Comments Relative bioavailability of BI 201335 at Day 66 vs. Day 9 −was estimated by the ratios of the adjusted geometric means (gMean). Standard deviation is actually Intra individual geometric coefficient variation (gCV).
4.Primary Outcome
Title Cmax of Deleobuvir (BI 207127)
Hide Description Maximum concentration of an analyte in plasma
Time Frame PK plasma samples were taken at: 5 minutes before drug administration and 1 hour (h), 2h, 3h, 4h, 5h, 5:55h, 8h, 10h, 11:55h, 15h, 23:55h after first drug administration on days 9, 17 and 66.
Hide Outcome Measure Data
Hide Analysis Population Description
The pharmacokinetic set (PKS): included all patients in the treated set who provided at least one observation for at least one primary (PK) endpoint without important protocol violations relevant to the evaluation of PK. This endpoint was not planned to be analysed for groups C, D and E.
Arm/Group Title Group A Group B
Hide Arm/Group Description:
600mg deleobuvir(DBV) tablet taken orally 3 times a day plus 120mg faldaprevir(FDV) capsule taken orally once daily plus ribavirin(RBV) tablet taken orally twice daily for 24 weeks along with pegylated interferon α-2a(PegIFN) injection and probe drugs(200 mg caffeine tablet, 500 mg tolbutamide tablet, and 2 mg midazolam syrup administered orally on days 1, 9, 17, and 66). In group A the effect of DBV on FDV, the effect of FDV, dual oral direct acting antiviral (DAAs) and their metabolites on caffeine, tolbutamide and midazolam were determined.
600mg deleobuvir(DBV) tablet taken orally 3 times a day plus 120mg faldaprevir(FDV) capsule taken orally once daily plus ribavirin(RBV) tablet taken orally twice daily for 24 weeks along with pegylated interferon α-2a (PegIFN) injection and probe drugs(200 mg caffeine tablet, 500 mg tolbutamide tablet, and 2 mg midazolam syrup administered orally on days 1, 9, 17, and 66). In group B the effect of FDV on DBV, the effect of DBV, dual oral direct acting antiviral (DAAs) and their metabolites on caffeine, tolbutamide and midazolam were determined.
Overall Number of Participants Analyzed 16 19
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: nmol/L
Day 9 (N=0, 17)
NA [1] 
(NA%)
10900
(85.3%)
Day 17 (N=14, 19)
27000
(64.6%)
31400
(45.8%)
Day 66 (N=13, 15)
10100
(78.2%)
16000
(100%)
[1]
Not calculated as this timepoint was not planned to be analysed for group A.
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Group B
Comments Day 17 vs. Day 9
Type of Statistical Test Non-Inferiority or Equivalence
Comments p-value for ratio outside 80% to 125%
Statistical Test of Hypothesis P-Value 1.0000
Comments [Not Specified]
Method ANOVA
Comments

ANOVA (analysis of variance) model on the logarithm scale was used with

‘subject’ as random, whereas the ‘treatment’ as fixed effect.

Method of Estimation Estimation Parameter Ratio of gmeans Day 17 vs. Day 9 (%)
Estimated Value 286.01
Confidence Interval (2-Sided) 90%
228.51 to 357.97
Parameter Dispersion
Type: Standard Deviation
Value: 39.4
Estimation Comments Relative bioavailability of BI 207127 at Day 17 vs. Day 9 −was estimated by the ratios of the adjusted geometric means (gMean). Standard deviation is actually Intra individual geometric coefficient variation (gCV).
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Group B
Comments Day 66 vs. Day 9
Type of Statistical Test Non-Inferiority or Equivalence
Comments p-value for ratio outside 80% to 125%
Statistical Test of Hypothesis P-Value 0.8210
Comments [Not Specified]
Method ANOVA
Comments

ANOVA (analysis of variance) model on the logarithm scale was used with

‘subject’ as random, whereas the ‘treatment’ as fixed effect.

Method of Estimation Estimation Parameter Ratio of gmeans Day 66 vs. Day 9 (%)
Estimated Value 150.45
Confidence Interval (2-Sided) 90%
106.81 to 211.91
Parameter Dispersion
Type: Standard Deviation
Value: 55.1
Estimation Comments Relative bioavailability of BI 207127 at Day 66 vs. Day 9 −was estimated by the ratios of the adjusted geometric means (gMean). Standard deviation is actually Intra individual geometric coefficient variation (gCV).
5.Primary Outcome
Title C6hr of Deleobuvir (BI 207127)
Hide Description Concentration of an analyte in plasma at 6 hours
Time Frame PK plasma samples were taken at: 5 minutes before drug administration and 1 hour (h), 2h, 3h, 4h, 5h, 5:55h, 8h, 10h, 11:55h, 15h, 23:55h after first drug administration on days 9, 17 and 66.
Hide Outcome Measure Data
Hide Analysis Population Description
The pharmacokinetic set (PKS): included all patients in the treated set who provided at least one observation for at least one primary (PK) endpoint without important protocol violations relevant to the evaluation of PK. This endpoint was not planned to be analysed for groups C, D and E.
Arm/Group Title Group A Group B
Hide Arm/Group Description:
600mg deleobuvir(DBV) tablet taken orally 3 times a day plus 120mg faldaprevir(FDV) capsule taken orally once daily plus ribavirin(RBV) tablet taken orally twice daily for 24 weeks along with pegylated interferon α-2a(PegIFN) injection and probe drugs(200 mg caffeine tablet, 500 mg tolbutamide tablet, and 2 mg midazolam syrup administered orally on days 1, 9, 17, and 66). In group A the effect of DBV on FDV, the effect of FDV, dual oral direct acting antiviral (DAAs) and their metabolites on caffeine, tolbutamide and midazolam were determined.
600mg deleobuvir(DBV) tablet taken orally 3 times a day plus 120mg faldaprevir(FDV) capsule taken orally once daily plus ribavirin(RBV) tablet taken orally twice daily for 24 weeks along with pegylated interferon α-2a (PegIFN) injection and probe drugs(200 mg caffeine tablet, 500 mg tolbutamide tablet, and 2 mg midazolam syrup administered orally on days 1, 9, 17, and 66). In group B the effect of FDV on DBV, the effect of DBV, dual oral direct acting antiviral (DAAs) and their metabolites on caffeine, tolbutamide and midazolam were determined.
Overall Number of Participants Analyzed 16 19
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: nmol/L
Day 9 (N=0, 17)
NA [1] 
(NA%)
5800
(129%)
Day 17 (N=14, 19)
17900
(84.2%)
20800
(83.8%)
Day 66 (N=13, 14)
5080
(108%)
10100
(133%)
[1]
Not calculated as this timepoint was not planned to be analysed for group A.
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Group B
Comments Day 17 vs. Day 9
Type of Statistical Test Non-Inferiority or Equivalence
Comments p-value for ratio outside 80% to 125%
Statistical Test of Hypothesis P-Value 1.0000
Comments [Not Specified]
Method ANOVA
Comments

ANOVA (analysis of variance) model on the logarithm scale was used with

‘subject’ as random, whereas the ‘treatment’ as fixed effect.

Method of Estimation Estimation Parameter Ratio of gmeans Day 17 vs. Day 9 (%)
Estimated Value 349.90
Confidence Interval (2-Sided) 90%
269.12 to 454.93
Parameter Dispersion
Type: Standard Deviation
Value: 46.4
Estimation Comments Relative bioavailability of BI 207127 at Day 17 vs. Day 9 −was estimated by the ratios of the adjusted geometric means (gMean). Standard deviation is actually Intra individual geometric coefficient variation (gCV).
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Group B
Comments Day 66 vs. Day 9
Type of Statistical Test Non-Inferiority or Equivalence
Comments p-value for ratio outside 80% to 125%
Statistical Test of Hypothesis P-Value 0.9533
Comments [Not Specified]
Method ANOVA
Comments

ANOVA (analysis of variance) model on the logarithm scale was used with

‘subject’ as random, whereas the ‘treatment’ as fixed effect.

Method of Estimation Estimation Parameter Ratio of gmeans Day 66 vs. Day 9 (%)
Estimated Value 176.56
Confidence Interval (2-Sided) 90%
125.95 to 247.50
Parameter Dispersion
Type: Standard Deviation
Value: 50.1
Estimation Comments Relative bioavailability of BI 207127 at Day 66 vs. Day 9 −was estimated by the ratios of the adjusted geometric means (gMean). Standard deviation is actually Intra individual geometric coefficient variation (gCV).
6.Primary Outcome
Title AUC 0-6hr of Deleobuvir (BI 207127)
Hide Description Area under the concentration-time curve of the analyte in plasma over the time interval from 0 to 6 hours
Time Frame PK plasma samples were taken at: 5 minutes before drug administration and 1 hour (h), 2h, 3h, 4h, 5h, 5:55h, 8h, 10h, 11:55h, 15h, 23:55h after first drug administration on days 9, 17 and 66.
Hide Outcome Measure Data
Hide Analysis Population Description
The pharmacokinetic set (PKS): included all patients in the treated set who provided at least one observation for at least one primary (PK) endpoint without important protocol violations relevant to the evaluation of PK. This endpoint was not planned to be analysed for groups C, D and E.
Arm/Group Title Group A Group B
Hide Arm/Group Description:
600mg deleobuvir(DBV) tablet taken orally 3 times a day plus 120mg faldaprevir(FDV) capsule taken orally once daily plus ribavirin(RBV) tablet taken orally twice daily for 24 weeks along with pegylated interferon α-2a(PegIFN) injection and probe drugs(200 mg caffeine tablet, 500 mg tolbutamide tablet, and 2 mg midazolam syrup administered orally on days 1, 9, 17, and 66). In group A the effect of DBV on FDV, the effect of FDV, dual oral direct acting antiviral (DAAs) and their metabolites on caffeine, tolbutamide and midazolam were determined.
600mg deleobuvir(DBV) tablet taken orally 3 times a day plus 120mg faldaprevir(FDV) capsule taken orally once daily plus ribavirin(RBV) tablet taken orally twice daily for 24 weeks along with pegylated interferon α-2a (PegIFN) injection and probe drugs(200 mg caffeine tablet, 500 mg tolbutamide tablet, and 2 mg midazolam syrup administered orally on days 1, 9, 17, and 66). In group B the effect of FDV on DBV, the effect of DBV, dual oral direct acting antiviral (DAAs) and their metabolites on caffeine, tolbutamide and midazolam were determined.
Overall Number of Participants Analyzed 16 19
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: nmol*h/L
Day 9 (N=0, 17)
NA [1] 
(NA%)
41100
(93.7%)
Day 17 (N=14, 19)
119000
(73.7%)
135000
(65.0%)
Day 66 (N=13, 15)
36200
(89.0%)
59200
(129%)
[1]
Not calculated as this timepoint was not planned to be analysed for group A.
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Group B
Comments Day 17 vs. Day 9
Type of Statistical Test Non-Inferiority or Equivalence
Comments p-value for ratio outside 80% to 125%
Statistical Test of Hypothesis P-Value 1.0000
Comments [Not Specified]
Method ANOVA
Comments

ANOVA (analysis of variance) model on the logarithm scale was used with

‘subject’ as random, whereas the ‘treatment’ as fixed effect.

Method of Estimation Estimation Parameter Ratio of gmeans Day 17 vs. Day 9 (%)
Estimated Value 322.68
Confidence Interval (2-Sided) 90%
256.24 to 406.34
Parameter Dispersion
Type: Standard Deviation
Value: 40.4
Estimation Comments Relative bioavailability of BI 207127 at Day 17 vs. Day 9 −was estimated by the ratios of the adjusted geometric means (gMean). Standard deviation is actually Intra individual geometric coefficient variation (gCV).
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Group B
Comments Day 66 vs. Day 9
Type of Statistical Test Non-Inferiority or Equivalence
Comments p-value for ratio outside 80% to 125%
Statistical Test of Hypothesis P-Value 0.7461
Comments [Not Specified]
Method ANOVA
Comments

ANOVA (analysis of variance) model on the logarithm scale was used with

‘subject’ as random, whereas the ‘treatment’ as fixed effect.

Method of Estimation Estimation Parameter Ratio of gmeans Day 66 vs. Day 9 (%)
Estimated Value 145.93
Confidence Interval (2-Sided) 90%
97.83 to 217.69
Parameter Dispersion
Type: Standard Deviation
Value: 66.2
Estimation Comments Relative bioavailability of BI 207127 at Day 66 vs. Day 9 −was estimated by the ratios of the adjusted geometric means (gMean). Standard deviation is actually Intra individual geometric coefficient variation (gCV).
7.Primary Outcome
Title Cmax of Deleobuvir Metabolite Acyl-glucuronide (BI 208333)
Hide Description Maximum concentration of an analyte in plasma
Time Frame PK plasma samples were taken at: 5 minutes before drug administration and 1 hour (h), 2h, 3h, 4h, 5h, 5:55h, 8h, 10h, 11:55h, 15h, 23:55h after first drug administration on days 9, 17 and 66.
Hide Outcome Measure Data
Hide Analysis Population Description
The pharmacokinetic set (PKS): included all patients in the treated set who provided at least one observation for at least one primary (PK) endpoint without important protocol violations relevant to the evaluation of PK. This endpoint was not planned to be analysed for groups C, D and E.
Arm/Group Title Group A Group B
Hide Arm/Group Description:
600mg deleobuvir(DBV) tablet taken orally 3 times a day plus 120mg faldaprevir(FDV) capsule taken orally once daily plus ribavirin(RBV) tablet taken orally twice daily for 24 weeks along with pegylated interferon α-2a(PegIFN) injection and probe drugs(200 mg caffeine tablet, 500 mg tolbutamide tablet, and 2 mg midazolam syrup administered orally on days 1, 9, 17, and 66). In group A the effect of DBV on FDV, the effect of FDV, dual oral direct acting antiviral (DAAs) and their metabolites on caffeine, tolbutamide and midazolam were determined.
600mg deleobuvir(DBV) tablet taken orally 3 times a day plus 120mg faldaprevir(FDV) capsule taken orally once daily plus ribavirin(RBV) tablet taken orally twice daily for 24 weeks along with pegylated interferon α-2a (PegIFN) injection and probe drugs(200 mg caffeine tablet, 500 mg tolbutamide tablet, and 2 mg midazolam syrup administered orally on days 1, 9, 17, and 66). In group B the effect of FDV on DBV, the effect of DBV, dual oral direct acting antiviral (DAAs) and their metabolites on caffeine, tolbutamide and midazolam were determined.
Overall Number of Participants Analyzed 16 19
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: nmol/L
Day 9 (N=0, 17)
NA [1] 
(NA%)
5620
(119%)
Day 17 (N=14, 19)
12700
(89.4%)
20200
(111%)
Day 66 (N=13, 15)
3790
(66.9%)
6550
(98.3%)
[1]
Not calculated as this timepoint was not planned to be analysed for group A.
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Group B
Comments Day 17 vs. Day 9
Type of Statistical Test Non-Inferiority or Equivalence
Comments p-value for ratio outside 80% to 125%
Statistical Test of Hypothesis P-Value 1.0000
Comments [Not Specified]
Method ANOVA
Comments

ANOVA (analysis of variance) model on the logarithm scale was used with

‘subject’ as random, whereas the ‘treatment’ as fixed effect.

Method of Estimation Estimation Parameter Ratio of gmeans Day 17 vs. Day 9 (%)
Estimated Value 355.04
Confidence Interval (2-Sided) 90%
298.13 to 422.83
Parameter Dispersion
Type: Standard Deviation
Value: 29.9
Estimation Comments Relative bioavailability of BI 208833 at Day 17 vs. Day 9 −was estimated by the ratios of the adjusted geometric means (gMean). Standard deviation is actually Intra individual geometric coefficient variation (gCV).
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Group B
Comments Day 66 vs. Day 9
Type of Statistical Test Non-Inferiority or Equivalence
Comments p-value for ratio outside 80% to 125%
Statistical Test of Hypothesis P-Value 0.4337
Comments [Not Specified]
Method ANOVA
Comments

ANOVA (analysis of variance) model on the logarithm scale was used with

‘subject’ as random, whereas the ‘treatment’ as fixed effect.

Method of Estimation Estimation Parameter Ratio of gmeans Day 66 vs. Day 9 (%)
Estimated Value 120.67
Confidence Interval (2-Sided) 90%
83.68 to 174.01
Parameter Dispersion
Type: Standard Deviation
Value: 58.3
Estimation Comments Relative bioavailability of BI 208833 at Day 66 vs. Day 9 −was estimated by the ratios of the adjusted geometric means (gMean). Standard deviation is actually Intra individual geometric coefficient variation (gCV).
8.Primary Outcome
Title C6hr of Deleobuvir Metabolite Acyl-glucuronide (BI 208333)
Hide Description Concentration of an analyte in plasma at 6 hours
Time Frame PK plasma samples were taken at: 5 minutes before drug administration and 1 hour (h), 2h, 3h, 4h, 5h, 5:55h, 8h, 10h, 11:55h, 15h, 23:55h after first drug administration on days 9, 17 and 66.
Hide Outcome Measure Data
Hide Analysis Population Description
The pharmacokinetic set (PKS): included all patients in the treated set who provided at least one observation for at least one primary (PK) endpoint without important protocol violations relevant to the evaluation of PK. This endpoint was not planned to be analysed for groups C, D and E.
Arm/Group Title Group A Group B
Hide Arm/Group Description:
600mg deleobuvir(DBV) tablet taken orally 3 times a day plus 120mg faldaprevir(FDV) capsule taken orally once daily plus ribavirin(RBV) tablet taken orally twice daily for 24 weeks along with pegylated interferon α-2a(PegIFN) injection and probe drugs(200 mg caffeine tablet, 500 mg tolbutamide tablet, and 2 mg midazolam syrup administered orally on days 1, 9, 17, and 66). In group A the effect of DBV on FDV, the effect of FDV, dual oral direct acting antiviral (DAAs) and their metabolites on caffeine, tolbutamide and midazolam were determined.
600mg deleobuvir(DBV) tablet taken orally 3 times a day plus 120mg faldaprevir(FDV) capsule taken orally once daily plus ribavirin(RBV) tablet taken orally twice daily for 24 weeks along with pegylated interferon α-2a (PegIFN) injection and probe drugs(200 mg caffeine tablet, 500 mg tolbutamide tablet, and 2 mg midazolam syrup administered orally on days 1, 9, 17, and 66). In group B the effect of FDV on DBV, the effect of DBV, dual oral direct acting antiviral (DAAs) and their metabolites on caffeine, tolbutamide and midazolam were determined.
Overall Number of Participants Analyzed 16 19
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: nmol/L
Day 9 (N=0, 17)
NA [1] 
(NA%)
4330
(154%)
Day 17 (N=14, 19)
11200
(83.7%)
17500
(119%)
Day 66 (N=13, 14)
2740
(85.9%)
5780
(132%)
[1]
Not calculated as this timepoint was not planned to be analysed for group A.
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Group B
Comments Day 17 vs. Day 9
Type of Statistical Test Non-Inferiority or Equivalence
Comments p-value for ratio outside 80% to 125%
Statistical Test of Hypothesis P-Value 1.0000
Comments [Not Specified]
Method ANOVA
Comments

ANOVA (analysis of variance) model on the logarithm scale was used with

‘subject’ as random, whereas the ‘treatment’ as fixed effect.

Method of Estimation Estimation Parameter Ratio of gmeans Day 17 vs. Day 9 (%)
Estimated Value 397.73
Confidence Interval (2-Sided) 90%
330.79 to 478.22
Parameter Dispersion
Type: Standard Deviation
Value: 31.6
Estimation Comments Relative bioavailability of BI 208833 at Day 17 vs. Day 9 −was estimated by the ratios of the adjusted geometric means (gMean). Standard deviation is actually Intra individual geometric coefficient variation (gCV).
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Group B
Comments Day 66 vs. Day 9
Type of Statistical Test Non-Inferiority or Equivalence
Comments p-value for ratio outside 80% to 125%
Statistical Test of Hypothesis P-Value 0.7346
Comments [Not Specified]
Method ANOVA
Comments

ANOVA (analysis of variance) model on the logarithm scale was used with

‘subject’ as random, whereas the ‘treatment’ as fixed effect.

Method of Estimation Estimation Parameter Ratio of gmeans Day 66 vs. Day 9 (%)
Estimated Value 142.27
Confidence Interval (2-Sided) 90%
99.49 to 203.44
Parameter Dispersion
Type: Standard Deviation
Value: 53.1
Estimation Comments Relative bioavailability of BI 208833 at Day 66 vs. Day 9 −was estimated by the ratios of the adjusted geometric means (gMean). Standard deviation is actually Intra individual geometric coefficient variation (gCV).
9.Primary Outcome
Title AUC 0-6hr of Deleobuvir Metabolite Acyl-glucuronide (BI 208333)
Hide Description Area under the concentration-time curve of the analyte in plasma over the time interval from 0 to 6 hours
Time Frame PK plasma samples were taken at: 5 minutes before drug administration and 1 hour (h), 2h, 3h, 4h, 5h, 5:55h, 8h, 10h, 11:55h, 15h, 23:55h after first drug administration on days 9, 17 and 66.
Hide Outcome Measure Data
Hide Analysis Population Description
The pharmacokinetic set (PKS): included all patients in the treated set who provided at least one observation for at least one primary (PK) endpoint without important protocol violations relevant to the evaluation of PK. This endpoint was not planned to be analysed for groups C, D and E.
Arm/Group Title Group A Group B
Hide Arm/Group Description:
600mg deleobuvir(DBV) tablet taken orally 3 times a day plus 120mg faldaprevir(FDV) capsule taken orally once daily plus ribavirin(RBV) tablet taken orally twice daily for 24 weeks along with pegylated interferon α-2a(PegIFN) injection and probe drugs(200 mg caffeine tablet, 500 mg tolbutamide tablet, and 2 mg midazolam syrup administered orally on days 1, 9, 17, and 66). In group A the effect of DBV on FDV, the effect of FDV, dual oral direct acting antiviral (DAAs) and their metabolites on caffeine, tolbutamide and midazolam were determined.
600mg deleobuvir(DBV) tablet taken orally 3 times a day plus 120mg faldaprevir(FDV) capsule taken orally once daily plus ribavirin(RBV) tablet taken orally twice daily for 24 weeks along with pegylated interferon α-2a (PegIFN) injection and probe drugs(200 mg caffeine tablet, 500 mg tolbutamide tablet, and 2 mg midazolam syrup administered orally on days 1, 9, 17, and 66). In group B the effect of FDV on DBV, the effect of DBV, dual oral direct acting antiviral (DAAs) and their metabolites on caffeine, tolbutamide and midazolam were determined.
Overall Number of Participants Analyzed 16 19
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: nmol*h/L
Day 9 (N=0, 17)
NA [1] 
(NA%)
24300
(131%)
Day 17 (N=14, 19)
61800
(97.9%)
98800
(124%)
Day 66 (N=13, 15)
15000
(81.2%)
27600
(128%)
[1]
Not calculated as this timepoint was not planned to be analysed for group A.
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Group B
Comments Day 17 vs. Day 9
Type of Statistical Test Non-Inferiority or Equivalence
Comments p-value for ratio outside 80% to 125%
Statistical Test of Hypothesis P-Value 1.0000
Comments [Not Specified]
Method ANOVA
Comments

ANOVA (analysis of variance) model on the logarithm scale was used with

‘subject’ as random, whereas the ‘treatment’ as fixed effect.

Method of Estimation Estimation Parameter Ratio of gmeans Day 17 vs. Day 9 (%)
Estimated Value 403.86
Confidence Interval (2-Sided) 90%
332.19 to 490.99
Parameter Dispersion
Type: Standard Deviation
Value: 33.6
Estimation Comments Relative bioavailability of BI 208833 at Day 17 vs. Day 9 −was estimated by the ratios of the adjusted geometric means (gMean). Standard deviation is actually Intra individual geometric coefficient variation (gCV).
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Group B
Comments Day 66 vs. Day 9
Type of Statistical Test Non-Inferiority or Equivalence
Comments p-value for ratio outside 80% to 125%
Statistical Test of Hypothesis P-Value 0.3968
Comments [Not Specified]
Method ANOVA
Comments

ANOVA (analysis of variance) model on the logarithm scale was used with

‘subject’ as random, whereas the ‘treatment’ as fixed effect.

Method of Estimation Estimation Parameter Ratio of gmeans Day 66 vs. Day 9 (%)
Estimated Value 116.96
Confidence Interval (2-Sided) 90%
75.38 to 181.47
Parameter Dispersion
Type: Standard Deviation
Value: 73.1
Estimation Comments Relative bioavailability of BI 208833 at Day 66 vs. Day 9 −was estimated by the ratios of the adjusted geometric means (gMean). Standard deviation is actually Intra individual geometric coefficient variation (gCV).
10.Primary Outcome
Title Cmax of Deleobuvir Reduction Metabolite CD 6168
Hide Description Maximum concentration of an analyte in plasma
Time Frame PK plasma samples were taken at: 5 minutes before drug administration and 1 hour (h), 2h, 3h, 4h, 5h, 5:55h, 8h, 10h, 11:55h, 15h, 23:55h after first drug administration on days 9, 17 and 66.
Hide Outcome Measure Data
Hide Analysis Population Description
The pharmacokinetic set (PKS): included all patients in the treated set who provided at least one observation for at least one primary (PK) endpoint without important protocol violations relevant to the evaluation of PK. This endpoint was not planned to be analysed for groups C, D and E.
Arm/Group Title Group A Group B
Hide Arm/Group Description:
600mg deleobuvir(DBV) tablet taken orally 3 times a day plus 120mg faldaprevir(FDV) capsule taken orally once daily plus ribavirin(RBV) tablet taken orally twice daily for 24 weeks along with pegylated interferon α-2a(PegIFN) injection and probe drugs(200 mg caffeine tablet, 500 mg tolbutamide tablet, and 2 mg midazolam syrup administered orally on days 1, 9, 17, and 66). In group A the effect of DBV on FDV, the effect of FDV, dual oral direct acting antiviral (DAAs) and their metabolites on caffeine, tolbutamide and midazolam were determined.
600mg deleobuvir(DBV) tablet taken orally 3 times a day plus 120mg faldaprevir(FDV) capsule taken orally once daily plus ribavirin(RBV) tablet taken orally twice daily for 24 weeks along with pegylated interferon α-2a (PegIFN) injection and probe drugs(200 mg caffeine tablet, 500 mg tolbutamide tablet, and 2 mg midazolam syrup administered orally on days 1, 9, 17, and 66). In group B the effect of FDV on DBV, the effect of DBV, dual oral direct acting antiviral (DAAs) and their metabolites on caffeine, tolbutamide and midazolam were determined.
Overall Number of Participants Analyzed 16 19
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: nmol/L
Day 9 (N=0, 17)
NA [1] 
(NA%)
3040
(115%)
Day 17 (N=14, 19)
8520
(119%)
12400
(70.9%)
Day 66 (N=13, 15)
4510
(117%)
8880
(111%)
[1]
Not calculated as this timepoint was not planned to be analysed for group A.
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Group B
Comments Day 17 vs. Day 9
Type of Statistical Test Non-Inferiority or Equivalence
Comments p-value for ratio outside 80% to 125%
Statistical Test of Hypothesis P-Value 1.0000
Comments [Not Specified]
Method ANOVA
Comments

ANOVA (analysis of variance) model on the logarithm scale was used with

‘subject’ as random, whereas the ‘treatment’ as fixed effect.

Method of Estimation Estimation Parameter Ratio of gmeans Day 17 vs. Day 9 (%)
Estimated Value 408.66
Confidence Interval (2-Sided) 90%
315.15 to 529.90
Parameter Dispersion
Type: Standard Deviation
Value: 45.9
Estimation Comments Relative bioavailability of BI CD 6168 at Day 17 vs. Day 9 −was estimated by the ratios of the adjusted geometric means (gMean). Standard deviation is actually Intra individual geometric coefficient variation (gCV).
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Group B
Comments Day 66 vs. Day 9
Type of Statistical Test Non-Inferiority or Equivalence
Comments p-value for ratio outside 80% to 125%
Statistical Test of Hypothesis P-Value 0.9993
Comments [Not Specified]
Method ANOVA
Comments

ANOVA (analysis of variance) model on the logarithm scale was used with

‘subject’ as random, whereas the ‘treatment’ as fixed effect.

Method of Estimation Estimation Parameter Ratio of gmeans Day 66 vs. Day 9 (%)
Estimated Value 301.19
Confidence Interval (2-Sided) 90%
204.61 to 443.35
Parameter Dispersion
Type: Standard Deviation
Value: 62.1
Estimation Comments Relative bioavailability of BI CD 6168 at Day 66 vs. Day 9 −was estimated by the ratios of the adjusted geometric means (gMean). Standard deviation is actually Intra individual geometric coefficient variation (gCV).
11.Primary Outcome
Title C6hr of Deleobuvir Reduction Metabolite CD 6168
Hide Description Concentration of an analyte in plasma at 6 hours
Time Frame PK plasma samples were taken at: 5 minutes before drug administration and 1 hour (h), 2h, 3h, 4h, 5h, 5:55h, 8h, 10h, 11:55h, 15h, 23:55h after first drug administration on days 9, 17 and 66.
Hide Outcome Measure Data
Hide Analysis Population Description
The pharmacokinetic set (PKS): included all patients in the treated set who provided at least one observation for at least one primary (PK) endpoint without important protocol violations relevant to the evaluation of PK. This endpoint was not planned to be analysed for groups C, D and E.
Arm/Group Title Group A Group B
Hide Arm/Group Description:
600mg deleobuvir(DBV) tablet taken orally 3 times a day plus 120mg faldaprevir(FDV) capsule taken orally once daily plus ribavirin(RBV) tablet taken orally twice daily for 24 weeks along with pegylated interferon α-2a(PegIFN) injection and probe drugs(200 mg caffeine tablet, 500 mg tolbutamide tablet, and 2 mg midazolam syrup administered orally on days 1, 9, 17, and 66). In group A the effect of DBV on FDV, the effect of FDV, dual oral direct acting antiviral (DAAs) and their metabolites on caffeine, tolbutamide and midazolam were determined.
600mg deleobuvir(DBV) tablet taken orally 3 times a day plus 120mg faldaprevir(FDV) capsule taken orally once daily plus ribavirin(RBV) tablet taken orally twice daily for 24 weeks along with pegylated interferon α-2a (PegIFN) injection and probe drugs(200 mg caffeine tablet, 500 mg tolbutamide tablet, and 2 mg midazolam syrup administered orally on days 1, 9, 17, and 66). In group B the effect of FDV on DBV, the effect of DBV, dual oral direct acting antiviral (DAAs) and their metabolites on caffeine, tolbutamide and midazolam were determined.
Overall Number of Participants Analyzed 16 19
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: nmol/L
Day 9 (N=0, 17)
NA [1] 
(NA%)
2250
(137%)
Day 17 (N=14, 19)
6980
(128%)
10200
(81.0%)
Day 66 (N=13, 14)
3360
(139%)
7460
(123%)
[1]
Not calculated as this timepoint was not planned to be analysed for group A.
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Group B
Comments Day 17 vs. Day 9
Type of Statistical Test Non-Inferiority or Equivalence
Comments p-value for ratio outside 80% to 125%
Statistical Test of Hypothesis P-Value 1.0000
Comments [Not Specified]
Method ANOVA
Comments

ANOVA (analysis of variance) model on the logarithm scale was used with

‘subject’ as random, whereas the ‘treatment’ as fixed effect.

Method of Estimation Estimation Parameter Ratio of gmeans Day 17 vs. Day 9 (%)
Estimated Value 450.51
Confidence Interval (2-Sided) 90%
343.67 to 590.57
Parameter Dispersion
Type: Standard Deviation
Value: 48.0
Estimation Comments Relative bioavailability of BI CD 6168 at Day 17 vs. Day 9 −was estimated by the ratios of the adjusted geometric means (gMean). Standard deviation is actually Intra individual geometric coefficient variation (gCV).
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Group B
Comments Day 66 vs. Day 9
Type of Statistical Test Non-Inferiority or Equivalence
Comments p-value for ratio outside 80% to 125%
Statistical Test of Hypothesis P-Value 0.9996
Comments [Not Specified]
Method ANOVA
Comments

ANOVA (analysis of variance) model on the logarithm scale was used with

‘subject’ as random, whereas the ‘treatment’ as fixed effect.

Method of Estimation Estimation Parameter Ratio of gmeans Day 66 vs. Day 9 (%)
Estimated Value 341.96
Confidence Interval (2-Sided) 90%
229.22 to 510.13
Parameter Dispersion
Type: Standard Deviation
Value: 61.1
Estimation Comments Relative bioavailability of BI CD 6168 at Day 66 vs. Day 9 −was estimated by the ratios of the adjusted geometric means (gMean). Standard deviation is actually Intra individual geometric coefficient variation (gCV).
12.Primary Outcome
Title AUC 0-6hr of Deleobuvir Reduction Metabolite CD 6168
Hide Description Area under the concentration-time curve of the analyte in plasma over the time interval from 0 to 6 hours
Time Frame PK plasma samples were taken at: 5 minutes before drug administration and 1 hour (h), 2h, 3h, 4h, 5h, 5:55h, 8h, 10h, 11:55h, 15h, 23:55h after first drug administration on days 9, 17 and 66.
Hide Outcome Measure Data
Hide Analysis Population Description
The pharmacokinetic set (PKS): included all patients in the treated set who provided at least one observation for at least one primary (PK) endpoint without important protocol violations relevant to the evaluation of PK. This endpoint was not planned to be analysed for groups C, D and E.
Arm/Group Title Group A Group B
Hide Arm/Group Description:
600mg deleobuvir(DBV) tablet taken orally 3 times a day plus 120mg faldaprevir(FDV) capsule taken orally once daily plus ribavirin(RBV) tablet taken orally twice daily for 24 weeks along with pegylated interferon α-2a(PegIFN) injection and probe drugs(200 mg caffeine tablet, 500 mg tolbutamide tablet, and 2 mg midazolam syrup administered orally on days 1, 9, 17, and 66). In group A the effect of DBV on FDV, the effect of FDV, dual oral direct acting antiviral (DAAs) and their metabolites on caffeine, tolbutamide and midazolam were determined.
600mg deleobuvir(DBV) tablet taken orally 3 times a day plus 120mg faldaprevir(FDV) capsule taken orally once daily plus ribavirin(RBV) tablet taken orally twice daily for 24 weeks along with pegylated interferon α-2a (PegIFN) injection and probe drugs(200 mg caffeine tablet, 500 mg tolbutamide tablet, and 2 mg midazolam syrup administered orally on days 1, 9, 17, and 66). In group B the effect of FDV on DBV, the effect of DBV, dual oral direct acting antiviral (DAAs) and their metabolites on caffeine, tolbutamide and midazolam were determined.
Overall Number of Participants Analyzed 16 19
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: nmol*h/L
Day 9 (N=0, 17)
NA [1] 
(NA%)
13300
(123%)
Day 17 (N=14, 19)
41700
(130%)
62200
(82.7%)
Day 66 (N=13, 15)
19300
(134%)
39100
(133%)
[1]
Not calculated as this timepoint was not planned to be analysed for group A.
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Group B
Comments Day 17 vs. Day 9
Type of Statistical Test Non-Inferiority or Equivalence
Comments p-value for ratio outside 80% to 125%
Statistical Test of Hypothesis P-Value 1.0000
Comments [Not Specified]
Method ANOVA
Comments

ANOVA (analysis of variance) model on the logarithm scale was used with

‘subject’ as random, whereas the ‘treatment’ as fixed effect.

Method of Estimation Estimation Parameter Ratio of gmeans Day 17 vs. Day 9 (%)
Estimated Value 466.92
Confidence Interval (2-Sided) 90%
357.02 to 610.66
Parameter Dispersion
Type: Standard Deviation
Value: 47.6
Estimation Comments Relative bioavailability of BI CD 6168 at Day 17 vs. Day 9 −was estimated by the ratios of the adjusted geometric means (gMean). Standard deviation is actually Intra individual geometric coefficient variation (gCV).
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Group B
Comments Day 66 vs. Day 9
Type of Statistical Test Non-Inferiority or Equivalence
Comments p-value for ratio outside 80% to 125%
Statistical Test of Hypothesis P-Value 0.9972
Comments [Not Specified]
Method ANOVA
Comments

ANOVA (analysis of variance) model on the logarithm scale was used with

‘subject’ as random, whereas the ‘treatment’ as fixed effect.

Method of Estimation Estimation Parameter Ratio of gmeans Day 66 vs. Day 9 (%)
Estimated Value 298.57
Confidence Interval (2-Sided) 90%
187.22 to 476.15
Parameter Dispersion
Type: Standard Deviation
Value: 79.2
Estimation Comments Relative bioavailability of BI CD 6168 at Day 66 vs. Day 9 −was estimated by the ratios of the adjusted geometric means (gMean). Standard deviation is actually Intra individual geometric coefficient variation (gCV).
13.Primary Outcome
Title Cmax of Deleobuvir Metabolite CD 6168 ag (Acylglucuronide)
Hide Description Maximum concentration of an analyte in plasma
Time Frame PK plasma samples were taken at: 5 minutes before drug administration and 1 hour (h), 2h, 3h, 4h, 5h, 5:55h, 8h, 10h, 11:55h, 15h, 23:55h after first drug administration on days 9, 17 and 66.
Hide Outcome Measure Data
Hide Analysis Population Description
The pharmacokinetic set (PKS): included all patients in the treated set who provided at least one observation for at least one primary (PK) endpoint without important protocol violations relevant to the evaluation of PK. This endpoint was not planned to be analysed for groups C, D and E.
Arm/Group Title Group A Group B
Hide Arm/Group Description:
600mg deleobuvir(DBV) tablet taken orally 3 times a day plus 120mg faldaprevir(FDV) capsule taken orally once daily plus ribavirin(RBV) tablet taken orally twice daily for 24 weeks along with pegylated interferon α-2a(PegIFN) injection and probe drugs(200 mg caffeine tablet, 500 mg tolbutamide tablet, and 2 mg midazolam syrup administered orally on days 1, 9, 17, and 66). In group A the effect of DBV on FDV, the effect of FDV, dual oral direct acting antiviral (DAAs) and their metabolites on caffeine, tolbutamide and midazolam were determined.
600mg deleobuvir(DBV) tablet taken orally 3 times a day plus 120mg faldaprevir(FDV) capsule taken orally once daily plus ribavirin(RBV) tablet taken orally twice daily for 24 weeks along with pegylated interferon α-2a (PegIFN) injection and probe drugs(200 mg caffeine tablet, 500 mg tolbutamide tablet, and 2 mg midazolam syrup administered orally on days 1, 9, 17, and 66). In group B the effect of FDV on DBV, the effect of DBV, dual oral direct acting antiviral (DAAs) and their metabolites on caffeine, tolbutamide and midazolam were determined.
Overall Number of Participants Analyzed 16 19
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: nmol/L
Day 9 (N=0, 17)
NA [1] 
(NA%)
203
(135%)
Day 17 (N=14, 19)
596
(143%)
1130
(115%)
Day 66 (N=13, 15)
386
(111%)
806
(125%)
[1]
Not calculated as this timepoint was not planned to be analysed for group A.
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Group B
Comments Day 17 vs. Day 9
Type of Statistical Test Non-Inferiority or Equivalence
Comments p-value for ratio outside 80% to 125%
Statistical Test of Hypothesis P-Value 1.0000
Comments [Not Specified]
Method ANOVA
Comments

ANOVA (analysis of variance) model on the logarithm scale was used with

‘subject’ as random, whereas the ‘treatment’ as fixed effect.

Method of Estimation Estimation Parameter Ratio of gmeans Day 17 vs. Day 9 (%)
Estimated Value 528.95
Confidence Interval (2-Sided) 90%
415.88 to 672.75
Parameter Dispersion
Type: Standard Deviation
Value: 42.0
Estimation Comments Relative bioavailability of BI CD 6168-ag at Day 17 vs. Day 9 −was estimated by the ratios of the adjusted geometric means (gMean). Standard deviation is actually Intra individual geometric coefficient variation (gCV).
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Group B
Comments Day 66 vs. Day 9
Type of Statistical Test Non-Inferiority or Equivalence
Comments p-value for ratio outside 80% to 125%
Statistical Test of Hypothesis P-Value 0.9998
Comments [Not Specified]
Method ANOVA
Comments

ANOVA (analysis of variance) model on the logarithm scale was used with

‘subject’ as random, whereas the ‘treatment’ as fixed effect.

Method of Estimation Estimation Parameter Ratio of gmeans Day 66 vs. Day 9 (%)
Estimated Value 384.00
Confidence Interval (2-Sided) 90%
251.56 to 586.16
Parameter Dispersion
Type: Standard Deviation
Value: 69.2
Estimation Comments Relative bioavailability of BI CD 6168-ag at Day 66 vs. Day 9 −was estimated by the ratios of the adjusted geometric means (gMean). Standard deviation is actually Intra individual geometric coefficient variation (gCV).
14.Primary Outcome
Title C6hr of Deleobuvir Metabolite CD 6168 ag (Acylglucuronide)
Hide Description Concentration of an analyte in plasma at 6 hours
Time Frame PK plasma samples were taken at: 5 minutes before drug administration and 1 hour (h), 2h, 3h, 4h, 5h, 5:55h, 8h, 10h, 11:55h, 15h, 23:55h after first drug administration on days 9, 17 and 66.
Hide Outcome Measure Data
Hide Analysis Population Description
The pharmacokinetic set (PKS): included all patients in the treated set who provided at least one observation for at least one primary (PK) endpoint without important protocol violations relevant to the evaluation of PK. This endpoint was not planned to be analysed for groups C, D and E.
Arm/Group Title Group A Group B
Hide Arm/Group Description:
600mg deleobuvir(DBV) tablet taken orally 3 times a day plus 120mg faldaprevir(FDV) capsule taken orally once daily plus ribavirin(RBV) tablet taken orally twice daily for 24 weeks along with pegylated interferon α-2a(PegIFN) injection and probe drugs(200 mg caffeine tablet, 500 mg tolbutamide tablet, and 2 mg midazolam syrup administered orally on days 1, 9, 17, and 66). In group A the effect of DBV on FDV, the effect of FDV, dual oral direct acting antiviral (DAAs) and their metabolites on caffeine, tolbutamide and midazolam were determined.
600mg deleobuvir(DBV) tablet taken orally 3 times a day plus 120mg faldaprevir(FDV) capsule taken orally once daily plus ribavirin(RBV) tablet taken orally twice daily for 24 weeks along with pegylated interferon α-2a (PegIFN) injection and probe drugs(200 mg caffeine tablet, 500 mg tolbutamide tablet, and 2 mg midazolam syrup administered orally on days 1, 9, 17, and 66). In group B the effect of FDV on DBV, the effect of DBV, dual oral direct acting antiviral (DAAs) and their metabolites on caffeine, tolbutamide and midazolam were determined.
Overall Number of Participants Analyzed 16 19
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: nmol/L
Day 9 (N=0, 17)
NA [1] 
(NA%)
159
(165%)
Day 17 (N=14, 19)
508
(138%)
962
(117%)
Day 66 (N=13, 14)
295
(128%)
712
(143%)
[1]
Not calculated as this timepoint was not planned to be analysed for group A.
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Group B
Comments Day 17 vs. Day 9
Type of Statistical Test Non-Inferiority or Equivalence
Comments p-value for ratio outside 80% to 125%
Statistical Test of Hypothesis P-Value 1.0000
Comments [Not Specified]
Method ANOVA
Comments

ANOVA (analysis of variance) model on the logarithm scale was used with

‘subject’ as random, whereas the ‘treatment’ as fixed effect.

Method of Estimation Estimation Parameter Ratio of gmeans Day 17 vs. Day 9 (%)
Estimated Value 569.81
Confidence Interval (2-Sided) 90%
447.49 to 725.57
Parameter Dispersion
Type: Standard Deviation
Value: 42.2
Estimation Comments Relative bioavailability of BI CD 6168-ag at Day 17 vs. Day 9 −was estimated by the ratios of the adjusted geometric means (gMean). Standard deviation is actually Intra individual geometric coefficient variation (gCV).
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Group B
Comments Day 66 vs. Day 9
Type of Statistical Test Non-Inferiority or Equivalence
Comments p-value for ratio outside 80% to 125%
Statistical Test of Hypothesis P-Value 0.9999
Comments [Not Specified]
Method ANOVA
Comments

ANOVA (analysis of variance) model on the logarithm scale was used with

‘subject’ as random, whereas the ‘treatment’ as fixed effect.

Method of Estimation Estimation Parameter Ratio of gmeans Day 66 vs. Day 9 (%)
Estimated Value 441.89
Confidence Interval (2-Sided) 90%
286.81 to 680.82
Parameter Dispersion
Type: Standard Deviation
Value: 66.9
Estimation Comments Relative bioavailability of BI CD 6168-ag at Day 66 vs. Day 9 −was estimated by the ratios of the adjusted geometric means (gMean). Standard deviation is actually Intra individual geometric coefficient variation (gCV).
15.Primary Outcome
Title AUC 0-6hr of Deleobuvir Metabolite CD 6168 ag (Acylglucuronide)
Hide Description Area under the concentration-time curve of the analyte in plasma over the time interval from 0 to 6 hours
Time Frame PK plasma samples were taken at: 5 minutes before drug administration and 1 hour (h), 2h, 3h, 4h, 5h, 5:55h, 8h, 10h, 11:55h, 15h, 23:55h after first drug administration on days 9, 17 and 66.
Hide Outcome Measure Data
Hide Analysis Population Description
The pharmacokinetic set (PKS): included all patients in the treated set who provided at least one observation for at least one primary (PK) endpoint without important protocol violations relevant to the evaluation of PK. This endpoint was not planned to be analysed for groups C, D and E.
Arm/Group Title Group A Group B
Hide Arm/Group Description:
600mg deleobuvir(DBV) tablet taken orally 3 times a day plus 120mg faldaprevir(FDV) capsule taken orally once daily plus ribavirin(RBV) tablet taken orally twice daily for 24 weeks along with pegylated interferon α-2a(PegIFN) injection and probe drugs(200 mg caffeine tablet, 500 mg tolbutamide tablet, and 2 mg midazolam syrup administered orally on days 1, 9, 17, and 66). In group A the effect of DBV on FDV, the effect of FDV, dual oral direct acting antiviral (DAAs) and their metabolites on caffeine, tolbutamide and midazolam were determined.
600mg deleobuvir(DBV) tablet taken orally 3 times a day plus 120mg faldaprevir(FDV) capsule taken orally once daily plus ribavirin(RBV) tablet taken orally twice daily for 24 weeks along with pegylated interferon α-2a (PegIFN) injection and probe drugs(200 mg caffeine tablet, 500 mg tolbutamide tablet, and 2 mg midazolam syrup administered orally on days 1, 9, 17, and 66). In group B the effect of FDV on DBV, the effect of DBV, dual oral direct acting antiviral (DAAs) and their metabolites on caffeine, tolbutamide and midazolam were determined.
Overall Number of Participants Analyzed 16 19
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: nmol*h/L
Day 9 (N=0, 17)
NA [1] 
(NA%)
893
(142%)
Day 17 (N=14, 19)
2980
(151%)
5700
(123%)
Day 66 (N=13, 15)
1620
(133%)
3510
(143%)
[1]
Not calculated as this timepoint was not planned to be analysed for group A.
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Group B
Comments Day 17 vs. Day 9
Type of Statistical Test Non-Inferiority or Equivalence
Comments p-value for ratio outside 80% to 125%
Statistical Test of Hypothesis P-Value 1.0000
Comments [Not Specified]
Method ANOVA
Comments

ANOVA (analysis of variance) model on the logarithm scale was used with

‘subject’ as random, whereas the ‘treatment’ as fixed effect.

Method of Estimation Estimation Parameter Ratio of gmeans Day 17 vs. Day 9 (%)
Estimated Value 606.29
Confidence Interval (2-Sided) 90%
471.42 to 779.74
Parameter Dispersion
Type: Standard Deviation
Value: 44.2
Estimation Comments Relative bioavailability of BI CD 6168-ag at Day 17 vs. Day 9 −was estimated by the ratios of the adjusted geometric means (gMean). Standard deviation is actually Intra individual geometric coefficient variation (gCV).
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Group B
Comments Day 66 vs. Day 9
Type of Statistical Test Non-Inferiority or Equivalence
Comments p-value for ratio outside 80% to 125%
Statistical Test of Hypothesis P-Value 0.9994
Comments [Not Specified]
Method ANOVA
Comments

ANOVA (analysis of variance) model on the logarithm scale was used with

‘subject’ as random, whereas the ‘treatment’ as fixed effect.

Method of Estimation Estimation Parameter Ratio of gmeans Day 66 vs. Day 9 (%)
Estimated Value 377.98
Confidence Interval (2-Sided) 90%
233.48 to 611.91
Parameter Dispersion
Type: Standard Deviation
Value: 82.0
Estimation Comments Relative bioavailability of BI CD 6168-ag at Day 66 vs. Day 9 −was estimated by the ratios of the adjusted geometric means (gMean). Standard deviation is actually Intra individual geometric coefficient variation (gCV).
16.Primary Outcome
Title Cmax of Caffeine
Hide Description Maximum concentration of an analyte in plasma
Time Frame 5 min before and 1 hour (h), 2h, 3h, 4h, 5h, 6h, 8h, 10h, 11:55h, 15h, 23:55h, 26h, 28h, 29:55h, 32h after first drug administration on day 1 also 5 min before, 1h, 2h, 3h, 4h, 5h, 5:55h, 8h, 10h, 11:55h, 15h, 23:55h after drug on days 9, 17 and 66.
Hide Outcome Measure Data
Hide Analysis Population Description
PKS. This endpoint was not planned to be analysed for groups C, D and E
Arm/Group Title Group A Group B
Hide Arm/Group Description:
600mg deleobuvir(DBV) tablet taken orally 3 times a day plus 120mg faldaprevir(FDV) capsule taken orally once daily plus ribavirin(RBV) tablet taken orally twice daily for 24 weeks along with pegylated interferon α-2a(PegIFN) injection and probe drugs(200 mg caffeine tablet, 500 mg tolbutamide tablet, and 2 mg midazolam syrup administered orally on days 1, 9, 17, and 66). In group A the effect of DBV on FDV, the effect of FDV, dual oral direct acting antiviral (DAAs) and their metabolites on caffeine, tolbutamide and midazolam were determined.
600mg deleobuvir(DBV) tablet taken orally 3 times a day plus 120mg faldaprevir(FDV) capsule taken orally once daily plus ribavirin(RBV) tablet taken orally twice daily for 24 weeks along with pegylated interferon α-2a (PegIFN) injection and probe drugs(200 mg caffeine tablet, 500 mg tolbutamide tablet, and 2 mg midazolam syrup administered orally on days 1, 9, 17, and 66). In group B the effect of FDV on DBV, the effect of DBV, dual oral direct acting antiviral (DAAs) and their metabolites on caffeine, tolbutamide and midazolam were determined.
Overall Number of Participants Analyzed 16 19
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ng/mL
Day 1 (N=16, 19)
5170
(46.2%)
5340
(38.2%)
Day 9 (N=15, 17)
4890
(57.7%)
7220
(37.1%)
Day 17 (N=14, 19)
4830
(47.5%)
6530
(52.3%)
Day 66 (N=13, 15)
5590
(49.6%)
6450
(32.4%)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Group A
Comments Day 9 vs. Day 1
Type of Statistical Test Non-Inferiority or Equivalence
Comments p-value for ratio outside 80% to 125%
Statistical Test of Hypothesis P-Value 0.0500
Comments [Not Specified]
Method ANOVA
Comments

ANOVA (analysis of variance) model on the logarithm scale was used with

‘subject’ as random, whereas the ‘treatment’ as fixed effect.

Method of Estimation Estimation Parameter Ratio of gmeans Day 9 vs. Day 1 (%)
Estimated Value 97.03
Confidence Interval (2-Sided) 90%
80.00 to 117.69
Parameter Dispersion
Type: Standard Deviation
Value: 30.8
Estimation Comments Relative bioavailability of caffeine at Day 9 vs. Day 1 −was estimated by the ratios of the adjusted geometric means (gMean). Standard deviation is actually Intra individual geometric coefficient variation (gCV).
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Group A
Comments Day 17 vs. Day 1
Type of Statistical Test Non-Inferiority or Equivalence
Comments p-value for ratio outside 80% to 125%
Statistical Test of Hypothesis P-Value 0.0564
Comments [Not Specified]
Method ANOVA
Comments

ANOVA (analysis of variance) model on the logarithm scale was used with

‘subject’ as random, whereas the ‘treatment’ as fixed effect.

Method of Estimation Estimation Parameter Ratio of gmeans Day 17 vs. Day 1 (%)
Estimated Value 97.10
Confidence Interval (2-Sided) 90%
79.37 to 118.79
Parameter Dispersion
Type: Standard Deviation
Value: 31.2
Estimation Comments Relative bioavailability of caffeine at Day 17 vs. Day 1 −was estimated by the ratios of the adjusted geometric means (gMean). Standard deviation is actually Intra individual geometric coefficient variation (gCV).
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Group A
Comments Day 66 vs. Day 1
Type of Statistical Test Non-Inferiority or Equivalence
Comments p-value for ratio outside 80% to 125%
Statistical Test of Hypothesis P-Value 0.2375
Comments [Not Specified]
Method ANOVA
Comments

ANOVA (analysis of variance) model on the logarithm scale was used with

‘subject’ as random, whereas the ‘treatment’ as fixed effect.

Method of Estimation Estimation Parameter Ratio of gmeans Day 66 vs. Day 1 (%)
Estimated Value 114.38
Confidence Interval (2-Sided) 90%
92.36 to 141.66
Parameter Dispersion
Type: Standard Deviation
Value: 31.9
Estimation Comments Relative bioavailability of caffeine at Day 66 vs. Day 1 −was estimated by the ratios of the adjusted geometric means (gMean). Standard deviation is actually Intra individual geometric coefficient variation (gCV).
Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Group B
Comments Day 9 vs. Day 1
Type of Statistical Test Non-Inferiority or Equivalence
Comments p-value for ratio outside 80% to 125%
Statistical Test of Hypothesis P-Value 0.9082
Comments [Not Specified]
Method ANOVA
Comments ANOVA (analysis of variance) model on the logarithm scale was used with ‘subject’ as random, whereas the ‘treatment’ as fixed effect.
Method of Estimation Estimation Parameter Ratio of gmeans Day 9 vs. Day 1 (%)
Estimated Value 139.07
Confidence Interval (2-Sided) 90%
121.63 to 159.00
Parameter Dispersion
Type: Standard Deviation
Value: 22.8
Estimation Comments Relative bioavailability of caffeine at Day 9 vs. Day 1 −was estimated by the ratios of the adjusted geometric means (gMean). Standard deviation is actually Intra individual geometric coefficient variation (gCV).
Show Statistical Analysis 5 Hide Statistical Analysis 5
Statistical Analysis Overview Comparison Group Selection Group B
Comments Day 17 vs. Day 1
Type of Statistical Test Non-Inferiority or Equivalence
Comments p-value for ratio outside 80% to 125%
Statistical Test of Hypothesis P-Value 0.4111
Comments [Not Specified]
Method ANOVA
Comments ANOVA (analysis of variance) model on the logarithm scale was used with ‘subject’ as random, whereas the ‘treatment’ as fixed effect.
Method of Estimation Estimation Parameter Ratio of gmeans Day 17 vs. Day 1 (%)
Estimated Value 122.37
Confidence Interval (2-Sided) 90%
104.11 to 143.84
Parameter Dispersion
Type: Standard Deviation
Value: 29.3
Estimation Comments Relative bioavailability of caffeine at Day 17 vs. Day 1 −was estimated by the ratios of the adjusted geometric means (gMean). Standard deviation is actually Intra individual geometric coefficient variation (gCV).
Show Statistical Analysis 6 Hide Statistical Analysis 6
Statistical Analysis Overview Comparison Group Selection Group B
Comments Day 66 vs. Day 1
Type of Statistical Test Non-Inferiority or Equivalence
Comments p-value for ratio outside 80% to 125%
Statistical Test of Hypothesis P-Value 0.3719
Comments [Not Specified]
Method ANOVA
Comments ANOVA (analysis of variance) model on the logarithm scale was used with ‘subject’ as random, whereas the ‘treatment’ as fixed effect.
Method of Estimation Estimation Parameter Ratio of gmeans Day 66 vs. Day 1 (%)
Estimated Value 121.43
Confidence Interval (2-Sided) 90%
104.24 to 141.45
Parameter Dispersion
Type: Standard Deviation
Value: 24.7
Estimation Comments Relative bioavailability of caffeine at Day 66 vs. Day 1 −was estimated by the ratios of the adjusted geometric means (gMean). Standard deviation is actually Intra individual geometric coefficient variation (gCV).
17.Primary Outcome
Title AUC 0-infinity of Caffeine
Hide Description Area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity.
Time Frame 5 min before and 1 hour (h), 2h, 3h, 4h, 5h, 6h, 8h, 10h, 11:55h, 15h, 23:55h, 26h, 28h, 29:55h, 32h after first drug administration on day 1 also 5 min before, 1h, 2h, 3h, 4h, 5h, 5:55h, 8h, 10h, 11:55h, 15h, 23:55h after drug on days 9, 17 and 66.
Hide Outcome Measure Data
Hide Analysis Population Description
PKS. This endpoint was not planned to be analysed for groups C, D and E
Arm/Group Title Group A Group B
Hide Arm/Group Description:
600mg deleobuvir(DBV) tablet taken orally 3 times a day plus 120mg faldaprevir(FDV) capsule taken orally once daily plus ribavirin(RBV) tablet taken orally twice daily for 24 weeks along with pegylated interferon α-2a(PegIFN) injection and probe drugs(200 mg caffeine tablet, 500 mg tolbutamide tablet, and 2 mg midazolam syrup administered orally on days 1, 9, 17, and 66). In group A the effect of DBV on FDV, the effect of FDV, dual oral direct acting antiviral (DAAs) and their metabolites on caffeine, tolbutamide and midazolam were determined.
600mg deleobuvir(DBV) tablet taken orally 3 times a day plus 120mg faldaprevir(FDV) capsule taken orally once daily plus ribavirin(RBV) tablet taken orally twice daily for 24 weeks along with pegylated interferon α-2a (PegIFN) injection and probe drugs(200 mg caffeine tablet, 500 mg tolbutamide tablet, and 2 mg midazolam syrup administered orally on days 1, 9, 17, and 66). In group B the effect of FDV on DBV, the effect of DBV, dual oral direct acting antiviral (DAAs) and their metabolites on caffeine, tolbutamide and midazolam were determined.
Overall Number of Participants Analyzed 16 19
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ng*h/mL
Day 1 (N=16, 19)
54900
(130%)
77500
(119%)
Day 9 (N=15, 15)
42100
(96%)
142000
(109%)
Day 17 (N=14, 19)
71900
(169%)
170000
(203%)
Day 66 (N=13, 15)
120000
(220%)
159000
(138%)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Group A
Comments Day 9 vs. Day 1
Type of Statistical Test Non-Inferiority or Equivalence
Comments p-value for ratio outside 80% to 125%
Statistical Test of Hypothesis P-Value 0.1037
Comments [Not Specified]
Method ANOVA
Comments

ANOVA (analysis of variance) model on the logarithm scale was used with

‘subject’ as random, whereas the ‘treatment’ as fixed effect.

Method of Estimation Estimation Parameter Ratio of gmeans Day 9 vs. Day 1 (%)
Estimated Value 88.37
Confidence Interval (2-Sided) 90%
77.39 to 100.89
Parameter Dispersion
Type: Standard Deviation
Value: 20.8
Estimation Comments Relative bioavailability of caffeine at Day 9 vs. Day 1 −was estimated by the ratios of the adjusted geometric means (gMean). Standard deviation is actually Intra individual geometric coefficient variation (gCV).
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Group A
Comments Day 17 vs. Day 1
Type of Statistical Test Non-Inferiority or Equivalence
Comments p-value for ratio outside 80% to 125%
Statistical Test of Hypothesis P-Value 0.8723
Comments [Not Specified]
Method ANOVA
Comments

ANOVA (analysis of variance) model on the logarithm scale was used with

‘subject’ as random, whereas the ‘treatment’ as fixed effect.

Method of Estimation Estimation Parameter Ratio of gmeans Day 17 vs. Day 1 (%)
Estimated Value 159.11
Confidence Interval (2-Sided) 90%
111.06 to 227.93
Parameter Dispersion
Type: Standard Deviation
Value: 57.8
Estimation Comments Relative bioavailability of caffeine at Day 17 vs. Day 1 −was estimated by the ratios of the adjusted geometric means (gMean). Standard deviation is actually Intra individual geometric coefficient variation (gCV).
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Group A
Comments Day 66 vs. Day 1
Type of Statistical Test Non-Inferiority or Equivalence
Comments p-value for ratio outside 80% to 125%
Statistical Test of Hypothesis P-Value 0.9830
Comments [Not Specified]
Method ANOVA
Comments

ANOVA (analysis of variance) model on the logarithm scale was used with

‘subject’ as random, whereas the ‘treatment’ as fixed effect.

Method of Estimation Estimation Parameter Ratio of gmeans Day 66 vs. Day 1 (%)
Estimated Value 259.57
Confidence Interval (2-Sided) 90%
150.65 to 447.21
Parameter Dispersion
Type: Standard Deviation
Value: 92.5
Estimation Comments Relative bioavailability of caffeine at Day 66 vs. Day 1 −was estimated by the ratios of the adjusted geometric means (gMean). Standard deviation is actually Intra individual geometric coefficient variation (gCV).
Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Group B
Comments Day 9 vs. Day 1
Type of Statistical Test Non-Inferiority or Equivalence
Comments p-value for ratio outside 80% to 125%
Statistical Test of Hypothesis P-Value 0.9689
Comments [Not Specified]
Method ANOVA
Comments ANOVA (analysis of variance) model on the logarithm scale was used with ‘subject’ as random, whereas the ‘treatment’ as fixed effect.
Method of Estimation Estimation Parameter Ratio of gmeans Day 9 vs. Day 1 (%)
Estimated Value 163.95
Confidence Interval (2-Sided) 90%
129.52 to 207.52
Parameter Dispersion
Type: Standard Deviation
Value: 38.1
Estimation Comments Relative bioavailability of caffeine at Day 9 vs. Day 1 −was estimated by the ratios of the adjusted geometric means (gMean). Standard deviation is actually Intra individual geometric coefficient variation (gCV).
Show Statistical Analysis 5 Hide Statistical Analysis 5
Statistical Analysis Overview Comparison Group Selection Group B
Comments Day 17 vs. Day 1
Type of Statistical Test Non-Inferiority or Equivalence
Comments p-value for ratio outside 80% to 125%
Statistical Test of Hypothesis P-Value 0.9933
Comments [Not Specified]
Method ANOVA
Comments ANOVA (analysis of variance) model on the logarithm scale was used with ‘subject’ as random, whereas the ‘treatment’ as fixed effect.
Method of Estimation Estimation Parameter Ratio of gmeans Day 17 vs. Day 1 (%)
Estimated Value 219.88
Confidence Interval (2-Sided) 90%
153.84 to 314.26
Parameter Dispersion
Type: Standard Deviation
Value: 70.4
Estimation Comments Relative bioavailability of caffeine at Day 17 vs. Day 1 −was estimated by the ratios of the adjusted geometric means (gMean). Standard deviation is actually Intra individual geometric coefficient variation (gCV).
Show Statistical Analysis 6 Hide Statistical Analysis 6
Statistical Analysis Overview Comparison Group Selection Group B
Comments Day 66 vs. Day 1
Type of Statistical Test Non-Inferiority or Equivalence
Comments p-value for ratio outside 80% to 125%
Statistical Test of Hypothesis P-Value 0.9865
Comments [Not Specified]
Method ANOVA
Comments ANOVA (analysis of variance) model on the logarithm scale was used with ‘subject’ as random, whereas the ‘treatment’ as fixed effect.
Method of Estimation Estimation Parameter Ratio of gmeans Day 66 vs. Day 1 (%)
Estimated Value 214.40
Confidence Interval (2-Sided) 90%
145.88 to 315.09
Parameter Dispersion
Type: Standard Deviation
Value: 66.8
Estimation Comments Relative bioavailability of caffeine at Day 66 vs. Day 1 −was estimated by the ratios of the adjusted geometric means (gMean). Standard deviation is actually Intra individual geometric coefficient variation (gCV).
18.Primary Outcome
Title Cmax of Tolbutamide
Hide Description Maximum concentration of an analyte in plasma
Time Frame 5 min before and 1 hour (h), 2h, 3h, 4h, 5h, 6h, 8h, 10h, 11:55h, 15h, 23:55h, 26h, 28h, 29:55h, 32h after first drug administration on day 1 also 5 min before, 1h, 2h, 3h, 4h, 5h, 5:55h, 8h, 10h, 11:55h, 15h, 23:55h after drug on days 9, 17 and 66.
Hide Outcome Measure Data
Hide Analysis Population Description
PKS. This endpoint was not planned to be analysed for groups C, D and E
Arm/Group Title Group A Group B
Hide Arm/Group Description:
600mg deleobuvir(DBV) tablet taken orally 3 times a day plus 120mg faldaprevir(FDV) capsule taken orally once daily plus ribavirin(RBV) tablet taken orally twice daily for 24 weeks along with pegylated interferon α-2a(PegIFN) injection and probe drugs(200 mg caffeine tablet, 500 mg tolbutamide tablet, and 2 mg midazolam syrup administered orally on days 1, 9, 17, and 66). In group A the effect of DBV on FDV, the effect of FDV, dual oral direct acting antiviral (DAAs) and their metabolites on caffeine, tolbutamide and midazolam were determined.
600mg deleobuvir(DBV) tablet taken orally 3 times a day plus 120mg faldaprevir(FDV) capsule taken orally once daily plus ribavirin(RBV) tablet taken orally twice daily for 24 weeks along with pegylated interferon α-2a (PegIFN) injection and probe drugs(200 mg caffeine tablet, 500 mg tolbutamide tablet, and 2 mg midazolam syrup administered orally on days 1, 9, 17, and 66). In group B the effect of FDV on DBV, the effect of DBV, dual oral direct acting antiviral (DAAs) and their metabolites on caffeine, tolbutamide and midazolam were determined.
Overall Number of Participants Analyzed 16 19
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: nmol/L
Day 1 (N=16, 19)
152000
(30.8%)
170000
(18.6%)
Day 9 (N=15, 17)
146000
(28.1%)
158000
(22.8%)
Day 17 (N=14, 19)
130000
(24.7%)
126000
(32.0%)
Day 66 (N=13, 15)
110000
(32.3%)
127000
(25.0%)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Group A
Comments Day 9 vs. Day 1
Type of Statistical Test Non-Inferiority or Equivalence
Comments p-value for ratio outside 80% to 125%
Statistical Test of Hypothesis P-Value 0.0015
Comments [Not Specified]
Method ANOVA
Comments

ANOVA (analysis of variance) model on the logarithm scale was used with

‘subject’ as random, whereas the ‘treatment’ as fixed effect.

Method of Estimation Estimation Parameter Ratio of gmeans Day 9 vs. Day 1 (%)
Estimated Value 96.06
Confidence Interval (2-Sided) 90%
87.77 to 105.13
Parameter Dispersion
Type: Standard Deviation
Value: 14.2
Estimation Comments Relative bioavailability of tolbutamide at Day 9 vs. Day 1 −was estimated by the ratios of the adjusted geometric means (gMean). Standard deviation is actually Intra individual geometric coefficient variation (gCV).
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Group A
Comments Day 17 vs. Day 1
Type of Statistical Test Non-Inferiority or Equivalence
Comments p-value for ratio outside 80% to 125%
Statistical Test of Hypothesis P-Value 0.1617
Comments [Not Specified]
Method ANOVA
Comments

ANOVA (analysis of variance) model on the logarithm scale was used with

‘subject’ as random, whereas the ‘treatment’ as fixed effect.

Method of Estimation Estimation Parameter Ratio of gmeans Day 17 vs. Day 1 (%)
Estimated Value 85.41
Confidence Interval (2-Sided) 90%
76.32 to 95.57
Parameter Dispersion
Type: Standard Deviation
Value: 17.2
Estimation Comments Relative bioavailability of tolbutamide at Day 17 vs. Day 1 −was estimated by the ratios of the adjusted geometric means (gMean). Standard deviation is actually Intra individual geometric coefficient variation (gCV).
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Group A
Comments Day 66 vs. Day 1
Type of Statistical Test Non-Inferiority or Equivalence
Comments p-value for ratio outside 80% to 125%
Statistical Test of Hypothesis P-Value 0.8930
Comments [Not Specified]
Method ANOVA
Comments

ANOVA (analysis of variance) model on the logarithm scale was used with

‘subject’ as random, whereas the ‘treatment’ as fixed effect.

Method of Estimation Estimation Parameter Ratio of gmeans Day 66 vs. Day 1 (%)
Estimated Value 73.26
Confidence Interval (2-Sided) 90%
65.03 to 82.54
Parameter Dispersion
Type: Standard Deviation
Value: 17.5
Estimation Comments Relative bioavailability of tolbutamide at Day 66 vs. Day 1 −was estimated by the ratios of the adjusted geometric means (gMean). Standard deviation is actually Intra individual geometric coefficient variation (gCV).
Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Group B
Comments Day 9 vs. Day 1
Type of Statistical Test Non-Inferiority or Equivalence
Comments p-value for ratio outside 80% to 125%
Statistical Test of Hypothesis P-Value 0.0005
Comments [Not Specified]
Method ANOVA
Comments ANOVA (analysis of variance) model on the logarithm scale was used with ‘subject’ as random, whereas the ‘treatment’ as fixed effect.
Method of Estimation Estimation Parameter Ratio of gmeans Day 9 vs. Day 1 (%)
Estimated Value 92.23
Confidence Interval (2-Sided) 90%
86.67 to 98.13
Parameter Dispersion
Type: Standard Deviation
Value: 10.5
Estimation Comments Relative bioavailability of tolbutamide at Day 9 vs. Day 1 −was estimated by the ratios of the adjusted geometric means (gMean). Standard deviation is actually Intra individual geometric coefficient variation (gCV).
Show Statistical Analysis 5 Hide Statistical Analysis 5
Statistical Analysis Overview Comparison Group Selection Group B
Comments Day 17 vs. Day 1
Type of Statistical Test Non-Inferiority or Equivalence
Comments p-value for ratio outside 80% to 125%
Statistical Test of Hypothesis P-Value 0.8646
Comments [Not Specified]
Method ANOVA
Comments ANOVA (analysis of variance) model on the logarithm scale was used with ‘subject’ as random, whereas the ‘treatment’ as fixed effect.
Method of Estimation Estimation Parameter Ratio of gmeans Day 17 vs. Day 1 (%)
Estimated Value 73.93
Confidence Interval (2-Sided) 90%
65.55 to 83.39
Parameter Dispersion
Type: Standard Deviation
Value: 21.6
Estimation Comments Relative bioavailability of tolbutamide at Day 17 vs. Day 1 −was estimated by the ratios of the adjusted geometric means (gMean). Standard deviation is actually Intra individual geometric coefficient variation (gCV).
Show Statistical Analysis 6 Hide Statistical Analysis 6
Statistical Analysis Overview Comparison Group Selection Group B
Comments Day 66 vs. Day 1
Type of Statistical Test Non-Inferiority or Equivalence
Comments p-value for ratio outside 80% to 125%
Statistical Test of Hypothesis P-Value 0.8378
Comments [Not Specified]
Method ANOVA
Comments ANOVA (analysis of variance) model on the logarithm scale was used with ‘subject’ as random, whereas the ‘treatment’ as fixed effect.
Method of Estimation Estimation Parameter Ratio of gmeans Day 66 vs. Day 1 (%)
Estimated Value 75.42
Confidence Interval (2-Sided) 90%
68.15 to 83.45
Parameter Dispersion
Type: Standard Deviation
Value: 16.4
Estimation Comments Relative bioavailability of tolbutamide at Day 66 vs. Day 1 −was estimated by the ratios of the adjusted geometric means (gMean). Standard deviation is actually Intra individual geometric coefficient variation (gCV).
19.Primary Outcome
Title AUC 0-infinity of Tolbutamide
Hide Description Area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity.
Time Frame 5 min before and 1 hour (h), 2h, 3h, 4h, 5h, 6h, 8h, 10h, 11:55h, 15h, 23:55h, 26h, 28h, 29:55h, 32h after first drug administration on day 1 also 5 min before, 1h, 2h, 3h, 4h, 5h, 5:55h, 8h, 10h, 11:55h, 15h, 23:55h after drug on days 9, 17 and 66.
Hide Outcome Measure Data
Hide Analysis Population Description
PKS. This endpoint was not planned to be analysed for groups C, D and E
Arm/Group Title Group A Group B
Hide Arm/Group Description:
600mg deleobuvir(DBV) tablet taken orally 3 times a day plus 120mg faldaprevir(FDV) capsule taken orally once daily plus ribavirin(RBV) tablet taken orally twice daily for 24 weeks along with pegylated interferon α-2a(PegIFN) injection and probe drugs(200 mg caffeine tablet, 500 mg tolbutamide tablet, and 2 mg midazolam syrup administered orally on days 1, 9, 17, and 66). In group A the effect of DBV on FDV, the effect of FDV, dual oral direct acting antiviral (DAAs) and their metabolites on caffeine, tolbutamide and midazolam were determined.
600mg deleobuvir(DBV) tablet taken orally 3 times a day plus 120mg faldaprevir(FDV) capsule taken orally once daily plus ribavirin(RBV) tablet taken orally twice daily for 24 weeks along with pegylated interferon α-2a (PegIFN) injection and probe drugs(200 mg caffeine tablet, 500 mg tolbutamide tablet, and 2 mg midazolam syrup administered orally on days 1, 9, 17, and 66). In group B the effect of FDV on DBV, the effect of DBV, dual oral direct acting antiviral (DAAs) and their metabolites on caffeine, tolbutamide and midazolam were determined.
Overall Number of Participants Analyzed 16 19
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: nmol*h/L
Day 1 (N=16, 19)
1940000
(42.5%)
2220000
(29.4%)
Day 9 (N=13, 17)
1800000
(41.3%)
1940000
(36.5%)
Day 17 (N=14, 18)
1520000
(36.4%)
1410000
(27.9%)
Day 66 (N=12, 15)
1330000
(40.1%)
1390000
(33.2%)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Group A
Comments Day 9 vs. Day 1
Type of Statistical Test Non-Inferiority or Equivalence
Comments p-value for ratio outside 80% to 125%
Statistical Test of Hypothesis P-Value 0.0005
Comments [Not Specified]
Method ANOVA
Comments

ANOVA (analysis of variance) model on the logarithm scale was used with

‘subject’ as random, whereas the ‘treatment’ as fixed effect.

Method of Estimation Estimation Parameter Ratio of gmeans Day 9 vs. Day 1 (%)
Estimated Value 98.17
Confidence Interval (2-Sided) 90%
90.15 to 106.91
Parameter Dispersion
Type: Standard Deviation
Value: 12.3
Estimation Comments Relative bioavailability of tolbutamide at Day 9 vs. Day 1 −was estimated by the ratios of the adjusted geometric means (gMean). Standard deviation is actually Intra individual geometric coefficient variation (gCV).
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Group A
Comments Day 17 vs. Day 1
Type of Statistical Test Non-Inferiority or Equivalence
Comments p-value for ratio outside 80% to 125%
Statistical Test of Hypothesis P-Value 0.3638
Comments [Not Specified]
Method ANOVA
Comments

ANOVA (analysis of variance) model on the logarithm scale was used with

‘subject’ as random, whereas the ‘treatment’ as fixed effect.

Method of Estimation Estimation Parameter Ratio of gmeans Day 17 vs. Day 1 (%)
Estimated Value 81.26
Confidence Interval (2-Sided) 90%
75.19 to 87.82
Parameter Dispersion
Type: Standard Deviation
Value: 11.7
Estimation Comments Relative bioavailability of tolbutamide at Day 17 vs. Day 1 −was estimated by the ratios of the adjusted geometric means (gMean). Standard deviation is actually Intra individual geometric coefficient variation (gCV).
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Group A
Comments Day 66 vs. Day 1
Type of Statistical Test Non-Inferiority or Equivalence
Comments p-value for ratio outside 80% to 125%
Statistical Test of Hypothesis P-Value 0.8975
Comments [Not Specified]
Method ANOVA
Comments

ANOVA (analysis of variance) model on the logarithm scale was used with

‘subject’ as random, whereas the ‘treatment’ as fixed effect.

Method of Estimation Estimation Parameter Ratio of gmeans Day 66 vs. Day 1 (%)
Estimated Value 70.93
Confidence Interval (2-Sided) 90%
60.44 to 83.22
Parameter Dispersion
Type: Standard Deviation
Value: 22.6
Estimation Comments Relative bioavailability of tolbutamide at Day 66 vs. Day 1 −was estimated by the ratios of the adjusted geometric means (gMean). Standard deviation is actually Intra individual geometric coefficient variation (gCV).
Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Group B
Comments Day 9 vs. Day 1
Type of Statistical Test Non-Inferiority or Equivalence
Comments p-value for ratio outside 80% to 125%
Statistical Test of Hypothesis P-Value 0.1144
Comments [Not Specified]
Method ANOVA
Comments ANOVA (analysis of variance) model on the logarithm scale was used with ‘subject’ as random, whereas the ‘treatment’ as fixed effect.
Method of Estimation Estimation Parameter Ratio of gmeans Day 9 vs. Day 1 (%)
Estimated Value 86.37
Confidence Interval (2-Sided) 90%
77.62 to 96.11
Parameter Dispersion
Type: Standard Deviation
Value: 18.1
Estimation Comments Relative bioavailability of tolbutamide at Day 9 vs. Day 1 −was estimated by the ratios of the adjusted geometric means (gMean). Standard deviation is actually Intra individual geometric coefficient variation (gCV).
Show Statistical Analysis 5 Hide Statistical Analysis 5
Statistical Analysis Overview Comparison Group Selection Group B
Comments Day 17 vs. Day 1
Type of Statistical Test Non-Inferiority or Equivalence
Comments p-value for ratio outside 80% to 125%
Statistical Test of Hypothesis P-Value 1.0000
Comments [Not Specified]
Method ANOVA
Comments ANOVA (analysis of variance) model on the logarithm scale was used with ‘subject’ as random, whereas the ‘treatment’ as fixed effect.
Method of Estimation Estimation Parameter Ratio of gmeans Day 17 vs. Day 1 (%)
Estimated Value 64.66
Confidence Interval (2-Sided) 90%
60.42 to 69.20
Parameter Dispersion
Type: Standard Deviation
Value: 11.8
Estimation Comments Relative bioavailability of tolbutamide at Day 17 vs. Day 1 −was estimated by the ratios of the adjusted geometric means (gMean). Standard deviation is actually Intra individual geometric coefficient variation (gCV).
Show Statistical Analysis 6 Hide Statistical Analysis 6
Statistical Analysis Overview Comparison Group Selection Group B
Comments Day 66 vs. Day 1
Type of Statistical Test Non-Inferiority or Equivalence
Comments p-value for ratio outside 80% to 125%
Statistical Test of Hypothesis P-Value 0.9988
Comments [Not Specified]
Method ANOVA
Comments ANOVA (analysis of variance) model on the logarithm scale was used with ‘subject’ as random, whereas the ‘treatment’ as fixed effect.
Method of Estimation Estimation Parameter Ratio of gmeans Day 66 vs. Day 1 (%)
Estimated Value 63.75
Confidence Interval (2-Sided) 90%
57.19 to 71.07
Parameter Dispersion
Type: Standard Deviation
Value: 17.3
Estimation Comments Relative bioavailability of tolbutamide at Day 66 vs. Day 1 −was estimated by the ratios of the adjusted geometric means (gMean). Standard deviation is actually Intra individual geometric coefficient variation (gCV).
20.Primary Outcome
Title Cmax of Midazolam
Hide Description Maximum concentration of an analyte in plasma
Time Frame 5 min before and 1 hour (h), 2h, 3h, 4h, 5h, 6h, 8h, 10h, 11:55h, 15h, 23:55h, 26h, 28h, 29:55h, 32h after first drug administration on day 1 also 5 min before, 1h, 2h, 3h, 4h, 5h, 5:55h, 8h, 10h, 11:55h, 15h, 23:55h after drug on days 9, 17 and 66.
Hide Outcome Measure Data
Hide Analysis Population Description
PKS. This endpoint was not planned to be analysed for groups C, D and E
Arm/Group Title Group A Group B
Hide Arm/Group Description:
600mg deleobuvir(DBV) tablet taken orally 3 times a day plus 120mg faldaprevir(FDV) capsule taken orally once daily plus ribavirin(RBV) tablet taken orally twice daily for 24 weeks along with pegylated interferon α-2a(PegIFN) injection and probe drugs(200 mg caffeine tablet, 500 mg tolbutamide tablet, and 2 mg midazolam syrup administered orally on days 1, 9, 17, and 66). In group A the effect of DBV on FDV, the effect of FDV, dual oral direct acting antiviral (DAAs) and their metabolites on caffeine, tolbutamide and midazolam were determined.
600mg deleobuvir(DBV) tablet taken orally 3 times a day plus 120mg faldaprevir(FDV) capsule taken orally once daily plus ribavirin(RBV) tablet taken orally twice daily for 24 weeks along with pegylated interferon α-2a (PegIFN) injection and probe drugs(200 mg caffeine tablet, 500 mg tolbutamide tablet, and 2 mg midazolam syrup administered orally on days 1, 9, 17, and 66). In group B the effect of FDV on DBV, the effect of DBV, dual oral direct acting antiviral (DAAs) and their metabolites on caffeine, tolbutamide and midazolam were determined.
Overall Number of Participants Analyzed 16 19
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: nmol/L
Day 1 (N=16, 19)
21.1
(38.3%)
23.8
(41.2%)
Day 9 (N=15, 17)
29.9
(34.7%)
29.8
(44.3%)
Day 17 (N=14, 19)
31.9
(36.6%)
28.8
(46.9%)
Day 66 (N=13, 15)
21.3
(34.0%)
23.2
(40.4%)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Group A
Comments Day 9 vs. Day 1
Type of Statistical Test Non-Inferiority or Equivalence
Comments p-value for ratio outside 80% to 125%
Statistical Test of Hypothesis P-Value 0.9749
Comments [Not Specified]
Method ANOVA
Comments

ANOVA (analysis of variance) model on the logarithm scale was used with

‘subject’ as random, whereas the ‘treatment’ as fixed effect.

Method of Estimation Estimation Parameter Ratio of gmeans Day 9 vs. Day 1 (%)
Estimated Value 144.78
Confidence Interval (2-Sided) 90%
128.30 to 163.36
Parameter Dispersion
Type: Standard Deviation
Value: 19.0
Estimation Comments Relative bioavailability of Midazolam at Day 9 vs. Day 1 −was estimated by the ratios of the adjusted geometric means (gMean). Standard deviation is actually Intra individual geometric coefficient variation (gCV).
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Group A
Comments Day 17 vs. Day 1
Type of Statistical Test Non-Inferiority or Equivalence
Comments p-value for ratio outside 80% to 125%
Statistical Test of Hypothesis P-Value 0.9703
Comments [Not Specified]
Method ANOVA
Comments

ANOVA (analysis of variance) model on the logarithm scale was used with

‘subject’ as random, whereas the ‘treatment’ as fixed effect.

Method of Estimation Estimation Parameter Ratio of gmeans Day 17 vs. Day 1 (%)
Estimated Value 152.94
Confidence Interval (2-Sided) 90%
128.60 to 181.89
Parameter Dispersion
Type: Standard Deviation
Value: 26.8
Estimation Comments Relative bioavailability of Midazolam at Day 17 vs. Day 1 −was estimated by the ratios of the adjusted geometric means (gMean). Standard deviation is actually Intra individual geometric coefficient variation (gCV).
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Group A
Comments Day 66 vs. Day 1
Type of Statistical Test Non-Inferiority or Equivalence
Comments p-value for ratio outside 80% to 125%
Statistical Test of Hypothesis P-Value 0.0500
Comments [Not Specified]
Method ANOVA
Comments

ANOVA (analysis of variance) model on the logarithm scale was used with

‘subject’ as random, whereas the ‘treatment’ as fixed effect.

Method of Estimation Estimation Parameter Ratio of gmeans Day 66 vs. Day 1 (%)
Estimated Value 102.99
Confidence Interval (2-Sided) 90%
84.85 to 124.99
Parameter Dispersion
Type: Standard Deviation
Value: 29.3
Estimation Comments Relative bioavailability of Midazolam at Day 66 vs. Day 1 −was estimated by the ratios of the adjusted geometric means (gMean). Standard deviation is actually Intra individual geometric coefficient variation (gCV).
Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Group B
Comments Day 9 vs. Day 1
Type of Statistical Test Non-Inferiority or Equivalence
Comments p-value for ratio outside 80% to 125%
Statistical Test of Hypothesis P-Value 0.4697
Comments [Not Specified]
Method ANOVA
Comments ANOVA (analysis of variance) model on the logarithm scale was used with ‘subject’ as random, whereas the ‘treatment’ as fixed effect.
Method of Estimation Estimation Parameter Ratio of gmeans Day 9 vs. Day 1 (%)
Estimated Value 124.22
Confidence Interval (2-Sided) 90%
107.91 to 142.99
Parameter Dispersion
Type: Standard Deviation
Value: 24.1
Estimation Comments Relative bioavailability of Midazolam at Day 9 vs. Day 1 −was estimated by the ratios of the adjusted geometric means (gMean). Standard deviation is actually Intra individual geometric coefficient variation (gCV).
Show Statistical Analysis 5 Hide Statistical Analysis 5
Statistical Analysis Overview Comparison Group Selection Group B
Comments Day 17 vs. Day 1
Type of Statistical Test Non-Inferiority or Equivalence
Comments p-value for ratio outside 80% to 125%
Statistical Test of Hypothesis P-Value 0.2906
Comments [Not Specified]
Method ANOVA
Comments ANOVA (analysis of variance) model on the logarithm scale was used with ‘subject’ as random, whereas the ‘treatment’ as fixed effect.
Method of Estimation Estimation Parameter Ratio of gmeans Day 17 vs. Day 1 (%)
Estimated Value 120.74
Confidence Interval (2-Sided) 90%
108.47 to 134.38
Parameter Dispersion
Type: Standard Deviation
Value: 19.2
Estimation Comments Relative bioavailability of Midazolam at Day 17 vs. Day 1 −was estimated by the ratios of the adjusted geometric means (gMean). Standard deviation is actually Intra individual geometric coefficient variation (gCV).
Show Statistical Analysis 6 Hide Statistical Analysis 6
Statistical Analysis Overview Comparison Group Selection Group B
Comments Day 66 vs. Day 1
Type of Statistical Test Non-Inferiority or Equivalence
Comments p-value for ratio outside 80% to 125%
Statistical Test of Hypothesis P-Value 0.0460
Comments [Not Specified]
Method ANOVA
Comments ANOVA (analysis of variance) model on the logarithm scale was used with ‘subject’ as random, whereas the ‘treatment’ as fixed effect.
Method of Estimation Estimation Parameter Ratio of gmeans Day 66 vs. Day 1 (%)
Estimated Value 93.95
Confidence Interval (2-Sided) 90%
80.33 to 109.86
Parameter Dispersion
Type: Standard Deviation
Value: 25.2
Estimation Comments Relative bioavailability of Midazolam at Day 66 vs. Day 1 −was estimated by the ratios of the adjusted geometric means (gMean). Standard deviation is actually Intra individual geometric coefficient variation (gCV).
21.Primary Outcome
Title AUC 0-infinity of Midazolam
Hide Description Area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity.
Time Frame 5 min before and 1 hour (h), 2h, 3h, 4h, 5h, 6h, 8h, 10h, 11:55h, 15h, 23:55h, 26h, 28h, 29:55h, 32h after first drug administration on day 1 also 5 min before, 1h, 2h, 3h, 4h, 5h, 5:55h, 8h, 10h, 11:55h, 15h, 23:55h after drug on days 9, 17 and 66.
Hide Outcome Measure Data
Hide Analysis Population Description
PKS. This endpoint was not planned to be analysed for groups C, D and E
Arm/Group Title Group A Group B
Hide Arm/Group Description:
600mg deleobuvir(DBV) tablet taken orally 3 times a day plus 120mg faldaprevir(FDV) capsule taken orally once daily plus ribavirin(RBV) tablet taken orally twice daily for 24 weeks along with pegylated interferon α-2a(PegIFN) injection and probe drugs(200 mg caffeine tablet, 500 mg tolbutamide tablet, and 2 mg midazolam syrup administered orally on days 1, 9, 17, and 66). In group A the effect of DBV on FDV, the effect of FDV, dual oral direct acting antiviral (DAAs) and their metabolites on caffeine, tolbutamide and midazolam were determined.
600mg deleobuvir(DBV) tablet taken orally 3 times a day plus 120mg faldaprevir(FDV) capsule taken orally once daily plus ribavirin(RBV) tablet taken orally twice daily for 24 weeks along with pegylated interferon α-2a (PegIFN) injection and probe drugs(200 mg caffeine tablet, 500 mg tolbutamide tablet, and 2 mg midazolam syrup administered orally on days 1, 9, 17, and 66). In group B the effect of FDV on DBV, the effect of DBV, dual oral direct acting antiviral (DAAs) and their metabolites on caffeine, tolbutamide and midazolam were determined.
Overall Number of Participants Analyzed 16 19
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: nmol*h/L
Day 1 (N=16, 19)
79.7
(59.1%)
107
(40.7%)
Day 9 (N=15, 17)
117
(58.2%)
130
(66.9%)
Day 17 (N=14, 19)
127
(50.2%)
140
(51.8%)
Day 66 (N=13, 15)
75.5
(46.7%)
95.6
(41.6%)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Group A
Comments Day 9 vs. Day 1
Type of Statistical Test Non-Inferiority or Equivalence
Comments p-value for ratio outside 80% to 125%
Statistical Test of Hypothesis P-Value 0.9941
Comments [Not Specified]
Method ANOVA
Comments

ANOVA (analysis of variance) model on the logarithm scale was used with

‘subject’ as random, whereas the ‘treatment’ as fixed effect.

Method of Estimation Estimation Parameter Ratio of gmeans Day 9 vs. Day 1 (%)
Estimated Value 151.66
Confidence Interval (2-Sided) 90%
134.79 to 170.64
Parameter Dispersion
Type: Standard Deviation
Value: 18.5
Estimation Comments Relative bioavailability of Midazolam at Day 9 vs. Day 1 −was estimated by the ratios of the adjusted geometric means (gMean). Standard deviation is actually Intra individual geometric coefficient variation (gCV).
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Group A
Comments Day 17 vs. Day 1
Type of Statistical Test Non-Inferiority or Equivalence
Comments p-value for ratio outside 80% to 125%
Statistical Test of Hypothesis P-Value 0.9926
Comments [Not Specified]
Method ANOVA
Comments

ANOVA (analysis of variance) model on the logarithm scale was used with

‘subject’ as random, whereas the ‘treatment’ as fixed effect.

Method of Estimation Estimation Parameter Ratio of gmeans Day 17 vs. Day 1 (%)
Estimated Value 163.42
Confidence Interval (2-Sided) 90%
137.91 to 193.64
Parameter Dispersion
Type: Standard Deviation
Value: 26.0
Estimation Comments Relative bioavailability of Midazolam at Day 17 vs. Day 1 −was estimated by the ratios of the adjusted geometric means (gMean). Standard deviation is actually Intra individual geometric coefficient variation (gCV).
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Group A
Comments Day 66 vs. Day 1
Type of Statistical Test Non-Inferiority or Equivalence
Comments p-value for ratio outside 80% to 125%
Statistical Test of Hypothesis P-Value 0.0392
Comments [Not Specified]
Method ANOVA
Comments

ANOVA (analysis of variance) model on the logarithm scale was used with

‘subject’ as random, whereas the ‘treatment’ as fixed effect.

Method of Estimation Estimation Parameter Ratio of gmeans Day 66 vs. Day 1 (%)
Estimated Value 98.14
Confidence Interval (2-Sided) 90%
81.20 to 118.63
Parameter Dispersion
Type: Standard Deviation
Value: 28.1
Estimation Comments Relative bioavailability of Midazolam at Day 66 vs. Day 1 −was estimated by the ratios of the adjusted geometric means (gMean). Standard deviation is actually Intra individual geometric coefficient variation (gCV).
Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Group B
Comments Day 9 vs. Day 1
Type of Statistical Test Non-Inferiority or Equivalence
Comments p-value for ratio outside 80% to 125%
Statistical Test of Hypothesis P-Value 0.4374
Comments [Not Specified]
Method ANOVA
Comments ANOVA (analysis of variance) model on the logarithm scale was used with ‘subject’ as random, whereas the ‘treatment’ as fixed effect.
Method of Estimation Estimation Parameter Ratio of gmeans Day 9 vs. Day 1 (%)
Estimated Value 122.58
Confidence Interval (2-Sided) 90%
99.15 to 151.55
Parameter Dispersion
Type: Standard Deviation
Value: 37.2
Estimation Comments Relative bioavailability of Midazolam at Day 9 vs. Day 1 −was estimated by the ratios of the adjusted geometric means (gMean). Standard deviation is actually Intra individual geometric coefficient variation (gCV).
Show Statistical Analysis 5 Hide Statistical Analysis 5
Statistical Analysis Overview Comparison Group Selection Group B
Comments Day 17 vs. Day 1
Type of Statistical Test Non-Inferiority or Equivalence
Comments p-value for ratio outside 80% to 125%
Statistical Test of Hypothesis P-Value 0.6470
Comments [Not Specified]
Method ANOVA
Comments ANOVA (analysis of variance) model on the logarithm scale was used with ‘subject’ as random, whereas the ‘treatment’ as fixed effect.
Method of Estimation Estimation Parameter Ratio of gmeans Day 17 vs. Day 1 (%)
Estimated Value 130.44
Confidence Interval (2-Sided) 90%
107.57 to 158.18
Parameter Dispersion
Type: Standard Deviation
Value: 35.3
Estimation Comments Relative bioavailability of Midazolam at Day 17 vs. Day 1 −was estimated by the ratios of the adjusted geometric means (gMean). Standard deviation is actually Intra individual geometric coefficient variation (gCV).
Show Statistical Analysis 6 Hide Statistical Analysis 6
Statistical Analysis Overview Comparison Group Selection Group B
Comments Day 66 vs. Day 1
Type of Statistical Test Non-Inferiority or Equivalence
Comments p-value for ratio outside 80% to 125%
Statistical Test of Hypothesis P-Value 0.2372
Comments [Not Specified]
Method ANOVA
Comments ANOVA (analysis of variance) model on the logarithm scale was used with ‘subject’ as random, whereas the ‘treatment’ as fixed effect.
Method of Estimation Estimation Parameter Ratio of gmeans Day 66 vs. Day 1 (%)
Estimated Value 87.77
Confidence Interval (2-Sided) 90%
70.32 to 109.54
Parameter Dispersion
Type: Standard Deviation
Value: 36.9
Estimation Comments Relative bioavailability of Midazolam at Day 66 vs. Day 1 −was estimated by the ratios of the adjusted geometric means (gMean). Standard deviation is actually Intra individual geometric coefficient variation (gCV).
22.Primary Outcome
Title Cmax of 1-OH-Midazolam (1-hydroxy-midazolam)
Hide Description Maximum concentration of an analyte in plasma
Time Frame 5 min before and 1 hour (h), 2h, 3h, 4h, 5h, 6h, 8h, 10h, 11:55h, 15h, 23:55h, 26h, 28h, 29:55h, 32h after first drug administration on day 1 also 5 min before, 1h, 2h, 3h, 4h, 5h, 5:55h, 8h, 10h, 11:55h, 15h, 23:55h after drug on days 9, 17 and 66.
Hide Outcome Measure Data
Hide Analysis Population Description
PKS. This endpoint was not planned to be analysed for groups C, D and E
Arm/Group Title Group A Group B
Hide Arm/Group Description:
600mg deleobuvir(DBV) tablet taken orally 3 times a day plus 120mg faldaprevir(FDV) capsule taken orally once daily plus ribavirin(RBV) tablet taken orally twice daily for 24 weeks along with pegylated interferon α-2a(PegIFN) injection and probe drugs(200 mg caffeine tablet, 500 mg tolbutamide tablet, and 2 mg midazolam syrup administered orally on days 1, 9, 17, and 66). In group A the effect of DBV on FDV, the effect of FDV, dual oral direct acting antiviral (DAAs) and their metabolites on caffeine, tolbutamide and midazolam were determined.
600mg deleobuvir(DBV) tablet taken orally 3 times a day plus 120mg faldaprevir(FDV) capsule taken orally once daily plus ribavirin(RBV) tablet taken orally twice daily for 24 weeks along with pegylated interferon α-2a (PegIFN) injection and probe drugs(200 mg caffeine tablet, 500 mg tolbutamide tablet, and 2 mg midazolam syrup administered orally on days 1, 9, 17, and 66). In group B the effect of FDV on DBV, the effect of DBV, dual oral direct acting antiviral (DAAs) and their metabolites on caffeine, tolbutamide and midazolam were determined.
Overall Number of Participants Analyzed 16 19
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: nmol/L
Day 1 (N=16, 19)
5.57
(36.4%)
6.68
(67.1%)
Day 9 (N=15, 17)
6.50
(46.3%)
6.52
(46.9%)
Day 17 (N=14, 19)
6.46
(42.7%)
5.02
(50.5%)
Day 66 (N=13, 15)
5.05
(45.6%)
4.67
(45.2%)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Group A
Comments Day 9 vs. Day 1
Type of Statistical Test Non-Inferiority or Equivalence
Comments p-value for ratio outside 80% to 125%
Statistical Test of Hypothesis P-Value 0.1519
Comments [Not Specified]
Method ANOVA
Comments

ANOVA (analysis of variance) model on the logarithm scale was used with

‘subject’ as random, whereas the ‘treatment’ as fixed effect.

Method of Estimation Estimation Parameter Ratio of gmeans Day 9 vs. Day 1 (%)
Estimated Value 117.67
Confidence Interval (2-Sided) 90%
106.49 to 130.00
Parameter Dispersion
Type: Standard Deviation
Value: 15.6
Estimation Comments Relative bioavailability of 1-OH-Midazolam at Day 9 vs. Day 1 −was estimated by the ratios of the adjusted geometric means (gMean). Standard deviation is actually Intra individual geometric coefficient variation (gCV).
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Group A
Comments Day17 vs. Day 1
Type of Statistical Test Non-Inferiority or Equivalence
Comments p-value for ratio outside 80% to 125%
Statistical Test of Hypothesis P-Value 0.2827
Comments [Not Specified]
Method ANOVA
Comments

ANOVA (analysis of variance) model on the logarithm scale was used with

‘subject’ as random, whereas the ‘treatment’ as fixed effect.

Method of Estimation Estimation Parameter Ratio of gmeans Day 17 vs. Day 1 (%)
Estimated Value 117.01
Confidence Interval (2-Sided) 90%
96.06 to 142.52
Parameter Dispersion
Type: Standard Deviation
Value: 30.9
Estimation Comments Relative bioavailability of 1-OH-Midazolam at Day 17 vs. Day 1 −was estimated by the ratios of the adjusted geometric means (gMean). Standard deviation is actually Intra individual geometric coefficient variation (gCV).
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Group A
Comments Day 66 vs. Day 1
Type of Statistical Test Non-Inferiority or Equivalence
Comments p-value for ratio outside 80% to 125%
Statistical Test of Hypothesis P-Value 0.1326
Comments [Not Specified]
Method ANOVA
Comments

ANOVA (analysis of variance) model on the logarithm scale was used with

‘subject’ as random, whereas the ‘treatment’ as fixed effect.

Method of Estimation Estimation Parameter Ratio of gmeans Day 66 vs. Day 1 (%)
Estimated Value 92.11
Confidence Interval (2-Sided) 90%
74.38 to 114.07
Parameter Dispersion
Type: Standard Deviation
Value: 32.6
Estimation Comments Relative bioavailability of 1-OH-Midazolam at Day 66 vs. Day 1 −was estimated by the ratios of the adjusted geometric means (gMean). Standard deviation is actually Intra individual geometric coefficient variation (gCV).
Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Group B
Comments Day 9 vs. Day 1
Type of Statistical Test Non-Inferiority or Equivalence
Comments p-value for ratio outside 80% to 125%
Statistical Test of Hypothesis P-Value 0.0432
Comments [Not Specified]
Method ANOVA
Comments ANOVA (analysis of variance) model on the logarithm scale was used with ‘subject’ as random, whereas the ‘treatment’ as fixed effect.
Method of Estimation Estimation Parameter Ratio of gmeans Day 9 vs. Day 1 (%)
Estimated Value 95.55
Confidence Interval (2-Sided) 90%
80.63 to 113.24
Parameter Dispersion
Type: Standard Deviation
Value: 29.2
Estimation Comments Relative bioavailability of 1-OH-Midazolam at Day 9 vs. Day 1 −was estimated by the ratios of the adjusted geometric means (gMean). Standard deviation is actually Intra individual geometric coefficient variation (gCV).
Show Statistical Analysis 5 Hide Statistical Analysis 5
Statistical Analysis Overview Comparison Group Selection Group B
Comments Day 17 vs. Day 1
Type of Statistical Test Non-Inferiority or Equivalence
Comments p-value for ratio outside 80% to 125%
Statistical Test of Hypothesis P-Value 0.7367
Comments [Not Specified]
Method ANOVA
Comments ANOVA (analysis of variance) model on the logarithm scale was used with ‘subject’ as random, whereas the ‘treatment’ as fixed effect.
Method of Estimation Estimation Parameter Ratio of gmeans Day 17 vs. Day 1 (%)
Estimated Value 75.19
Confidence Interval (2-Sided) 90%
63.64 to 88.82
Parameter Dispersion
Type: Standard Deviation
Value: 30.3
Estimation Comments Relative bioavailability of 1-OH-Midazolam at Day 17 vs. Day 1 −was estimated by the ratios of the adjusted geometric means (gMean). Standard deviation is actually Intra individual geometric coefficient variation (gCV).
Show Statistical Analysis 6 Hide Statistical Analysis 6
Statistical Analysis Overview Comparison Group Selection Group B
Comments Day 66 vs. Day 1
Type of Statistical Test Non-Inferiority or Equivalence
Comments p-value for ratio outside 80% to 125%
Statistical Test of Hypothesis P-Value 0.8547
Comments [Not Specified]
Method ANOVA
Comments ANOVA (analysis of variance) model on the logarithm scale was used with ‘subject’ as random, whereas the ‘treatment’ as fixed effect.
Method of Estimation Estimation Parameter Ratio of gmeans Day 66 vs. Day 1 (%)
Estimated Value 70.14
Confidence Interval (2-Sided) 90%
56.84 to 86.56
Parameter Dispersion
Type: Standard Deviation
Value: 34.3
Estimation Comments Relative bioavailability of 1-OH-Midazolam at Day 66 vs. Day 1 −was estimated by the ratios of the adjusted geometric means (gMean). Standard deviation is actually Intra individual geometric coefficient variation (gCV).
23.Primary Outcome
Title AUC 0-infinity of 1-OH-Midazolam (1-hydroxy-midazolam)
Hide Description Area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity.
Time Frame 5 min before and 1 hour (h), 2h, 3h, 4h, 5h, 6h, 8h, 10h, 11:55h, 15h, 23:55h, 26h, 28h, 29:55h, 32h after first drug administration on day 1 also 5 min before, 1h, 2h, 3h, 4h, 5h, 5:55h, 8h, 10h, 11:55h, 15h, 23:55h after drug on days 9, 17 and 66.
Hide Outcome Measure Data
Hide Analysis Population Description
PKS. This endpoint was not planned to be analysed for groups C, D and E
Arm/Group Title Group A Group B
Hide Arm/Group Description:
600mg deleobuvir(DBV) tablet taken orally 3 times a day plus 120mg faldaprevir(FDV) capsule taken orally once daily plus ribavirin(RBV) tablet taken orally twice daily for 24 weeks along with pegylated interferon α-2a(PegIFN) injection and probe drugs(200 mg caffeine tablet, 500 mg tolbutamide tablet, and 2 mg midazolam syrup administered orally on days 1, 9, 17, and 66). In group A the effect of DBV on FDV, the effect of FDV, dual oral direct acting antiviral (DAAs) and their metabolites on caffeine, tolbutamide and midazolam were determined.
600mg deleobuvir(DBV) tablet taken orally 3 times a day plus 120mg faldaprevir(FDV) capsule taken orally once daily plus ribavirin(RBV) tablet taken orally twice daily for 24 weeks along with pegylated interferon α-2a (PegIFN) injection and probe drugs(200 mg caffeine tablet, 500 mg tolbutamide tablet, and 2 mg midazolam syrup administered orally on days 1, 9, 17, and 66). In group B the effect of FDV on DBV, the effect of DBV, dual oral direct acting antiviral (DAAs) and their metabolites on caffeine, tolbutamide and midazolam were determined.
Overall Number of Participants Analyzed 16 19
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: nmol*h/L
Day 1 (N=16, 19)
23.6
(59.8%)
26.0
(65.2%)
Day 9 (N=15, 17)
24.2
(35.9%)
28.5
(63.9%)
Day 17 (N=14, 19)
23.5
(37.4%)
22.8
(49.8%)
Day 66 (N=13, 13)
18.3
(26.7%)
20.8
(46.1%)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Group A
Comments Day 9 vs. Day 1
Type of Statistical Test Non-Inferiority or Equivalence
Comments p-value for ratio outside 80% to 125%
Statistical Test of Hypothesis P-Value 0.1159
Comments [Not Specified]
Method ANOVA
Comments

ANOVA (analysis of variance) model on the logarithm scale was used with

‘subject’ as random, whereas the ‘treatment’ as fixed effect.

Method of Estimation Estimation Parameter Ratio of gmeans Day 9 vs. Day 1 (%)
Estimated Value 102.70
Confidence Interval (2-Sided) 90%
77.89 to 135.39
Parameter Dispersion
Type: Standard Deviation
Value: 45.9
Estimation Comments Relative bioavailability of 1-OH-Midazolam at Day 9 vs. Day 1 −was estimated by the ratios of the adjusted geometric means (gMean). Standard deviation is actually Intra individual geometric coefficient variation (gCV).
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Group A
Comments Day 17 vs. Day 1
Type of Statistical Test Non-Inferiority or Equivalence
Comments p-value for ratio outside 80% to 125%
Statistical Test of Hypothesis P-Value 0.0651
Comments [Not Specified]
Method ANOVA
Comments

ANOVA (analysis of variance) model on the logarithm scale was used with

‘subject’ as random, whereas the ‘treatment’ as fixed effect.

Method of Estimation Estimation Parameter Ratio of gmeans Day 17 vs. Day 1 (%)
Estimated Value 99.99
Confidence Interval (2-Sided) 90%
78.33 to 127.64
Parameter Dispersion
Type: Standard Deviation
Value: 38.7
Estimation Comments Relative bioavailability of 1-OH-Midazolam at Day 17 vs. Day 1 −was estimated by the ratios of the adjusted geometric means (gMean). Standard deviation is actually Intra individual geometric coefficient variation (gCV).
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Group A
Comments Day 66 vs. Day 1
Type of Statistical Test Non-Inferiority or Equivalence
Comments p-value for ratio outside 80% to 125%
Statistical Test of Hypothesis P-Value 0.5658
Comments [Not Specified]
Method ANOVA
Comments

ANOVA (analysis of variance) model on the logarithm scale was used with

‘subject’ as random, whereas the ‘treatment’ as fixed effect.

Method of Estimation Estimation Parameter Ratio of gmeans Day 66 vs. Day 1 (%)
Estimated Value 78.29
Confidence Interval (2-Sided) 90%
62.50 to 98.07
Parameter Dispersion
Type: Standard Deviation
Value: 34.3
Estimation Comments Relative bioavailability of 1-OH-Midazolam at Day 66 vs. Day 1 −was estimated by the ratios of the adjusted geometric means (gMean). Standard deviation is actually Intra individual geometric coefficient variation (gCV).
Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Group B
Comments Day 9 vs. Day 1
Type of Statistical Test Non-Inferiority or Equivalence
Comments p-value for ratio outside 80% to 125%
Statistical Test of Hypothesis P-Value 0.1286
Comments [Not Specified]
Method ANOVA
Comments ANOVA (analysis of variance) model on the logarithm scale was used with ‘subject’ as random, whereas the ‘treatment’ as fixed effect.
Method of Estimation Estimation Parameter Ratio of gmeans Day 9 vs. Day 1 (%)
Estimated Value 108.25
Confidence Interval (2-Sided) 90%
87.46 to 133.99
Parameter Dispersion
Type: Standard Deviation
Value: 37.2
Estimation Comments Relative bioavailability of 1-OH-Midazolam at Day 9 vs. Day 1 −was estimated by the ratios of the adjusted geometric means (gMean). Standard deviation is actually Intra individual geometric coefficient variation (gCV).
Show Statistical Analysis 5 Hide Statistical Analysis 5
Statistical Analysis Overview Comparison Group Selection Group B
Comments Day 17 vs. Day 1
Type of Statistical Test Non-Inferiority or Equivalence
Comments p-value for ratio outside 80% to 125%
Statistical Test of Hypothesis P-Value 0.1898
Comments [Not Specified]
Method ANOVA
Comments ANOVA (analysis of variance) model on the logarithm scale was used with ‘subject’ as random, whereas the ‘treatment’ as fixed effect.
Method of Estimation Estimation Parameter Ratio of gmeans Day 17 vs. Day 1 (%)
Estimated Value 87.59
Confidence Interval (2-Sided) 90%
73.56 to 104.30
Parameter Dispersion
Type: Standard Deviation
Value: 31.8
Estimation Comments Relative bioavailability of 1-OH-Midazolam at Day 17 vs. Day 1 −was estimated by the ratios of the adjusted geometric means (gMean). Standard deviation is actually Intra individual geometric coefficient variation (gCV).
Show Statistical Analysis 6 Hide Statistical Analysis 6
Statistical Analysis Overview Comparison Group Selection Group B
Comments Day 66 vs. Day 1
Type of Statistical Test Non-Inferiority or Equivalence
Comments p-value for ratio outside 80% to 125%
Statistical Test of Hypothesis P-Value 0.5575
Comments [Not Specified]
Method ANOVA
Comments ANOVA (analysis of variance) model on the logarithm scale was used with ‘subject’ as random, whereas the ‘treatment’ as fixed effect.
Method of Estimation Estimation Parameter Ratio of gmeans Day 66 vs. Day 1 (%)
Estimated Value 78.42
Confidence Interval (2-Sided) 90%
61.81 to 99.51
Parameter Dispersion
Type: Standard Deviation
Value: 36.3
Estimation Comments Relative bioavailability of 1-OH-Midazolam at Day 66 vs. Day 1 −was estimated by the ratios of the adjusted geometric means (gMean). Standard deviation is actually Intra individual geometric coefficient variation (gCV).
24.Primary Outcome
Title Cmax of Tenofovir
Hide Description Maximum concentration of an analyte in plasma.
Time Frame PK plasma samples were taken at: 5 minutes before drug administration and 1 hour (h), 2h, 3h, 4h, 5h, 5:55h, 8h, 10h, 11:55h, 15h, 23:55h after first drug administration on days 9 and 17
Hide Outcome Measure Data
Hide Analysis Population Description
PKS. Due to Boehringer Ingelheim’s decision not to pursue the development of this substance, the extent of the statistical analysis was limited to selected endpoints. No further analysis is planned for the endpoints which were not related to patient efficacy or safety.
Arm/Group Title Group C
Hide Arm/Group Description:
600mg deleobuvir(DBV) tablet taken twice a day plus 120mg faldaprevir(FDV) capsule taken orally once daily plus ribavirin(RBV) tablet taken orally twice daily for 24 weeks with tenofovir tablet 300mg daily on days 1-17.
Overall Number of Participants Analyzed 0
No data displayed because Outcome Measure has zero total analyzed.
25.Primary Outcome
Title C24hr of Tenofovir
Hide Description Concentration of an analyte in plasma at 24 hours.
Time Frame PK plasma samples were taken at: 5 minutes before drug administration and 1 hour (h), 2h, 3h, 4h, 5h, 5:55h, 8h, 10h, 11:55h, 15h, 23:55h after first drug administration on days 9 and 17
Hide Outcome Measure Data
Hide Analysis Population Description
PKS. Due to Boehringer Ingelheim’s decision not to pursue the development of this substance, the extent of the statistical analysis was limited to selected endpoints. No further analysis is planned for the endpoints which were not related to patient efficacy or safety.
Arm/Group Title Group C
Hide Arm/Group Description:
600mg deleobuvir(DBV) tablet taken twice a day plus 120mg faldaprevir(FDV) capsule taken orally once daily plus ribavirin(RBV) tablet taken orally twice daily for 24 weeks with tenofovir tablet 300mg daily on days 1-17.
Overall Number of Participants Analyzed 0
No data displayed because Outcome Measure has zero total analyzed.
26.Primary Outcome
Title AUC 0-24hr of Tenofovir
Hide Description Area under the concentration-time curve of the analyte in plasma over the time interval from 0 to 24 hours.
Time Frame PK plasma samples were taken at: 5 minutes before drug administration and 1 hour (h), 2h, 3h, 4h, 5h, 5:55h, 8h, 10h, 11:55h, 15h, 23:55h after first drug administration on days 9 and 17
Hide Outcome Measure Data
Hide Analysis Population Description
PKS. Due to Boehringer Ingelheim’s decision not to pursue the development of this substance, the extent of the statistical analysis was limited to selected endpoints. No further analysis is planned for the endpoints which were not related to patient efficacy or safety.
Arm/Group Title Group C
Hide Arm/Group Description:
600mg deleobuvir(DBV) tablet taken twice a day plus 120mg faldaprevir(FDV) capsule taken orally once daily plus ribavirin(RBV) tablet taken orally twice daily for 24 weeks with tenofovir tablet 300mg daily on days 1-17.
Overall Number of Participants Analyzed 0
No data displayed because Outcome Measure has zero total analyzed.
27.Primary Outcome
Title Cmax of Raltegravir
Hide Description Maximum concentration of an analyte in plasma.
Time Frame PK plasma samples were taken at: 5 minutes before drug administration and 1 hour (h), 2h, 3h, 4h, 5h, 5:55h, 8h, 10h, 11:55h, 15h, 23:55h after first drug administration on days 9 and 17
Hide Outcome Measure Data
Hide Analysis Population Description
PKS. Due to Boehringer Ingelheim’s decision not to pursue the development of this substance, the extent of the statistical analysis was limited to selected endpoints. No further analysis is planned for the endpoints which were not related to patient efficacy or safety.
Arm/Group Title Group E
Hide Arm/Group Description:
600mg deleobuvir(DBV) tablet taken twice a day plus 120mg faldaprevir(FDV) capsule taken orally once daily plus ribavirin(RBV) tablet taken orally twice daily for 24 weeks with raltegravir tablet 400mg twice daily on days 1-17.
Overall Number of Participants Analyzed 0
No data displayed because Outcome Measure has zero total analyzed.
28.Primary Outcome
Title C12hr of Raltegravir
Hide Description Concentration of an analyte in plasma at 12 hours.
Time Frame PK plasma samples were taken at: 5 minutes before drug administration and 1 hour (h), 2h, 3h, 4h, 5h, 5:55h, 8h, 10h, 11:55h, 15h, 23:55h after first drug administration on days 9 and 17
Hide Outcome Measure Data
Hide Analysis Population Description
PKS. Due to Boehringer Ingelheim’s decision not to pursue the development of this substance, the extent of the statistical analysis was limited to selected endpoints. No further analysis is planned for the endpoints which were not related to patient efficacy or safety.
Arm/Group Title Group E
Hide Arm/Group Description:
600mg deleobuvir(DBV) tablet taken twice a day plus 120mg faldaprevir(FDV) capsule taken orally once daily plus ribavirin(RBV) tablet taken orally twice daily for 24 weeks with raltegravir tablet 400mg twice daily on days 1-17.
Overall Number of Participants Analyzed 0
No data displayed because Outcome Measure has zero total analyzed.
29.Primary Outcome
Title AUC 0-12hr of Raltegravir
Hide Description Area under the concentration-time curve of the analyte in plasma over the time interval from 0 to 12 hours.
Time Frame PK plasma samples were taken at: 5 minutes before drug administration and 1 hour (h), 2h, 3h, 4h, 5h, 5:55h, 8h, 10h, 11:55h, 15h, 23:55h after first drug administration on days 9 and 17
Hide Outcome Measure Data
Hide Analysis Population Description
PKS. Due to Boehringer Ingelheim’s decision not to pursue the development of this substance, the extent of the statistical analysis was limited to selected endpoints. No further analysis is planned for the endpoints which were not related to patient efficacy or safety.
Arm/Group Title Group E
Hide Arm/Group Description:
600mg deleobuvir(DBV) tablet taken twice a day plus 120mg faldaprevir(FDV) capsule taken orally once daily plus ribavirin(RBV) tablet taken orally twice daily for 24 weeks with raltegravir tablet 400mg twice daily on days 1-17.
Overall Number of Participants Analyzed 0
No data displayed because Outcome Measure has zero total analyzed.
30.Secondary Outcome
Title Number of Participants With Sustained Virological Response (SVR12)
Hide Description Sustained virologic response (SVR12): Plasma Hepatitis C virus Ribonucleic acid (HCV RNA) level <25 IU/mL(international units per millilitre) undetectable at 12 weeks after the end of treatment. SVR12 was analyzed in a descriptive manner using frequency of participants who achieved SVR12.
Time Frame 12 weeks post treatment
Hide Outcome Measure Data
Hide Analysis Population Description
Treated set (TRT): This subject set includes all patients who were dispensed trial medication and were documented to have taken at least one dose of trial drug.
Arm/Group Title Group A Group B Group C Group D Group E
Hide Arm/Group Description:
600mg deleobuvir(DBV) tablet taken orally 3 times a day plus 120mg faldaprevir(FDV) capsule taken orally once daily plus ribavirin(RBV) tablet taken orally twice daily for 24 weeks along with pegylated interferon α-2a(PegIFN) injection and probe drugs(200 mg caffeine tablet, 500 mg tolbutamide tablet, and 2 mg midazolam syrup administered orally on days 1, 9, 17, and 66). In group A the effect of DBV on FDV, the effect of FDV, dual oral direct acting antiviral (DAAs) and their metabolites on caffeine, tolbutamide and midazolam were determined.
600mg deleobuvir(DBV) tablet taken orally 3 times a day plus 120mg faldaprevir(FDV) capsule taken orally once daily plus ribavirin(RBV) tablet taken orally twice daily for 24 weeks along with pegylated interferon α-2a (PegIFN) injection and probe drugs(200 mg caffeine tablet, 500 mg tolbutamide tablet, and 2 mg midazolam syrup administered orally on days 1, 9, 17, and 66). In group B the effect of FDV on DBV, the effect of DBV, dual oral direct acting antiviral (DAAs) and their metabolites on caffeine, tolbutamide and midazolam were determined.
600mg deleobuvir(DBV) tablet taken twice a day plus 120mg faldaprevir(FDV) capsule taken orally once daily plus ribavirin(RBV) tablet taken orally twice daily for 24 weeks with tenofovir tablet 300mg daily on days 1-17.
600mg deleobuvir(DBV) tablet taken twice a day plus 120mg faldaprevir(FDV) capsule taken orally once daily plus ribavirin(RBV) tablet taken orally twice daily with probe drugs(200 mg caffeine tablet, 500 mg tolbutamide tablet, and 2 mg midazolam syrup administered orally on days 1, 9, 17, and 66).
600mg deleobuvir(DBV) tablet taken twice a day plus 120mg faldaprevir(FDV) capsule taken orally once daily plus ribavirin(RBV) tablet taken orally twice daily for 24 weeks with raltegravir tablet 400mg twice daily on days 1-17.
Overall Number of Participants Analyzed 16 19 16 14 7
Measure Type: Number
Unit of Measure: Participants
13 13 11 10 3
Time Frame From first drug administration until last drug administration plus 28 days, up to 28 weeks.
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Group A Group B Group C Group D Group E
Hide Arm/Group Description 600mg deleobuvir(DBV) tablet taken orally 3 times a day plus 120mg faldaprevir(FDV) capsule taken orally once daily plus ribavirin(RBV) tablet taken orally twice daily for 24 weeks along with pegylated interferon α-2a(PegIFN) injection and probe drugs(200 mg caffeine tablet, 500 mg tolbutamide tablet, and 2 mg midazolam syrup administered orally on days 1, 9, 17, and 66). In group A the effect of DBV on FDV, the effect of FDV, dual oral direct acting antiviral (DAAs) and their metabolites on caffeine, tolbutamide and midazolam were determined. 600mg deleobuvir(DBV) tablet taken orally 3 times a day plus 120mg faldaprevir(FDV) capsule taken orally once daily plus ribavirin(RBV) tablet taken orally twice daily for 24 weeks along with pegylated interferon α-2a (PegIFN) injection and probe drugs(200 mg caffeine tablet, 500 mg tolbutamide tablet, and 2 mg midazolam syrup administered orally on days 1, 9, 17, and 66). In group B the effect of FDV on DBV, the effect of DBV, dual oral direct acting antiviral (DAAs) and their metabolites on caffeine, tolbutamide and midazolam were determined. 600mg deleobuvir(DBV) tablet taken twice a day plus 120mg faldaprevir(FDV) capsule taken orally once daily plus ribavirin(RBV) tablet taken orally twice daily for 24 weeks with tenofovir tablet 300mg daily on days 1-17. 600mg deleobuvir(DBV) tablet taken twice a day plus 120mg faldaprevir(FDV) capsule taken orally once daily plus ribavirin(RBV) tablet taken orally twice daily with probe drugs(200 mg caffeine tablet, 500 mg tolbutamide tablet, and 2 mg midazolam syrup administered orally on days 1, 9, 17, and 66). 600mg deleobuvir(DBV) tablet taken twice a day plus 120mg faldaprevir(FDV) capsule taken orally once daily plus ribavirin(RBV) tablet taken orally twice daily for 24 weeks with raltegravir tablet 400mg twice daily on days 1-17.
All-Cause Mortality
Group A Group B Group C Group D Group E
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/--   --/--   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Group A Group B Group C Group D Group E
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   0/16 (0.00%)   0/19 (0.00%)   1/16 (6.25%)   2/14 (14.29%)   0/7 (0.00%) 
Gastrointestinal disorders           
Colitis ulcerative  1  0/16 (0.00%)  0/19 (0.00%)  0/16 (0.00%)  1/14 (7.14%)  0/7 (0.00%) 
Nausea  1  0/16 (0.00%)  0/19 (0.00%)  0/16 (0.00%)  1/14 (7.14%)  0/7 (0.00%) 
Nervous system disorders           
Complex partial seizures  1  0/16 (0.00%)  0/19 (0.00%)  1/16 (6.25%)  0/14 (0.00%)  0/7 (0.00%) 
Psychiatric disorders