Drug Drug Interaction Study Between BI 201335 and BI 207127 in Chronic Hepatitis C Infected Patients
Sponsor
Boehringer Ingelheim (Industry)
Overall Status
Completed
CT.gov ID
NCT01525628
Collaborator
(none)
72
16
5
30
4.5
0.2
Study Details
Study Description
Brief Summary
To evaluate the drug-drug interactions between BI 201335 and BI 207127 as well as their combined effect on CYP probe drug substrates and on tenofovir and raltegravir in treatment naive or prior treatment relapse patients with chronic hepatitis C infection.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 1 |
Study Design
Study Type:
Interventional
Actual Enrollment
:
72 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Multi-centre, Open Label, Parallel Group Trial to Evaluate the Pharmacokinetic Interactions Between BI 207127 (600 mg t.i.d. or 600 mg b.i.d.) and BI 201335 (120 mg q.d.) Given in Combination With Ribavirin for 24 Weeks, and Their Combined Effect on the Pharmacokinetics of Tenofovir, Raltegravir, Caffeine (the Probe Drug Substrate for CYP1A2), Tolbutamide (the Probe Drug Substrate for CYP2C9) and Midazolam (the Probe Drug Substrate for CYP3A4) in Treatment naïve Patients and Prior Treatment Relapse or Partial Responder Patients With Genotype 1 Chronic Hepatitis C Infection
Study Start Date
:
Apr 1, 2012
Actual Primary Completion Date
:
Dec 1, 2013
Actual Study Completion Date
:
Oct 1, 2014
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Group A Effect of BI 207127 on BI 201335, the effect of BI 201335 and dual oral direct acting antiviral (DAAs) on caffeine, tolbutamide and midazolam |
Drug: tolbutamide
CYP2C9 probe drug
Drug: midazolam
CYP3A probe drug
Drug: caffeine
CYP1A2 probe drug
Drug: BI 201335
HCV protease inhibitor
Drug: pegylated interferon
HCV treatment
Drug: BI 207127
HCV polymerase inhibitor
Drug: ribavirin
HCV treatment
|
| Experimental: Group B Effect of BI 201335 on BI 207127, the effect of BI 207127 and metabolites and dual oral DAAs on caffeine, tolbutamide and midazolam |
Drug: BI 201335
HCV protease inhibitor
Drug: caffeine
CYP1A2 probe drug
Drug: tolbutamide
CYP2C9 probe drug
Drug: pegylated interferon
HCV treatment
Drug: BI 207127
HCV polymerase inhibitor
Drug: ribavirin
HCV treatment
Drug: midazolam
CYP3A probe drug
|
| Experimental: Group C Effect of Dual oral DAAs on tenofovir |
Drug: tenofovir
nucleoside analogue
Drug: BI 207127
HCV polymerase inhibitor
Drug: ribavirin
HCV treatment
Drug: BI 201335
HCV protease inhibitor
|
| Experimental: Group D Effect of BI 201335 and BI 207127 at 600 mg b.i.d. on caffeine, tolbutamide and midazolam |
Drug: midazolam
CYP3A probe drug
Drug: BI 201335
HCV protease inhibitor
Drug: BI 207127
HCV polymerase inhibitor
Drug: ribavirin
HCV treatment
Drug: caffeine
CYP1A2 probe drug
Drug: tolbutamide
CYP2C9 probe drug
|
| Experimental: Group E Effect of BI 201335 and BI 207127 on raltegravir |
Drug: BI 201335
HCV protease inhibitor
Drug: ribavirin
HCV treatment
Drug: BI 207127
HCV polymerase inhibitor
|
Outcome Measures
Primary Outcome Measures
- Cmax of Faldaprevir (BI 201335) [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.]
Maximum concentration of an analyte in plasma
- C24hr of Faldaprevir (BI 201335) [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.]
Concentration of an analyte in plasma at 24 hours
- Area Under the Concentration-time Curve (AUC) of Faldaprevir (BI 201335) From 0 to 24 Hours [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.]
Area under the concentration-time curve of the analyte in plasma over the time interval from 0 to 24 hours
- Cmax of Deleobuvir (BI 207127) [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.]
Maximum concentration of an analyte in plasma
- C6hr of Deleobuvir (BI 207127) [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.]
Concentration of an analyte in plasma at 6 hours
- AUC 0-6hr of Deleobuvir (BI 207127) [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.]
Area under the concentration-time curve of the analyte in plasma over the time interval from 0 to 6 hours
- Cmax of Deleobuvir Metabolite Acyl-glucuronide (BI 208333) [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.]
Maximum concentration of an analyte in plasma
- C6hr of Deleobuvir Metabolite Acyl-glucuronide (BI 208333) [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.]
Concentration of an analyte in plasma at 6 hours
- AUC 0-6hr of Deleobuvir Metabolite Acyl-glucuronide (BI 208333) [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.]
Area under the concentration-time curve of the analyte in plasma over the time interval from 0 to 6 hours
- Cmax of Deleobuvir Reduction Metabolite CD 6168 [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.]
Maximum concentration of an analyte in plasma
- C6hr of Deleobuvir Reduction Metabolite CD 6168 [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.]
Concentration of an analyte in plasma at 6 hours
- AUC 0-6hr of Deleobuvir Reduction Metabolite CD 6168 [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.]
Area under the concentration-time curve of the analyte in plasma over the time interval from 0 to 6 hours
- Cmax of Deleobuvir Metabolite CD 6168 ag (Acylglucuronide) [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.]
Maximum concentration of an analyte in plasma
- C6hr of Deleobuvir Metabolite CD 6168 ag (Acylglucuronide) [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.]
Concentration of an analyte in plasma at 6 hours
- AUC 0-6hr of Deleobuvir Metabolite CD 6168 ag (Acylglucuronide) [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.]
Area under the concentration-time curve of the analyte in plasma over the time interval from 0 to 6 hours
- Cmax of Caffeine [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.]
Maximum concentration of an analyte in plasma
- AUC 0-infinity of Caffeine [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.]
Area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity.
- Cmax of Tolbutamide [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.]
Maximum concentration of an analyte in plasma
- AUC 0-infinity of Tolbutamide [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.]
Area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity.
- Cmax of Midazolam [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.]
Maximum concentration of an analyte in plasma
- AUC 0-infinity of Midazolam [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.]
Area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity.
- Cmax of 1-OH-Midazolam (1-hydroxy-midazolam) [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.]
Maximum concentration of an analyte in plasma
- AUC 0-infinity of 1-OH-Midazolam (1-hydroxy-midazolam) [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.]
Area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity.
- Cmax of Tenofovir [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]
Maximum concentration of an analyte in plasma.
- C24hr of Tenofovir [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]
Concentration of an analyte in plasma at 24 hours.
- AUC 0-24hr of Tenofovir [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]
Area under the concentration-time curve of the analyte in plasma over the time interval from 0 to 24 hours.
- Cmax of Raltegravir [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]
Maximum concentration of an analyte in plasma.
- C12hr of Raltegravir [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]
Concentration of an analyte in plasma at 12 hours.
- AUC 0-12hr of Raltegravir [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]
Area under the concentration-time curve of the analyte in plasma over the time interval from 0 to 12 hours.
Secondary Outcome Measures
- Number of Participants With Sustained Virological Response (SVR12) [12 weeks post treatment]
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.
Eligibility Criteria
Criteria
Ages Eligible for Study:
18 Years
to 70 Years
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
Inclusion criteria:
-
Chronic hepatitis C genotype 1 infection, diagnosed at least 6 months prior to screening
-
Treatment naive or confirmed prior treatment relapse or partial response following treatment with interferon and ribavirin
-
Age 18 to 70 years
-
HCV RNA (Hepatitis C Virus RiboNucleic Acid) = 1,000 IU/mL at screening
-
Liver biopsy or fibroscan to exclude cirrhosis
Exclusion criteria:
-
Hepatitis C Virus (HCV) infection of mixed genotype; Hepatitis B Virus (HBV) or Human Immunodeficiency Virus (HIV) co-infection
-
Evidence of acute or chronic liver disease due to causes other than chronic HCV infection,
-
Decompensated liver disease, or history of decompensated liver disease,
-
Body weight < 40 or > 125 kg,
-
Clinical evidence of significant or unstable cardiovascular disease, chronic pulmonary disease, history or evidence of retinopathy or clinically significant ophthalmological disorder
-
Pre-existing psychiatric condition that could interfere with the subject's participation in and completion of the study
-
Laboratory parameters disorders (thalassemia major, sickle cell anemia or glucose 6 phosphate dehydrogenase deficit)
-
Hemoglobin < 12 g/dL for women and < 13 g/dL for men
-
Patients who have been previously treated with at least one dose of any antiviral or immunomodulatory drug other than interferon alfa or ribavirin for acute or chronic HCV infection
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | 1241.27.0006 Boehringer Ingelheim Investigational Site | La Mesa | California | United States | |
| 2 | 1241.27.0005 Boehringer Ingelheim Investigational Site | Rockville | Maryland | United States | |
| 3 | 1241.27.0004 Boehringer Ingelheim Investigational Site | Marlton | New Jersey | United States | |
| 4 | 1241.27.0003 Boehringer Ingelheim Investigational Site | Philadelphia | Pennsylvania | United States | |
| 5 | 1241.27.0001 Boehringer Ingelheim Investigational Site | Salt Lake City | Utah | United States | |
| 6 | 1241.27.0200 Boehringer Ingelheim Investigational Site | Vancouver | British Columbia | Canada | |
| 7 | 1241.27.0600 Boehringer Ingelheim Investigational Site | Vancouver | British Columbia | Canada | |
| 8 | 1241.27.0700 Boehringer Ingelheim Investigational Site | Vancouver | British Columbia | Canada | |
| 9 | 1241.27.0400 Boehringer Ingelheim Investigational Site | Victoria | British Columbia | Canada | |
| 10 | 1241.27.0100 Boehringer Ingelheim Investigational Site | London | Ontario | Canada | |
| 11 | 1241.27.0300 Boehringer Ingelheim Investigational Site | Ottawa | Ontario | Canada | |
| 12 | 1241.27.0500 Boehringer Ingelheim Investigational Site | Montreal | Quebec | Canada | |
| 13 | 1241.27.4901 Boehringer Ingelheim Investigational Site | Frankfurt am Main | Germany | ||
| 14 | 1241.27.4907 Boehringer Ingelheim Investigational Site | Köln | Germany | ||
| 15 | 1241.27.4903 Boehringer Ingelheim Investigational Site | Leipzig | Germany | ||
| 16 | 1241.27.4906 Boehringer Ingelheim Investigational Site | Mainz | Germany |
Sponsors and Collaborators
- Boehringer Ingelheim
Investigators
- Study Chair: Boehringer Ingelheim, Boehringer Ingelheim
Study Documents (Full-Text)
None provided.More Information
Additional Information:
Publications
None provided.Responsible Party:
Boehringer Ingelheim
ClinicalTrials.gov Identifier:
NCT01525628
Other Study ID Numbers:
- 1241.27
- 2012-004102-10
First Posted:
Feb 3, 2012
Last Update Posted:
Jun 10, 2016
Last Verified:
May 1, 2016
Additional relevant MeSH terms:
Study Results
Participant Flow
| Recruitment Details | 72 patients were treated and analysed. |
|---|---|
| Pre-assignment Detail | 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 |
|---|---|---|---|---|---|
| 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 |
Baseline Characteristics
| Arm/Group Title | Group A | Group B | Group C | Group D | Group E | Total |
|---|---|---|---|---|---|---|
| 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 Participants | 16 | 19 | 16 | 14 | 7 | 72 |
| Age (Years) [Mean (Standard Deviation) ] | ||||||
| Mean (Standard Deviation) [Years] |
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 (Count of Participants) | ||||||
| Female |
7
43.8%
|
8
42.1%
|
5
31.3%
|
7
50%
|
1
14.3%
|
28
38.9%
|
| Male |
9
56.3%
|
11
57.9%
|
11
68.8%
|
7
50%
|
6
85.7%
|
44
61.1%
|
Outcome Measures
| Title | Cmax of Faldaprevir (BI 201335) |
|---|---|
| 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. |
Outcome Measure Data
| 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 |
|---|---|---|
| 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. |
| Measure Participants | 16 | 19 |
| Day 9 (N=15,0) |
3520
(54.8)
|
NA
(NA)
|
| Day 17 (N=14,14) |
8780
(47.5)
|
9950
(51.0)
|
| Day 66 (N=13,15) |
4410
(48.7)
|
6690
(78.8)
|
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 | ||
| 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). | |
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 | ||
| 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). | |
| Title | C24hr of Faldaprevir (BI 201335) |
|---|---|
| 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. |
Outcome Measure Data
| 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 |
|---|---|---|
| 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. |
| Measure Participants | 16 | 19 |
| Day 9 (N=15,0) |
983
(65.5)
|
NA
(NA)
|
| Day 17 (N=14,19) |
3670
(90.4)
|
5410
(91.6)
|
| Day 66 (N=13,14) |
1140
(107)
|
2580
(135)
|
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 | ||
| 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). | |
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 | ||
| 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). | |
| Title | Area Under the Concentration-time Curve (AUC) of Faldaprevir (BI 201335) From 0 to 24 Hours |
|---|---|
| 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. |
Outcome Measure Data
| 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 |
|---|---|---|
| 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. |
| Measure Participants | 16 | 19 |
| Day 9 (N=15,0) |
45600
(54.5)
|
NA
(NA)
|
| Day 17 (N=14,19) |
138000
(62.1)
|
173000
(60.8)
|
| Day 66 (N=13,15) |
56200
(58.2)
|
97300
(114)
|
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 | ||
| 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). | |
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 | ||
| 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). | |
| Title | Cmax of Deleobuvir (BI 207127) |
|---|---|
| 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. |
Outcome Measure Data
| 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 |
|---|---|---|
| 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. |
| Measure Participants | 16 | 19 |
| Day 9 (N=0, 17) |
NA
(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)
|
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 | ||
| 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). | |
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 | ||
| 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). | |
| Title | C6hr of Deleobuvir (BI 207127) |
|---|---|
| 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. |
Outcome Measure Data
| 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 |
|---|---|---|
| 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. |
| Measure Participants | 16 | 19 |
| Day 9 (N=0, 17) |
NA
(NA)
|
5800
(129)
|
| Day 17 (N=14, 19) |
17900
(84.2)
|
20800
(83.8)
|
| Day 66 (N=13, 14) |
5080
(108)
|
10100
(133)
|
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 | ||
| 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). | |
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 | ||
| 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). | |
| Title | AUC 0-6hr of Deleobuvir (BI 207127) |
|---|---|
| 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. |
Outcome Measure Data
| 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 |
|---|---|---|
| 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. |
| Measure Participants | 16 | 19 |
| Day 9 (N=0, 17) |
NA
(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)
|
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 | ||
| 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). | |
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 | ||
| 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). | |
| Title | Cmax of Deleobuvir Metabolite Acyl-glucuronide (BI 208333) |
|---|---|
| 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. |
Outcome Measure Data
| 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 |
|---|---|---|
| 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. |
| Measure Participants | 16 | 19 |
| Day 9 (N=0, 17) |
NA
(NA)
|
5620
(119)
|
| Day 17 (N=14, 19) |
12700
(89.4)
|
20200
(111)
|
| Day 66 (N=13, 15) |
3790
(66.9)
|
6550
(98.3)
|
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 | ||
| 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). | |
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 | ||
| 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). | |
| Title | C6hr of Deleobuvir Metabolite Acyl-glucuronide (BI 208333) |
|---|---|
| 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. |
Outcome Measure Data
| 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 |
|---|---|---|
| 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. |
| Measure Participants | 16 | 19 |
| Day 9 (N=0, 17) |
NA
(NA)
|
4330
(154)
|
| Day 17 (N=14, 19) |
11200
(83.7)
|
17500
(119)
|
| Day 66 (N=13, 14) |
2740
(85.9)
|
5780
(132)
|
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 | ||
| 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). | |
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 | ||
| 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). | |
| Title | AUC 0-6hr of Deleobuvir Metabolite Acyl-glucuronide (BI 208333) |
|---|---|
| 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. |
Outcome Measure Data
| 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 |
|---|---|---|
| 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. |
| Measure Participants | 16 | 19 |
| Day 9 (N=0, 17) |
NA
(NA)
|
24300
(131)
|
| Day 17 (N=14, 19) |
61800
(97.9)
|
98800
(124)
|
| Day 66 (N=13, 15) |
15000
(81.2)
|
27600
(128)
|
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 | ||
| 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). | |
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 | ||
| 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). | |
| Title | Cmax of Deleobuvir Reduction Metabolite CD 6168 |
|---|---|
| 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. |
Outcome Measure Data
| 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 |
|---|---|---|
| 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. |
| Measure Participants | 16 | 19 |
| Day 9 (N=0, 17) |
NA
(NA)
|
3040
(115)
|
| Day 17 (N=14, 19) |
8520
(119)
|
12400
(70.9)
|
| Day 66 (N=13, 15) |
4510
(117)
|
8880
(111)
|
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 | ||
| 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). | |
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 | ||
| 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). | |
| Title | C6hr of Deleobuvir Reduction Metabolite CD 6168 |
|---|---|
| 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. |
Outcome Measure Data
| 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 |
|---|---|---|
| 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. |
| Measure Participants | 16 | 19 |
| Day 9 (N=0, 17) |
NA
(NA)
|
2250
(137)
|
| Day 17 (N=14, 19) |
6980
(128)
|
10200
(81.0)
|
| Day 66 (N=13, 14) |
3360
(139)
|
7460
(123)
|
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 | ||
| 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). | |
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 | ||
| 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). | |
| Title | AUC 0-6hr of Deleobuvir Reduction Metabolite CD 6168 |
|---|---|
| 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. |
Outcome Measure Data
| 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 |
|---|---|---|
| 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. |
| Measure Participants | 16 | 19 |
| Day 9 (N=0, 17) |
NA
(NA)
|
13300
(123)
|
| Day 17 (N=14, 19) |
41700
(130)
|
62200
(82.7)
|
| Day 66 (N=13, 15) |
19300
(134)
|
39100
(133)
|
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 | ||
| 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). | |
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 | ||
| 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). | |
| Title | Cmax of Deleobuvir Metabolite CD 6168 ag (Acylglucuronide) |
|---|---|
| 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. |
Outcome Measure Data
| 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 |
|---|---|---|
| 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. |
| Measure Participants | 16 | 19 |
| Day 9 (N=0, 17) |
NA
(NA)
|
203
(135)
|
| Day 17 (N=14, 19) |
596
(143)
|
1130
(115)
|
| Day 66 (N=13, 15) |
386
(111)
|
806
(125)
|
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 | ||
| 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). | |
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 | ||
| 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). | |
| Title | C6hr of Deleobuvir Metabolite CD 6168 ag (Acylglucuronide) |
|---|---|
| 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. |
Outcome Measure Data
| 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 |
|---|---|---|
| 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. |
| Measure Participants | 16 | 19 |
| Day 9 (N=0, 17) |
NA
(NA)
|
159
(165)
|
| Day 17 (N=14, 19) |
508
(138)
|
962
(117)
|
| Day 66 (N=13, 14) |
295
(128)
|
712
(143)
|
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 | ||
| 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). | |
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 | ||
| 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). | |
| Title | AUC 0-6hr of Deleobuvir Metabolite CD 6168 ag (Acylglucuronide) |
|---|---|
| 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. |
Outcome Measure Data
| 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 |
|---|---|---|
| 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. |
| Measure Participants | 16 | 19 |
| Day 9 (N=0, 17) |
NA
(NA)
|
893
(142)
|
| Day 17 (N=14, 19) |
2980
(151)
|
5700
(123)
|
| Day 66 (N=13, 15) |
1620
(133)
|
3510
(143)
|
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 | ||
| 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). | |
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 | ||
| 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). | |
| Title | Cmax of Caffeine |
|---|---|
| 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. |
Outcome Measure Data
| 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 |
|---|---|---|
| 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. |
| Measure Participants | 16 | 19 |
| 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)
|
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 | ||
| 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). | |
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 | ||
| 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). | |
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 | ||
| 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). | |
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 | ||
| 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). | |
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 | ||
| 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). | |
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 | ||
| 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). | |
| Title | AUC 0-infinity of Caffeine |
|---|---|
| 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. |
Outcome Measure Data
| 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 |
|---|---|---|
| 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. |
| Measure Participants | 16 | 19 |
| 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)
|
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 | ||
| 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). | |
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 | ||
| 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). | |
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 | ||
| 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). | |
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 | ||
| 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). | |
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 | ||
| 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). | |
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 | ||
| 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). | |
| Title | Cmax of Tolbutamide |
|---|---|
| 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. |
Outcome Measure Data
| 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 |
|---|---|---|
| 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. |
| Measure Participants | 16 | 19 |
| 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)
|
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 | ||
| 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). | |
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 | ||
| 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). | |
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 | ||
| 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). | |
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 | ||
| 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). | |
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 | ||
| 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). | |
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 | ||
| 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). | |
| Title | AUC 0-infinity of Tolbutamide |
|---|---|
| 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. |
Outcome Measure Data
| 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 |
|---|---|---|
| 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. |
| Measure Participants | 16 | 19 |
| 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)
|
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 | ||
| 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). | |
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 | ||
| 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). | |
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 | ||
| 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). | |
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 | ||
| 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). | |
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 | ||
| 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). | |
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 | ||
| 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). | |
| Title | Cmax of Midazolam |
|---|---|
| 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. |
Outcome Measure Data
| 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 |
|---|---|---|
| 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. |
| Measure Participants | 16 | 19 |
| 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)
|
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 | ||
| 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). | |
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 | ||
| 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). | |
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 | ||
| 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). | |
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 | ||
| 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). | |
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 | ||
| 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). | |
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 | ||
| 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). | |
| Title | AUC 0-infinity of Midazolam |
|---|---|
| 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. |
Outcome Measure Data
| 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 |
|---|---|---|
| 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. |
| Measure Participants | 16 | 19 |
| 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)
|
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 | ||
| 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). | |
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 | ||
| 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). | |
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 | ||
| 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). | |
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 | ||
| 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). | |
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 | ||
| 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). | |
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 | ||
| 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). | |
| Title | Cmax of 1-OH-Midazolam (1-hydroxy-midazolam) |
|---|---|
| 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. |
Outcome Measure Data
| 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 |
|---|---|---|
| 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. |
| Measure Participants | 16 | 19 |
| 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)
|
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 | ||
| 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). | |
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 | ||
| 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). | |
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 | ||
| 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). | |
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 | ||
| 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). | |
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 | ||
| 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). | |
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 | ||
| 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). | |
| Title | AUC 0-infinity of 1-OH-Midazolam (1-hydroxy-midazolam) |
|---|---|
| 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. |
Outcome Measure Data
| 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 |
|---|---|---|
| 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. |
| Measure Participants | 16 | 19 |
| 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)
|
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 | ||
| 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). | |
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 | ||
| 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). | |
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 | ||
| 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). | |
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 | ||
| 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). | |
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 | ||
| 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). | |
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 | ||
| 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). | |
| Title | Cmax of Tenofovir |
|---|---|
| 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 |
Outcome Measure Data
| 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 |
|---|---|
| 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. |
| Measure Participants | 0 |
| Title | C24hr of Tenofovir |
|---|---|
| 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 |
Outcome Measure Data
| 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 |
|---|---|
| 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. |
| Measure Participants | 0 |
| Title | AUC 0-24hr of Tenofovir |
|---|---|
| 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 |
Outcome Measure Data
| 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 |
|---|---|
| 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. |
| Measure Participants | 0 |
| Title | Cmax of Raltegravir |
|---|---|
| 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 |
Outcome Measure Data
| 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 |
|---|---|
| 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. |
| Measure Participants | 0 |
| Title | C12hr of Raltegravir |
|---|---|
| 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 |
Outcome Measure Data
| 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 |
|---|---|
| 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. |
| Measure Participants | 0 |
| Title | AUC 0-12hr of Raltegravir |
|---|---|
| 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 |
Outcome Measure Data
| 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 |
|---|---|
| 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. |
| Measure Participants | 0 |
| Title | Number of Participants With Sustained Virological Response (SVR12) |
|---|---|
| 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 |
Outcome Measure Data
| 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 |
|---|---|---|---|---|---|
| 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. |
| Measure Participants | 16 | 19 | 16 | 14 | 7 |
| Number [Participants] |
13
81.3%
|
13
68.4%
|
11
68.8%
|
10
71.4%
|
3
42.9%
|
Adverse Events
| Time Frame | From first drug administration until last drug administration plus 28 days, up to 28 weeks. | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Adverse Event Reporting Description | ||||||||||
| Arm/Group Title | Group A | Group B | Group C | Group D | Group E | |||||
| 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 (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | / (NaN) | / (NaN) | / (NaN) | / (NaN) | / (NaN) | |||||
Serious Adverse Events |
||||||||||
| Group A | Group B | Group C | Group D | Group E | ||||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 0/16 (0%) | 0/19 (0%) | 1/16 (6.3%) | 2/14 (14.3%) | 0/7 (0%) | |||||
| Gastrointestinal disorders | ||||||||||
| Colitis ulcerative | 0/16 (0%) | 0/19 (0%) | 0/16 (0%) | 1/14 (7.1%) | 0/7 (0%) | |||||
| Nausea | 0/16 (0%) | 0/19 (0%) | 0/16 (0%) | 1/14 (7.1%) | 0/7 (0%) | |||||
| Nervous system disorders | ||||||||||
| Complex partial seizures | 0/16 (0%) | 0/19 (0%) | 1/16 (6.3%) | 0/14 (0%) | 0/7 (0%) | |||||
| Psychiatric disorders | ||||||||||
| Acute psychosis | 0/16 (0%) | 0/19 (0%) | 1/16 (6.3%) | 0/14 (0%) | 0/7 (0%) | |||||
| Bipolar disorder | 0/16 (0%) | 0/19 (0%) | 1/16 (6.3%) | 0/14 (0%) | 0/7 (0%) | |||||
| Reactive psychosis | 0/16 (0%) | 0/19 (0%) | 1/16 (6.3%) | 0/14 (0%) | 0/7 (0%) | |||||
Other (Not Including Serious) Adverse Events |
||||||||||
| Group A | Group B | Group C | Group D | Group E | ||||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 16/16 (100%) | 19/19 (100%) | 16/16 (100%) | 14/14 (100%) | 5/7 (71.4%) | |||||
| Blood and lymphatic system disorders | ||||||||||
| Anaemia | 1/16 (6.3%) | 3/19 (15.8%) | 3/16 (18.8%) | 1/14 (7.1%) | 2/7 (28.6%) | |||||
| Leukopenia | 0/16 (0%) | 0/19 (0%) | 0/16 (0%) | 1/14 (7.1%) | 0/7 (0%) | |||||
| Neutropenia | 1/16 (6.3%) | 1/19 (5.3%) | 0/16 (0%) | 2/14 (14.3%) | 0/7 (0%) | |||||
| Cardiac disorders | ||||||||||
| Angina pectoris | 0/16 (0%) | 0/19 (0%) | 1/16 (6.3%) | 0/14 (0%) | 0/7 (0%) | |||||
| Cardiovascular disorder | 0/16 (0%) | 0/19 (0%) | 1/16 (6.3%) | 0/14 (0%) | 2/7 (28.6%) | |||||
| Palpitations | 3/16 (18.8%) | 0/19 (0%) | 1/16 (6.3%) | 1/14 (7.1%) | 0/7 (0%) | |||||
| Ear and labyrinth disorders | ||||||||||
| Ear discomfort | 0/16 (0%) | 1/19 (5.3%) | 0/16 (0%) | 0/14 (0%) | 0/7 (0%) | |||||
| Ear pain | 0/16 (0%) | 0/19 (0%) | 1/16 (6.3%) | 0/14 (0%) | 0/7 (0%) | |||||
| Tinnitus | 0/16 (0%) | 1/19 (5.3%) | 0/16 (0%) | 0/14 (0%) | 0/7 (0%) | |||||
| Vertigo | 0/16 (0%) | 2/19 (10.5%) | 0/16 (0%) | 0/14 (0%) | 0/7 (0%) | |||||
| Endocrine disorders | ||||||||||
| Hypothyroidism | 0/16 (0%) | 0/19 (0%) | 0/16 (0%) | 0/14 (0%) | 1/7 (14.3%) | |||||
| Eye disorders | ||||||||||
| Blepharospasm | 1/16 (6.3%) | 0/19 (0%) | 0/16 (0%) | 0/14 (0%) | 0/7 (0%) | |||||
| Conjunctival haemorrhage | 1/16 (6.3%) | 0/19 (0%) | 0/16 (0%) | 0/14 (0%) | 0/7 (0%) | |||||
| Eye irritation | 0/16 (0%) | 0/19 (0%) | 0/16 (0%) | 1/14 (7.1%) | 0/7 (0%) | |||||
| Eye pain | 2/16 (12.5%) | 0/19 (0%) | 0/16 (0%) | 0/14 (0%) | 0/7 (0%) | |||||
| Eyelids pruritus | 0/16 (0%) | 0/19 (0%) | 1/16 (6.3%) | 0/14 (0%) | 0/7 (0%) | |||||
| Lacrimation increased | 0/16 (0%) | 1/19 (5.3%) | 0/16 (0%) | 0/14 (0%) | 0/7 (0%) | |||||
| Ocular hyperaemia | 0/16 (0%) | 0/19 (0%) | 1/16 (6.3%) | 0/14 (0%) | 0/7 (0%) | |||||
| Ocular icterus | 1/16 (6.3%) | 3/19 (15.8%) | 2/16 (12.5%) | 5/14 (35.7%) | 1/7 (14.3%) | |||||
| Periorbital oedema | 0/16 (0%) | 1/19 (5.3%) | 0/16 (0%) | 0/14 (0%) | 0/7 (0%) | |||||
| Photophobia | 1/16 (6.3%) | 0/19 (0%) | 0/16 (0%) | 0/14 (0%) | 0/7 (0%) | |||||
| Retinal exudates | 0/16 (0%) | 1/19 (5.3%) | 0/16 (0%) | 0/14 (0%) | 0/7 (0%) | |||||
| Vision blurred | 1/16 (6.3%) | 3/19 (15.8%) | 1/16 (6.3%) | 0/14 (0%) | 0/7 (0%) | |||||
| Visual acuity reduced | 1/16 (6.3%) | 0/19 (0%) | 0/16 (0%) | 1/14 (7.1%) | 0/7 (0%) | |||||
| Gastrointestinal disorders | ||||||||||
| Abdominal discomfort | 0/16 (0%) | 3/19 (15.8%) | 2/16 (12.5%) | 0/14 (0%) | 0/7 (0%) | |||||
| Abdominal distension | 1/16 (6.3%) | 4/19 (21.1%) | 0/16 (0%) | 0/14 (0%) | 2/7 (28.6%) | |||||
| Abdominal pain | 2/16 (12.5%) | 2/19 (10.5%) | 4/16 (25%) | 4/14 (28.6%) | 2/7 (28.6%) | |||||
| Abdominal pain upper | 0/16 (0%) | 2/19 (10.5%) | 4/16 (25%) | 3/14 (21.4%) | 0/7 (0%) | |||||
| Abdominal rigidity | 1/16 (6.3%) | 0/19 (0%) | 0/16 (0%) | 0/14 (0%) | 0/7 (0%) | |||||
| Abdominal tenderness | 0/16 (0%) | 1/19 (5.3%) | 0/16 (0%) | 0/14 (0%) | 0/7 (0%) | |||||
| Anal pruritus | 0/16 (0%) | 0/19 (0%) | 1/16 (6.3%) | 1/14 (7.1%) | 0/7 (0%) | |||||
| Anorectal discomfort | 0/16 (0%) | 0/19 (0%) | 0/16 (0%) | 0/14 (0%) | 1/7 (14.3%) | |||||
| Chapped lips | 1/16 (6.3%) | 0/19 (0%) | 0/16 (0%) | 0/14 (0%) | 0/7 (0%) | |||||
| Cheilitis | 1/16 (6.3%) | 1/19 (5.3%) | 0/16 (0%) | 0/14 (0%) | 0/7 (0%) | |||||
| Constipation | 1/16 (6.3%) | 3/19 (15.8%) | 4/16 (25%) | 3/14 (21.4%) | 1/7 (14.3%) | |||||
| Diarrhoea | 5/16 (31.3%) | 10/19 (52.6%) | 4/16 (25%) | 3/14 (21.4%) | 3/7 (42.9%) | |||||
| Dry mouth | 4/16 (25%) | 0/19 (0%) | 0/16 (0%) | 1/14 (7.1%) | 0/7 (0%) | |||||
| Dyspepsia | 6/16 (37.5%) | 3/19 (15.8%) | 3/16 (18.8%) | 4/14 (28.6%) | 2/7 (28.6%) | |||||
| Faeces discoloured | 1/16 (6.3%) | 0/19 (0%) | 0/16 (0%) | 0/14 (0%) | 0/7 (0%) | |||||
| Flatulence | 0/16 (0%) | 2/19 (10.5%) | 0/16 (0%) | 1/14 (7.1%) | 0/7 (0%) | |||||
| Gastrointestinal motility disorder | 1/16 (6.3%) | 0/19 (0%) | 0/16 (0%) | 0/14 (0%) | 0/7 (0%) | |||||
| Gastrooesophageal reflux disease | 2/16 (12.5%) | 1/19 (5.3%) | 0/16 (0%) | 0/14 (0%) | 0/7 (0%) | |||||
| Gingival pain | 1/16 (6.3%) | 0/19 (0%) | 0/16 (0%) | 0/14 (0%) | 0/7 (0%) | |||||
| Glossodynia | 1/16 (6.3%) | 1/19 (5.3%) | 0/16 (0%) | 0/14 (0%) | 0/7 (0%) | |||||
| Haematochezia | 1/16 (6.3%) | 0/19 (0%) | 1/16 (6.3%) | 1/14 (7.1%) | 0/7 (0%) | |||||
| Haemorrhoids | 1/16 (6.3%) | 0/19 (0%) | 0/16 (0%) | 0/14 (0%) | 0/7 (0%) | |||||
| Lip dry | 1/16 (6.3%) | 0/19 (0%) | 0/16 (0%) | 0/14 (0%) | 0/7 (0%) | |||||
| Lip erosion | 0/16 (0%) | 0/19 (0%) | 0/16 (0%) | 0/14 (0%) | 1/7 (14.3%) | |||||
| Lip haemorrhage | 0/16 (0%) | 1/19 (5.3%) | 0/16 (0%) | 0/14 (0%) | 0/7 (0%) | |||||
| Lip oedema | 0/16 (0%) | 1/19 (5.3%) | 0/16 (0%) | 0/14 (0%) | 0/7 (0%) | |||||
| Lip pain | 1/16 (6.3%) | 1/19 (5.3%) | 0/16 (0%) | 0/14 (0%) | 0/7 (0%) | |||||
| Mucous stools | 0/16 (0%) | 0/19 (0%) | 0/16 (0%) | 0/14 (0%) | 1/7 (14.3%) | |||||
| Nausea | 12/16 (75%) | 16/19 (84.2%) | 12/16 (75%) | 10/14 (71.4%) | 2/7 (28.6%) | |||||
| Oral discomfort | 1/16 (6.3%) | 0/19 (0%) | 0/16 (0%) | 0/14 (0%) | 0/7 (0%) | |||||
| Oral disorder | 1/16 (6.3%) | 0/19 (0%) | 0/16 (0%) | 0/14 (0%) | 0/7 (0%) | |||||
| Oral pain | 0/16 (0%) | 1/19 (5.3%) | 0/16 (0%) | 0/14 (0%) | 0/7 (0%) | |||||
| Paraesthesia oral | 1/16 (6.3%) | 0/19 (0%) | 1/16 (6.3%) | 0/14 (0%) | 0/7 (0%) | |||||
| Salivary hypersecretion | 1/16 (6.3%) | 0/19 (0%) | 0/16 (0%) | 0/14 (0%) | 0/7 (0%) | |||||
| Stomatitis | 0/16 (0%) | 0/19 (0%) | 0/16 (0%) | 0/14 (0%) | 1/7 (14.3%) | |||||
| Tongue discolouration | 1/16 (6.3%) | 0/19 (0%) | 0/16 (0%) | 0/14 (0%) | 0/7 (0%) | |||||
| Toothache | 2/16 (12.5%) | 0/19 (0%) | 0/16 (0%) | 0/14 (0%) | 0/7 (0%) | |||||
| Vomiting | 5/16 (31.3%) | 11/19 (57.9%) | 7/16 (43.8%) | 5/14 (35.7%) | 1/7 (14.3%) | |||||
| General disorders | ||||||||||
| Asthenia | 0/16 (0%) | 6/19 (31.6%) | 1/16 (6.3%) | 1/14 (7.1%) | 0/7 (0%) | |||||
| Chest discomfort | 1/16 (6.3%) | 0/19 (0%) | 1/16 (6.3%) | 0/14 (0%) | 0/7 (0%) | |||||
| Chills | 6/16 (37.5%) | 7/19 (36.8%) | 1/16 (6.3%) | 0/14 (0%) | 1/7 (14.3%) | |||||
| Energy increased | 0/16 (0%) | 0/19 (0%) | 1/16 (6.3%) | 0/14 (0%) | 0/7 (0%) | |||||
| Fatigue | 9/16 (56.3%) | 11/19 (57.9%) | 8/16 (50%) | 8/14 (57.1%) | 2/7 (28.6%) | |||||
| Feeling hot | 0/16 (0%) | 0/19 (0%) | 0/16 (0%) | 1/14 (7.1%) | 1/7 (14.3%) | |||||
| Feeling of body temperature change | 0/16 (0%) | 0/19 (0%) | 0/16 (0%) | 1/14 (7.1%) | 0/7 (0%) | |||||
| Feeling of relaxation | 0/16 (0%) | 1/19 (5.3%) | 0/16 (0%) | 0/14 (0%) | 0/7 (0%) | |||||
| Influenza like illness | 3/16 (18.8%) | 3/19 (15.8%) | 0/16 (0%) | 0/14 (0%) | 1/7 (14.3%) | |||||
| Injection site bruising | 0/16 (0%) | 1/19 (5.3%) | 0/16 (0%) | 0/14 (0%) | 0/7 (0%) | |||||
| Injection site haematoma | 1/16 (6.3%) | 0/19 (0%) | 0/16 (0%) | 0/14 (0%) | 0/7 (0%) | |||||
| Injection site pain | 1/16 (6.3%) | 0/19 (0%) | 0/16 (0%) | 0/14 (0%) | 0/7 (0%) | |||||
| Injection site reaction | 0/16 (0%) | 1/19 (5.3%) | 0/16 (0%) | 0/14 (0%) | 0/7 (0%) | |||||
| Local swelling | 0/16 (0%) | 0/19 (0%) | 0/16 (0%) | 0/14 (0%) | 1/7 (14.3%) | |||||
| Malaise | 0/16 (0%) | 3/19 (15.8%) | 0/16 (0%) | 0/14 (0%) | 0/7 (0%) | |||||
| Nodule | 1/16 (6.3%) | 0/19 (0%) | 0/16 (0%) | 0/14 (0%) | 0/7 (0%) | |||||
| Oedema | 0/16 (0%) | 0/19 (0%) | 0/16 (0%) | 0/14 (0%) | 1/7 (14.3%) | |||||
| Oedema peripheral | 0/16 (0%) | 0/19 (0%) | 0/16 (0%) | 0/14 (0%) | 1/7 (14.3%) | |||||
| Pain | 1/16 (6.3%) | 1/19 (5.3%) | 0/16 (0%) | 0/14 (0%) | 0/7 (0%) | |||||
| Peripheral swelling | 0/16 (0%) | 1/19 (5.3%) | 0/16 (0%) | 1/14 (7.1%) | 0/7 (0%) | |||||
| Pyrexia | 3/16 (18.8%) | 2/19 (10.5%) | 0/16 (0%) | 0/14 (0%) | 0/7 (0%) | |||||
| Temperature intolerance | 0/16 (0%) | 1/19 (5.3%) | 0/16 (0%) | 0/14 (0%) | 0/7 (0%) | |||||
| Tenderness | 0/16 (0%) | 1/19 (5.3%) | 0/16 (0%) | 0/14 (0%) | 0/7 (0%) | |||||
| Unevaluable event | 1/16 (6.3%) | 0/19 (0%) | 0/16 (0%) | 0/14 (0%) | 0/7 (0%) | |||||
| Vessel puncture site pain | 0/16 (0%) | 2/19 (10.5%) | 0/16 (0%) | 0/14 (0%) | 0/7 (0%) | |||||
| Hepatobiliary disorders | ||||||||||
| Cholelithiasis | 0/16 (0%) | 0/19 (0%) | 1/16 (6.3%) | 0/14 (0%) | 0/7 (0%) | |||||
| Hepatomegaly | 1/16 (6.3%) | 0/19 (0%) | 0/16 (0%) | 0/14 (0%) | 0/7 (0%) | |||||
| Hyperbilirubinaemia | 0/16 (0%) | 1/19 (5.3%) | 4/16 (25%) | 7/14 (50%) | 4/7 (57.1%) | |||||
| Jaundice | 1/16 (6.3%) | 2/19 (10.5%) | 3/16 (18.8%) | 4/14 (28.6%) | 0/7 (0%) | |||||
| Infections and infestations | ||||||||||
| Body tinea | 1/16 (6.3%) | 0/19 (0%) | 0/16 (0%) | 0/14 (0%) | 0/7 (0%) | |||||
| Bronchitis | 1/16 (6.3%) | 1/19 (5.3%) | 0/16 (0%) | 1/14 (7.1%) | 0/7 (0%) | |||||
| Cellulitis | 0/16 (0%) | 1/19 (5.3%) | 0/16 (0%) | 0/14 (0%) | 0/7 (0%) | |||||
| Fungal infection | 1/16 (6.3%) | 0/19 (0%) | 0/16 (0%) | 0/14 (0%) | 0/7 (0%) | |||||
| Gastritis viral | 1/16 (6.3%) | 0/19 (0%) | 0/16 (0%) | 0/14 (0%) | 0/7 (0%) | |||||
| Genital herpes | 0/16 (0%) | 1/19 (5.3%) | 0/16 (0%) | 0/14 (0%) | 0/7 (0%) | |||||
| Influenza | 3/16 (18.8%) | 0/19 (0%) | 0/16 (0%) | 0/14 (0%) | 0/7 (0%) | |||||
| Localised infection | 0/16 (0%) | 1/19 (5.3%) | 0/16 (0%) | 0/14 (0%) | 0/7 (0%) | |||||
| Lower respiratory tract infection | 2/16 (12.5%) | 0/19 (0%) | 0/16 (0%) | 0/14 (0%) | 0/7 (0%) | |||||
| Nasopharyngitis | 1/16 (6.3%) | 1/19 (5.3%) | 2/16 (12.5%) | 3/14 (21.4%) | 2/7 (28.6%) | |||||
| Oral herpes | 2/16 (12.5%) | 0/19 (0%) | 0/16 (0%) | 0/14 (0%) | 0/7 (0%) | |||||
| Otitis externa | 0/16 (0%) | 1/19 (5.3%) | 0/16 (0%) | 0/14 (0%) | 0/7 (0%) | |||||
| Post procedural infection | 0/16 (0%) | 0/19 (0%) | 1/16 (6.3%) | 0/14 (0%) | 0/7 (0%) | |||||
| Staphylococcal infection | 0/16 (0%) | 1/19 (5.3%) | 0/16 (0%) | 0/14 (0%) | 0/7 (0%) | |||||
| Tinea pedis | 0/16 (0%) | 1/19 (5.3%) | 0/16 (0%) | 0/14 (0%) | 0/7 (0%) | |||||
| Tooth infection | 0/16 (0%) | 2/19 (10.5%) | 0/16 (0%) | 0/14 (0%) | 0/7 (0%) | |||||
| Urinary tract infection | 0/16 (0%) | 0/19 (0%) | 1/16 (6.3%) | 0/14 (0%) | 0/7 (0%) | |||||
| Injury, poisoning and procedural complications | ||||||||||
| Animal bite | 1/16 (6.3%) | 0/19 (0%) | 0/16 (0%) | 0/14 (0%) | 0/7 (0%) | |||||
| Foot fracture | 0/16 (0%) | 0/19 (0%) | 0/16 (0%) | 1/14 (7.1%) | 0/7 (0%) | |||||
| Laceration | 1/16 (6.3%) | 1/19 (5.3%) | 0/16 (0%) | 0/14 (0%) | 0/7 (0%) | |||||
| Ligament sprain | 1/16 (6.3%) | 0/19 (0%) | 0/16 (0%) | 0/14 (0%) | 0/7 (0%) | |||||
| Scratch | 0/16 (0%) | 1/19 (5.3%) | 0/16 (0%) | 0/14 (0%) | 0/7 (0%) | |||||
| Skin wound | 0/16 (0%) | 0/19 (0%) | 0/16 (0%) | 1/14 (7.1%) | 0/7 (0%) | |||||
| Sunburn | 3/16 (18.8%) | 2/19 (10.5%) | 1/16 (6.3%) | 3/14 (21.4%) | 2/7 (28.6%) | |||||
| Wound | 0/16 (0%) | 1/19 (5.3%) | 0/16 (0%) | 0/14 (0%) | 0/7 (0%) | |||||
| Investigations | ||||||||||
| Blood bilirubin increased | 0/16 (0%) | 2/19 (10.5%) | 1/16 (6.3%) | 0/14 (0%) | 0/7 (0%) | |||||
| Blood creatinine increased | 0/16 (0%) | 0/19 (0%) | 0/16 (0%) | 1/14 (7.1%) | 0/7 (0%) | |||||
| Blood pressure increased | 0/16 (0%) | 0/19 (0%) | 1/16 (6.3%) | 0/14 (0%) | 0/7 (0%) | |||||
| Blood uric acid increased | 0/16 (0%) | 0/19 (0%) | 0/16 (0%) | 1/14 (7.1%) | 0/7 (0%) | |||||
| Glomerular filtration rate decreased | 0/16 (0%) | 0/19 (0%) | 0/16 (0%) | 0/14 (0%) | 1/7 (14.3%) | |||||
| Haemoglobin decreased | 0/16 (0%) | 1/19 (5.3%) | 0/16 (0%) | 0/14 (0%) | 0/7 (0%) | |||||
| Weight decreased | 0/16 (0%) | 1/19 (5.3%) | 1/16 (6.3%) | 2/14 (14.3%) | 0/7 (0%) | |||||
| Metabolism and nutrition disorders | ||||||||||
| Decreased appetite | 6/16 (37.5%) | 8/19 (42.1%) | 3/16 (18.8%) | 5/14 (35.7%) | 1/7 (14.3%) | |||||
| Dehydration | 0/16 (0%) | 1/19 (5.3%) | 0/16 (0%) | 0/14 (0%) | 0/7 (0%) | |||||
| Food craving | 1/16 (6.3%) | 0/19 (0%) | 0/16 (0%) | 0/14 (0%) | 0/7 (0%) | |||||
| Gout | 0/16 (0%) | 0/19 (0%) | 1/16 (6.3%) | 0/14 (0%) | 0/7 (0%) | |||||
| Hypertriglyceridaemia | 0/16 (0%) | 0/19 (0%) | 0/16 (0%) | 1/14 (7.1%) | 0/7 (0%) | |||||
| Hypokalaemia | 0/16 (0%) | 0/19 (0%) | 1/16 (6.3%) | 0/14 (0%) | 0/7 (0%) | |||||
| Increased appetite | 0/16 (0%) | 0/19 (0%) | 1/16 (6.3%) | 0/14 (0%) | 0/7 (0%) | |||||
| Musculoskeletal and connective tissue disorders | ||||||||||
| Arthralgia | 6/16 (37.5%) | 4/19 (21.1%) | 0/16 (0%) | 0/14 (0%) | 1/7 (14.3%) | |||||
| Back pain | 1/16 (6.3%) | 3/19 (15.8%) | 1/16 (6.3%) | 0/14 (0%) | 1/7 (14.3%) | |||||
| Fibromyalgia | 1/16 (6.3%) | 0/19 (0%) | 0/16 (0%) | 0/14 (0%) | 0/7 (0%) | |||||
| Flank pain | 1/16 (6.3%) | 0/19 (0%) | 0/16 (0%) | 0/14 (0%) | 0/7 (0%) | |||||
| Joint swelling | 0/16 (0%) | 1/19 (5.3%) | 0/16 (0%) | 0/14 (0%) | 0/7 (0%) | |||||
| Muscle spasms | 2/16 (12.5%) | 0/19 (0%) | 1/16 (6.3%) | 0/14 (0%) | 0/7 (0%) | |||||
| Musculoskeletal pain | 0/16 (0%) | 0/19 (0%) | 0/16 (0%) | 1/14 (7.1%) | 0/7 (0%) | |||||
| Musculoskeletal stiffness | 1/16 (6.3%) | 0/19 (0%) | 0/16 (0%) | 0/14 (0%) | 0/7 (0%) | |||||
| Myalgia | 5/16 (31.3%) | 4/19 (21.1%) | 3/16 (18.8%) | 0/14 (0%) | 0/7 (0%) | |||||
| Neck pain | 0/16 (0%) | 0/19 (0%) | 2/16 (12.5%) | 0/14 (0%) | 0/7 (0%) | |||||
| Pain in extremity | 0/16 (0%) | 1/19 (5.3%) | 0/16 (0%) | 0/14 (0%) | 0/7 (0%) | |||||
| Nervous system disorders | ||||||||||
| Amnesia | 1/16 (6.3%) | 0/19 (0%) | 0/16 (0%) | 0/14 (0%) | 0/7 (0%) | |||||
| Balance disorder | 1/16 (6.3%) | 0/19 (0%) | 0/16 (0%) | 0/14 (0%) | 0/7 (0%) | |||||
| Burning sensation | 3/16 (18.8%) | 1/19 (5.3%) | 0/16 (0%) | 0/14 (0%) | 1/7 (14.3%) | |||||
| Cognitive disorder | 0/16 (0%) | 1/19 (5.3%) | 0/16 (0%) | 0/14 (0%) | 0/7 (0%) | |||||
| Disturbance in attention | 1/16 (6.3%) | 1/19 (5.3%) | 1/16 (6.3%) | 1/14 (7.1%) | 0/7 (0%) | |||||
| Dizziness | 6/16 (37.5%) | 5/19 (26.3%) | 1/16 (6.3%) | 1/14 (7.1%) | 0/7 (0%) | |||||
| Dysaesthesia | 0/16 (0%) | 0/19 (0%) | 0/16 (0%) | 1/14 (7.1%) | 0/7 (0%) | |||||
| Dysgeusia | 3/16 (18.8%) | 2/19 (10.5%) | 1/16 (6.3%) | 1/14 (7.1%) | 0/7 (0%) | |||||
| Headache | 9/16 (56.3%) | 9/19 (47.4%) | 5/16 (31.3%) | 5/14 (35.7%) | 1/7 (14.3%) | |||||
| Hyperaesthesia | 2/16 (12.5%) | 0/19 (0%) | 0/16 (0%) | 0/14 (0%) | 0/7 (0%) | |||||
| Hypertonia | 0/16 (0%) | 0/19 (0%) | 0/16 (0%) | 1/14 (7.1%) | 0/7 (0%) | |||||
| Hypoaesthesia | 1/16 (6.3%) | 1/19 (5.3%) | 0/16 (0%) | 0/14 (0%) | 1/7 (14.3%) | |||||
| Hypogeusia | 1/16 (6.3%) | 0/19 (0%) | 0/16 (0%) | 0/14 (0%) | 0/7 (0%) | |||||
| Lethargy | 0/16 (0%) | 1/19 (5.3%) | 0/16 (0%) | 0/14 (0%) | 0/7 (0%) | |||||
| Memory impairment | 2/16 (12.5%) | 0/19 (0%) | 0/16 (0%) | 0/14 (0%) | 0/7 (0%) | |||||
| Mental impairment | 0/16 (0%) | 1/19 (5.3%) | 0/16 (0%) | 0/14 (0%) | 0/7 (0%) | |||||
| Migraine | 1/16 (6.3%) | 0/19 (0%) | 0/16 (0%) | 0/14 (0%) | 0/7 (0%) | |||||
| Paraesthesia | 1/16 (6.3%) | 2/19 (10.5%) | 2/16 (12.5%) | 1/14 (7.1%) | 1/7 (14.3%) | |||||
| Parosmia | 0/16 (0%) | 1/19 (5.3%) | 0/16 (0%) | 0/14 (0%) | 0/7 (0%) | |||||
| Presyncope | 1/16 (6.3%) | 0/19 (0%) | 0/16 (0%) | 0/14 (0%) | 0/7 (0%) | |||||
| Psychomotor hyperactivity | 0/16 (0%) | 0/19 (0%) | 1/16 (6.3%) | 0/14 (0%) | 0/7 (0%) | |||||
| Restless legs syndrome | 1/16 (6.3%) | 0/19 (0%) | 0/16 (0%) | 0/14 (0%) | 0/7 (0%) | |||||
| Sciatica | 0/16 (0%) | 1/19 (5.3%) | 1/16 (6.3%) | 1/14 (7.1%) | 0/7 (0%) | |||||
| Sleep phase rhythm disturbance | 0/16 (0%) | 0/19 (0%) | 1/16 (6.3%) | 0/14 (0%) | 0/7 (0%) | |||||
| Somnolence | 0/16 (0%) | 0/19 (0%) | 0/16 (0%) | 0/14 (0%) | 1/7 (14.3%) | |||||
| Syncope | 0/16 (0%) | 1/19 (5.3%) | 0/16 (0%) | 0/14 (0%) | 0/7 (0%) | |||||
| Tremor | 0/16 (0%) | 0/19 (0%) | 1/16 (6.3%) | 0/14 (0%) | 0/7 (0%) | |||||
| Psychiatric disorders | ||||||||||
| Affect lability | 0/16 (0%) | 1/19 (5.3%) | 1/16 (6.3%) | 0/14 (0%) | 0/7 (0%) | |||||
| Agitation | 0/16 (0%) | 0/19 (0%) | 1/16 (6.3%) | 1/14 (7.1%) | 0/7 (0%) | |||||
| Anxiety | 1/16 (6.3%) | 1/19 (5.3%) | 0/16 (0%) | 0/14 (0%) | 0/7 (0%) | |||||
| Depressed mood | 0/16 (0%) | 0/19 (0%) | 0/16 (0%) | 1/14 (7.1%) | 0/7 (0%) | |||||
| Depression | 1/16 (6.3%) | 2/19 (10.5%) | 2/16 (12.5%) | 0/14 (0%) | 1/7 (14.3%) | |||||
| Disorientation | 0/16 (0%) | 0/19 (0%) | 1/16 (6.3%) | 0/14 (0%) | 0/7 (0%) | |||||
| Flat affect | 1/16 (6.3%) | 0/19 (0%) | 0/16 (0%) | 0/14 (0%) | 0/7 (0%) | |||||
| Frustration | 0/16 (0%) | 0/19 (0%) | 1/16 (6.3%) | 0/14 (0%) | 0/7 (0%) | |||||
| Hallucination, visual | 1/16 (6.3%) | 0/19 (0%) | 0/16 (0%) | 0/14 (0%) | 0/7 (0%) | |||||
| Impatience | 0/16 (0%) | 0/19 (0%) | 0/16 (0%) | 1/14 (7.1%) | 0/7 (0%) | |||||
| Insomnia | 8/16 (50%) | 5/19 (26.3%) | 3/16 (18.8%) | 0/14 (0%) | 0/7 (0%) | |||||
| Irritability | 5/16 (31.3%) | 4/19 (21.1%) | 1/16 (6.3%) | 0/14 (0%) | 1/7 (14.3%) | |||||
| Libido increased | 0/16 (0%) | 0/19 (0%) | 1/16 (6.3%) | 0/14 (0%) | 0/7 (0%) | |||||
| Sleep disorder | 0/16 (0%) | 0/19 (0%) | 1/16 (6.3%) | 3/14 (21.4%) | 1/7 (14.3%) | |||||
| Stress | 1/16 (6.3%) | 1/19 (5.3%) | 1/16 (6.3%) | 0/14 (0%) | 0/7 (0%) | |||||
| Renal and urinary disorders | ||||||||||
| Chromaturia | 2/16 (12.5%) | 2/19 (10.5%) | 0/16 (0%) | 0/14 (0%) | 0/7 (0%) | |||||
| Dysuria | 1/16 (6.3%) | 0/19 (0%) | 0/16 (0%) | 0/14 (0%) | 0/7 (0%) | |||||
| Nocturia | 0/16 (0%) | 0/19 (0%) | 0/16 (0%) | 1/14 (7.1%) | 0/7 (0%) | |||||
| Pollakiuria | 2/16 (12.5%) | 1/19 (5.3%) | 0/16 (0%) | 0/14 (0%) | 0/7 (0%) | |||||
| Renal disorder | 0/16 (0%) | 0/19 (0%) | 0/16 (0%) | 0/14 (0%) | 1/7 (14.3%) | |||||
| Renal failure | 0/16 (0%) | 1/19 (5.3%) | 0/16 (0%) | 0/14 (0%) | 0/7 (0%) | |||||
| Reproductive system and breast disorders | ||||||||||
| Dysmenorrhoea | 0/16 (0%) | 0/19 (0%) | 0/16 (0%) | 0/14 (0%) | 1/7 (14.3%) | |||||
| Erectile dysfunction | 1/16 (6.3%) | 0/19 (0%) | 0/16 (0%) | 0/14 (0%) | 0/7 (0%) | |||||
| Vaginal discharge | 0/16 (0%) | 1/19 (5.3%) | 1/16 (6.3%) | 0/14 (0%) | 0/7 (0%) | |||||
| Respiratory, thoracic and mediastinal disorders | ||||||||||
| Cough | 4/16 (25%) | 3/19 (15.8%) | 1/16 (6.3%) | 0/14 (0%) | 0/7 (0%) | |||||
| Dyspnoea | 3/16 (18.8%) | 2/19 (10.5%) | 1/16 (6.3%) | 1/14 (7.1%) | 0/7 (0%) | |||||
| Dyspnoea exertional | 1/16 (6.3%) | 3/19 (15.8%) | 1/16 (6.3%) | 0/14 (0%) | 0/7 (0%) | |||||
| Epistaxis | 1/16 (6.3%) | 2/19 (10.5%) | 2/16 (12.5%) | 1/14 (7.1%) | 0/7 (0%) | |||||
| Nasal dryness | 0/16 (0%) | 0/19 (0%) | 1/16 (6.3%) | 0/14 (0%) | 0/7 (0%) | |||||
| Oropharyngeal pain | 0/16 (0%) | 1/19 (5.3%) | 0/16 (0%) | 1/14 (7.1%) | 0/7 (0%) | |||||
| Rhinorrhoea | 0/16 (0%) | 1/19 (5.3%) | 1/16 (6.3%) | 0/14 (0%) | 0/7 (0%) | |||||
| Throat irritation | 0/16 (0%) | 0/19 (0%) | 0/16 (0%) | 1/14 (7.1%) | 0/7 (0%) | |||||
| Skin and subcutaneous tissue disorders | ||||||||||
| Acne | 0/16 (0%) | 0/19 (0%) | 0/16 (0%) | 0/14 (0%) | 1/7 (14.3%) | |||||
| Acute febrile neutrophilic dermatosis | 1/16 (6.3%) | 0/19 (0%) | 0/16 (0%) | 0/14 (0%) | 0/7 (0%) | |||||
| Alopecia | 1/16 (6.3%) | 3/19 (15.8%) | 0/16 (0%) | 0/14 (0%) | 1/7 (14.3%) | |||||
| Angioedema | 0/16 (0%) | 1/19 (5.3%) | 0/16 (0%) | 0/14 (0%) | 0/7 (0%) | |||||
| Blister | 0/16 (0%) | 0/19 (0%) | 1/16 (6.3%) | 0/14 (0%) | 1/7 (14.3%) | |||||
| Dermatitis contact | 2/16 (12.5%) | 0/19 (0%) | 0/16 (0%) | 0/14 (0%) | 1/7 (14.3%) | |||||
| Dry skin | 5/16 (31.3%) | 4/19 (21.1%) | 3/16 (18.8%) | 2/14 (14.3%) | 2/7 (28.6%) | |||||
| Eczema | 0/16 (0%) | 0/19 (0%) | 1/16 (6.3%) | 0/14 (0%) | 1/7 (14.3%) | |||||
| Erythema | 3/16 (18.8%) | 2/19 (10.5%) | 0/16 (0%) | 3/14 (21.4%) | 1/7 (14.3%) | |||||
| Hyperhidrosis | 0/16 (0%) | 4/19 (21.1%) | 1/16 (6.3%) | 0/14 (0%) | 0/7 (0%) | |||||
| Macule | 1/16 (6.3%) | 0/19 (0%) | 0/16 (0%) | 0/14 (0%) | 0/7 (0%) | |||||
| Nail atrophy | 0/16 (0%) | 1/19 (5.3%) | 0/16 (0%) | 0/14 (0%) | 0/7 (0%) | |||||
| Nail discolouration | 1/16 (6.3%) | 1/19 (5.3%) | 0/16 (0%) | 0/14 (0%) | 0/7 (0%) | |||||
| Night sweats | 0/16 (0%) | 1/19 (5.3%) | 0/16 (0%) | 0/14 (0%) | 0/7 (0%) | |||||
| Pain of skin | 3/16 (18.8%) | 6/19 (31.6%) | 3/16 (18.8%) | 0/14 (0%) | 2/7 (28.6%) | |||||
| Papule | 1/16 (6.3%) | 0/19 (0%) | 0/16 (0%) | 0/14 (0%) | 0/7 (0%) | |||||
| Petechiae | 1/16 (6.3%) | 0/19 (0%) | 0/16 (0%) | 0/14 (0%) | 0/7 (0%) | |||||
| Photosensitivity reaction | 9/16 (56.3%) | 8/19 (42.1%) | 2/16 (12.5%) | 0/14 (0%) | 0/7 (0%) | |||||
| Pruritus | 7/16 (43.8%) | 10/19 (52.6%) | 6/16 (37.5%) | 9/14 (64.3%) | 2/7 (28.6%) | |||||
| Pruritus generalised | 2/16 (12.5%) | 2/19 (10.5%) | 1/16 (6.3%) | 0/14 (0%) | 0/7 (0%) | |||||
| Psoriasis | 1/16 (6.3%) | 0/19 (0%) | 0/16 (0%) | 0/14 (0%) | 0/7 (0%) | |||||
| Rash | 6/16 (37.5%) | 7/19 (36.8%) | 5/16 (31.3%) | 0/14 (0%) | 4/7 (57.1%) | |||||
| Rash erythematous | 0/16 (0%) | 2/19 (10.5%) | 0/16 (0%) | 0/14 (0%) | 0/7 (0%) | |||||
| Rash maculo-papular | 1/16 (6.3%) | 0/19 (0%) | 0/16 (0%) | 0/14 (0%) | 0/7 (0%) | |||||
| Rash papular | 0/16 (0%) | 1/19 (5.3%) | 0/16 (0%) | 0/14 (0%) | 0/7 (0%) | |||||
| Rash pruritic | 0/16 (0%) | 1/19 (5.3%) | 0/16 (0%) | 0/14 (0%) | 0/7 (0%) | |||||
| Skin burning sensation | 0/16 (0%) | 0/19 (0%) | 1/16 (6.3%) | 0/14 (0%) | 0/7 (0%) | |||||
| Skin irritation | 1/16 (6.3%) | 0/19 (0%) | 0/16 (0%) | 0/14 (0%) | 0/7 (0%) | |||||
| Skin lesion | 1/16 (6.3%) | 0/19 (0%) | 0/16 (0%) | 0/14 (0%) | 0/7 (0%) | |||||
| Skin mass | 0/16 (0%) | 0/19 (0%) | 1/16 (6.3%) | 0/14 (0%) | 0/7 (0%) | |||||
| Skin reaction | 0/16 (0%) | 0/19 (0%) | 0/16 (0%) | 3/14 (21.4%) | 0/7 (0%) | |||||
| Skin warm | 0/16 (0%) | 1/19 (5.3%) | 0/16 (0%) | 0/14 (0%) | 0/7 (0%) | |||||
| Vitiligo | 1/16 (6.3%) | 0/19 (0%) | 0/16 (0%) | 0/14 (0%) | 0/7 (0%) | |||||
| Xeroderma | 0/16 (0%) | 0/19 (0%) | 0/16 (0%) | 0/14 (0%) | 1/7 (14.3%) | |||||
| Surgical and medical procedures | ||||||||||
| Tooth extraction | 0/16 (0%) | 2/19 (10.5%) | 0/16 (0%) | 0/14 (0%) | 0/7 (0%) | |||||
| Vascular disorders | ||||||||||
| Haematoma | 0/16 (0%) | 0/19 (0%) | 0/16 (0%) | 0/14 (0%) | 1/7 (14.3%) | |||||
| Hot flush | 0/16 (0%) | 1/19 (5.3%) | 1/16 (6.3%) | 0/14 (0%) | 0/7 (0%) | |||||
| Hypertension | 0/16 (0%) | 1/19 (5.3%) | 0/16 (0%) | 2/14 (14.3%) | 0/7 (0%) | |||||
| Pallor | 0/16 (0%) | 1/19 (5.3%) | 0/16 (0%) | 0/14 (0%) | 0/7 (0%) | |||||
Limitations/Caveats
BI decided to stop the further development of the interferon-free combination therapy for Hepatitis C in December 2013 so the recruitment was stopped after 7 patients had entered Group E also PK analyses for Groups C to E were not performed.
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
Boehringer Ingelheim (BI) acknowledges that investigators have the right to publish the study results. Investigators shall provide BI with a copy of any publication or presentation for review prior to any submission. Such review will be done with regard to proprietary information, information related to patentable inventions, medical, scientific, and statistical accuracy within 60 days. BI may request a delay of the publication in order to protect BI's intellectual property rights.
Results Point of Contact
| Name/Title | Boehringer Ingelheim, Call Center |
|---|---|
| Organization | Boehringer Ingelheim |
| Phone | 1-800-243-0127 |
| clintriage.rdg@boehringer-ingelheim.com |
Responsible Party:
Boehringer Ingelheim
ClinicalTrials.gov Identifier:
NCT01525628
Other Study ID Numbers:
- 1241.27
- 2012-004102-10
First Posted:
Feb 3, 2012
Last Update Posted:
Jun 10, 2016
Last Verified:
May 1, 2016