Investigation of Interactions Between Faldaprevir, Itraconazole, Atorvastatin and Rosuvastatin

• Sponsor: Boehringer Ingelheim (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01795937
• Collaborator: (none)
• Enrollment: 51
• Location: 1
• Arms: 2
• Duration (Days): 28
• Patients Per Site Per Month: 55.4

Study Details

Study Description

Brief Summary

To investigate the effect of steady-state itraconazole on the pharmacokinetics of steady-state of faldaprevir and the effect of steady-state of faldaprevir on the single-dose pharmacokinetics of atorvastatin as well as the effect of steady-state of faldaprevir on the single-dose pharmacokinetics of rosuvastatin

Condition or Disease	Intervention/Treatment	Phase
Healthy	Drug: Itraconazole; Drug: Atorvastatin; Drug: Faldaprevir; Drug: Rosuvastatin; Drug: Faldaprevir	Phase 1

Study Design

• Study Type: Interventional
• Actual Enrollment: 51 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Investigation of Interactions Between Faldaprevir, Itraconazole, Atorvastatin and Rosuvastatin in Healthy Male and Female Subjects (Open-label, Fixed-sequence)
• Study Start Date: Feb 1, 2013
• Actual Primary Completion Date: Mar 1, 2013
• Actual Study Completion Date: Mar 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Part 1: Faldaprevir + Itraconazole Interaction of Faldaprevir and Itraconazole	Drug: Itraconazole; twice daily; Drug: Faldaprevir; once daily
Experimental: Part 2:Faldaprevir+Rosuvastatin+Atorvast Interaction of Faldaprevir, Rosuvastatin and Atorvastatin	Drug: Atorvastatin; single dose; Drug: Faldaprevir; once daily; Drug: Rosuvastatin; single dose

Outcome Measures

Primary Outcome Measures

1. AUCτ,ss (Itraconazole Part) [-1:30, 0:30, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 8:00, 10:00, 11:00, 12:00 h (hours) after administration of faldaprevir on Day 1 of both periods]

   Area under the concentration-time curve of the analyte in plasma at steady state over the dosing interval τ (AUCτ,ss) of faldaprevir. Outcome measure for the itraconazole part (treatment sequence A_B) of this trial. The measured values show inter-individual variabilities, whereas the statistical analyses show intra-individual variabilities.

2. Cmax,ss (Itraconazole Part) [-1:30, 0:30, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 8:00, 10:00, 11:00, 12:00 h after administration of faldaprevir on Day 1 of both periods.]

   Maximum measured concentration of the analyte in plasma at steady state over the dosing interval (Cmax,ss) of faldaprevir. Outcome measure for the itraconazole part (Treatment sequence A_B) of this trial. The measured values show inter-individual variabilities, whereas the statistical analyses show intra-individual variabilities.

3. AUC0-∞ of Atorvastatin (Statins Part) [-1:30, 0:30, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 8:00, 10:00, 11:00, 12:00, 24:00, 36:00, 48:00, 60:00 h after administration of atorvastatin on Day 1 of both periods.]

   Area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity (AUC0-∞) of atorvastatin after single dose administration. Outcome measure for the statins part of this trial, treatment sequence C_D. The measured values show inter-individual variabilities, whereas the statistical analyses show intra-individual variabilities.

4. Cmax of Atorvastatin (Statins Part) [-1:30, 0:30, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 8:00, 10:00, 11:00, 12:00, 24:00, 36:00, 48:00, 60:00 h after administration of atorvastatin on Day 1 of both periods]

   Maximum measured concentration of the analyte in plasma of atorvastatin (Cmax). Outcome measure for the statins part of this trial, treatment sequence C_D. The measured values show inter-individual variabilities, whereas the statistical analyses show intra-individual variabilities.

5. AUC0-∞ of Rosuvastatin (Statins Part) [-1:30, 0:30, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 8:00, 10:00, 11:00, 12:00, 24:00, 36:00, 48:00, 60:00 h after administration of rosuvastatin on Day 1 of both periods]

   Area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity (AUC0-∞) of rosuvastatin after single dose administration of rosuvastatin. Outcome measure for the statins part of this trial, treatment sequence E_F. The measured values show inter-individual variabilities, whereas the statistical analyses show intra-individual variabilities.

6. Cmax of Rosuvastatin [-1:30, 0:30, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 8:00, 10:00, 11:00, 12:00, 24:00, 36:00, 48:00, 60:00 h after administration of rosuvastatin on Day 1 of both periods]

   Maximum measured concentration of the analyte in plasma of rosuvastatin (Cmax). Outcome measure for the statins part of this trial, treatment sequence E_F. The measured values show inter-individual variabilities, whereas the statistical analyses show intra-individual variabilities.

Secondary Outcome Measures

1. AUCτ,ss of Faldaprevir (Statins Part) [-1:30, 0:30, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 8:00, 10:00, 11:00, 12:00, 24:00, 36:00, 48:00, 60:00 h after administration of rosuvastatin/atorvastatin on Day 1 of the second periods of each treatment sequence.]

   Area under the concentration-time curve of the analyte in plasma at steady state over the dosing interval τ (AUCτ,ss) of faldaprevir. Outcome measure for the statins part of this trial, treatment sequences C_D and E_F.

2. Cmax,ss of Faldaprevir (Statins Part) [-1:30, 0:30, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 8:00, 10:00, 11:00, 12:00, 24:00, 36:00, 48:00, 60:00 h after administration of rosuvastatin/atorvastatin on Day 1 of the second periods of each treatment sequence.]

   Maximum measured concentration of the analyte in plasma at steady state over the dosing interval (Cmax,ss) of faldaprevir. Outcome measure for the statins part of this trial, treatment sequences C_D and E_F.

3. AUC0-tz of Atorvastatin [-1:30, 0:30, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 8:00, 10:00, 11:00, 12:00, 24:00, 36:00, 48:00, 60:00 h after administration of atorvastatin on Day 1 of both periods]

   Area under the plasma concentration-time curve of the analyte over the time interval from 0 to the time tz of the last measurable concentration (AUC0-tz) of atorvastatin. Outcome measure for the statins part of this trial, treatment sequence C_D. The measured values show inter-individual variabilities, whereas the statistical analyses show intra-individual variabilities.

4. AUC0-tz of Rosuvastatin [-1:30, 0:30, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 8:00, 10:00, 11:00, 12:00, 24:00, 36:00, 48:00, 60:00 h after administration of rosuvastatin on Day 1 of both periods]

   Area under the plasma concentration-time curve of the analyte over the time interval from 0 to the time tz of the last measurable concentration (AUC0-tz) of rosuvastatin. Outcome measure for the statins part of this trial, treatment sequence E_F. The measured values show inter-individual variabilities, whereas the statistical analyses show intra-individual variabilities.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 50 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion criteria:

1. Healthy male and female subjects

Exclusion criteria:

1. Any relevant deviation from healthy conditions

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	1220.61.1 Boehringer Ingelheim Investigational Site	Ingelheim		Germany

Sponsors and Collaborators

• Boehringer Ingelheim

Investigators

• Study Chair: Boehringer Ingelheim, Boehringer Ingelheim

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Related Info

Publications

None provided.

• Responsible Party: Boehringer Ingelheim
• ClinicalTrials.gov Identifier: NCT01795937
• Other Study ID Numbers: 1220.61; 2012-005518-20
• First Posted: Feb 21, 2013
• Last Update Posted: Aug 3, 2015
• Last Verified: Jul 1, 2015

• Additional relevant MeSH terms: Itraconazole; Atorvastatin; Rosuvastatin Calcium

Study Results

Participant Flow

Arm/Group Title	Treatment Sequence A_B (Itraconazole Part)	Treatment Sequence C_D (Statins Part)	Treatment Sequence E_F (Statins Part)
Arm/Group Description	The itraconazole part (interaction of steady state faldaprevir with itraconazole) of this trial was done open-label with a fixed-sequence, 2-period design; performed independently from the statins part. Treatment A: Faldaprevir (120 mg) was given twice daily on Day -5 and once daily from Day -4 to Day 1 (6 days in total). Treatment B: Faldaprevir (120 mg) was given once daily from Day -3 to Day 1 (4 days). In addition, itraconazole (200 mg) was given twice daily on Day -3 and once daily from Day -2 to Day 1 (4 days in total). Treatment A directly preceded treatment B, without an intermittent washout period. Oral administration with 240 mL water.	The statins part (interaction of multiple dose faldaprevir with either atorvastatin or rosuvastatin) was done open-label with a fixed-sequence, 2-period design; performed independently from the itraconazole part. Treatment C: Atorvastatin (10 mg) was given as a single dose on Day 1. Treatment D: Faldaprevir (240 mg) was given twice daily on Day -5 and once daily from Day -4 to Day 2 (7 days in total). In addition, atorvastatin (10 mg) was given as a single dose on Day 1. Treatment C preceded treatment D. Oral administration with 240 mL water.	The statins part (interaction of multiple dose faldaprevir with either atorvastatin or rosuvastatin) was done open-label with a fixed-sequence, 2-period design; performed independently from the itraconazole part. Treatment E: Rosuvastatin (10 mg) was given as a single dose on Day 1. Treatment F: Faldaprevir (240 mg) was given twice daily on Day -5 and once daily from Day -4 to Day 2 (7 days in total). In addition, rosuvastatin (10 mg) was given as a single dose on Day 1. Treatment E preceded treatment F. Oral administration with 240 mL water.
Period Title: Overall Study
STARTED	18	16	17
COMPLETED	17	15	17
NOT COMPLETED	1	1	0

Baseline Characteristics

Arm/Group Title	Treatment Sequence A_B (Itraconazole Part)	Treatment Sequence C_D (Statins Part)	Treatment Sequence E_F (Statins Part)	Total
Arm/Group Description	The itraconazole part (interaction of steady state faldaprevir with itraconazole) of this trial was done open-label with a fixed-sequence, 2-period design; performed independently from the statins part. Treatment A: Faldaprevir (120 mg) was given twice daily on Day -5 and once daily from Day -4 to Day 1 (6 days in total). Treatment B: Faldaprevir (120 mg) was given once daily from Day -3 to Day 1 (4 days). In addition, itraconazole (200 mg) was given twice daily on Day -3 and once daily from Day -2 to Day 1 (4 days in total). Treatment A directly preceded treatment B, without an intermittent washout period. Oral administration with 240 mL water.	The statins part (interaction of multiple dose faldaprevir with either atorvastatin or rosuvastatin) was done open-label with a fixed-sequence, 2-period design; performed independently from the itraconazole part. Treatment C: Atorvastatin (10 mg) was given as a single dose on Day 1. Treatment D: Faldaprevir (240 mg) was given twice daily on Day -5 and once daily from Day -4 to Day 2 (7 days in total). In addition, atorvastatin (10 mg) was given as a single dose on Day 1. Treatment C preceded treatment D. Oral administration with 240 mL water.	The statins part (interaction of multiple dose faldaprevir with either atorvastatin or rosuvastatin) was done open-label with a fixed-sequence, 2-period design; performed independently from the itraconazole part. Treatment E: Rosuvastatin (10 mg) was given as a single dose on Day 1. Treatment F: Faldaprevir (240 mg) was given twice daily on Day -5 and once daily from Day -4 to Day 2 (7 days in total). In addition, rosuvastatin (10 mg) was given as a single dose on Day 1. Treatment E preceded treatment F. Oral administration with 240 mL water.	Total of all reporting groups
Overall Participants	18	16	17	51
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	39.8 (6.8)	40.0 (8.3)	38.1 (7.4)	39.3 (7.6)
Sex: Female, Male (Count of Participants)
Female	8 44.4%	4 25%	10 58.8%	22 43.1%
Male	10 55.6%	12 75%	7 41.2%	29 56.9%

Outcome Measures

1. Primary Outcome

Title	AUCτ,ss (Itraconazole Part)
Description	Area under the concentration-time curve of the analyte in plasma at steady state over the dosing interval τ (AUCτ,ss) of faldaprevir. Outcome measure for the itraconazole part (treatment sequence A_B) of this trial. The measured values show inter-individual variabilities, whereas the statistical analyses show intra-individual variabilities.
Time Frame	-1:30, 0:30, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 8:00, 10:00, 11:00, 12:00 h (hours) after administration of faldaprevir on Day 1 of both periods

Outcome Measure Data

Analysis Population Description

pharmacokinetic (PK) set of the itraconazole part of this trial. The PK set included all treated subjects of the itraconazole part that provided at least 1 observation for at least 1 primary endpoint without important protocal violations with respect to the statistical evaluation of the PK endpoints.

Arm/Group Title	Faldaprevir	Faldaprevir+Itraconazole
Arm/Group Description	Faldaprevir 120 mg once daily from Day -4 to Day 1 with a 120 mg twice daily loading dose on Day -5 (6 days in total). Treatment A.	Faldaprevir 120 mg once daily from Day -3 to Day 1 + itraconazole 200 mg twice daily on Day -3 and once daily from Day -2 to Day 1 (4 days in total). Treatment B.
Measure Participants	17	17
Geometric Mean (Geometric Coefficient of Variation) [ng*h/mL]	29900 (62.8)	59500 (53.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Faldaprevir, Faldaprevir+Itraconazole
	Comments	Relative bioavailability comparison faldaprevir+itraconazole : faldaprevir
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Investigation of relative bioavailability (no formal testing)
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Geometric Mean Ratio
	Estimated Value	198.55
	Confidence Interval	(2-Sided) 90%; 182.43 to 216.09
	Parameter Dispersion	Type: Standard Deviation; Value: 14.2
	Estimation Comments	The standard deviation is actually the geometric coefficient of variation.

2. Primary Outcome

Title	Cmax,ss (Itraconazole Part)
Description	Maximum measured concentration of the analyte in plasma at steady state over the dosing interval (Cmax,ss) of faldaprevir. Outcome measure for the itraconazole part (Treatment sequence A_B) of this trial. The measured values show inter-individual variabilities, whereas the statistical analyses show intra-individual variabilities.
Time Frame	-1:30, 0:30, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 8:00, 10:00, 11:00, 12:00 h after administration of faldaprevir on Day 1 of both periods.

Outcome Measure Data

Analysis Population Description

PK set of the itraconazole part of this trial.

Arm/Group Title	Faldaprevir	Faldaprevir+Itraconazole
Arm/Group Description	Faldaprevir 120 mg once daily from Day -4 to Day 1 with a 120 mg twice daily loading dose on Day -5 (6 days in total). Treatment A.	Faldaprevir 120 mg once daily from Day -3 to Day 1 + itraconazole 200 mg twice daily on Day -3 and once daily from Day -2 to Day 1 (4 days in total). Treatment B.
Measure Participants	17	17
Geometric Mean (Geometric Coefficient of Variation) [ng/mL]	2780 (61.0)	5030 (49.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Faldaprevir, Faldaprevir+Itraconazole
	Comments	Relative bioavailability comparison faldaprevir+itraconazole : faldaprevir.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Investigation of relative bioavailability (no formal testing).
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Geometric Mean Ratio
	Estimated Value	180.63
	Confidence Interval	(2-Sided) 90%; 165.68 to 196.93
	Parameter Dispersion	Type: Standard Deviation; Value: 14.5
	Estimation Comments	The standard deviation is actually the geometric coefficient of variation.

3. Primary Outcome

Title	AUC0-∞ of Atorvastatin (Statins Part)
Description	Area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity (AUC0-∞) of atorvastatin after single dose administration. Outcome measure for the statins part of this trial, treatment sequence C_D. The measured values show inter-individual variabilities, whereas the statistical analyses show intra-individual variabilities.
Time Frame	-1:30, 0:30, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 8:00, 10:00, 11:00, 12:00, 24:00, 36:00, 48:00, 60:00 h after administration of atorvastatin on Day 1 of both periods.

Outcome Measure Data

Analysis Population Description

PK set of the statins part and assigned to atorvastatin (treatment sequence C_D). Pharmacokinetic set (PK set): all treated subjects of the statins part that provided at least 1 observation for at least 1 primary endpoint without important protocol violations with respect to the statistical evaluation of the pharmacokinetic endpoints.

Arm/Group Title	Atorvastatin	Atorvastatin+Faldaprevir
Arm/Group Description	Atorvastatin (10 mg) was given as a single dose on Day 1. Treatment C.	Faldaprevir (240 mg) was given twice daily on Day -5 and once daily from Day -4 to Day 2 (7 days in total). In addition, atorvastatin (10 mg) was given as a single dose on Day 1. Treatment D.
Measure Participants	16	15
Geometric Mean (Geometric Coefficient of Variation) [ng*h/mL]	13.7 (51.5)	129.0 (43.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Faldaprevir, Faldaprevir+Itraconazole
	Comments	Relative bioavailability comparison atorvastatin+faldaprevir : atorvastatin.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Investigation of relative bioavailability (no formal testing).
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Geometric Mean Ratio
	Estimated Value	946.45
	Confidence Interval	(2-Sided) 90%; 797.61 to 1123.07
	Parameter Dispersion	Type: Standard Deviation; Value: 27.3
	Estimation Comments	The standard deviation is actually the geometric coefficient of variation.

4. Primary Outcome

Title	Cmax of Atorvastatin (Statins Part)
Description	Maximum measured concentration of the analyte in plasma of atorvastatin (Cmax). Outcome measure for the statins part of this trial, treatment sequence C_D. The measured values show inter-individual variabilities, whereas the statistical analyses show intra-individual variabilities.
Time Frame	-1:30, 0:30, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 8:00, 10:00, 11:00, 12:00, 24:00, 36:00, 48:00, 60:00 h after administration of atorvastatin on Day 1 of both periods

Outcome Measure Data

Analysis Population Description

PK set of the statins part and assigned to atorvastatin (treatment sequence C_D).

Arm/Group Title	Atorvastatin	Atorvastatin+Faldaprevir
Arm/Group Description	Atorvastatin (10 mg) was given as a single dose on Day 1. Treatment C.	Faldaprevir (240 mg) was given twice daily on Day -5 and once daily from Day -4 to Day 2 (7 days in total). In addition, atorvastatin (10 mg) was given as a single dose on Day 1. Treatment D.
Measure Participants	16	15
Geometric Mean (Geometric Coefficient of Variation) [ng/mL]	0.94 (35.2)	31.10 (52.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Faldaprevir, Faldaprevir+Itraconazole
	Comments	Relative bioavailability comparison atorvastatin+faldaprevir : atorvastatin.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Investigation of relative bioavailability (no formal testing).
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Geometric Mean Ratio
	Estimated Value	3372.72
	Confidence Interval	(2-Sided) 90%; 2961.95 to 3840.47
	Parameter Dispersion	Type: Standard Deviation; Value: 20.5
	Estimation Comments	The standard deviation is actually the geometric coefficient of variation.

5. Secondary Outcome

Title	AUCτ,ss of Faldaprevir (Statins Part)
Description	Area under the concentration-time curve of the analyte in plasma at steady state over the dosing interval τ (AUCτ,ss) of faldaprevir. Outcome measure for the statins part of this trial, treatment sequences C_D and E_F.
Time Frame	-1:30, 0:30, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 8:00, 10:00, 11:00, 12:00, 24:00, 36:00, 48:00, 60:00 h after administration of rosuvastatin/atorvastatin on Day 1 of the second periods of each treatment sequence.

Outcome Measure Data

Analysis Population Description

PK set of the statins part.

Arm/Group Title	Atorvastatin+Faldaprevir	Rosuvastatin+Faldaprevir
Arm/Group Description	Faldaprevir (240 mg) was given twice daily on Day -5 and once daily from Day -4 to Day 2 (7 days in total). In addition, atorvastatin (10 mg) was given as a single dose on Day 1. Treatment D.	Faldaprevir (240 mg) was given twice daily on Day -5 and once daily from Day -4 to Day 2 (7 days in total). In addition, rosuvastatin (10 mg) was given as a single dose on Day 1. Treatment F.
Measure Participants	15	17
Geometric Mean (Geometric Coefficient of Variation) [ng*h/mL]	145000 (34.3)	136000 (43.9)

6. Secondary Outcome

Title	Cmax,ss of Faldaprevir (Statins Part)
Description	Maximum measured concentration of the analyte in plasma at steady state over the dosing interval (Cmax,ss) of faldaprevir. Outcome measure for the statins part of this trial, treatment sequences C_D and E_F.
Time Frame	-1:30, 0:30, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 8:00, 10:00, 11:00, 12:00, 24:00, 36:00, 48:00, 60:00 h after administration of rosuvastatin/atorvastatin on Day 1 of the second periods of each treatment sequence.

Outcome Measure Data

Analysis Population Description

PK set of the statins part.

Arm/Group Title	Atorvastatin+Faldaprevir	Rosuvastatin+Faldaprevir
Arm/Group Description	Faldaprevir (240 mg) was given twice daily on Day -5 and once daily from Day -4 to Day 2 (7 days in total). In addition, atorvastatin (10 mg) was given as a single dose on Day 1. Treatment D.	Faldaprevir (240 mg) was given twice daily on Day -5 and once daily from Day -4 to Day 2 (7 days in total). In addition, rosuvastatin (10 mg) was given as a single dose on Day 1. Treatment F.
Measure Participants	15	17
Geometric Mean (Geometric Coefficient of Variation) [ng/mL]	12900 (27.8)	12200 (36.8)

7. Secondary Outcome

Title	AUC0-tz of Atorvastatin
Description	Area under the plasma concentration-time curve of the analyte over the time interval from 0 to the time tz of the last measurable concentration (AUC0-tz) of atorvastatin. Outcome measure for the statins part of this trial, treatment sequence C_D. The measured values show inter-individual variabilities, whereas the statistical analyses show intra-individual variabilities.
Time Frame	-1:30, 0:30, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 8:00, 10:00, 11:00, 12:00, 24:00, 36:00, 48:00, 60:00 h after administration of atorvastatin on Day 1 of both periods

Outcome Measure Data

Analysis Population Description

PK set of the statins part and assigned to atorvastatin (treatment sequence C_D).

Arm/Group Title	Atorvastatin	Atorvastatin+Faldaprevir
Arm/Group Description	Atorvastatin (10 mg) was given as a single dose on Day 1. Treatment C.	Faldaprevir (240 mg) was given twice daily on Day -5 and once daily from Day -4 to Day 2 (7 days in total). In addition, atorvastatin (10 mg) was given as a single dose on Day 1. Treatment D.
Measure Participants	16	15
Geometric Mean (Geometric Coefficient of Variation) [ng*h/mL]	9.5 (40.2)	129.6 (44.9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Faldaprevir, Faldaprevir+Itraconazole
	Comments	Relative bioavailability comparison atorvastatin+faldaprevir : atorvastatin.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Investigation of relative bioavailability (no formal testing).
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Geometric Mean Ratio
	Estimated Value	1358.91
	Confidence Interval	(2-Sided) 90%; 1224.32 to 1508.29
	Parameter Dispersion	Type: Standard Deviation; Value: 16.4
	Estimation Comments	The standard deviation is actually the geometric coefficient of variation.

8. Primary Outcome

Title	AUC0-∞ of Rosuvastatin (Statins Part)
Description	Area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity (AUC0-∞) of rosuvastatin after single dose administration of rosuvastatin. Outcome measure for the statins part of this trial, treatment sequence E_F. The measured values show inter-individual variabilities, whereas the statistical analyses show intra-individual variabilities.
Time Frame	-1:30, 0:30, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 8:00, 10:00, 11:00, 12:00, 24:00, 36:00, 48:00, 60:00 h after administration of rosuvastatin on Day 1 of both periods

Outcome Measure Data

Analysis Population Description

PK set of the statins part and assigned to rosuvastatin (treatment sequence E_F).

Arm/Group Title	Rosuvastatin	Rosuvastatin+Faldaprevir
Arm/Group Description	Rosuvastatin (10 mg) was given as a single dose on Day 1. Treatment E.	Faldaprevir (240 mg) was given twice daily on Day -5 and once daily from Day -4 to Day 2 (7 days in total). In addition, rosuvastatin (10 mg) was given as a single dose on Day 1. Treatment F.
Measure Participants	17	17
Geometric Mean (Geometric Coefficient of Variation) [ng*h/mL]	24.9 (49.3)	365.0 (28.6)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Faldaprevir, Faldaprevir+Itraconazole
	Comments	Relative bioavailability comparison rosuvastatin+faldaprevir : rosuvastatin.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Investigation of relative bioavailability (no formal testing).
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Geometric Mean Ratio
	Estimated Value	1466.35
	Confidence Interval	(2-Sided) 90%; 1277.62 to 1682.95
	Parameter Dispersion	Type: Standard Deviation; Value: 23.3
	Estimation Comments	The standard deviation is actually the geometric coefficient of variation.

9. Primary Outcome

Title	Cmax of Rosuvastatin
Description	Maximum measured concentration of the analyte in plasma of rosuvastatin (Cmax). Outcome measure for the statins part of this trial, treatment sequence E_F. The measured values show inter-individual variabilities, whereas the statistical analyses show intra-individual variabilities.
Time Frame	-1:30, 0:30, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 8:00, 10:00, 11:00, 12:00, 24:00, 36:00, 48:00, 60:00 h after administration of rosuvastatin on Day 1 of both periods

Outcome Measure Data

Analysis Population Description

PK set of the statins part and assigned to rosuvastatin (treatment sequence E_F).

Arm/Group Title	Rosuvastatin	Rosuvastatin+Faldaprevir
Arm/Group Description	Rosuvastatin (10 mg) was given as a single dose on Day 1. Treatment E.	Faldaprevir (240 mg) was given twice daily on Day -5 and once daily from Day -4 to Day 2 (7 days in total). In addition, rosuvastatin (10 mg) was given as a single dose on Day 1. Treatment F.
Measure Participants	17	17
Geometric Mean (Geometric Coefficient of Variation) [ng/mL]	2.73 (53.0)	89.6 (33.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Faldaprevir, Faldaprevir+Itraconazole
	Comments	Relative bioavailability comparison rosuvastatin+faldaprevir : rosuvastatin.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Investigation of relative bioavailability (no formal testing).
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Geometric Mean Ratio
	Estimated Value	3288.70
	Confidence Interval	(2-Sided) 90%; 2782.04 to 3887.63
	Parameter Dispersion	Type: Standard Deviation; Value: 28.5
	Estimation Comments	The standard deviation is actually the geometric coefficient of variation.

10. Secondary Outcome

Title	AUC0-tz of Rosuvastatin
Description	Area under the plasma concentration-time curve of the analyte over the time interval from 0 to the time tz of the last measurable concentration (AUC0-tz) of rosuvastatin. Outcome measure for the statins part of this trial, treatment sequence E_F. The measured values show inter-individual variabilities, whereas the statistical analyses show intra-individual variabilities.
Time Frame	-1:30, 0:30, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 8:00, 10:00, 11:00, 12:00, 24:00, 36:00, 48:00, 60:00 h after administration of rosuvastatin on Day 1 of both periods

Outcome Measure Data

Analysis Population Description

PK set of the statins part and assigned to rosuvastatin (treatment sequence E_F).

Arm/Group Title	Rosuvastatin	Rosuvastatin+Faldaprevir
Arm/Group Description	Rosuvastatin (10 mg) was given as a single dose on Day 1. Treatment E.	Faldaprevir (240 mg) was given twice daily on Day -5 and once daily from Day -4 to Day 2 (7 days in total). In addition, rosuvastatin (10 mg) was given as a single dose on Day 1. Treatment F.
Measure Participants	17	17
Geometric Mean (Geometric Coefficient of Variation) [ng*h/mL]	21.5 (48.0)	361.0 (28.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Faldaprevir, Faldaprevir+Itraconazole
	Comments	Relative bioavailability comparison rosuvastatin+faldaprevir : rosuvastatin.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Investigation of relative bioavailability (no formal testing).
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Geometric Mean Ratio
	Estimated Value	1678.23
	Confidence Interval	(2-Sided) 90%; 1468.52 to 1917.89
	Parameter Dispersion	Type: Standard Deviation; Value: 22.6
	Estimation Comments	The standard deviation is actually the geometric coefficient of variation.

Adverse Events

Time Frame	Adverse events were to be recorded from screening until the end-of-trial examination. Itraconazole part: up to 25 days. Statins part: up to 33 days.
Adverse Event Reporting Description	Adverse events were recorded throughout the clinical trial, but were specifically asked for at prespecified time points and additionally whenever the investigator deemed necessary. Subjects were asked to spontaneously report any adverse events as well as the time of onset, end, and intensity.
Arm/Group Title	Faldaprevir (Itraconazole Part)		Faldaprevir+Itraconazole (Itraconazole Part)		Atorvastatin (Statins Part)		Rosuvastatin (Statins Part)		Faldaprevir (Statins Part)		Faldaprevir + Atorvastatin (Statins Part)		Faldaprevir + Rosuvastatin (Statins Part)
Arm/Group Description	Faldaprevir: 120 mg once daily with a 120 mg twice daily loading dose on Day -5. Treatment A.		Faldaprevir: 120 mg once daily. Itraconazole: 200 mg once daily with a 200 mg twice daily loading dose on Day -3. Treatment B.		Atorvastatin: 10 mg was given as a single dose on Day 1. Treatment C. From the time of the single dose atorvastatin administration in treatment C until the time of the first faldaprevir administration in treatment D or until 1 day after the trial completion date of the respective subject.		Rosuvastatin: 10 mg was given as a single dose on Day 1. Treatment E. From the time of the single dose rosuvastatin administration in treatment E until the time of the first faldaprevir administration in treatment F or until 1 day after the trial completion date.		From the time of the first faldaprevir administration in treatment D or F until the combined administration of faldaprevir with atorvastatin or rosuvastatin in treatment D or F, respectively, or until 1 day after the trial completion date.		Faldaprevir: 240 mg was given twice daily on Day -5 and once daily from Day -4 to Day 2. Atorvastatin: 10 mg was given as a single dose on Day 1. Treatment D. From the time of the combined administration of faldaprevir with atorvastatin in treatment D until 1 day after the trial completion date.		Faldaprevir: 240 mg was given twice daily on Day -5 and once daily from Day -4 to Day 2. Rosuvastatin: 10 mg was given as a single dose on Day 1. Treatment F. From the time of the combined administration of faldaprevir with rosuvastatin in treatment F until 1 day after the trial completion date.
All Cause Mortality
	Faldaprevir (Itraconazole Part)		Faldaprevir+Itraconazole (Itraconazole Part)		Atorvastatin (Statins Part)		Rosuvastatin (Statins Part)		Faldaprevir (Statins Part)		Faldaprevir + Atorvastatin (Statins Part)		Faldaprevir + Rosuvastatin (Statins Part)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	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)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Faldaprevir (Itraconazole Part)		Faldaprevir+Itraconazole (Itraconazole Part)		Atorvastatin (Statins Part)		Rosuvastatin (Statins Part)		Faldaprevir (Statins Part)		Faldaprevir + Atorvastatin (Statins Part)		Faldaprevir + Rosuvastatin (Statins Part)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/18 (0%)		0/17 (0%)		0/16 (0%)		0/17 (0%)		0/32 (0%)		0/15 (0%)		0/17 (0%)
Other (Not Including Serious) Adverse Events
	Faldaprevir (Itraconazole Part)		Faldaprevir+Itraconazole (Itraconazole Part)		Atorvastatin (Statins Part)		Rosuvastatin (Statins Part)		Faldaprevir (Statins Part)		Faldaprevir + Atorvastatin (Statins Part)		Faldaprevir + Rosuvastatin (Statins Part)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	13/18 (72.2%)		3/17 (17.6%)		5/16 (31.3%)		4/17 (23.5%)		23/32 (71.9%)		8/15 (53.3%)		9/17 (52.9%)
Cardiac disorders
Palpitations	0/18 (0%)		1/17 (5.9%)		0/16 (0%)		0/17 (0%)		0/32 (0%)		0/15 (0%)		0/17 (0%)
Eye disorders
Ocular icterus	1/18 (5.6%)		0/17 (0%)		0/16 (0%)		0/17 (0%)		4/32 (12.5%)		5/15 (33.3%)		3/17 (17.6%)
Gastrointestinal disorders
Nausea	2/18 (11.1%)		1/17 (5.9%)		0/16 (0%)		0/17 (0%)		13/32 (40.6%)		0/15 (0%)		2/17 (11.8%)
Dry mouth	0/18 (0%)		1/17 (5.9%)		0/16 (0%)		1/17 (5.9%)		0/32 (0%)		0/15 (0%)		0/17 (0%)
Abdominal pain	1/18 (5.6%)		0/17 (0%)		0/16 (0%)		0/17 (0%)		0/32 (0%)		0/15 (0%)		0/17 (0%)
Diarrhoea	1/18 (5.6%)		0/17 (0%)		0/16 (0%)		0/17 (0%)		6/32 (18.8%)		0/15 (0%)		0/17 (0%)
Flatulence	0/18 (0%)		0/17 (0%)		0/16 (0%)		0/17 (0%)		3/32 (9.4%)		0/15 (0%)		0/17 (0%)
Dyspepsia	0/18 (0%)		0/17 (0%)		1/16 (6.3%)		0/17 (0%)		2/32 (6.3%)		1/15 (6.7%)		0/17 (0%)
Vomiting	1/18 (5.6%)		0/17 (0%)		0/16 (0%)		0/17 (0%)		0/32 (0%)		0/15 (0%)		0/17 (0%)
General disorders
Fatigue	6/18 (33.3%)		0/17 (0%)		0/16 (0%)		1/17 (5.9%)		5/32 (15.6%)		0/15 (0%)		0/17 (0%)
Thirst	0/18 (0%)		0/17 (0%)		0/16 (0%)		1/17 (5.9%)		0/32 (0%)		0/15 (0%)		0/17 (0%)
Hepatobiliary disorders
Jaundice	0/18 (0%)		0/17 (0%)		0/16 (0%)		0/17 (0%)		0/32 (0%)		1/15 (6.7%)		0/17 (0%)
Immune system disorders
Seasonal allergy	0/18 (0%)		0/17 (0%)		1/16 (6.3%)		0/17 (0%)		0/32 (0%)		0/15 (0%)		0/17 (0%)
Infections and infestations
Nasopharyngitis	2/18 (11.1%)		0/17 (0%)		1/16 (6.3%)		1/17 (5.9%)		1/32 (3.1%)		0/15 (0%)		0/17 (0%)
Rhinitis	0/18 (0%)		0/17 (0%)		1/16 (6.3%)		0/17 (0%)		0/32 (0%)		0/15 (0%)		0/17 (0%)
Sinusitis	0/18 (0%)		0/17 (0%)		0/16 (0%)		1/17 (5.9%)		0/32 (0%)		0/15 (0%)		0/17 (0%)
Injury, poisoning and procedural complications
Sunburn	0/18 (0%)		0/17 (0%)		0/16 (0%)		0/17 (0%)		0/32 (0%)		2/15 (13.3%)		0/17 (0%)
Hand fracture	0/18 (0%)		0/17 (0%)		0/16 (0%)		0/17 (0%)		0/32 (0%)		0/15 (0%)		1/17 (5.9%)
Musculoskeletal and connective tissue disorders
Muscle spasms	0/18 (0%)		0/17 (0%)		0/16 (0%)		0/17 (0%)		0/32 (0%)		1/15 (6.7%)		0/17 (0%)
Nervous system disorders
Headache	10/18 (55.6%)		0/17 (0%)		0/16 (0%)		2/17 (11.8%)		3/32 (9.4%)		2/15 (13.3%)		3/17 (17.6%)
Dizziness	2/18 (11.1%)		0/17 (0%)		0/16 (0%)		0/17 (0%)		2/32 (6.3%)		1/15 (6.7%)		0/17 (0%)
Respiratory, thoracic and mediastinal disorders
Rhinitis allergic	0/18 (0%)		0/17 (0%)		0/16 (0%)		0/17 (0%)		0/32 (0%)		1/15 (6.7%)		0/17 (0%)
Oropharyngeal pain	0/18 (0%)		0/17 (0%)		1/16 (6.3%)		1/17 (5.9%)		0/32 (0%)		0/15 (0%)		0/17 (0%)
Skin and subcutaneous tissue disorders
Dry skin	0/18 (0%)		1/17 (5.9%)		0/16 (0%)		0/17 (0%)		0/32 (0%)		0/15 (0%)		0/17 (0%)
Pruritus	0/18 (0%)		0/17 (0%)		0/16 (0%)		0/17 (0%)		0/32 (0%)		2/15 (13.3%)		0/17 (0%)
Erythema	0/18 (0%)		0/17 (0%)		1/16 (6.3%)		0/17 (0%)		0/32 (0%)		1/15 (6.7%)		0/17 (0%)
Vascular disorders
Haematoma	0/18 (0%)		0/17 (0%)		0/16 (0%)		0/17 (0%)		0/32 (0%)		0/15 (0%)		1/17 (5.9%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.