Study to Evaluate Effect of Sofosbuvir/Velpatasvir/GS-9857 Fixed-Dose Combination on the Pharmacokinetics of a Representative Hormonal Contraceptive Medication, Norgestimate/Ethinyl Estradiol

Study Overview
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Brief Summary
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This study will evaluate the effect of sofosbuvir (SOF)/velpatasvir (VEL)/voxilaprevir (VOX) fixed-dose combination (FDC) + voxilaprevir on the pharmacokinetics (PK) of a representative hormonal contraceptive medication, norgestimate/ethinyl estradiol (Ortho Tri-Cyclen® Lo (OC)) and will assess the effect of norgestimate/ethinyl estradiol on the PK of SOF/VEL/VOX+VOX.

Official Title
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A Phase 1, Open-Label, Drug Interaction Study Evaluating the Effect of Sofosbuvir/Velpatasvir/GS-9857 Fixed-Dose Combination on the Pharmacokinetics of a Representative Hormonal Contraceptive Medication, Norgestimate/Ethinyl Estradiol

Conditions
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HCV Infection

Intervention / Treatment
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* Drug: SOF/VEL/VOX
* Drug: VOX
* Drug: Norgestimate/ethinyl estradiol


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Premenopausal female Must have a calculated body mass index (BMI) ≥ 19.0 and ≤ 30.0 kg/m^2 at screening Must have a negative serum pregnancy test at screening and urine pregnancy test at Day -1 Be willing and able to comply with all study requirements. Exclusion Criteria: Lactating female Have a history of any of the following: Significant drug sensitivity or drug allergy (such as anaphylaxis or hepatoxicity) Known hypersensitivity to the study drugs, the metabolites or formulation excipients Believed, by the study investigator, to be inappropriate for study participation for any reason

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SOF/VEL/VOX + VOX<br>Part A: Participants without a documented history of taking norgestimate/ethinyl estradiol for at least one menstrual cycle will receive norgestimate/ethinyl estradiol. Participants with a documented history of taking norgestimate/ethinyl estradiol may enroll directly into Part B of the study. Part B: Participants will continue taking norgestimate/ethinyl estradiol for the remainder of the study and will receive SOF/VEL/VOX FDC plus VOX. | Drug: SOF/VEL/VOX<br>* 400/100/100 mg FDC tablet administered orally once daily<br>* Other names: Epclusa®;Drug: VOX<br>* 100 mg tablet administered orally once daily<br>* Other names: GS-9857;Drug: Norgestimate/ethinyl estradiol<br>* Norgestimate 0.180 mg/0.215 mg/0.25 mg/ethinyl estradiol 0.025 mg tablet administered orally once daily according to the package insert<br>* Other names: Ortho-Tri-Cyclen® Lo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetic (PK) Parameter: AUCtau of Norelgestromin | AUCtau is defined as concentration of drug over time (the area under the concentration verses time curve over the dosing interval). | Cycle 1,Study Day 14: Predose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 14, 16, 20, and 24 hours postdose; Cycle 2,Study Day 42: Predose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 14, 16, 20, and 24 hours postdose | 
| PK Parameter: AUCtau of Norgestrel | AUCtau is defined as concentration of drug over time (the area under the concentration verses time curve over the dosing interval). | Cycle 1,Study Day 14: Predose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 14, 16, 20, and 24 hours postdose; Cycle 2,Study Day 42: Predose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 14, 16, 20, and 24 hours postdose | 
| PK Parameter: AUCtau of Ethinyl Estradiol | AUCtau is defined as concentration of drug over time (the area under the concentration verses time curve over the dosing interval). | Cycle 1,Study Day 14: Predose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 14, 16, 20, and 24 hours postdose; Cycle 2,Study Day 42: Predose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 14, 16, 20, and 24 hours postdose | 
| Pharmacokinetic (PK) Parameter: AUCtau of Norgestimate | AUCtau is defined as concentration of drug over time (the area under the concentration verses time curve over the dosing interval). | Cycle 1,Study Day 14:Predose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 14, 16, 20, and 24 hours postdose; Cycle 2,Study Day 42: Predose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 14, 16, 20, and 24 hours postdose | 
| PK Parameter: Cmax of Norelgestromin | Cmax is defined as the maximum concentration of drug. | Cycle 1,Study Day 14:Predose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 14, 16, 20, and 24 hours postdose; Cycle 2,Study Day 42: Predose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 14, 16, 20, and 24 hours postdose | 
| PK Parameter: Cmax of Norgestrel | Cmax is defined as the maximum concentration of drug. | Cycle 1,Study Day 14: Predose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 14, 16, 20, and 24 hours postdose; Cycle 2,Study Day 42: Predose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 14, 16, 20, and 24 hours postdose | 
| PK Parameter: Cmax of Ethinyl Estradiol | Cmax is defined as the maximum concentration of drug. | Cycle 1,Study Day 14: Predose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 14, 16, 20, and 24 hours postdose; Cycle 2,Study Day 42: Predose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 14, 16, 20, and 24 hours postdose | 
| PK Parameter: Cmax of Norgestimate | Cmax is defined as the maximum concentration of drug. | Cycle 1,Study Day 14: Predose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 14, 16, 20, and 24 hours postdose; Cycle 2,Study Day 42: Predose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 14, 16, 20, and 24 hours postdose | 
| PK Parameter: Ctau of Norelgestromin | Ctau is defined as the observed drug concentration at the end of the dosing interval. | Part A:Cycle 1,Study Day 14:Predose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 14, 16, 20, and 24 hours postdose; Part B:Cycle 2,Study Day 42:Predose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 14, 16, 20, and 24 hours postdose | 
| PK Parameter: Ctau of Norgestrel | Ctau is defined as the observed drug concentration at the end of the dosing interval. | Cycle 1,Study Day 14: Predose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 14, 16, 20, and 24 hours postdose; Cycle 2,Study Day 42: Predose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 14, 16, 20, and 24 hours postdose | 
| PK Parameter: Ctau of Ethinyl Estradiol | Ctau is defined as the observed drug concentration at the end of the dosing interval. | Cycle 1,Study Day 14: Predose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 14, 16, 20, and 24 hours postdose; Cycle 2,Study Day 42: Predose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 14, 16, 20, and 24 hours postdose | 
| PK Parameter: Ctau of Norgestimate | Ctau is defined as the observed drug concentration at the end of the dosing interval. | Cycle 1,Study Day 14: Predose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 14, 16, 20, and 24 hours postdose;Cycle 2,Study Day 42: Predose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 14, 16, 20, and 24 hours postdose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Who Experienced Treatment-Emergent Adverse Events |  | First dose date up to the last dose date (maximum: 84 days) plus 10 days | 
| Percentage of Participants Who Experienced Laboratory Abnormalities | Treatment-emergent laboratory abnormalities were defined as values that increase at least one toxicity grade from baseline. The most severe graded abnormality from all tests was counted for each participant. Grade 1: mild; Grade 2: moderate;Grade 3: severe or medically significant but not immediately life-threatening; Grade 4: life-threatening consequences. | First dose date up to the last dose date (maximum: 84 days) plus 10 days | 
| PK Parameter: Tmax of Norelgestromin, Norgestrel, Ethinyl Estradiol, and Norgestimate | Tmax is defined as the time (observed time point) of Cmax. | Cycle 1,Study Day 14: Predose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 14, 16, 20, and 24 hours postdose; Cycle 2,Study Day 42: Predose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 14, 16, 20, and 24 hours postdose | 
| PK Parameter: Tlast of Norelgestromin, Norgestrel, Ethinyl Estradiol, and Norgestimate | Tlast is defined as the time (observed time point) of Clast. | Cycle 1,Study Day 14: Predose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 14, 16, 20, and 24 hours postdose; Cycle 2,Study Day 42: Predose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 14, 16, 20, and 24 hours postdose | 
| PK Parameter: λz of Norelgestromin, Norgestrel, Ethinyl Estradiol, and Norgestimate | λz is defined as the terminal elimination rate constant, estimated by linear regression of the terminal elimination phase of the log plasma concentration of drug versus time curve of the drug. | Cycle 1,Study Day 14: Predose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 14, 16, 20, and 24 hours postdose; Cycle 2,Study Day 42:Predose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 14, 16, 20, and 24 hours postdose | 
| PK Parameter: t1/2 of Norelgestromin, Norgestrel, Ethinyl Estradiol, and Norgestimate | t1/2 is defined as the estimate of the terminal elimination half-life of the drug. | Cycle 1,Study Day 14: Predose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 14, 16, 20, and 24 hours postdose; Cycle 2,Study Day 42: Predose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 14, 16, 20, and 24 hours postdose | 
| PK Parameter: CLss/F Ethinyl Estradiol, and Norgestimate | CLss/F is defined as the apparent steady state oral clearance following administration of the drug. | \Cycle 1,Study Day 14: Predose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 14, 16, 20, and 24 hours postdose; Cycle 2,Study Day 42: Predose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 14, 16, 20, and 24 hours postdose | 
| PK Parameter: Cmax of Sofosbuvir (SOF), SOF Metabolites (GS-566500 and GS-331007), Velpatasvir (VEL), and Voxilaprevir (VOX) | Cmax is defined as the maximum concentration of drug. | Cycle 2, Study Day 42: Predose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 14, 16, 20, and 24 hours postdose | 
| PK Parameter: Tmax of SOF, SOF Metabolites (GS-566500 and GS-331007), VEL, and VOX | Tmax is defined as the time (observed time point) of Cmax. | Cycle 2, Study Day 42: Predose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 14, 16, 20, and 24 hours postdose | 
| PK Parameter: Tlast of SOF, SOF Metabolites (GS-566500 and GS-331007), VEL, and VOX | Tlast is defined as the time (observed time point) of Clast. | Cycle 2, Study Day 42: Predose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 14, 16, 20, and 24 hours postdose | 
| PK Parameter: Ctau of SOF Metabolites (GS-566500 and GS-331007), VEL, and VOX | Ctau is defined as the observed drug concentration at the end of the dosing interval. | Cycle 2, Study Day 42: Predose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 14, 16, 20, and 24 hours postdose | 
| PK Parameter: λz of SOF, SOF Metabolites (GS-566500 and GS-331007), VEL, and VOX | λz is defined as the terminal elimination rate constant, estimated by linear regression of the terminal elimination phase of the log plasma concentration of drug versus time curve of the drug. | Cycle 2, Study Day 42: Predose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 14, 16, 20, and 24 hours postdose | 
| PK Parameter: AUCtau of SOF, SOF Metabolites (GS-566500 and GS-331007), VEL, and VOX | AUCtau is defined as concentration of drug over time (the area under the concentration verses time curve over the dosing interval). | Cycle 2, Study Day 42: Predose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 14, 16, 20, and 24 hours postdose | 
| PK Parameter: CLss/F of SOF, VEL, and VOX | CLss/F is defined as the apparent steady state oral clearance following administration of the drug. | Cycle 2, Study Day 42: Predose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 14, 16, 20, and 24 hours postdose | 
| PK Parameter: t1/2 of SOF, SOF Metabolites (GS-566500 and GS-331007), VEL, and VOX | t1/2 is defined as the estimate of the terminal elimination half-life of the drug. | Cycle 2, Study Day 42: Predose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 14, 16, 20, and 24 hours postdose |