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

• ClinicalTrials.gov Identifier: NCT02533427
• Recruitment Status: Completed
• First Posted: August 26, 2015
• Results First Posted: September 2, 2020
• Last Update Posted: September 2, 2020
• Sponsor: Gilead Sciences
• Information provided by (Responsible Party): Gilead Sciences

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
HCV Infection	Drug: SOF/VEL/VOX; Drug: VOX; Drug: Norgestimate/ethinyl estradiol	Phase 1

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 15 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: October 29, 2015
• Actual Primary Completion Date: March 18, 2016
• Actual Study Completion Date: March 18, 2016

Arms and Interventions

Arm

Intervention/treatment

Experimental: SOF/VEL/VOX + VOX; 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; 400/100/100 mg FDC tablet administered orally once daily; Other Name: Epclusa®; Drug: VOX; 100 mg tablet administered orally once daily; Other Name: GS-9857; Drug: Norgestimate/ethinyl estradiol; 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; Other Name: Ortho-Tri-Cyclen® Lo

Outcome Measures

Primary Outcome Measures :

1. Pharmacokinetic (PK) Parameter: AUCtau of Norelgestromin [ Time Frame: 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 ]
   AUCtau is defined as concentration of drug over time (the area under the concentration verses time curve over the dosing interval).
2. PK Parameter: AUCtau of Norgestrel [ Time Frame: 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 ]
   AUCtau is defined as concentration of drug over time (the area under the concentration verses time curve over the dosing interval).
3. PK Parameter: AUCtau of Ethinyl Estradiol [ Time Frame: 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 ]
   AUCtau is defined as concentration of drug over time (the area under the concentration verses time curve over the dosing interval).
4. Pharmacokinetic (PK) Parameter: AUCtau of Norgestimate [ Time Frame: 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 ]
   AUCtau is defined as concentration of drug over time (the area under the concentration verses time curve over the dosing interval).
5. PK Parameter: Cmax of Norelgestromin [ Time Frame: 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 ]
   Cmax is defined as the maximum concentration of drug.
6. PK Parameter: Cmax of Norgestrel [ Time Frame: 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 ]
   Cmax is defined as the maximum concentration of drug.
7. PK Parameter: Cmax of Ethinyl Estradiol [ Time Frame: 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 ]
   Cmax is defined as the maximum concentration of drug.
8. PK Parameter: Cmax of Norgestimate [ Time Frame: 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 ]
   Cmax is defined as the maximum concentration of drug.
9. PK Parameter: Ctau of Norelgestromin [ Time Frame: 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 ]
   Ctau is defined as the observed drug concentration at the end of the dosing interval.
10. PK Parameter: Ctau of Norgestrel [ Time Frame: 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 ]
    Ctau is defined as the observed drug concentration at the end of the dosing interval.
11. PK Parameter: Ctau of Ethinyl Estradiol [ Time Frame: 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 ]
    Ctau is defined as the observed drug concentration at the end of the dosing interval.
12. PK Parameter: Ctau of Norgestimate [ Time Frame: 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 ]
    Ctau is defined as the observed drug concentration at the end of the dosing interval.

Secondary Outcome Measures :

1. Percentage of Participants Who Experienced Treatment-Emergent Adverse Events [ Time Frame: First dose date up to the last dose date (maximum: 84 days) plus 10 days ]
2. Percentage of Participants Who Experienced Laboratory Abnormalities [ Time Frame: First dose date up to the last dose date (maximum: 84 days) plus 10 days ]
   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.
3. PK Parameter: Tmax of Norelgestromin, Norgestrel, Ethinyl Estradiol, and Norgestimate [ Time Frame: 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 ]
   Tmax is defined as the time (observed time point) of Cmax.
4. PK Parameter: Tlast of Norelgestromin, Norgestrel, Ethinyl Estradiol, and Norgestimate [ Time Frame: 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 ]
   Tlast is defined as the time (observed time point) of Clast.
5. PK Parameter: λz of Norelgestromin, Norgestrel, Ethinyl Estradiol, and Norgestimate [ Time Frame: 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 ]
   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.
6. PK Parameter: t1/2 of Norelgestromin, Norgestrel, Ethinyl Estradiol, and Norgestimate [ Time Frame: 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 ]
   t1/2 is defined as the estimate of the terminal elimination half-life of the drug.
7. PK Parameter: CLss/F Ethinyl Estradiol, and Norgestimate [ Time Frame: \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 ]
   CLss/F is defined as the apparent steady state oral clearance following administration of the drug.
8. PK Parameter: Cmax of Sofosbuvir (SOF), SOF Metabolites (GS-566500 and GS-331007), Velpatasvir (VEL), and Voxilaprevir (VOX) [ Time Frame: 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 ]
   Cmax is defined as the maximum concentration of drug.
9. PK Parameter: Tmax of SOF, SOF Metabolites (GS-566500 and GS-331007), VEL, and VOX [ Time Frame: 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 ]
   Tmax is defined as the time (observed time point) of Cmax.
10. PK Parameter: Tlast of SOF, SOF Metabolites (GS-566500 and GS-331007), VEL, and VOX [ Time Frame: 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 ]
    Tlast is defined as the time (observed time point) of Clast.
11. PK Parameter: Ctau of SOF Metabolites (GS-566500 and GS-331007), VEL, and VOX [ Time Frame: 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 ]
    Ctau is defined as the observed drug concentration at the end of the dosing interval.
12. PK Parameter: λz of SOF, SOF Metabolites (GS-566500 and GS-331007), VEL, and VOX [ Time Frame: 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 ]
    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.
13. PK Parameter: AUCtau of SOF, SOF Metabolites (GS-566500 and GS-331007), VEL, and VOX [ Time Frame: 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 ]
    AUCtau is defined as concentration of drug over time (the area under the concentration verses time curve over the dosing interval).
14. PK Parameter: CLss/F of SOF, VEL, and VOX [ Time Frame: 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 ]
    CLss/F is defined as the apparent steady state oral clearance following administration of the drug.
15. PK Parameter: t1/2 of SOF, SOF Metabolites (GS-566500 and GS-331007), VEL, and VOX [ Time Frame: 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 ]
    t1/2 is defined as the estimate of the terminal elimination half-life of the drug.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 45 Years (Adult)
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: Yes

Criteria

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

Contacts and Locations

Locations

New Zealand

Christchurch, New Zealand

Sponsors and Collaborators

Gilead Sciences

Investigators

• Study Director: Gilead Study Director; Gilead Sciences

More Information

• Responsible Party: Gilead Sciences
• ClinicalTrials.gov Identifier: NCT02533427
• Other Study ID Numbers: GS-US-367-1909
• First Posted: August 26, 2015
• Results First Posted: September 2, 2020
• Last Update Posted: September 2, 2020
• Last Verified: August 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: Qualified external researchers may request IPD for this study after study completion. For more information, please visit our website at https://www.gilead.com/science-and-medicine/research/clinical-trials-transparency-and-data-sharing-policy
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP)
• Time Frame: 18 months after study completion
• Access Criteria: A secured external environment with username, password, and RSA code.
• URL: https://www.gilead.com/science-and-medicine/research/clinical-trials-transparency-and-data-sharing-policy

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Hepatitis C; Blood-Borne Infections; Communicable Diseases; Infections; Hepatitis, Viral, Human; Virus Diseases; Flaviviridae Infections; RNA Virus Infections; Hepatitis; Liver Diseases; Digestive System Diseases; Ethinyl Estradiol; Norgestimate; Norgestimate, ethinyl estradiol drug combination; Estradiol; Estrogens; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Physiological Effects of Drugs; Contraceptive Agents, Hormonal; Contraceptive Agents; Reproductive Control Agents; Contraceptive Agents, Female; Contraceptives, Oral, Hormonal; Contraceptives, Oral; Contraceptives, Oral, Synthetic; Contraceptives, Oral, Combined