Clinical trial NCT02357602: Dose Proportionality of TFV-DP After a Single Dose of GS-7340 in Women
Official title: Dose Proportionality of TFV-DP in Mucosal Tissue, and Endogenous Nucleotide Quantification, After a Single Dose of GS-7340 in Women
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Healthy
Keywords: Participants
HIV-1 negative
Lead sponsor: University of North Carolina, Chapel Hill
Sponsor class: OTHER
Collaborators: name: Gilead Sciences
First posted: 2015-02-06
Enrollment: 24
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 49
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: PREVENTION

Brief summary: Purpose:

The purpose of this study is to characterize the dose-proportionality in the distribution of tenofovir alafenamide (TAF) and tenofovir (TFV) in plasma and mucosal tissues, and TFV-diphosphate (TFV-DP) in peripheral blood mononuclear cells (PBMCs) and mucosal tissues of healthy female subjects following a single oral dose of GS-7430 at 5mg, 10mg, and 25mg.

Detailed description: Participants:

This study will consist of approximately 24 premenopausal healthy volunteer women between 18-49 years of age with an intact cervix, uterus, and gastrointestinal tract. Women will be enrolled in the study within 42 days of screening depending on the timing of their menstrual cycle in comparison to the screening visit, and then will be on study for 14 days, with follow-up 1-14 days after the end of study sampling. All study visits will be conducted in the North Carolina Translational and Clinical Sciences (NCTraCS) Clinical Translational Research Center (CTRC) at the University of North Carolina at Chapel Hill.

Procedures (methods):This is a Phase 1, single center, open-label, dose-ranging pharmacokinetic study of TFV and TFV-DP mucosal tissue concentrations measured after a single dose of GS-7340. Each arm is divided into three dosing groups: 5, 10, or 25mg. Participants will take a single dose of study drug within 7-14 days following the end of the subjects' menstrual period. Participants will be sequentially assigned to one of the three TAF doses and four biopsy schedules. Two women from each of the dosing groups will be assigned to one of four biopsy schedules for a total of 8 women per dosing group. Samples of blood plasma, cervicovaginal fluid (CVF), cervical tissue, vaginal tissue, and rectal tissue will be collected from participants at varying time points over the 14 days post-dose. Subjects will return to clinic within 14 days after the last sampling to complete a follow-up safety visit.

Eligibility criteria: Inclusion Criteria

1. Healthy pre-menopausal female subjects between the ages of 18 and 49 years, inclusive on the date of screening, with an intact gastrointestinal tract, uterus, and cervix.
2. All subjects must have an estimated calculated creatinine clearance (eCcr) of at least 80 mL/min
3. All subjects must have negative pregnancy tests, and be using an acceptable form of birth control
4. Body Mass Index (BMI) of approximately 18 to 34 kg/m²; and a total body weight \> 45 kg (99 lbs).
5. Evidence of a personally signed and dated informed consent document indicating that the subject has been informed of all pertinent aspects of the trial.
6. Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other trial procedures.
7. Subject must have documentation of a normal pap smear within 36 months of the screening visit, no procedures for abnormal cervical/vaginal pathology in the last six months, at least one prior gynecological visit as part of subject's routine medical history.
8. Subject must be willing to abstain from sexual intercourse, douching, and all intravaginal and intrarectal objects and products for at least 72 hours prior to Day 1 until study completion.
9. Subject must be HIV-1 and Hepatitis B surface antigen negative
10. Subject must not be actively involved in the conception process.
11. Subject must be able to swallow pills and have no allergies to any component of the study products

Exclusion Criteria

1. Evidence or history of clinically significant hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurologic, or allergic disease (including documented drug allergies, but excluding untreated, asymptomatic, seasonal allergies at time of dosing).
2. Subjects with a history of hysterectomy
3. Subjects who are pregnant, possibly pregnant or lactating
4. Subjects with a presence of vaginal discharge or genital bleeding at screening
5. History of febrile illness within five days prior to first dose.
6. Any condition possibly affecting drug absorption (eg, gastrectomy).
7. A positive urine drug screen.
8. A positive result for HIV, Hepatitis B or C
9. An untreated-positive test for syphilis, gonorrhea, Chlamydia, or trichomonas at screening, or symptomatic bacterial vaginosis.
10. Any laboratory chemistry or hematology result Grade 2 or greater according to the Division of Acquired Immunodeficiency Syndrome (DAIDS) Laboratory Grading Tables
11. Treatment with an investigational drug within 4 months preceding the first dose of trial medication.
12. History of regular alcohol consumption exceeding study limits
13. Participation in a clinical trial involving vaginal or rectal biopsies within 6 months preceding the first dose of trial medication.
14. Use of prescription or nonprescription drugs, vitamins, and dietary supplements within 7 days or 5 half-lives (whichever is longer) prior to the first dose of trial medication and unable to avoid use during the study period until after the last sample is collected.
15. Blood donation of approximately 1 pint (500 mL) within 56 days prior to dosing.
16. History of sensitivity to heparin or heparin-induced thrombocytopenia.
17. Allergy to lidocaine or Monsel's solution.
18. Allergy to latex.
19. Abnormal pap smear in the past 36 months
20. Any degree of ectopy or abnormality evident during the pelvic exam at screening.
21. Any condition which, in the opinion of the investigator, is likely to interfere with follow-up or ability to take the study medication appropriately.
22. Unwilling or unable to comply with the dietary and concomitant drug restrictions in regard to study drug administration as outlined in the study procedures and prohibited medications sections.

Primary outcomes:
measure: Plasma Dose-Proportionality
timeFrame: Pre-dose and 1, 3, 6, 12, 24 hours, and 3, 7, 10, and 14 days following single dose
measure: Tissue Dose-Proportionality
timeFrame: At 3, 6, 12 and 24 hours and 3, 7, 10 and 14 days following single dose
measure: PBMC Dose-Proportionality
timeFrame: Pre-dose and 3, 6, 12, 24 hours and 3, 7, 10, and 14 days following single dose
Secondary outcomes:
measure: Intra-subject variability in intracellular deoxyadenosine triphosphate (dATP) in peripheral blood
timeFrame: Pre-dose and 3, 6, 12, 24 hours and 3, 7, 10, and 14 days following single dose
measure: Inter-subject variability in intracellular deoxyadenosine triphosphate (dATP) in peripheral blood
timeFrame: Pre-dose and 3, 6, 12, 24 hours and 3, 7, 10, and 14 days following single dose
measure: Intra-subject variability in intracellular deoxyadenosine triphosphate (dATP) in mucosal tissues
timeFrame: At 3, 6, 12 and 24 hours and 3, 7, 10 and 14 days following single dose
measure: Inter-subject variability in intracellular deoxyadenosine triphosphate (dATP) in mucosal tissues
timeFrame: At 3, 6, 12 and 24 hours and 3, 7, 10 and 14 days following single dose
Other outcomes:
measure: Cervicovaginal Fluid (CVF) Concentration
timeFrame: At 1, 3, 6, 12, 24 hours and 3, 7, 10, and 14 days following single dose.
Locations:
city: Chapel Hill
country: United States
facility: University of North Carolina at Chapel Hill
state: North Carolina
Study officials:
affiliation: UNC Chapel Hill
name: Angela DM Kashuba, PharmD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Cottrell ML, Garrett KL, Prince HMA, Sykes C, Schauer A, Emerson CW, Peery A, Rooney JF, McCallister S, Gay C, Kashuba ADM. Single-dose pharmacokinetics of tenofovir alafenamide and its active metabolite in the mucosal tissues. J Antimicrob Chemother. 2017 Jun 1;72(6):1731-1740. doi: 10.1093/jac/dkx064.