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Dose Proportionality of TFV-DP After a Single Dose of GS-7340 in Women

29 novembre 2016 mis à jour par: University of North Carolina, Chapel Hill

Dose Proportionality of TFV-DP in Mucosal Tissue, and Endogenous Nucleotide Quantification, After a Single Dose of GS-7340 in Women

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.

Aperçu de l'étude

Statut

Complété

Les conditions

Intervention / Traitement

Description détaillée

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.

Type d'étude

Interventionnel

Inscription (Réel)

24

Phase

  • La phase 1

Contacts et emplacements

Cette section fournit les coordonnées de ceux qui mènent l'étude et des informations sur le lieu où cette étude est menée.

Lieux d'étude

    • North Carolina
      • Chapel Hill, North Carolina, États-Unis, 27599
        • University of North Carolina at Chapel Hill

Critères de participation

Les chercheurs recherchent des personnes qui correspondent à une certaine description, appelée critères d'éligibilité. Certains exemples de ces critères sont l'état de santé général d'une personne ou des traitements antérieurs.

Critère d'éligibilité

Âges éligibles pour étudier

18 ans à 49 ans (Adulte)

Accepte les volontaires sains

Oui

Sexes éligibles pour l'étude

Femelle

La description

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.

Plan d'étude

Cette section fournit des détails sur le plan d'étude, y compris la façon dont l'étude est conçue et ce que l'étude mesure.

Comment l'étude est-elle conçue ?

Détails de conception

  • Objectif principal: La prévention
  • Répartition: Non randomisé
  • Modèle interventionnel: Affectation à un seul groupe
  • Masquage: Aucun (étiquette ouverte)

Armes et Interventions

Groupe de participants / Bras
Intervention / Traitement
Expérimental: 1. GS-7340 25mg
The first 8 women on study will be assigned to take a single dose of 25mg TAF (1 tablet) orally.
Medication is supplied in 10 or 25mg tablets, so subjects will receive either 1/2 or one tablet in a single dose.
Autres noms:
  • TAF
  • Tenofovir Alafenamide
Expérimental: 2. GS-7340 10mg
The 2nd group of 8 women will be sequentially assigned to take a single dose of 10mg TAF (1 tablet) orally.
Medication is supplied in 10 or 25mg tablets, so subjects will receive either 1/2 or one tablet in a single dose.
Autres noms:
  • TAF
  • Tenofovir Alafenamide
Expérimental: 3. GS-7340 5mg
The final 8 women on study will be sequentially assigned to take a single dose of 5mg TAF (1/2 tablet) orally.
Medication is supplied in 10 or 25mg tablets, so subjects will receive either 1/2 or one tablet in a single dose.
Autres noms:
  • TAF
  • Tenofovir Alafenamide

Que mesure l'étude ?

Principaux critères de jugement

Mesure des résultats
Description de la mesure
Délai
Plasma Dose-Proportionality
Délai: Pre-dose and 1, 3, 6, 12, 24 hours, and 3, 7, 10, and 14 days following single dose
To characterize the dose-proportionality in the distribution of TAF and TFV in the plasma of healthy female subjects following a single oral dose of GS-7340 at 5mg, 10mg, and 25mg. This will be used to develop a predictive pharmacokinetic model for TAF which will allow for TFVdp exposure predictions given a specific dose and dosing interval.
Pre-dose and 1, 3, 6, 12, 24 hours, and 3, 7, 10, and 14 days following single dose
Tissue Dose-Proportionality
Délai: At 3, 6, 12 and 24 hours and 3, 7, 10 and 14 days following single dose
To characterize the dose-proportionality in the distribution of TAF and TFV in mucosal tissues, and TFV-DP in mucosal tissues of healthy female subjects following a single oral dose of GS-7340 at 5mg, 10mg, and 25mg. This will be used to develop a predictive pharmacokinetic model for TAF which will allow for TFVdp exposure predictions given a specific dose and dosing interval.
At 3, 6, 12 and 24 hours and 3, 7, 10 and 14 days following single dose
PBMC Dose-Proportionality
Délai: Pre-dose and 3, 6, 12, 24 hours and 3, 7, 10, and 14 days following single dose
To characterize the dose-proportionality in the distribution of TFV-DP in PBMCs of healthy female subjects following a single oral dose of GS-7340 at 5mg, 10mg, and 25mg. This will be used to develop a predictive pharmacokinetic model for TAF which will allow for TFVdp exposure predictions given a specific dose and dosing interval.
Pre-dose and 3, 6, 12, 24 hours and 3, 7, 10, and 14 days following single dose

Mesures de résultats secondaires

Mesure des résultats
Description de la mesure
Délai
Intra-subject variability in intracellular deoxyadenosine triphosphate (dATP) in peripheral blood
Délai: Pre-dose and 3, 6, 12, 24 hours and 3, 7, 10, and 14 days following single dose
To determine intra-subject variability in intracellular dATP in PBMCs and ratios of TFVdp:dATP.
Pre-dose and 3, 6, 12, 24 hours and 3, 7, 10, and 14 days following single dose
Inter-subject variability in intracellular deoxyadenosine triphosphate (dATP) in peripheral blood
Délai: Pre-dose and 3, 6, 12, 24 hours and 3, 7, 10, and 14 days following single dose
To determine inter-subject variability in intracellular dATP in PBMCs and ratios of TFVdp:dATP.
Pre-dose and 3, 6, 12, 24 hours and 3, 7, 10, and 14 days following single dose
Intra-subject variability in intracellular deoxyadenosine triphosphate (dATP) in mucosal tissues
Délai: At 3, 6, 12 and 24 hours and 3, 7, 10 and 14 days following single dose
To determine intra-subject variability in intracellular dATP in cervical, vaginal, and rectal tissues and ratios of TFVdp:dATP.
At 3, 6, 12 and 24 hours and 3, 7, 10 and 14 days following single dose
Inter-subject variability in intracellular deoxyadenosine triphosphate (dATP) in mucosal tissues
Délai: At 3, 6, 12 and 24 hours and 3, 7, 10 and 14 days following single dose
To determine inter-subject variability in intracellular dATP in cervical, vaginal, and rectal tissues and ratios of TFVdp:dATP.
At 3, 6, 12 and 24 hours and 3, 7, 10 and 14 days following single dose

Autres mesures de résultats

Mesure des résultats
Description de la mesure
Délai
Cervicovaginal Fluid (CVF) Concentration
Délai: At 1, 3, 6, 12, 24 hours and 3, 7, 10, and 14 days following single dose.
To determine if TFV and TAF concentration in CVF changes in proportion to TFV, TAF, and TFV-DP concentration in cervical and vaginal tissue
At 1, 3, 6, 12, 24 hours and 3, 7, 10, and 14 days following single dose.

Collaborateurs et enquêteurs

C'est ici que vous trouverez les personnes et les organisations impliquées dans cette étude.

Collaborateurs

Les enquêteurs

  • Chercheur principal: Angela DM Kashuba, PharmD, UNC Chapel Hill

Publications et liens utiles

La personne responsable de la saisie des informations sur l'étude fournit volontairement ces publications. Il peut s'agir de tout ce qui concerne l'étude.

Dates d'enregistrement des études

Ces dates suivent la progression des dossiers d'étude et des soumissions de résultats sommaires à ClinicalTrials.gov. Les dossiers d'étude et les résultats rapportés sont examinés par la Bibliothèque nationale de médecine (NLM) pour s'assurer qu'ils répondent à des normes de contrôle de qualité spécifiques avant d'être publiés sur le site Web public.

Dates principales de l'étude

Début de l'étude

1 mars 2015

Achèvement primaire (Réel)

1 octobre 2015

Achèvement de l'étude (Réel)

1 novembre 2016

Dates d'inscription aux études

Première soumission

14 janvier 2015

Première soumission répondant aux critères de contrôle qualité

2 février 2015

Première publication (Estimation)

6 février 2015

Mises à jour des dossiers d'étude

Dernière mise à jour publiée (Estimation)

30 novembre 2016

Dernière mise à jour soumise répondant aux critères de contrôle qualité

29 novembre 2016

Dernière vérification

1 novembre 2016

Plus d'information

Ces informations ont été extraites directement du site Web clinicaltrials.gov sans aucune modification. Si vous avez des demandes de modification, de suppression ou de mise à jour des détails de votre étude, veuillez contacter register@clinicaltrials.gov. Dès qu'un changement est mis en œuvre sur clinicaltrials.gov, il sera également mis à jour automatiquement sur notre site Web .

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