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

29 de noviembre de 2016 actualizado por: 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.

Descripción general del estudio

Estado

Terminado

Condiciones

Intervención / Tratamiento

Descripción detallada

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.

Tipo de estudio

Intervencionista

Inscripción (Actual)

24

Fase

  • Fase 1

Contactos y Ubicaciones

Esta sección proporciona los datos de contacto de quienes realizan el estudio e información sobre dónde se lleva a cabo este estudio.

Ubicaciones de estudio

    • North Carolina
      • Chapel Hill, North Carolina, Estados Unidos, 27599
        • University of North Carolina at Chapel Hill

Criterios de participación

Los investigadores buscan personas que se ajusten a una determinada descripción, denominada criterio de elegibilidad. Algunos ejemplos de estos criterios son el estado de salud general de una persona o tratamientos previos.

Criterio de elegibilidad

Edades elegibles para estudiar

18 años a 49 años (Adulto)

Acepta Voluntarios Saludables

Géneros elegibles para el estudio

Femenino

Descripción

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 de estudios

Esta sección proporciona detalles del plan de estudio, incluido cómo está diseñado el estudio y qué mide el estudio.

¿Cómo está diseñado el estudio?

Detalles de diseño

  • Propósito principal: Prevención
  • Asignación: No aleatorizado
  • Modelo Intervencionista: Asignación de un solo grupo
  • Enmascaramiento: Ninguno (etiqueta abierta)

Armas e Intervenciones

Grupo de participantes/brazo
Intervención / Tratamiento
Experimental: 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.
Otros nombres:
  • TAF
  • Tenofovir Alafenamide
Experimental: 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.
Otros nombres:
  • TAF
  • Tenofovir Alafenamide
Experimental: 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.
Otros nombres:
  • TAF
  • Tenofovir Alafenamide

¿Qué mide el estudio?

Medidas de resultado primarias

Medida de resultado
Medida Descripción
Periodo de tiempo
Plasma Dose-Proportionality
Periodo de tiempo: 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
Periodo de tiempo: 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
Periodo de tiempo: 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

Medidas de resultado secundarias

Medida de resultado
Medida Descripción
Periodo de tiempo
Intra-subject variability in intracellular deoxyadenosine triphosphate (dATP) in peripheral blood
Periodo de tiempo: 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
Periodo de tiempo: 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
Periodo de tiempo: 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
Periodo de tiempo: 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

Otras medidas de resultado

Medida de resultado
Medida Descripción
Periodo de tiempo
Cervicovaginal Fluid (CVF) Concentration
Periodo de tiempo: 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.

Colaboradores e Investigadores

Aquí es donde encontrará personas y organizaciones involucradas en este estudio.

Colaboradores

Investigadores

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

Publicaciones y enlaces útiles

La persona responsable de ingresar información sobre el estudio proporciona voluntariamente estas publicaciones. Estos pueden ser sobre cualquier cosa relacionada con el estudio.

Fechas de registro del estudio

Estas fechas rastrean el progreso del registro del estudio y los envíos de resultados resumidos a ClinicalTrials.gov. Los registros del estudio y los resultados informados son revisados ​​por la Biblioteca Nacional de Medicina (NLM) para asegurarse de que cumplan con los estándares de control de calidad específicos antes de publicarlos en el sitio web público.

Fechas importantes del estudio

Inicio del estudio

1 de marzo de 2015

Finalización primaria (Actual)

1 de octubre de 2015

Finalización del estudio (Actual)

1 de noviembre de 2016

Fechas de registro del estudio

Enviado por primera vez

14 de enero de 2015

Primero enviado que cumplió con los criterios de control de calidad

2 de febrero de 2015

Publicado por primera vez (Estimar)

6 de febrero de 2015

Actualizaciones de registros de estudio

Última actualización publicada (Estimar)

30 de noviembre de 2016

Última actualización enviada que cumplió con los criterios de control de calidad

29 de noviembre de 2016

Última verificación

1 de noviembre de 2016

Más información

Esta información se obtuvo directamente del sitio web clinicaltrials.gov sin cambios. Si tiene alguna solicitud para cambiar, eliminar o actualizar los detalles de su estudio, comuníquese con register@clinicaltrials.gov. Tan pronto como se implemente un cambio en clinicaltrials.gov, también se actualizará automáticamente en nuestro sitio web. .

Ensayos clínicos sobre GS-7340

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