A Phase I Study to Assess Safety, Pharmacokinetics, and Pharmacodynamics of a Vaginal Insert Containing Tenofovir Alafenamide and Elvitegravir
Overview
- Phase
- Phase 1
- Intervention
- TAF/EVG Vaginal Insert
- Conditions
- Hiv
- Sponsor
- CONRAD
- Enrollment
- 16
- Locations
- 1
- Primary Endpoint
- Number of participants with adverse events
- Status
- Completed
- Last Updated
- 6 years ago
Overview
Brief Summary
The purpose of this Phase I study is to assess the safety, pharmacokinetics, and pharmacodynamics of a combination vaginal insert containing tenofovir alafenamide (TAF) and elvitegravir (EVG).
This study will be the first-in-human study for a vaginally administered TAF/EVG insert and will evaluate safety, PK and PD after a single dose. It is hypothesized that the combination insert will be safe and well-tolerated by study participants and that the insert will offer an expanded window of preventive activity and a regimen with flexibility and forgiveness.
Detailed Description
This Phase I study aims to complete at least 16 healthy, non-pregnant, HIV-uninfected women aged 18-50 years who are not at risk for pregnancy and are at low risk for sexually transmitted infections (STIs) at one clinical site. The study will examine the safety, PK, PD, disintegration, and acceptability of vaginal inserts containing the combination of tenofovir alafenamide (TAF) and elvitegravir (EVG). Participants will be randomized (1:1) into one of two sample collection time point groups: \[Timepoint group 1: 4 and 48 hours after using the single combination insert\] or \[Timepoint group 2: 24 and 72 hours after using the single combination insert\] There will be 5 scheduled visits: Visit 1 (Screening/Enrollment): Volunteers will be consented and undergo tests and procedures to confirm they are eligible to continue in the study. Visit 2 (Baseline): Once it has been confirmed that participants are eligible and willing to continue, they will be asked to complete a short baseline questionnaire about the insert. Participants will be randomized to Timepoint group 1 or Timepoint group 2 for sample collection and will then undergo baseline sampling \[cervicovaginal (CV) fluid and tissue\]. Visit 3 (Insert use and sampling): Participants will use a single combination insert of TAF/EVG in the clinic. Depending upon timepoint randomization, percentage disintegration of the vaginal inserts will be assessed at either 4 hours or 24 hours, and PK and PD sample collection (plasma, CV fluid, and CV tissue) will occur. Participants will also be asked to complete a short acceptability questionnaire. Visit 4 (Post-Dose Sampling): Participants will undergo sample collection of blood for safety and PK evaluations; and CV fluid and CV tissue for PK at either 48 hours or 72 hours depending upon timepoint randomization. Visit 5 (Post-Dose Sampling): Participants will undergo a PK sample collection (CV fluid) 7 (±2) days post dose. Participants will be asked about adverse events and concomitant medications taken. Participants will then be exited from the study, unless they have symptoms that require follow-up. There will be 5 scheduled visits over approximately 1-3 months.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Age 18 to 50 years, inclusive
- •General good health (by volunteer history and per investigator judgment) without any clinically significant systemic disease (including, but not limited to significant liver disease/hepatitis, gastrointestinal disease, kidney disease, thyroid disease, bone disease, and diabetes) and with an intact uterus and cervix.
- •History of regular menstrual cycles, by volunteer report (for cycling women)
- •History of Pap smears and follow-up consistent with standard clinical practice as outlined in the Study Manual or willing to undergo a Pap smear at Visit 1
- •Able to communicate in spoken and written English
- •Willing to give voluntary consent and sign an informed consent form
- •Willing and able to comply with protocol requirements, including abstaining from vaginal activity and product use at specified times
- •Must be protected from pregnancy by one of the following:
- •Hormonal methods, except vaginal rings and DMPA
- •Copper IUD
Exclusion Criteria
- •Positive pregnancy test or plans to become pregnant during the course of the study
- •Currently breastfeeding or planning to breastfeed during the course of the study
- •History of sensitivity/allergy to any component of the study product, topical anesthetic, or to both silver nitrate and Monsel's solution
- •In the last three months, diagnosed with or treated for any STI (For HSV, ideally no outbreaks in the past year. More than two outbreaks in previous 12 month period is exclusionary.)
- •Positive test for Trichomonas vaginalis (TV), Neisseria gonorrhea (GC), Chlamydia trachomatis (CT), HIV, or Hepatitis B surface antigen (HBsAg)
- •Symptomatic bacterial vaginosis (BV)
- •Chronic or acute vulvar or vaginal symptoms (pain, irritation, spotting/bleeding, discharge, etc.)
- •Known blood disorder, including deep vein thrombosis (DVT) and pulmonary embolism (PE), or those that could lead to prolonged or continuous bleeding with biopsy
- •NSAIDS, systemic corticosteroids (e.g. dexamethasone), Endothelin Receptor Antagonists (e.g bosentan), antibiotics, Anticonvulsants (e.g. carbamazepine, oxcarbazepine, phenobarbital, phenytoin), Antimycobacterials (Rifbutin, Rifampin, Rifapentine) anticoagulants or other drugs known to prolong bleeding and/or clotting, antifungals (i.e ketoconazole), or antivirals or antiretroviral (e.g. acyclovir, valacyclovir, Viread®, Atripla®, Emtriva®, or Complera®), St. John's Wort or drugs that may interact with TAF or EVG as specified in the Vitekta and Vemlidy Investigator Brochure, should not be used during the study.
- •Current or anticipated chronic use of non-steroidal anti-inflammatory drugs (NSAIDs) or acetominophen for the duration of the study.
Arms & Interventions
TAF/EVG vaginal insert
Post-dose sampling at 4 and 48 hours or at 24 and 72 hours, per randomization
Intervention: TAF/EVG Vaginal Insert
Outcomes
Primary Outcomes
Number of participants with adverse events
Time Frame: Changes from baseline up to a maximum of 12 days post-dose
Adverse events for this outcome are those that are product-related urogenital in nature
systemic laboratory assessments
Time Frame: Changes from baseline up to 72 hours post-dose
Number of participants with abnormal serum chemistry
Systemic Laboratory Assessments
Time Frame: Changes from baseline up to 72 hours post-dose
Number of participants with abnormal complete blood count
Drug Concentrations of EVG, TFV, and TAF
Time Frame: From dosing to a maximum of 12 days post-dose
Concentrations of EVG, TFV, and TAF in CV fluid
Number of Participants with Grade 2 or higher treatment-emergent adverse events (TEAEs)
Time Frame: Changes from baseline up to a maximum of 12 days post-dose
TEAEs are defined as adverse events starting or worsening after administration of the study product; Grade is determined by the DAIDS Grading Table
Drug Concentrations of EVG, TFV, TFV-DP, and TAF
Time Frame: From dosing to 72 hours post-dose
Concentrations of EVG, TFV, TFV-DP, TAF in CV tissue
Secondary Outcomes
- Percent (%) inhibition of HIV in vaginal cell assay (Anti-HIV activity)(Changes from baseline to 24 hours post-dose)
- Percent (%) inhibition of HSV in vaginal cell assay (Anti-HSV activity)(Changes from baseline to 24 hours post-dose)
- Number of participant tissue samples demonstrating HIV-1 infectivity(Changes from baseline to 4 hours post-dose)
- Disintegration of insert(At 4 or 24 hours post-dose (per randomized time point))
- Acceptability of insert: questionnaire(At baseline and at 48 or 72 hours post-dose (per randomized time point))