Clinical trial NCT06087913: Safety and PK Multi-dose Study of TAF/EVG Vaginal Insert
Official title: A Phase I Randomized, Placebo-controlled, Double-blind Study to Assess Safety, Pharmacokinetics, and Modeled Pharmacodynamics of a Vaginal Insert Containing Tenofovir Alafenamide and Elvitegravir
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
Conditions: Safety Issues
Keywords: vaginal insert
HIV
pre-exposure prophylaxis (PrEP)
Lead sponsor: Eastern Virginia Medical School
Sponsor class: OTHER
Collaborators: name: CONRAD
name: University of Pittsburgh
name: Centre for the AIDS Programme of Research in South Africa
name: Kenya Medical Research Institute
name: United States Agency for International Development (USAID)
First posted: 2023-10-18
Enrollment: 60
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 50
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Randomized, Placebo-Controlled, Double-Blind
Primary purpose: OTHER

Brief summary: MATRIX-001 will examine the safety, PK, modeled PD, and acceptability of inserts containing the combination of TAF and EVG applied vaginally, daily for 3 days, then every other day for 14 days. The inserts are ultimately intended to be the basis of an event-driven, on-demand method for prevention of HIV and HSV sexual infection.

Detailed description: Participants will be enrolled across three sites, in USA, Kenya, and South Africa, approximately 20 per site. Participants will be randomized (1:1) to receive either a placebo or TAF/EVG vaginal insert as well as be randomized (1:1:1) to 3 different tissue sampling time points post-treatment (24hr, 48hr and 72hr after the last dose). Participants will be asked to complete 8 study visits with clinical and behavioral evaluations, and a subset will complete an in-depth interview to assess acceptability of vaginal insert use.

Eligibility criteria: Inclusion Criteria:

1. Aged 18 to 50 years (inclusive) at Screening.
2. Assigned female sex at birth.
3. Able and willing to provide written informed consent to be screened for and enrolled in MATRIX-001 in one of the study languages (as specified in site SOP).
4. General good health (by volunteer history) without any evidence of clinically significant systemic disease (as determined by Investigator of Record \[IoR\] or designee).
5. Has had vaginal sex and has an intact uterus and cervix.
6. Has a regular and/or predictable bleeding pattern based on the opinion of the investigator, or is oligomenorrheic or amenorrhoeic.
7. HIV-uninfected based on testing performed at Screening and Enrollment (per protocol algorithms in Appendix II).
8. Negative urine pregnancy test at Screening and Enrollment.
9. Protected from pregnancy by an effective contraceptive method as confirmed by site SOP; effective methods include:

   * minimum of 3 months of use of a combined hormonal contraceptive method (except vaginal rings)
   * minimum of 6 months of use of a progestin only contraceptive method or copper IUD
   * Sterilization of participant or partner
   * Correct and consistent condom use (for US site only)
   * Abstinence from penile-vaginal intercourse (for US site only)
10. Participants over the age of 21 (inclusive) must have documentation of a Grade 0 Pap smear within the past 3 years prior to Enrollment, per the Female Genital Grading Table for Use in Microbicide Studies Addendum 1 (Dated November 2007) to the DAIDS Table for Grading Adult and Pediatric Adverse Events, Corrected Version 2.1, July 2017, or Grade 1 Pap smear at Screening with no treatment required.
11. Normal cervicovaginal mucosa (as defined in MATRIX-001 Study Specific Procedures \[SSP\] manual).
12. Willing and able to comply with protocol requirements, including abstaining from vaginal activity and product use at specified times.
13. Per participant report, if in a relationship, must be in a mutually monogamous relationship with a partner who is not known to be HIV positive or to currently have an STI.

Exclusion Criteria:

1. Per participant report, intends to do any of the following during the study participation period:

   * Become pregnant.
   * Breastfeed.
   * Relocate away from the study site.
   * Travel away from the study site for a time period that would interfere with product resupply and/or study participation.
2. Currently breastfeeding.
3. Positive HIV test at Screening or Enrollment.
4. History of sensitivity/allergy to any component of the study product, topical anesthetic, cellulose based thrombogenic material, or to both silver nitrate and Monsel's solution.
5. Positive test for Trichomonas vaginalis (TV), Neisseria gonorrhea (GC), Chlamydia trachomatis (CT), Treponema pallidum (Syphilis), or Hepatitis B surface antigen (HBsAg) at Screening or (per participant report) treated for GC, CT, TV, HBsAg or syphilis in the past 12 months.
6. Chronic or acute vulvar, vaginal or cervical symptoms (pain, irritation, spotting/bleeding other than what would be expected from contraceptive use, discharge, etc.).
7. Known bleeding/clotting disorder, including use of anti-coagulation.
8. Need for continued use of any contraindicated concomitant medications (as listed in Appendix III).
9. Participation in any other trial with use of an investigational drug/device within the last 30 days or planned participation in any other investigational trial with use of a drug/device during the study.
10. Participants who previously received an HIV vaccine or HIV broadly neutralizing antibody (bNAb) are not eligible. Individuals may be eligible if they participated in an HIV vaccine or bNAb study but have documentation that they did not receive active product (e.g., placebo recipients).
11. Prior use of PEP or oral PrEP (including FTC/TDF) in the past 4 weeks or any prior use of long-acting systemic PrEP (including cabotegravir or islatravir).
12. Grade 2 or higher pelvic finding or laboratory abnormality, per the DAIDS Table for Grading Adult and Pediatric Adverse Events, Corrected Version 2.1, July 2017 and/or Addenda 1 (Female Genital Grading Tables for Use in Microbicide Studies \[Dated November 2007\]) or clinically significant laboratory abnormality as determined by the clinician.
13. Use of any of the following in the past 12 months: stimulants (cocaine \[including crack\], methamphetamine, or non-physician prescribed pharmaceutical-grade stimulants), or inhaled nitrates, or illicit injection drug use of any kind.
14. Has any other condition that, based on the opinion of the IoR or designee, would preclude provision of informed consent, make participation in the study unsafe, complicate interpretation of study outcome data, or otherwise interfere with achieving the study objectives.

Primary outcomes:
measure: Number and Severity of Adverse Events
timeFrame: Randomization through study completion, an average of 3 months
Secondary outcomes:
measure: Pharmacokinetics (PK) in cervicovaginal fluid (CVF)
timeFrame: through completion of study, an average of 3 months
measure: Pharmacokinetics (PK) in plasma
timeFrame: through completion of study, an average of 3 months
measure: Pharmacokinetics (PK) in cervicovaginal tissue
timeFrame: through completion of study, an average of 3 months
measure: Modeled in vitro Pharmacodynamics (PD) for HIV
timeFrame: Enrollment through study completion, an average of 3 months
measure: Modeled in vitro Pharmacodynamics (PD) for Herpes simplex virus (HSV)
timeFrame: Enrollment through study completion, an average of 3 months
measure: Number of participants who find using the vaginal insert acceptable.
timeFrame: Enrollment through study completion, an average of 3 months
measure: Number of participants with changes to vaginal microbiome
timeFrame: Enrollment through study completion, an average of 3 months
Other outcomes:
measure: Modeled Tissue PD
timeFrame: Enrollment through study completion, an average of 3 months
Locations:
city: Norfolk
country: United States
facility: Eastern Virginia Medical School Clinical Research Clinic (EVMS CRC)
state: Virginia
city: Thika
country: Kenya
facility: Kenya Medical Research Institute (KEMRI)
city: Durban
country: South Africa
facility: CAPRISA eThekwini Clinical Research Site
Study officials:
affiliation: Centre for the AIDS Programme of Research in South Africa
name: Leila Mansoor, BPharm, PhD
role: STUDY_CHAIR
affiliation: Kenya Medical Research Institute
name: Nelly Mugo, MBChB
role: STUDY_CHAIR
References:
citation: Dobard CW, Peet MM, Nishiura K, Holder A, Dinh C, Mitchell J, Khalil G, Pan Y, Singh ON, McCormick TJ, Agrahari V, Gupta P, Jonnalagadda S, Heneine W, Clark MR, Garcia-Lerma JG, Doncel GF. Single dose topical inserts containing tenofovir alafenamide fumarate and elvitegravir provide pre- and post-exposure protection against vaginal SHIV infection in macaques. EBioMedicine. 2022 Dec;86:104361. doi: 10.1016/j.ebiom.2022.104361. Epub 2022 Nov 21.
citation: Thurman AR, Ouattara LA, Yousefieh N, Anderson PL, Bushman LR, Fang X, Hanif H, Clark M, Singh O, Doncel GF. A phase I study to assess safety, pharmacokinetics, and pharmacodynamics of a vaginal insert containing tenofovir alafenamide and elvitegravir. Front Cell Infect Microbiol. 2023 Apr 19;13:1130101. doi: 10.3389/fcimb.2023.1130101. eCollection 2023.