Safety and Pharmacokinetic Trial in Healthy HIV-Negative Women to Assess the Delivery of Dapivirine From a Vaginal Ring

A Double-Blind, Randomised, Placebo-Controlled Safety and Pharmacokinetic Trial in Healthy HIV-Negative Women to Assess Delivery of Dapivirine From the Matrix Vaginal Ring Containing 25 MG of Dapivirine

The proposed study is a single center, double-blind placebo-controlled trial to assess the safety and tolerability of the dapivirine ring as compared to a placebo ring when inserted for 28 days in 16 healthy, HIV-negative women.

The objective of this trial was to evaluate the feasibility of using a platinum-catalyzed matrix vaginal ring, containing 25 mg of dapivirine, to deliver investigational product for 28 continuous days. The specific objectives were to:

1. Assess the safety and tolerability of the vaginal ring containing dapivirine, when used continuously for 28 days, compared to a placebo ring
2. Assess dapivirine concentrations in plasma before, during and after 28 days' use of a silicone elastomer matrix vaginal ring containing dapivirine
3. Assess dapivirine concentrations in vaginal fluids before, during and after 28 days' use of a silicone elastomer matrix vaginal ring containing dapivirine. Safety was evaluated from clinical evaluations, clinical laboratory test results and adverse events (AEs). The pharmacokinetic (PK) evaluation was made based on systemic absorption from plasma concentrations and local disposition from vaginal fluid concentrations.

Inclusion Criteria:

• were females between 18 and 40 years of age, inclusive
• were willing and able to give written, informed consent
• were available for all visits and consented to follow all procedures scheduled for the trial
• were healthy, based on medical history, vital signs, physical examination, urinalysis (dipstick and microscopy), laboratory evaluations for genital infections (gonorrhea, chlamydia and trichomonas), and laboratory evaluations for hematology and biochemistry
• were HIV-negative, as determined by an HIV test at screening
• were willing to abstain from sexual activity for the duration of the period of ring use
• were on a stable form of contraception, defined as a stable oral contraceptive regimen for at least two months prior to enrollment; OR a transdermal contraceptive patch for at least three months prior to enrollment; OR long-acting progestins for at least six months prior to enrollment; OR had an intra-uterine device (IUD) inserted (with no vaginal or gynecological complaints associated with its use) at least three months prior to enrollment; OR had undergone surgical sterilization at least three months prior to enrollment; AND were willing to use oral contraceptives, if necessary, to avoid menstruation while taking part in this trial
• were asymptomatic for genital infections at the time of enrollment, and the cervix and vagina appeared normal upon pelvic examination and colposcopy, as determined by the investigator
• were willing to refrain from the use of vaginal products or objects including, but not limited to, tampons, cotton wool, rags, diaphragms, cervical caps (or any other vaginal barrier method), douches, lubricants, vibrators/dildos, non-trial vaginal rings and drying agents for 14 days prior to enrollment and for the duration of the trial
• were willing to refrain from participation in any other research trial for the duration of this trial
• were willing to provide adequate locator information for trial retention purposes and were reachable per local standard procedures (e.g. by home visit or telephone, or via family or close neighbor contacts (confidentiality was to be maintained))
• were hepatitis B and C negative at the time of screening.

Exclusion Criteria:

• had a history of anaphylaxis or severe allergy resulting in angioedema, or a history of sensitivity/allergy to latex or silicone
• were pregnant or breast-feeding, or had their last pregnancy outcome within three months prior to screening
• were participating in any other clinical research trial involving investigational or marketed products at the time of this trial or within two months prior to screening
• had a history or diagnosis of and/or treatment for a sexually transmitted disease within the previous three months
• had a history of genital tract surgery within the previous two months
• had a current diagnosis of sexually transmitted infections (STIs) (gonorrhea, chlamydia and/or trichomonas)
• had current vulvar or vaginal symptoms/abnormalities that could influence the trial results
• had a history of significant urogenital or uterine prolapse, undiagnosed vaginal bleeding or urethral obstruction, incontinence or urge incontinence
• had symptomatic genital herpes simplex virus (HSV) infection or a history of genital herpetic infection
• had current non-iatrogenic pelvic/colposcopic examination findings involving deep epithelial disruption
• had any Grade 2, 3 or 4 hematology, biochemistry or urinalysis laboratory abnormality at baseline (screening), according to the Division of Acquired Immunodeficiency Syndrome (DAIDS) Table for Grading Adverse Events
• had a Pap test result at screening that required cryotherapy, biopsy, treatment (other than for infection) or further evaluation; this included any findings of atypical squamous cells of undetermined significance (ASCUS)
• had any condition(s) that, in the opinion of the investigator, could interfere with adherence to trial requirements or evaluation of the trial objectives.