HIV Infections
Conditions
Brief summary
The purpose of this study is to evaluate the safety and pharmacokinetics (PK) of dapivirine gel (0.05%) administered rectally to HIV-1 seronegative adults.
Detailed description
This study will evaluate the safety and pharmacokinetics (PK) of dapivirine gel (0.05%) administered rectally to HIV-1 seronegative adults. Participants will be randomized to receive a single dose of either rectally administered dapivirine gel (0.05%) or placebo gel at study entry (Day 0). Following a minimum 2-week washout period, participants or study staff will administer daily rectal doses of the assigned gel for 7 consecutive days under direct observation in the clinic. Participants will be in the study for approximately 40 days, and they will attend 16 study visits. Study visits may include behavioral assessments, physical examinations, blood and urine collection, and pelvic and anorectal sample collection. Some visits will include intensive PK sampling. Study staff will contact participants 1 week after Visit 16 for follow-up safety monitoring.
Interventions
DRUGDapivirine gel
Dapivirine gel (0.05%); administered rectally
DRUGPlacebo gel
Universal HEC placebo gel; administered rectally
Sponsors
National Institute of Allergy and Infectious Diseases (NIAID)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 45 Years
Healthy volunteers
Yes
Inclusion criteria
* Age of 18 - 45 years (inclusive) at Screening, verified per site standard operating procedure (SOP) * Able and willing to provide written informed consent * HIV-1/2 uninfected at Screening and Enrollment, per applicable algorithm in Appendix II of the protocol and willing to receive HIV test results * Able and willing to provide adequate locator information, as defined in site SOP * Available to return for all study visits and willing to comply with study participation requirements * In general good health at Screening and Enrollment, as determined by the site Investigator of Record (IoR) or designee * Per participant report, a history of consensual receptive anal intercourse (RAI) at least once in the past calendar year * Willing to not take part in other research studies involving drugs, medical devices, genital or rectal products, or vaccines for the duration of study participation, including the time between Screening and Enrollment * Willing to be sexually abstinent for 72 hours prior to each study visit, during the study product use periods and for 72 hours after biopsy collection. Note: See Criteria 12 and 13 for additional restrictions for female participants * Willing to abstain from inserting any non-study products into the rectum for 72 hours prior to each study visit and during the study product use periods. Note: See Criteria 12 and 13 for additional restrictions for female participants Females must also meet the following additional inclusion criteria to be eligible for study inclusion: * Women over the age of 21 (inclusive) must have documentation of a satisfactory Pap within the past 3 years prior to Enrollment consistent with Grade 0 according to 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 satisfactory evaluation with no treatment required of Grade 1 or higher Pap result * Willing to be sexually abstinent for 72 hours prior to each study visit and during the study product use periods and for 7 days after biopsy collection * Willing to abstain from inserting any non-study products into the vagina for 72 hours prior to each study visit, during the study product use periods and for 7 days after biopsy collection * Willing to use an effective method of contraception for at least 30 days (inclusive) prior to Enrollment and intending to continue use of an effective method for the duration of study participation; effective methods include: hormonal methods (except contraceptive ring), intrauterine device (IUD), sterilization (of participant and/or partner, as defined in site SOPs), or sexually abstinent for 90 days prior to Screening
Exclusion criteria
* At Screening: * Hemoglobin Grade 1 or higher\* * Platelet count Grade 1 or higher\* * White blood count Grade 2 or higher\* * Serum creatinine greater than 1.3× the site laboratory upper limit of normal (ULN) * International normalized ratio (INR) greater than 1.5× the site laboratory ULN * Aspartate aminotransferase (AST) or alanine transaminase (ALT) Grade 1 or higher\* * Positive for hepatitis C antibody * Positive for hepatitis B surface antigen * History of inflammatory bowel disease by participant report * \*As per the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events Corrected Version 2.1, July 2017 * Note: Otherwise eligible participants with an exclusionary test result (other than HIV, HBV or HCV) can be re-tested during the screening process. If a participant is re-tested and a non-exclusionary result is documented within 45 days of providing informed consent for screening, the participant may be enrolled. * Anticipated use of and/or unwillingness to abstain from the following medications during study participation: * Heparin, including Lovenox® * Warfarin * Plavix® (clopidogrel bisulfate) * Aspirin (greater than 81 mg) * Non-steroidal anti-inflammatory drugs (NSAIDS) * Any other drugs that are associated with increased likelihood of bleeding * CYP3A inducer(s) and/or inhibitor(s) as specified in the MTN-026 Study-Specific Procedures (SSP) Manual * Hormone-replacement therapy in tablet, injectable or gel form * Known adverse reaction to any of the components of the study products * Use of post-exposure prophylaxis (PEP) for potential HIV exposure within the 6 months prior to Enrollment * Use of pre-exposure prophylaxis (PrEP) for HIV prevention within the 6 months prior to Enrollment, and/or anticipated use during trial participation * Use of systemic immunomodulatory medications within the 6 months prior to Enrollment, and/or anticipated use during trial participation * RAI without a condom and/or penile-vaginal intercourse with a partner who is known to be HIV-positive in the past 6 months * Non-therapeutic injection drug use in the 12 months prior to Screening and Enrollment * Participation in research studies involving drugs, medical devices, genital or rectal products, or vaccines within 45 days of the Enrollment Visit * At Screening, participant report of treatment for an anogenital STI within the past 3 months * At Screening, participant-reported symptoms and/or clinical or laboratory diagnosis of active anorectal or reproductive tract infection requiring treatment per current World Health Organization (WHO) guidelines (http://www.who.int/hiv/pub/sti/pub6/en/) or symptomatic urinary tract infection (UTI). Infections requiring treatment include symptomatic Neisseria gonorrhea (GC), Chlamydia trachomatis (CT) infection, syphilis, active herpes simplex virus (HSV) lesions, anogenital sores or ulcers, or symptomatic genital warts, cervicitis, chancroid, pelvic inflammatory disease (PID), bacterial vaginosis (BV), symptomatic vaginal candidiasis, other vaginitis, trichomoniasis. Note: Otherwise eligible participants with an exclusionary UTI, BV and/or candida finding may be re-tested during the screening process. * At Enrollment, active anorectal or reproductive tract infection requiring treatment per current WHO guidelines (http://www.who.int/hiv/pub/sti/pub6/en/) or symptomatic urinary tract infection (UTI). Infections requiring treatment include symptomatic GC, CT, syphilis, active HSV lesions, anogenital sores or ulcers, symptomatic genital warts, bacterial vaginosis, symptomatic vaginal candidiasis, other vaginitis, trichomoniasis, chancroid, cervicitis and PID. Note: HSV-1 or HSV-2 seropositive diagnosis with no active lesions is permitted since treatment is not required * Has any other condition that, in the opinion of the IoR/designee, would preclude informed consent, make study participation unsafe, complicate interpretation of study outcome data, or otherwise interfere with achieving study objectives. Females who meet any of the following additional criteria will be excluded from the study: * Pregnant or breastfeeding at either Screening or Enrollment or intends to become pregnant or start breastfeeding during study participation. Note: A documented negative pregnancy test performed by study staff is required for inclusion; however, a self-reported pregnancy is adequate for exclusion from screening/enrollment into the study. * Last pregnancy outcome 90 days or less prior to Screening * Has had a hysterectomy * At Enrollment, has a clinically apparent Grade 1 or higher pelvic exam finding (observed by study clinician or designee) per the Female Genital Grading Table for Use in Microbicide Studies \[Addendum 1, Dated November 2007\]. Note: Cervical friability bleeding associated with speculum insertion and/or specimen collection judged to be within the range of normal according to the clinical judgment of the IoR/designee is considered expected non-menstrual bleeding and is not exclusionary.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Frequency of Grade 2 or Higher Adverse Events (AEs) | Measured after the participant has started study product until the participant's study termination at approximately Day 40 | As defined by the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, Corrected Version 2.1, July 2017 and/or Addenda 1, 2 and 3 (Female Genital \[Dated November 2007\], Male Genital \[Dated November 2007\] and Rectal \[Clarification Dated May 2012\] Grading Tables for Use in Microbicide Studies) |
| Measurement of Dapivirine Concentrations in Plasma | Sample collected at approximately 1, 2, 24, 48 and 72 hours after first single dose, 24 hours after first dose during daily dosing, before last dose and 1,2, 24,48, and 72 hours after last dose. | As assessed by pharmacokinetic sampling and analysis |
| Measurement of Dapivirine Concentrations in Rectal Fluid | Sample collected at approximately 1, 2, 24, 48 and 72 hours after first single dose, 24 hours after first dose during daily dosing, and 1,2, 24,48, and 72 hours after last dose. | As assessed by pharmacokinetic rectal fluid sampling and analysis |
| Measurement of Dapivirine Concentrations in Rectal Mucosal Tissue Homogenates | Sample collected at approximately 1, 2, 24, 48 and 72 hours after first single dose and 1,2, 24,48, and 72 hours after last dose. | As assessed by pharmacokinetic rectal mucosal tissue homogenates sampling and analysis |
| Terminal Half-life of Dapivirine Concentrations in Plasma | From samples collected 24 hours after first dose to 72 hours after last daily dose | The terminal half-life of dapivirine in plasma samples was estimated by fitting a linear regression on the log-transformed concentrations from the 24, 48 and 72 hour time-points after the single and multiple doses.Each regression model includes an adjustment for the difference in concentration after multiple dosing. For each participant, Beta was calculated as the negative of the slope of their repression and half-life was log(2)/Beta. Due to the large number of concentrations below the limit of quantification after the single dose, the estimateion of Beta and half-life relied only on concentration after the multiple dosing for most of the participants. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Acceptability: Ease of Use | after completing the study (study day 40) | The number of participants who responded by questionnaire that the study product was easy or very easy to use. |
| Acceptability: Comfort | after completing the study (study day 40) | The number of participants who responded on a questionnaire that the study product was comfortable or very comfortable. |
Countries
Thailand, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Dapivirine Gel Participants will receive a single dose of dapivirine gel rectally, followed by 7 daily doses of dapivirine gel to be administered under direct observation in the clinic.
Dapivirine gel: Dapivirine gel (0.05%); administered rectally | 19 |
| Placebo Gel Participants will receive a single dose of placebo gel rectally, followed by 7 daily doses of placebo gel to be administered under direct observation in the clinic.
Placebo gel: Universal HEC placebo gel; administered rectally | 9 |
| Total | 28 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 1 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Dapivirine Gel | Placebo Gel | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 19 Participants | 9 Participants | 28 Participants |
| Age, Continuous | 26 years | 35 years | 33 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 18 Participants | 9 Participants | 27 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 7 Participants | 4 Participants | 11 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 3 Participants | 4 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 11 Participants | 2 Participants | 13 Participants |
| Region of Enrollment Thailand | 6 participants | 3 participants | 9 participants |
| Region of Enrollment United States | 13 participants | 6 participants | 19 participants |
| Sex: Female, Male Female | 4 Participants | 5 Participants | 9 Participants |
| Sex: Female, Male Male | 15 Participants | 4 Participants | 19 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 18 | 0 / 9 |
| other Total, other adverse events | 6 / 18 | 7 / 9 |
| serious Total, serious adverse events | 0 / 18 | 0 / 9 |
Outcome results
Primary
Frequency of Grade 2 or Higher Adverse Events (AEs)
As defined by the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, Corrected Version 2.1, July 2017 and/or Addenda 1, 2 and 3 (Female Genital \[Dated November 2007\], Male Genital \[Dated November 2007\] and Rectal \[Clarification Dated May 2012\] Grading Tables for Use in Microbicide Studies)
Time frame: Measured after the participant has started study product until the participant's study termination at approximately Day 40
Population: enrolled participants receiving at least one dose of study product
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dapivirine Gel | Frequency of Grade 2 or Higher Adverse Events (AEs) | 3 Participants |
| Placebo Gel | Frequency of Grade 2 or Higher Adverse Events (AEs) | 5 Participants |
Comparison: two-sided Fisher's Exact Testp-value: 0.072Fisher Exact
Primary
Measurement of Dapivirine Concentrations in Plasma
As assessed by pharmacokinetic sampling and analysis
Time frame: Sample collected at approximately 1, 2, 24, 48 and 72 hours after first single dose, 24 hours after first dose during daily dosing, before last dose and 1,2, 24,48, and 72 hours after last dose.
Population: enrolled participants on the Dapivirine arm who received at least one dose of study product and had a sample collected at the specific time-point. 0 is an estimate for values below the limit of quantification (LLOQ = 20 pg/mL) since only numeric values are allowed. The value would be somewhere between the LLOQ and 0.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Dapivirine Gel | Measurement of Dapivirine Concentrations in Plasma | 120 minutes after last daily dose | 403 pg/mL |
| Dapivirine Gel | Measurement of Dapivirine Concentrations in Plasma | 30 to 60 minutes after single dose | 31.5 pg/mL |
| Dapivirine Gel | Measurement of Dapivirine Concentrations in Plasma | 120 minutes after single dose | 326 pg/mL |
| Dapivirine Gel | Measurement of Dapivirine Concentrations in Plasma | 24 hours after single dose | 20.1 pg/mL |
| Dapivirine Gel | Measurement of Dapivirine Concentrations in Plasma | 48 hours after single dose | 0 pg/mL |
| Dapivirine Gel | Measurement of Dapivirine Concentrations in Plasma | 72 hours after single dose | 0 pg/mL |
| Dapivirine Gel | Measurement of Dapivirine Concentrations in Plasma | 24 hours after first daily dose | 67.9 pg/mL |
| Dapivirine Gel | Measurement of Dapivirine Concentrations in Plasma | Before last daily dose | 167 pg/mL |
| Dapivirine Gel | Measurement of Dapivirine Concentrations in Plasma | 30 to 60 minutes after last daily dose | 290.5 pg/mL |
| Dapivirine Gel | Measurement of Dapivirine Concentrations in Plasma | 24 hours after last daily dose | 119.0 pg/mL |
| Dapivirine Gel | Measurement of Dapivirine Concentrations in Plasma | 48 hours after last daily dose | 113 pg/mL |
| Dapivirine Gel | Measurement of Dapivirine Concentrations in Plasma | 72 hours after last daily dose | 80.3 pg/mL |
Primary
Measurement of Dapivirine Concentrations in Rectal Fluid
As assessed by pharmacokinetic rectal fluid sampling and analysis
Time frame: Sample collected at approximately 1, 2, 24, 48 and 72 hours after first single dose, 24 hours after first dose during daily dosing, and 1,2, 24,48, and 72 hours after last dose.
Population: enrolled participants on the Dapivirine arm who received at least one dose of product and had a sample collected at the specific time-point. 0 is an estimate for values below the limit of quantification (LLOQ = 0.001 ng/mg) since only numeric values are allowed. The value would be somewhere between the lower limit of quantification and 0.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Dapivirine Gel | Measurement of Dapivirine Concentrations in Rectal Fluid | 30 to 60 minutes after first application | 30.1 ng/mg |
| Dapivirine Gel | Measurement of Dapivirine Concentrations in Rectal Fluid | 120 minutes after single dose | 12.765 ng/mg |
| Dapivirine Gel | Measurement of Dapivirine Concentrations in Rectal Fluid | 24 hours after single dose | 0 ng/mg |
| Dapivirine Gel | Measurement of Dapivirine Concentrations in Rectal Fluid | 48 hours after single dose | 0.009 ng/mg |
| Dapivirine Gel | Measurement of Dapivirine Concentrations in Rectal Fluid | 72 hours after single dose | 0 ng/mg |
| Dapivirine Gel | Measurement of Dapivirine Concentrations in Rectal Fluid | 24 hours after first daily dose | 0.180 ng/mg |
| Dapivirine Gel | Measurement of Dapivirine Concentrations in Rectal Fluid | 30 to 60 minutes after last daily dose | 89.7 ng/mg |
| Dapivirine Gel | Measurement of Dapivirine Concentrations in Rectal Fluid | 120 minutes after last daily dose | 26.65 ng/mg |
| Dapivirine Gel | Measurement of Dapivirine Concentrations in Rectal Fluid | 24 hours after last daily dose | 0.007 ng/mg |
| Dapivirine Gel | Measurement of Dapivirine Concentrations in Rectal Fluid | 48 hours after last daily dose | 0 ng/mg |
| Dapivirine Gel | Measurement of Dapivirine Concentrations in Rectal Fluid | 72 hours after last daily dose | 0 ng/mg |
Primary
Measurement of Dapivirine Concentrations in Rectal Mucosal Tissue Homogenates
As assessed by pharmacokinetic rectal mucosal tissue homogenates sampling and analysis
Time frame: Sample collected at approximately 1, 2, 24, 48 and 72 hours after first single dose and 1,2, 24,48, and 72 hours after last dose.
Population: enrolled participants on the Dapivirine gel arm who received at least one dose of study product and had a sample collected at the specific time-point. 0 is an estimate for values below the limit of quantification (LLOQ = 0.001 ng/mg) since only numeric values are allowed. The value would be somewhere between the LLOQ and 0.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Dapivirine Gel | Measurement of Dapivirine Concentrations in Rectal Mucosal Tissue Homogenates | 30 to 60 minutes after single dose | 0.256 ng/mg |
| Dapivirine Gel | Measurement of Dapivirine Concentrations in Rectal Mucosal Tissue Homogenates | 120 minutes after single dose | 0 ng/mg |
| Dapivirine Gel | Measurement of Dapivirine Concentrations in Rectal Mucosal Tissue Homogenates | 24 hours after single dose | 0 ng/mg |
| Dapivirine Gel | Measurement of Dapivirine Concentrations in Rectal Mucosal Tissue Homogenates | 48 hours after single dose | 0 ng/mg |
| Dapivirine Gel | Measurement of Dapivirine Concentrations in Rectal Mucosal Tissue Homogenates | 72 hours after single dose | 0 ng/mg |
| Dapivirine Gel | Measurement of Dapivirine Concentrations in Rectal Mucosal Tissue Homogenates | 30 to 60 minutes after last daily dose | 0 ng/mg |
| Dapivirine Gel | Measurement of Dapivirine Concentrations in Rectal Mucosal Tissue Homogenates | 120 minutes after last daily dose | 0 ng/mg |
| Dapivirine Gel | Measurement of Dapivirine Concentrations in Rectal Mucosal Tissue Homogenates | 24 hours after last daily dose | 0 ng/mg |
| Dapivirine Gel | Measurement of Dapivirine Concentrations in Rectal Mucosal Tissue Homogenates | 48 hours after last daily dose | 0 ng/mg |
| Dapivirine Gel | Measurement of Dapivirine Concentrations in Rectal Mucosal Tissue Homogenates | 72 hours after last daily dose | 0 ng/mg |
Primary
Terminal Half-life of Dapivirine Concentrations in Plasma
The terminal half-life of dapivirine in plasma samples was estimated by fitting a linear regression on the log-transformed concentrations from the 24, 48 and 72 hour time-points after the single and multiple doses.Each regression model includes an adjustment for the difference in concentration after multiple dosing. For each participant, Beta was calculated as the negative of the slope of their repression and half-life was log(2)/Beta. Due to the large number of concentrations below the limit of quantification after the single dose, the estimateion of Beta and half-life relied only on concentration after the multiple dosing for most of the participants.
Time frame: From samples collected 24 hours after first dose to 72 hours after last daily dose
Population: enrolled participants on the Dapivirine gel arm who received at least one dose of study product. One participant with a negative estimate for the elimination rate due to an increasing trend in their concentration after multiple dosing and one participant with no values above the limit of quantification were excluded.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dapivirine Gel | Terminal Half-life of Dapivirine Concentrations in Plasma | 52.6 hours |
Secondary
Acceptability: Comfort
The number of participants who responded on a questionnaire that the study product was comfortable or very comfortable.
Time frame: after completing the study (study day 40)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dapivirine Gel | Acceptability: Comfort | 15 Participants |
| Placebo Gel | Acceptability: Comfort | 7 Participants |
p-value: 0.591Fisher Exact
Secondary
Acceptability: Ease of Use
The number of participants who responded by questionnaire that the study product was easy or very easy to use.
Time frame: after completing the study (study day 40)
Population: All enrolled participants who completed the exit behavioral questionnaire.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dapivirine Gel | Acceptability: Ease of Use | 16 Participants |
| Placebo Gel | Acceptability: Ease of Use | 9 Participants |
p-value: 1Fisher Exact