Human Immunodeficiency Virus
Conditions
Keywords
Human Immunodeficiency Virus
Brief summary
To assess the safety of dapivirine (25 mg) administered via a silicone vaginal ring in HIV-uninfected adolescent females, when inserted once every 4 weeks during 24-week of study product use.
Detailed description
MTN-023/IPM 030 is a Phase 2a, two-arm, placebo-controlled, double-blinded, multi-site, randomized trial of dapivirine vaginal ring (VR) versus placebo VR. The clinical trial is designed to assess the safety of dapivirine (25 mg) administered via a silicone vaginal ring (primary objective) and evaluate the acceptability of the dapivirine or placebo VR in sexually experienced, HIV-uninfected adolescent females, when inserted once every 4 weeks during 24-weeks of study product use. Approximately 96 participants will be randomized in a 3:1 ratio to receive either a silicone elastomer vaginal ring containing 25 mg of dapivirine or a placebo VR. The ring will be replaced every 4 weeks during the 24 week study product use period. Use of a VR to provide sustained delivery of microbicides is a novel investigational method for prevention of heterosexual transmission of HIV in women. This drug delivery method may circumvent potential difficulties related to adherence to daily or coitally-dependent uses of microbicide regimens.
Interventions
COMBINATION_PRODUCTplacebo ring
intravaginal ring silicone elastomer intravaginal ring containing no drug product
COMBINATION_PRODUCTdapivirine ring
intravaginal ring silicone elastomer intravaginal ring containing 25 mg dapivirine
Sponsors
Microbicide Trials Network
National Institutes of Health (NIH)
International Partnership for Microbicides, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
15 Years to 17 Years
Healthy volunteers
Yes
Inclusion criteria
1. Age 15 through 17 years (inclusive) at Enrollment, verified per site SOPs 2. Able and willing to provide written informed assent/consent and able to obtain written parental or guardian permission (as specified in site SOP) to be screened for and to enroll in MTN-023/IPM 030 3. Able and willing to provide adequate locator information, as defined in site SOPs 4. Able to communicate in spoken and written English 5. Able and willing to comply with all study procedural requirements 6. Per participant report at Screening and Enrollment, willing to abstain from inserting anything into the vagina for 72 hours prior to each follow-up visit, including abstaining from penile-vaginal intercourse. Note: In the event the vaginal ring has been expelled and requires reinsertion, repositioning the vaginal ring is permitted 7. In general good health as determined by the Investigator of Record (IoR)/designee at Screening and Enrollment 8. Assessment of onset and progression of puberty, as measured by Tanner stage 4 or 5 at Screening, per participant report and/or clinician assessment 9. HIV-uninfected based on testing performed at Screening and Enrollment (per protocol algorithm in Appendix II) 10. Per participant report at Screening, history of sexual intercourse (at least one episode in participant's lifetime) 11. Per participant report at Screening and Enrollment, agrees to use condoms for sexual intercourse 12. Negative pregnancy test at Screening and Enrollment 13. Per participant report, using 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, as defined in site SOPs) 14. At Screening and Enrollment, participant states a willingness to refrain from inserting the following vaginal products and/or objects into the vagina; spermicides, diaphragms, contraceptive vaginal rings, menstrual cups, cervical caps (or any other vaginal barrier method), douches, lubricants, for the 5 days prior to Enrollment throughout the duration of study participation. Note: Neither the use of tampons or sex toys, nor participant engagement in coitus is restricted. 15. At Screening and Enrollment, agrees not to participate in other research studies involving drugs, medical devices, vaginal products, or vaccines for the duration of study participation, unless approved by the PSRT
Exclusion criteria
1. Per participant report at Screening, intends to do any of the following during the study participation period: 1. become pregnant 2. relocate away from the study site 3. travel away from the study site for more than 4 consecutive weeks 2. Diagnosed with a urinary tract infection (UTI) and/or reproductive tract infection (RTI) at Screening and/or Enrollment. Note: Otherwise eligible participants diagnosed with UTI during Screening will be offered treatment and may be enrolled after completing treatment and all symptoms have resolved. If treatment is completed and symptoms have resolved within 56 days of obtaining informed consent for Screening, the participant may be enrolled. 3. Diagnosed with pelvic inflammatory disease and/or an sexually transmitted infection (STI) requiring treatment per current Centers for Disease Control and Prevention (CDC) guidelines within 60 days of Enrollment (inclusive) 4. At Enrollment, has a clinically apparent Grade 2 or higher pelvic exam finding (observed by study staff)\*\* Note: Cervical 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. Note: Otherwise eligible participants with exclusionary pelvic exam findings may be enrolled/randomized after the findings have improved to a non-exclusionary severity grading or resolved. If improvement to a non-exclusionary grade or resolution is documented within 56 days of providing informed consent for screening, the participant may be enrolled. 5. Participant report and/or clinical evidence of any of the following: 1. Known adverse reaction to any of the study products (ever) 2. Known HIV-infected partner 3. Non-therapeutic injection drug use in the 12 months prior to Screening 4. The use of HIV Post-exposure prophylaxis (PEP) and/or Pre-exposure prophylaxis (PrEP) within the 6 months prior to Enrollment 5. Currently breastfeeding 6. Last pregnancy outcome within 90 days or less of Screening 7. Participation in any other research study involving drugs, medical devices, vaginal products, or vaccines, within 60 days of Screening 8. Participant report of 3 or more penile-vaginal sexual partners in the month prior to Screening 9. At Enrollment, as determined by the IoR/designee, has any significant uncontrolled active or chronic cardiovascular, renal, liver, hematologic, neurologic, gastrointestinal, psychiatric, endocrine, respiratory, immunologic disorder or infectious disease 6. Has any of the following Grade 1 or higher\* laboratory abnormalities at Screening Visit: 1. Aspartate aminotransferase (AST) or alanine transaminase (ALT) 2. Creatinine 3. Hemoglobin 4. Platelet count Note: Otherwise eligible participants with an exclusionary test may be re-tested during the screening process. Please see the MTN-023/IPM 030 SSP for additional details. 7. Has any other condition that, in the opinion of the IoR/designee, would preclude informed assent/consent, make study participation unsafe, complicate interpretation of study outcome data, or otherwise interfere with achieving the study objectives * Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events Version 1.0, December, 2004 (Clarification dated August 2009) \*\*Female Genital Grading Table for Use in Microbicide Studies Addendum 1 to the DAIDS Table for Grading Adult and Pediatric Adverse Events, Version 1.0, December 2004 (Clarification dated August 2009)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Safety of Dapivirine (25 mg) Administered Via a Silicone Vaginal Ring in HIV-uninfected Adolescent Females, When Inserted Once Every 4 Weeks During 24 Weeks of Study Product Use | 6 months | Grade 2 AEs as defined by the DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, Version 1.0, dated December 2004 (Clarification dated August 2009), Addendum 1 (Female Genital Grading Table for Use in Microbicide Studies) judged to be related to IP. Grade 3 or higher AEs as defined by the DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, Version 1.0, dated December 2004 (Clarification dated August 2009). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| The Acceptability of the Study VR (Dapivirine or Placebo) in HIV Uninfected Adolescent Females, When Inserted Once Every 4 Weeks for a 24 Week Period | 6 months | Participant's self-report on multiple components of acceptability via attitudinal questions (discreetness, likes and dislikes concerning the ring, attitude toward product characteristics, comfort and ease of use, partner reactions, and effect on sex) in categorical scales |
| Adherence to the Study VR (Dapivirine or Placebo) in HIV Uninfected Adolescent Females, When Inserted Once Every 4 Weeks for a 24 Week Period | 6 months | Frequency of ring removals and expulsions based on the participant's self-report of ring use at monthly clinic visits according to the Ring Adherence CRF. |
| The Systemic Dapivirine Exposure | 6 months | Dapivirine plasma concentrations measured at weeks 2, 4, 12 and 24. |
| Local Dapivirine Exposure | 6 months | Vaginal fluid dapivirine concentrations. |
Countries
United States
Participant flow
Recruitment details
As part of participant outreach and recruitment strategies, trial staff pre-screened potential trial participants at either on-site or off-site locations. During these interactions, trial staff explained the trial to potential participants, ascertained elements of presumptive eligibility.
Pre-assignment details
Screening Visit were done up to 56 days prior to Enrollment Visit. Some cases, multiple visits were conducted to complete all screening procedures. Written informed participant assent and parental/guardian consent for screening were obtained. Participants who expressed an interest in involving her current sexual partner regarding trial participation was encouraged to bring her partner to the research center where a staff member explained the trial.
Participants by arm
| Arm | Count |
|---|---|
| Dapivirine Ring dapivirine vaginal ring (25 mg)
dapivirine ring: intravaginal ring silicone elastomer intravaginal ring containing 25 mg dapivirine | 73 |
| Placebo Ring silicone vaginal ring
placebo ring: intravaginal ring silicone elastomer intravaginal ring containing no drug product | 23 |
| Total | 96 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Unable to contact participant | 1 | 0 |
| Overall Study | Withdrawal by Subject | 3 | 1 |
Baseline characteristics
| Characteristic | Dapivirine Ring | Total | Placebo Ring |
|---|---|---|---|
| Age, Continuous | 16.3 Years STANDARD_DEVIATION 0.8 | 16.3 Years STANDARD_DEVIATION 0.8 | 16.2 Years STANDARD_DEVIATION 0.7 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 16 Participants | 20 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 57 Participants | 76 Participants | 19 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 34 Participants | 47 Participants | 13 Participants |
| Race (NIH/OMB) More than one race | 8 Participants | 11 Participants | 3 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 10 Participants | 11 Participants | 1 Participants |
| Race (NIH/OMB) White | 20 Participants | 24 Participants | 4 Participants |
| Region of Enrollment United States | 73 Participants | 96 Participants | 23 Participants |
| Sex: Female, Male Female | 73 Participants | 96 Participants | 23 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 73 | 0 / 23 |
| other Total, other adverse events | 63 / 73 | 22 / 23 |
| serious Total, serious adverse events | 2 / 73 | 0 / 23 |
Outcome results
Primary
The Safety of Dapivirine (25 mg) Administered Via a Silicone Vaginal Ring in HIV-uninfected Adolescent Females, When Inserted Once Every 4 Weeks During 24 Weeks of Study Product Use
Grade 2 AEs as defined by the DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, Version 1.0, dated December 2004 (Clarification dated August 2009), Addendum 1 (Female Genital Grading Table for Use in Microbicide Studies) judged to be related to IP. Grade 3 or higher AEs as defined by the DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, Version 1.0, dated December 2004 (Clarification dated August 2009).
Time frame: 6 months
Population: All participants randomized into the clinical trial were included in the primary analysis according to the principle of intent-to-treat (ITT).
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Dapivirine Ring | The Safety of Dapivirine (25 mg) Administered Via a Silicone Vaginal Ring in HIV-uninfected Adolescent Females, When Inserted Once Every 4 Weeks During 24 Weeks of Study Product Use | Grade 2 Adverse Events related to IP | 8 Participants |
| Dapivirine Ring | The Safety of Dapivirine (25 mg) Administered Via a Silicone Vaginal Ring in HIV-uninfected Adolescent Females, When Inserted Once Every 4 Weeks During 24 Weeks of Study Product Use | Grade 3 or higher events | 3 Participants |
| Placebo Ring | The Safety of Dapivirine (25 mg) Administered Via a Silicone Vaginal Ring in HIV-uninfected Adolescent Females, When Inserted Once Every 4 Weeks During 24 Weeks of Study Product Use | Grade 2 Adverse Events related to IP | 2 Participants |
| Placebo Ring | The Safety of Dapivirine (25 mg) Administered Via a Silicone Vaginal Ring in HIV-uninfected Adolescent Females, When Inserted Once Every 4 Weeks During 24 Weeks of Study Product Use | Grade 3 or higher events | 0 Participants |
Secondary
Adherence to the Study VR (Dapivirine or Placebo) in HIV Uninfected Adolescent Females, When Inserted Once Every 4 Weeks for a 24 Week Period
Frequency of ring removals and expulsions based on the participant's self-report of ring use at monthly clinic visits according to the Ring Adherence CRF.
Time frame: 6 months
Population: The ITT population included all participants who were randomized to one of the two treatment groups, Dapivirine Vaginal Ring-004 or placebo ring. All participants who were included in a treatment group were analyzed as members of the group in which they were enrolled, regardless of adherence to the planned course of treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dapivirine Ring | Adherence to the Study VR (Dapivirine or Placebo) in HIV Uninfected Adolescent Females, When Inserted Once Every 4 Weeks for a 24 Week Period | 29 Participants |
| Placebo Ring | Adherence to the Study VR (Dapivirine or Placebo) in HIV Uninfected Adolescent Females, When Inserted Once Every 4 Weeks for a 24 Week Period | 11 Participants |
Secondary
Local Dapivirine Exposure
Vaginal fluid dapivirine concentrations.
Time frame: 6 months
Population: The PK analysis population included all participants who were randomized to the Dapivirine Vaginal Ring-004 treatment group and had detectable dapivirine plasma or vaginal fluid concentrations at any time during follow-up.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dapivirine Ring | Local Dapivirine Exposure | Week 2 | 27.8 nanogram/milligram | Standard Deviation 22.7 |
| Dapivirine Ring | Local Dapivirine Exposure | Week 4 | 45.0 nanogram/milligram | Standard Deviation 40.9 |
| Dapivirine Ring | Local Dapivirine Exposure | Week 12 | 49.2 nanogram/milligram | Standard Deviation 53.6 |
| Dapivirine Ring | Local Dapivirine Exposure | Week 24 | 51.9 nanogram/milligram | Standard Deviation 58.2 |
Secondary
The Acceptability of the Study VR (Dapivirine or Placebo) in HIV Uninfected Adolescent Females, When Inserted Once Every 4 Weeks for a 24 Week Period
Participant's self-report on multiple components of acceptability via attitudinal questions (discreetness, likes and dislikes concerning the ring, attitude toward product characteristics, comfort and ease of use, partner reactions, and effect on sex) in categorical scales
Time frame: 6 months
Population: The ITT population included all participants who were randomized to one of the two treatment groups, Dapivirine Vaginal Ring-004 or placebo ring. All participants who were included in a treatment group were analyzed as members of the group in which they were enrolled, regardless of adherence to the planned course of treatment.
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| Dapivirine Ring | The Acceptability of the Study VR (Dapivirine or Placebo) in HIV Uninfected Adolescent Females, When Inserted Once Every 4 Weeks for a 24 Week Period | Discreetness | At least one negative report | 39 Participants |
| Dapivirine Ring | The Acceptability of the Study VR (Dapivirine or Placebo) in HIV Uninfected Adolescent Females, When Inserted Once Every 4 Weeks for a 24 Week Period | Discreetness | All responses positive | 9 Participants |
| Dapivirine Ring | The Acceptability of the Study VR (Dapivirine or Placebo) in HIV Uninfected Adolescent Females, When Inserted Once Every 4 Weeks for a 24 Week Period | Likes and dislikes concerning the ring | At least one negative report | 18 Participants |
| Dapivirine Ring | The Acceptability of the Study VR (Dapivirine or Placebo) in HIV Uninfected Adolescent Females, When Inserted Once Every 4 Weeks for a 24 Week Period | Likes and dislikes concerning the ring | All responses positive | 37 Participants |
| Dapivirine Ring | The Acceptability of the Study VR (Dapivirine or Placebo) in HIV Uninfected Adolescent Females, When Inserted Once Every 4 Weeks for a 24 Week Period | Attitude toward product characteristics | At least one negative report | 14 Participants |
| Dapivirine Ring | The Acceptability of the Study VR (Dapivirine or Placebo) in HIV Uninfected Adolescent Females, When Inserted Once Every 4 Weeks for a 24 Week Period | Attitude toward product characteristics | All responses positive | 34 Participants |
| Dapivirine Ring | The Acceptability of the Study VR (Dapivirine or Placebo) in HIV Uninfected Adolescent Females, When Inserted Once Every 4 Weeks for a 24 Week Period | Comfort and ease of use | At least one negative report | 27 Participants |
| Dapivirine Ring | The Acceptability of the Study VR (Dapivirine or Placebo) in HIV Uninfected Adolescent Females, When Inserted Once Every 4 Weeks for a 24 Week Period | Comfort and ease of use | All responses positive | 36 Participants |
| Dapivirine Ring | The Acceptability of the Study VR (Dapivirine or Placebo) in HIV Uninfected Adolescent Females, When Inserted Once Every 4 Weeks for a 24 Week Period | Partner reaction | At least one negative report | 12 Participants |
| Dapivirine Ring | The Acceptability of the Study VR (Dapivirine or Placebo) in HIV Uninfected Adolescent Females, When Inserted Once Every 4 Weeks for a 24 Week Period | Partner reaction | All responses positive | 16 Participants |
| Dapivirine Ring | The Acceptability of the Study VR (Dapivirine or Placebo) in HIV Uninfected Adolescent Females, When Inserted Once Every 4 Weeks for a 24 Week Period | Effect on sex | At least one negative report | 9 Participants |
| Dapivirine Ring | The Acceptability of the Study VR (Dapivirine or Placebo) in HIV Uninfected Adolescent Females, When Inserted Once Every 4 Weeks for a 24 Week Period | Effect on sex | All responses positive | 34 Participants |
| Placebo Ring | The Acceptability of the Study VR (Dapivirine or Placebo) in HIV Uninfected Adolescent Females, When Inserted Once Every 4 Weeks for a 24 Week Period | Effect on sex | At least one negative report | 6 Participants |
| Placebo Ring | The Acceptability of the Study VR (Dapivirine or Placebo) in HIV Uninfected Adolescent Females, When Inserted Once Every 4 Weeks for a 24 Week Period | Discreetness | At least one negative report | 12 Participants |
| Placebo Ring | The Acceptability of the Study VR (Dapivirine or Placebo) in HIV Uninfected Adolescent Females, When Inserted Once Every 4 Weeks for a 24 Week Period | Comfort and ease of use | At least one negative report | 10 Participants |
| Placebo Ring | The Acceptability of the Study VR (Dapivirine or Placebo) in HIV Uninfected Adolescent Females, When Inserted Once Every 4 Weeks for a 24 Week Period | Discreetness | All responses positive | 1 Participants |
| Placebo Ring | The Acceptability of the Study VR (Dapivirine or Placebo) in HIV Uninfected Adolescent Females, When Inserted Once Every 4 Weeks for a 24 Week Period | Partner reaction | All responses positive | 5 Participants |
| Placebo Ring | The Acceptability of the Study VR (Dapivirine or Placebo) in HIV Uninfected Adolescent Females, When Inserted Once Every 4 Weeks for a 24 Week Period | Likes and dislikes concerning the ring | At least one negative report | 7 Participants |
| Placebo Ring | The Acceptability of the Study VR (Dapivirine or Placebo) in HIV Uninfected Adolescent Females, When Inserted Once Every 4 Weeks for a 24 Week Period | Comfort and ease of use | All responses positive | 12 Participants |
| Placebo Ring | The Acceptability of the Study VR (Dapivirine or Placebo) in HIV Uninfected Adolescent Females, When Inserted Once Every 4 Weeks for a 24 Week Period | Likes and dislikes concerning the ring | All responses positive | 12 Participants |
| Placebo Ring | The Acceptability of the Study VR (Dapivirine or Placebo) in HIV Uninfected Adolescent Females, When Inserted Once Every 4 Weeks for a 24 Week Period | Effect on sex | All responses positive | 7 Participants |
| Placebo Ring | The Acceptability of the Study VR (Dapivirine or Placebo) in HIV Uninfected Adolescent Females, When Inserted Once Every 4 Weeks for a 24 Week Period | Attitude toward product characteristics | At least one negative report | 4 Participants |
| Placebo Ring | The Acceptability of the Study VR (Dapivirine or Placebo) in HIV Uninfected Adolescent Females, When Inserted Once Every 4 Weeks for a 24 Week Period | Partner reaction | At least one negative report | 3 Participants |
| Placebo Ring | The Acceptability of the Study VR (Dapivirine or Placebo) in HIV Uninfected Adolescent Females, When Inserted Once Every 4 Weeks for a 24 Week Period | Attitude toward product characteristics | All responses positive | 11 Participants |
Secondary
The Systemic Dapivirine Exposure
Dapivirine plasma concentrations measured at weeks 2, 4, 12 and 24.
Time frame: 6 months
Population: The PK analysis population included all participants who were randomized to the Dapivirine Vaginal Ring-004 treatment group and had detectable dapivirine plasma or vaginal fluid concentrations at any time during follow-up.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dapivirine Ring | The Systemic Dapivirine Exposure | Week 2 | 310.5 picograms/millilitre | Standard Deviation 102 |
| Dapivirine Ring | The Systemic Dapivirine Exposure | Week 4 | 255.5 picograms/millilitre | Standard Deviation 91.1 |
| Dapivirine Ring | The Systemic Dapivirine Exposure | Week 12 | 250.9 picograms/millilitre | Standard Deviation 96.6 |
| Dapivirine Ring | The Systemic Dapivirine Exposure | Week 24 | 243.1 picograms/millilitre | Standard Deviation 116.3 |