HIV Prevention
Conditions
Brief summary
A follow-on, open label trial to assess continued safety of and adherence to the Dapivirine(25mg) vaginal ring-004 in healthy, HIV-negative women
Detailed description
Phase IIIb, multicenter follow-on open-label trial to evaluate the continued adherence to and safety of the DVR, inserted at monthly intervals by healthy, HIV negative women who had participated in the IPM 027 Phase III DVR trial. All women who participated in IPM 027 (NCT 01539226) and were HIV-negative at screening for IPM 032, were eligible. Participants who provided written informed consent at screening were invited to undergo screening assessments for the trial. The Enrollment Visit had to occur within 45 days after the Screening Visit. Note: In the event that participation in IPM 027 was stopped prematurely and IPM 032 was activated at the RC, the IPM 027 Last Product Use Visit (LPUV) and the IPM 032 Screening and Enrollment Visits could be combined for participants who were eligible to enroll in IPM 032. All participants received the DVR containing 25 mg dapivirine at the Enrollment Visit, and attended a visit at the RC, 1 month after enrollment. Following this visit, a participant could continue on a 3 monthly visit schedule, at the Investigator's discretion. Monthly visits could, however, be extended up to the first 3 months of participation. From then on, all participants needed to switch to a 3-monthly schedule. Once the 3-monthly trial visit schedule commenced, three rings were dispensed at each visit. One ring was self-inserted at the RC and two additional rings were dispensed for the participant to take home, or dispensing took place as arranged with the participant. The protocol made provision for at least 12 months of DVR use (with the LPUV scheduled at Month 12), which could also have been extended. Participants could continue with ring use past Month 12 and the RCs could continue scheduling the 3-monthly visits as per the participant visit schedule. Exit Visits of participants who completed 12 months or more on the trial commenced in October 2017 and ended in January 2019. Participants who were still enrolled in the trial in October 2017 and those who had been enrolled at a later stage in the trial were scheduled to attend the Month 12 Visit, irrespective of their visit schedule assignments. Exit Visits were then scheduled as per protocol, ie, 1 to 2 months after the Month 12 Visit. Exit Visits were optional for participants who discontinued early from the trial. Adherence assessments included analysis of dapivirine residual levels in returned used rings, correlation analysis of dapivirine residual levels with visual inspection of used rings, and self-reported acceptability and adherence. The HIV-1 incidence and the occurrence of HIV-1 drug resistance were assessed using HIV rapid testing and genotyping, respectively. Social and behavioral parameters were assessed qualitatively and quantitatively. Quantitative assessments included evaluation of the feasibility of 3-monthly follow-up visits and evaluation of the proportion of participants undergoing unscheduled HIV rapid tests (ie, in between the scheduled 3 monthly follow-up visits). Safety assessments included adverse event (AE) reporting, safety laboratory assessments, pregnancy testing, physical examination, vital sign assessments, pelvic examination, sexually transmitted infection (STI) tests, cervical cytology, and assessments of social harms. Throughout the trial, all participants received pre- and post-test HIV counseling, HIV/STI risk reduction counseling, and contraceptive, condom and vaginal ring adherence counseling.
Interventions
DRUGDapivirine Vaginal Ring-004
To assess the safety profile of the 25 mg Dapivirine Vaginal Ring-004, when inserted at monthly intervals, in an open-label trial
Sponsors
International Partnership for Microbicides, Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 40 Years
Healthy volunteers
Yes
Inclusion criteria
Women must meet all the following criteria to be eligible to enrol in the trial: 1. Previously enrolled in the IPM 027 trial 2. Available for all visits and consent to follow all procedures scheduled for the trial 3. Using an effective method of contraception at the Enrolment Visit, and intending to use an effective contraceptive method for the duration of trial participation, unless post-menopausal with no history of menses for one year prior to screening 4. HIV-negative as determined by the HIV algorithm applied at Screening/Pre- Enrolment 5. Willing to refrain from participation in another research trial using drugs, vaccines, medical devices and microbicides for the duration of the IPM 032 trial 6. Willing to provide adequate locator information for trial retention purposes and be reachable per local standard procedures (e.g., by home visit or telephone; or via family or close neighbour contacts); confidentiality to be maintained.
Exclusion criteria
Women who meet any of the following criteria are NOT eligible to enrol in the trial: 1. Investigational product use permanently discontinued in response to an AE (where the AE was considered related to investigational product) or safety-related concern while taking part in the IPM 027 trial 2. Participant self-report of taking post-exposure prophylaxis (PEP) within ≤ 2 months at Screening Visit Note: Participants may be enrolled after completing the PEP regimen and a negative HIV test was documented at least 2 months prior to screening for IPM 032 3. Currently pregnant, intends to become pregnant or currently breast-feeding 4. Known drug abuse or alcohol dependence in the 12 months prior to screening 5. Participated in another research trial (other than IPM 027) using drugs, medical devices, microbicides or oral pre-exposure prophylaxis agents within 30 days prior to screening 6. Any new illness or condition(s), chronic condition(s) or abnormal laboratory finding(s) that, in the opinion of the investigator, might put the participant at risk, or interfere with the trial objectives or the participant's adherence to trial requirements
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Safety Profile of the 25 mg Dapivirine Vaginal Ring-004, When Inserted at Monthly Intervals. Participants Attended RC at Monthly Visits (up to Max of Three Monthly Visits) Followed by 3-monthly Follow-up Visits. | at least 12 months and up to 17 months | Safety assessments included adverse event (AE) reporting; all product-related AEs, Grade 3 or 4 AEs, SAEs. |
| Adherence to the Use of the 25 mg Dapivirine Vaginal Ring-004 Inserted at Monthly Intervals, in an Open-label Trial | at least 12 months and up to 17 months | Determined dapivirine residual amounts in returned used vaginal rings. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of HIV-1 Seroconversion | at least 12 months and up to 17 months | Rapid and specialised laboratory testing according to a pre-specified HIV testing algorithm |
| Number of Participants Who Acquired HIV-1 With HIV-1 Drug Resistance-associated Mutations. Infection | at least 12 months and up to 17 months | Viral genotype (including NGS) resistance testing methods which include sensitive methods to detect low frequency drug-resistant variants. |
Countries
South Africa, Uganda
Participant flow
Recruitment details
Up to 1,400 former IPM 027 participants were to be enrolled at 6 Research Centres (RC) - 5 RCs in SA and one RC in Uganda.
Pre-assignment details
Overall, 1,034 participants who had participated in IPM 027 were screened for inclusion in IPM 032 open-label trial. Of these, 941 (941/1,034; 91.0%) participants were enrolled, and 848 (848/941; 90.1%) participants completed the trial. Of the 941 enrolled participants, 150 rolled over directly from IPM 027, without any interruption in DVR use.
Participants by arm
| Arm | Count |
|---|---|
| Dapivirine Vaginal Ring-004 Dapivirine Vaginal Ring, 25 mg.Each participant will engage in the screening process for up to 45 days prior to enrolment and will use the monthly Dapivirine Vaginal Ring for a period of up to 12 months. IPM will have the option to extend this trial period.
Dapivirine Vaginal Ring-004: To assess the safety profile of the 25 mg Dapivirine Vaginal Ring-004, when inserted at monthly intervals, in an open-label trial | 941 |
| Total | 941 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Death | 1 |
| Overall Study | HIV-1 seroconversion | 18 |
| Overall Study | Lost to Follow-up | 13 |
| Overall Study | Non-compliance | 4 |
| Overall Study | Withdrawal by Subject | 57 |
Baseline characteristics
| Characteristic | Dapivirine Vaginal Ring-004 |
|---|---|
| Age, Customized 18 - 45 years | 30.1 years STANDARD_DEVIATION 6.32 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 931 Participants |
| Race (NIH/OMB) More than one race | 10 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 0 Participants |
| Region of Enrollment South Africa | 820 participants |
| Region of Enrollment Uganda | 121 participants |
| Sex: Female, Male Female | 941 Participants |
| Sex: Female, Male Male | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 1 / 941 |
| other Total, other adverse events | 616 / 941 |
| serious Total, serious adverse events | 20 / 941 |
Outcome results
Primary
Adherence to the Use of the 25 mg Dapivirine Vaginal Ring-004 Inserted at Monthly Intervals, in an Open-label Trial
Determined dapivirine residual amounts in returned used vaginal rings.
Time frame: at least 12 months and up to 17 months
Population: The safety population included all participants who were enrolled, and received and inserted at least one DVR.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dapivirine Vaginal Ring-004 | Adherence to the Use of the 25 mg Dapivirine Vaginal Ring-004 Inserted at Monthly Intervals, in an Open-label Trial | Trial Month 4. The month the ring was used is defined as the month the ring was dispensed | 20.61 mg | Standard Deviation 1.503 |
| Dapivirine Vaginal Ring-004 | Adherence to the Use of the 25 mg Dapivirine Vaginal Ring-004 Inserted at Monthly Intervals, in an Open-label Trial | Trial Month 5. The month the ring was used is defined as the month the ring was dispensed | 20.70 mg | Standard Deviation 1.448 |
| Dapivirine Vaginal Ring-004 | Adherence to the Use of the 25 mg Dapivirine Vaginal Ring-004 Inserted at Monthly Intervals, in an Open-label Trial | Enrollment. The month the ring was used is defined as the month the ring was dispensed. | 20.77 mg | Standard Deviation 1.271 |
| Dapivirine Vaginal Ring-004 | Adherence to the Use of the 25 mg Dapivirine Vaginal Ring-004 Inserted at Monthly Intervals, in an Open-label Trial | Trial Month 1. The month the ring was used is defined as the month the ring was dispensed. | 20.57 mg | Standard Deviation 1.453 |
| Dapivirine Vaginal Ring-004 | Adherence to the Use of the 25 mg Dapivirine Vaginal Ring-004 Inserted at Monthly Intervals, in an Open-label Trial | Trial Month 2.The month the ring was used is defined as the month the ring was dispensed. | 20.59 mg | Standard Deviation 1.478 |
| Dapivirine Vaginal Ring-004 | Adherence to the Use of the 25 mg Dapivirine Vaginal Ring-004 Inserted at Monthly Intervals, in an Open-label Trial | Trial Month 3. The month the ring was used is defined as the month the ring was dispensed. | 20.83 mg | Standard Deviation 1.513 |
| Dapivirine Vaginal Ring-004 | Adherence to the Use of the 25 mg Dapivirine Vaginal Ring-004 Inserted at Monthly Intervals, in an Open-label Trial | Trial Month 6. The month the ring was used is defined as the month the ring was dispensed. | 20.77 mg | Standard Deviation 1.406 |
| Dapivirine Vaginal Ring-004 | Adherence to the Use of the 25 mg Dapivirine Vaginal Ring-004 Inserted at Monthly Intervals, in an Open-label Trial | Trial Month 7. The month the ring was used is defined as the month the ring was dispensed | 20.44 mg | Standard Deviation 1.445 |
| Dapivirine Vaginal Ring-004 | Adherence to the Use of the 25 mg Dapivirine Vaginal Ring-004 Inserted at Monthly Intervals, in an Open-label Trial | Trial Month 8. The month the ring was used is defined as the month the ring was dispensed. | 20.59 mg | Standard Deviation 1.446 |
| Dapivirine Vaginal Ring-004 | Adherence to the Use of the 25 mg Dapivirine Vaginal Ring-004 Inserted at Monthly Intervals, in an Open-label Trial | Trial Month 9.The month the ring was used is defined as the month the ring was dispensed. | 20.72 mg | Standard Deviation 1.583 |
| Dapivirine Vaginal Ring-004 | Adherence to the Use of the 25 mg Dapivirine Vaginal Ring-004 Inserted at Monthly Intervals, in an Open-label Trial | Trial Month 10. The month the ring was used is defined as the month the ring was dispensed. | 20.47 mg | Standard Deviation 1.575 |
| Dapivirine Vaginal Ring-004 | Adherence to the Use of the 25 mg Dapivirine Vaginal Ring-004 Inserted at Monthly Intervals, in an Open-label Trial | Trial Month 11. The month the ring was used is defined as the month the ring was dispensed. | 20.82 mg | Standard Deviation 1.626 |
| Dapivirine Vaginal Ring-004 | Adherence to the Use of the 25 mg Dapivirine Vaginal Ring-004 Inserted at Monthly Intervals, in an Open-label Trial | Trial Month 12. The month the ring was used is defined as the month the ring was dispensed | 20.84 mg | Standard Deviation 1.459 |
| Dapivirine Vaginal Ring-004 | Adherence to the Use of the 25 mg Dapivirine Vaginal Ring-004 Inserted at Monthly Intervals, in an Open-label Trial | Trial Month 13. The month the ring was used is defined as the month the ring was dispensed | 20.49 mg | Standard Deviation 1.371 |
| Dapivirine Vaginal Ring-004 | Adherence to the Use of the 25 mg Dapivirine Vaginal Ring-004 Inserted at Monthly Intervals, in an Open-label Trial | Trial Month 14. The month the ring was used is defined as the month the ring was dispensed. | 20.81 mg | Standard Deviation 1.355 |
| Dapivirine Vaginal Ring-004 | Adherence to the Use of the 25 mg Dapivirine Vaginal Ring-004 Inserted at Monthly Intervals, in an Open-label Trial | Trial Month 15. The month the ring was used is defined as the month the ring was dispensed. | 20.92 mg | Standard Deviation 1.668 |
| Dapivirine Vaginal Ring-004 | Adherence to the Use of the 25 mg Dapivirine Vaginal Ring-004 Inserted at Monthly Intervals, in an Open-label Trial | Trial Month 16. The month the ring was used is defined as the month the ring was dispensed. | 20.20 mg | Standard Deviation 1.273 |
Primary
The Safety Profile of the 25 mg Dapivirine Vaginal Ring-004, When Inserted at Monthly Intervals. Participants Attended RC at Monthly Visits (up to Max of Three Monthly Visits) Followed by 3-monthly Follow-up Visits.
Safety assessments included adverse event (AE) reporting; all product-related AEs, Grade 3 or 4 AEs, SAEs.
Time frame: at least 12 months and up to 17 months
Population: The safety population included all participants who were enrolled, and received and inserted at least one DVR.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Dapivirine Vaginal Ring-004 | The Safety Profile of the 25 mg Dapivirine Vaginal Ring-004, When Inserted at Monthly Intervals. Participants Attended RC at Monthly Visits (up to Max of Three Monthly Visits) Followed by 3-monthly Follow-up Visits. | At least one product-related TEAE | 6 Participants |
| Dapivirine Vaginal Ring-004 | The Safety Profile of the 25 mg Dapivirine Vaginal Ring-004, When Inserted at Monthly Intervals. Participants Attended RC at Monthly Visits (up to Max of Three Monthly Visits) Followed by 3-monthly Follow-up Visits. | TEAEs leading to death | 1 Participants |
| Dapivirine Vaginal Ring-004 | The Safety Profile of the 25 mg Dapivirine Vaginal Ring-004, When Inserted at Monthly Intervals. Participants Attended RC at Monthly Visits (up to Max of Three Monthly Visits) Followed by 3-monthly Follow-up Visits. | TEAEs leading to temporary IP discontinuation | 2 Participants |
| Dapivirine Vaginal Ring-004 | The Safety Profile of the 25 mg Dapivirine Vaginal Ring-004, When Inserted at Monthly Intervals. Participants Attended RC at Monthly Visits (up to Max of Three Monthly Visits) Followed by 3-monthly Follow-up Visits. | At least one treatment emergent adverse event (TEAE) | 616 Participants |
| Dapivirine Vaginal Ring-004 | The Safety Profile of the 25 mg Dapivirine Vaginal Ring-004, When Inserted at Monthly Intervals. Participants Attended RC at Monthly Visits (up to Max of Three Monthly Visits) Followed by 3-monthly Follow-up Visits. | At least one serious TEAE | 20 Participants |
| Dapivirine Vaginal Ring-004 | The Safety Profile of the 25 mg Dapivirine Vaginal Ring-004, When Inserted at Monthly Intervals. Participants Attended RC at Monthly Visits (up to Max of Three Monthly Visits) Followed by 3-monthly Follow-up Visits. | At least one serious non-TEAE | 3 Participants |
| Dapivirine Vaginal Ring-004 | The Safety Profile of the 25 mg Dapivirine Vaginal Ring-004, When Inserted at Monthly Intervals. Participants Attended RC at Monthly Visits (up to Max of Three Monthly Visits) Followed by 3-monthly Follow-up Visits. | At least one DAIDS Grade 3 or 4 TEAE | 37 Participants |
| Dapivirine Vaginal Ring-004 | The Safety Profile of the 25 mg Dapivirine Vaginal Ring-004, When Inserted at Monthly Intervals. Participants Attended RC at Monthly Visits (up to Max of Three Monthly Visits) Followed by 3-monthly Follow-up Visits. | Urogenital TEAEs | 410 Participants |
| Dapivirine Vaginal Ring-004 | The Safety Profile of the 25 mg Dapivirine Vaginal Ring-004, When Inserted at Monthly Intervals. Participants Attended RC at Monthly Visits (up to Max of Three Monthly Visits) Followed by 3-monthly Follow-up Visits. | Social harms reported as TEAEs | 8 Participants |
| Dapivirine Vaginal Ring-004 | The Safety Profile of the 25 mg Dapivirine Vaginal Ring-004, When Inserted at Monthly Intervals. Participants Attended RC at Monthly Visits (up to Max of Three Monthly Visits) Followed by 3-monthly Follow-up Visits. | Non-TEAEs | 31 Participants |
Secondary
Incidence of HIV-1 Seroconversion
Rapid and specialised laboratory testing according to a pre-specified HIV testing algorithm
Time frame: at least 12 months and up to 17 months
Population: This population excluded all participants who were included in the safety population but who were found to have been HIV-1 infected at the Enrollment Visit (ie, participants who had seroconverted after enrollment but were retrospectively found to be HIV-1 infected at enrollment).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dapivirine Vaginal Ring-004 | Incidence of HIV-1 Seroconversion | 1.8 events per 100 person-years |
Secondary
Number of Participants Who Acquired HIV-1 With HIV-1 Drug Resistance-associated Mutations. Infection
Viral genotype (including NGS) resistance testing methods which include sensitive methods to detect low frequency drug-resistant variants.
Time frame: at least 12 months and up to 17 months
Population: The virology population included all HIV infected participants in the m-ITT population, with the exception of those participants who seroconverted after LPUV. That is, participants who were HIV-1 RNA negative at LPUV, and who became infected after LPUV, were excluded. Genotypic analyses from the small numbers of participants with infection at enrollment, or with no detectable HIV-1 RNA at the LPUV but with seroconversion at the Exit Visit, were described individually.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dapivirine Vaginal Ring-004 | Number of Participants Who Acquired HIV-1 With HIV-1 Drug Resistance-associated Mutations. Infection | 5 Participants |