Trial Outcomes & Findings for To Assess Continued Safety of and Adherence to the Dapivirine (25 mg) Vaginal Ring-004 in Healthy, HIV-negative Women (NCT NCT02862171)

NCT ID: NCT02862171

Last Updated: 2022-10-25

Results Overview

Safety assessments included adverse event (AE) reporting; all product-related AEs, Grade 3 or 4 AEs, SAEs.

• Recruitment status: COMPLETED
• Study phase: PHASE3
• Target enrollment: 941 participants
• Primary outcome timeframe: at least 12 months and up to 17 months
• Results posted on: 2022-10-25

Participant Flow

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.

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.

Participant milestones

Measure	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 at least 12 months. 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
Overall Study STARTED	941
Overall Study COMPLETED	848
Overall Study NOT COMPLETED	93

Reasons for withdrawal

Measure	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 at least 12 months. 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
Overall Study Death	1
Overall Study Lost to Follow-up	13
Overall Study Withdrawal by Subject	57
Overall Study Non-compliance	4
Overall Study HIV-1 seroconversion	18

Baseline Characteristics

To Assess Continued Safety of and Adherence to the Dapivirine (25 mg) Vaginal Ring-004 in Healthy, HIV-negative Women

Baseline characteristics by cohort

Measure	Dapivirine Vaginal Ring-004 n=941 Participants 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
Age, Customized 18 - 45 years	30.1 years STANDARD_DEVIATION 6.32 • n=5 Participants
Sex: Female, Male Female	941 Participants n=5 Participants
Sex: Female, Male Male	0 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	931 Participants n=5 Participants
Race (NIH/OMB) White	0 Participants n=5 Participants
Race (NIH/OMB) More than one race	10 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants
Region of Enrollment South Africa	820 participants n=5 Participants
Region of Enrollment Uganda	121 participants n=5 Participants

PRIMARY outcome

Timeframe: 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.

Safety assessments included adverse event (AE) reporting; all product-related AEs, Grade 3 or 4 AEs, SAEs.

Outcome measures

Measure	Dapivirine Vaginal Ring-004 n=941 Participants 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 at least 12 months. 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
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
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
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
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
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
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
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
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
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
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

PRIMARY outcome

Timeframe: 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.

Determined dapivirine residual amounts in returned used vaginal rings.

Outcome measures

Measure	Dapivirine Vaginal Ring-004 n=941 Participants 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 at least 12 months. 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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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

SECONDARY outcome

Timeframe: 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).

Rapid and specialised laboratory testing according to a pre-specified HIV testing algorithm

Outcome measures

Measure

Dapivirine Vaginal Ring-004 n=938 Participants 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 at least 12 months. 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

Incidence of HIV-1 Seroconversion

1.8 events per 100 person-years

SECONDARY outcome

Timeframe: 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.

Viral genotype (including NGS) resistance testing methods which include sensitive methods to detect low frequency drug-resistant variants.

Outcome measures

Measure

Dapivirine Vaginal Ring-004 n=18 Participants 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 at least 12 months. 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

Number of Participants Who Acquired HIV-1 With HIV-1 Drug Resistance-associated Mutations. Infection

5 Participants

Adverse Events

Dapivirine Vaginal Ring-004

Serious events: 20 serious events

Other events: 616 other events

Deaths: 1 deaths

Serious adverse events

Measure	Dapivirine Vaginal Ring-004 n=941 participants at risk 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 at least 12 months. 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
Injury, poisoning and procedural complications Stab wound, ankle fracture, fibula fracture, muscle strain, soft tissue injury, thermal burn	0.74% 7/941 • Number of events 7 • Adverse events were collected over a minimum period of 12 months and a maximum of 17 months per participant. Treatment-emergent adverse events were defined as AEs which occurred/worsened after the first insertion of the IP, up to 6 weeks after last ring use.
Infections and infestations Meningitis tuberculous, Pyelonephritis, Sepsis, vuval abscess	0.43% 4/941 • Number of events 4 • Adverse events were collected over a minimum period of 12 months and a maximum of 17 months per participant. Treatment-emergent adverse events were defined as AEs which occurred/worsened after the first insertion of the IP, up to 6 weeks after last ring use.
Pregnancy, puerperium and perinatal conditions Abortion spontaneous	0.21% 2/941 • Number of events 2 • Adverse events were collected over a minimum period of 12 months and a maximum of 17 months per participant. Treatment-emergent adverse events were defined as AEs which occurred/worsened after the first insertion of the IP, up to 6 weeks after last ring use.
Vascular disorders Hypertension, Hypertensive crisis	0.21% 2/941 • Number of events 2 • Adverse events were collected over a minimum period of 12 months and a maximum of 17 months per participant. Treatment-emergent adverse events were defined as AEs which occurred/worsened after the first insertion of the IP, up to 6 weeks after last ring use.
General disorders Sudden death	0.11% 1/941 • Number of events 1 • Adverse events were collected over a minimum period of 12 months and a maximum of 17 months per participant. Treatment-emergent adverse events were defined as AEs which occurred/worsened after the first insertion of the IP, up to 6 weeks after last ring use.
Metabolism and nutrition disorders Diabetes mellitus	0.11% 1/941 • Number of events 1 • Adverse events were collected over a minimum period of 12 months and a maximum of 17 months per participant. Treatment-emergent adverse events were defined as AEs which occurred/worsened after the first insertion of the IP, up to 6 weeks after last ring use.
Nervous system disorders Headache	0.11% 1/941 • Number of events 1 • Adverse events were collected over a minimum period of 12 months and a maximum of 17 months per participant. Treatment-emergent adverse events were defined as AEs which occurred/worsened after the first insertion of the IP, up to 6 weeks after last ring use.
Psychiatric disorders Anxiety	0.11% 1/941 • Number of events 1 • Adverse events were collected over a minimum period of 12 months and a maximum of 17 months per participant. Treatment-emergent adverse events were defined as AEs which occurred/worsened after the first insertion of the IP, up to 6 weeks after last ring use.
Reproductive system and breast disorders Cervical dysplasia	0.11% 1/941 • Number of events 1 • Adverse events were collected over a minimum period of 12 months and a maximum of 17 months per participant. Treatment-emergent adverse events were defined as AEs which occurred/worsened after the first insertion of the IP, up to 6 weeks after last ring use.

Other adverse events

Measure	Dapivirine Vaginal Ring-004 n=941 participants at risk 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 at least 12 months. 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
Infections and infestations Infections	49.1% 462/941 • Number of events 462 • Adverse events were collected over a minimum period of 12 months and a maximum of 17 months per participant. Treatment-emergent adverse events were defined as AEs which occurred/worsened after the first insertion of the IP, up to 6 weeks after last ring use.
Reproductive system and breast disorders Reproductive system	20.9% 197/941 • Number of events 197 • Adverse events were collected over a minimum period of 12 months and a maximum of 17 months per participant. Treatment-emergent adverse events were defined as AEs which occurred/worsened after the first insertion of the IP, up to 6 weeks after last ring use.
Nervous system disorders Headache	3.5% 33/941 • Number of events 51 • Adverse events were collected over a minimum period of 12 months and a maximum of 17 months per participant. Treatment-emergent adverse events were defined as AEs which occurred/worsened after the first insertion of the IP, up to 6 weeks after last ring use.
Gastrointestinal disorders Gastritis	3.0% 28/941 • Number of events 105 • Adverse events were collected over a minimum period of 12 months and a maximum of 17 months per participant. Treatment-emergent adverse events were defined as AEs which occurred/worsened after the first insertion of the IP, up to 6 weeks after last ring use.
Musculoskeletal and connective tissue disorders Back pain	2.8% 26/941 • Number of events 73 • Adverse events were collected over a minimum period of 12 months and a maximum of 17 months per participant. Treatment-emergent adverse events were defined as AEs which occurred/worsened after the first insertion of the IP, up to 6 weeks after last ring use.
Vascular disorders Hypertension	2.0% 19/941 • Number of events 20 • Adverse events were collected over a minimum period of 12 months and a maximum of 17 months per participant. Treatment-emergent adverse events were defined as AEs which occurred/worsened after the first insertion of the IP, up to 6 weeks after last ring use.

Additional Information

Dr John Steytler

International Partnership for Microbicides

Phone: +27 21 8602300

Email: jsteytler@ipmglobal.org

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place