HIV Infections
Conditions
Keywords
HIV Infections, Anti-HIV agents, HIV-1
Brief summary
This is a double-blind, randomised, placebo-controlled study to assess the safety and efficacy of a silicone elastomer vaginal matrix ring.
Detailed description
A Multi-Center, Randomized, Double-Blind, Placebo-Controlled Phase 3 Safety and Effectiveness Trial of a Vaginal Matrix Ring Containing Dapivirine for the Prevention of HIV-1 Infection in Women. MTN-020 will enroll approximately 3676 sexually active HIVnegative women aged 18-45 years randomized in a 1:1 ratio to receive either a vaginal ring containing 25 mg of dapivirine or a placebo vaginal ring. Rings will be inserted once every 28 days for 12 consecutive months. MTN expects to initiate this study in August 2012.
Interventions
COMBINATION_PRODUCTDapivirine Vaginal Ring
Dosage form: vaginal ring Dosage: 25mg Frequency: monthly Duration: 12 months
COMBINATION_PRODUCTPlacebo Ring
Vaginal ring containing no drug substance
Sponsors
National Institute of Allergy and Infectious Diseases (NIAID)
International Partnership for Microbicides, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 45 Years
Healthy volunteers
Yes
Inclusion criteria
* Age 18 through 45 years (inclusive) at screening, verified per site SOPs; within this range, sites may restrict the upper age limit per site SOPs, to target women at high risk of HIV infection * Able and willing to provide written informed consent to be screened for and to take part in the study * Able and willing to provide adequate locator information, as defined in site SOPs * HIV-uninfected based on testing performed by study staff at screening and enrollment (per applicable algorithm in Appendix II) * Per participant report, sexually active, defined as having vaginal intercourse at least once in the 3 months prior to screening * Using an effective method of contraception at enrollment, and intending to use an effective method for the duration of study participation; effective methods include hormonal methods (except contraceptive ring); intrauterine device (IUD); and sterilization (of participant, as defined in site SOPs) * 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 -- Note: Tampons may be used for the duration of the trial.
Exclusion criteria
* Per participant report at screening: * Intends to become pregnant during study participation * Plans to relocate away from the study site during study participation * Plans to travel away from the study site for more than 8 consecutive weeks during study participation * Is pregnant \-- Note: A documented negative pregnancy test performed by study staff is required for inclusion; however a self-reported pregnancy is adequate for exclusion from the study. * Currently breastfeeding * Diagnosed with urinary tract infection (UTI) \-- Note: Otherwise eligible participants diagnosed with UTI during screening are offered treatment and may be enrolled after completing treatment and all symptoms have resolved. If treatment is completed and symptoms have resolved within 28 days of obtaining informed consent for screening, the participant may be enrolled. * Diagnosed with pelvic inflammatory disease, an STI or reproductive tract infection (RTI) requiring treatment per current WHO guidelines \-- Note: Otherwise eligible participants diagnosed during screening with pelvic inflammatory disease or STI/RTI requiring treatment per WHO guidelines - other than asymptomatic BV and asymptomatic candidiasis - are offered treatment and may be enrolled after completing treatment and all symptoms have resolved. If treatment is completed and symptoms have resolved within 28 days of obtaining informed consent for screening, the participant may be enrolled. Genital warts requiring treatment also must be treated prior to enrollment. Genital warts requiring therapy are defined as those that cause undue burden or discomfort to the participant, including bulky size, unacceptable appearance, or physical discomfort. * Has a clinically apparent Grade 2 or higher pelvic exam finding (observed by study staff) as per the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events Version 1.0, December, 2004 (Clarification dated August 2009), Addendum 1-Female Genital Grading Table for Use in Microbicide Studies * 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 Investigator of Record (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 28 days of providing informed consent for screening, the participant may be enrolled. * Participant report and/or clinical evidence of any of the following: * Known adverse reaction to any of the study products (ever) * Known adverse reaction to latex (ever) * Chronic vaginal candidiasis * Non-therapeutic injection drug use in the 12 months prior to Screening * Post-exposure prophylaxis (PEP) for HIV exposure within 6 months prior to enrollment * Last pregnancy outcome 90 days or less prior to enrollment * Gynecologic or genital procedure (e.g., tubal ligation, dilation and curettage, piercing) 90 days or less prior to enrollment * Recent participation in any other research study involving drugs, medical devices, vaginal products, or vaccines, within 60 days of enrollment * Participation in the MTN-003, Vaginal and Oral Interventions to Control the Epidemic (VOICE) clinical trial, or any other HIV prevention study using systemic or topical antiretroviral medications, within 12 months of enrollment * As determined by the IoR/designee, any significant uncontrolled active or chronic cardiovascular, renal, liver, hematologic, neurologic, gastrointestinal, psychiatric, endocrine, respiratory, immunologic disorder or infectious disease, including active tuberculosis * Has any of the following laboratory abnormalities at Screening Visit: * Aspartate aminotransferase (AST) or alanine transaminase (ALT) Grade 1 or higher as per the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events Version 1.0, December, 2004 (Clarification dated August 2009) * Creatinine Grade 2 or higher as per the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events Version 1.0, December, 2004 (Clarification dated August 2009) * Hemoglobin Grade 2 or higher as per the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events Version 1.0, December, 2004 (Clarification dated August 2009) * Platelet count Grade 1 or higher as per the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events Version 1.0, December, 2004 (Clarification dated August 2009) * Pap result Grade 2 or higher according to the 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) * Note: Otherwise eligible participants with an exclusionary test may be re-tested during the screening process. * Note: Women with a documented normal result within the 12 months prior to enrollment need not have Pap smear during the screening period. Women with a Grade 1 abnormal Pap smear can be enrolled upon completion of the initial phase of evaluation if no current treatment is indicated (based on local standard of care for management of abnormal cervical cytology). Need for a repeat Pap within 6 months does not preclude enrollment prior to that result becoming available. * 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 the study objectives
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Efficacy as Determined by the Proportion of Women in Each Arm With HIV-1 Seroconversion After 120 Endpoints Are Observed in the Trial. | minimum of 12 months and a maximum of 14 months per participant | The primary endpoint is HIV-1 seroconversion as measured by rapid and specialised laboratory testing according to comprehensive HIV testing algorithm. Endpoint confirmation of HIV infection is by Western Blot. |
| The Number of Participants That Experienced Grade 2, 3, 4 and Serious Adverse Events Over the Investigational Product Used Period (25 mg Dapivirine Administered in a Silicone Elastomer Vaginal Matrix Ring (DVR), Inserted Once Every 4 Weeks). | minimum of 12 months and a maximum of 14 months per participant | Participants with grade 2 adverse events, judged to be related to investigational product, grade 3 and grade 4 adverse events and all serious adverse events. DAIDS severity grades are defined as follows: Grade 1 = mild Grade 2 = moderate Grade 3 = severe Grade 4 = potentially life-threatening Grade 5 = death |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Adherence to the Dapivirine Vaginal Ring. | 12 months per participant | Dapivirine residual levels in used rings and dapivirine plasma concentrations are two objective measures of adherence to DVR ring use. Adherence was defined as a dapivirine ring residual level \<=23.5 mg and dapivirine plasma level \>= 95 pg/mL. |
| Acceptability of the DVR and Placebo Vaginal Ring | 12 months per participant | Questionnaires and qualitative data regarding the acceptability of use of a vaginal ring inserted once every 4 weeks over the trial period; Percentage of participants with positive response. Response of 'likely' or 'very likely' to the question: 'If in the future a vaginal ring was available that provided some protection against HIV, and it was similar to the one you used in this trial, how likely would you be to keep it inserted in your vagina every day?' |
| Human Immunodeficiency Virus Type 1 Drug Resistance Mutations Among Participants Who Acquired HIV-1 Infection. | minimum of 12 months and a maximum of 14 months per participant | The analysis of HIV-1 drug resistance will be primarily descriptive in nature, and will depend on the pattern of resistance mutations observed in the HIV-1 seroconverters. The percentage of HIV-1 seroconverters with at least one HIV-1 drug resistant mutation will be presented overall, and by treatment arm, with corresponding 95% CIs. |
Countries
Malawi, South Africa, Uganda, Zimbabwe
Participant flow
Recruitment details
Participants provided written informed consent were invited to screen for the clinical trial. Each participant engaged in the screening process for up to 4 weeks (28 days) prior to enrollment. Participants who complied with inclusion and exclusion criteria were invited to enroll in the trial. Participants were randomized in a 1:1 ratio to either the Dapivirine Vaginal Ring or placebo ring group.
Pre-assignment details
Healthy, sexually active HIV-negative women who provided written informed consent were invited to screen for the clinical trial. Each participant engaged in the screening process for up to 4 weeks (28 days) prior to enrollment. Participants who complied with all the inclusion and none of the exclusion criteria were invited to enroll in the clinical trial. Eligible participants were randomly assigned in a 1:1 ratio to either the Dapivirine Vaginal Ring-004 or placebo ring group.
Participants by arm
| Arm | Count |
|---|---|
| Dapivirine Vaginal Ring Vaginal ring containing 25mg dapivirine
Dapivirine Vaginal Ring: Dosage form: vaginal ring Dosage: 25mg Frequency: monthly Duration: 12 months | 1,313 |
| Placebo Ring Vaginal ring containing no drug substance
Placebo Ring: Vaginal ring containing no drug substance | 1,316 |
| Total | 2,629 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 4 | 3 |
| Overall Study | Lost to Follow-up | 37 | 32 |
| Overall Study | Other | 1 | 3 |
| Overall Study | Physician Decision | 10 | 18 |
| Overall Study | Withdrawal by Subject | 96 | 81 |
Baseline characteristics
| Characteristic | Dapivirine Vaginal Ring | Placebo Ring | Total |
|---|---|---|---|
| Age, Continuous | 27.2 years STANDARD_DEVIATION 6.09 | 27.3 years STANDARD_DEVIATION 6.28 | 27.2 years STANDARD_DEVIATION 6.18 |
| BMI | 26.8 kg/(m^2) STANDARD_DEVIATION 6.41 | 27.2 kg/(m^2) STANDARD_DEVIATION 6.93 | 27.0 kg/(m^2) STANDARD_DEVIATION 6.68 |
| Education Status Less than Secondary School | 212 Participants | 192 Participants | 404 Participants |
| Education Status Secondary School and Higher | 1101 Participants | 1124 Participants | 2225 Participants |
| Has children | 1188 Participants | 1177 Participants | 2365 Participants |
| Has main partner Missing | 0 Participants | 1 Participants | 1 Participants |
| Has main partner No | 6 Participants | 6 Participants | 12 Participants |
| Has main partner Yes | 1307 Participants | 1309 Participants | 2616 Participants |
| Marital Status Married | 527 Participants | 547 Participants | 1074 Participants |
| Marital Status Missing | 0 Participants | 2 Participants | 2 Participants |
| Marital Status Non-Married | 786 Participants | 767 Participants | 1553 Participants |
| Number of sex partners in the last 3 months 0-1 partners | 1101 Participants | 1089 Participants | 2190 Participants |
| Number of sex partners in the last 3 months >2 | 212 Participants | 227 Participants | 439 Participants |
| Partner knowledge of ring use Missing | 0 Participants | 1 Participants | 1 Participants |
| Partner knowledge of ring use No | 478 Participants | 470 Participants | 948 Participants |
| Partner knowledge of ring use Yes | 835 Participants | 845 Participants | 1680 Participants |
| Presence of STIs | 268 Participants | 265 Participants | 533 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 13 Participants | 3 Participants | 16 Participants |
| Race (NIH/OMB) Black or African American | 1228 Participants | 1226 Participants | 2454 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 | 70 Participants | 87 Participants | 157 Participants |
| Race (NIH/OMB) White | 2 Participants | 0 Participants | 2 Participants |
| Region of Enrollment Malawi | 135 Participants | 137 Participants | 272 Participants |
| Region of Enrollment South Africa | 713 Participants | 713 Participants | 1426 Participants |
| Region of Enrollment Uganda | 127 Participants | 126 Participants | 253 Participants |
| Region of Enrollment Zimbabwe | 338 Participants | 340 Participants | 678 Participants |
| Sex: Female, Male Female | 1313 Participants | 1316 Participants | 2629 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 | 4 / 1,313 | 3 / 1,316 |
| other Total, other adverse events | 1,237 / 1,313 | 1,041 / 1,316 |
| serious Total, serious adverse events | 116 / 1,313 | 130 / 1,316 |
Outcome results
Primary
Efficacy as Determined by the Proportion of Women in Each Arm With HIV-1 Seroconversion After 120 Endpoints Are Observed in the Trial.
The primary endpoint is HIV-1 seroconversion as measured by rapid and specialised laboratory testing according to comprehensive HIV testing algorithm. Endpoint confirmation of HIV infection is by Western Blot.
Time frame: minimum of 12 months and a maximum of 14 months per participant
Population: The primary effectiveness Cohort included all eligible randomised participants excluding participants deemed to be HIV-1 RNA positive at the time of randomization, based on retrospective PCR testing of stored blood samples taken at enrollment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dapivirine Vaginal Ring | Efficacy as Determined by the Proportion of Women in Each Arm With HIV-1 Seroconversion After 120 Endpoints Are Observed in the Trial. | 71 Participants |
| Placebo Ring | Efficacy as Determined by the Proportion of Women in Each Arm With HIV-1 Seroconversion After 120 Endpoints Are Observed in the Trial. | 97 Participants |
Primary
The Number of Participants That Experienced Grade 2, 3, 4 and Serious Adverse Events Over the Investigational Product Used Period (25 mg Dapivirine Administered in a Silicone Elastomer Vaginal Matrix Ring (DVR), Inserted Once Every 4 Weeks).
Participants with grade 2 adverse events, judged to be related to investigational product, grade 3 and grade 4 adverse events and all serious adverse events. DAIDS severity grades are defined as follows: Grade 1 = mild Grade 2 = moderate Grade 3 = severe Grade 4 = potentially life-threatening Grade 5 = death
Time frame: minimum of 12 months and a maximum of 14 months per participant
Population: The Primary Safety Cohort (or ITT Cohort) included all eligible, randomized participants. All participants were analyzed as members of the treatment group to which they were randomized regardless of adherence to the planned course of treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dapivirine Vaginal Ring | The Number of Participants That Experienced Grade 2, 3, 4 and Serious Adverse Events Over the Investigational Product Used Period (25 mg Dapivirine Administered in a Silicone Elastomer Vaginal Matrix Ring (DVR), Inserted Once Every 4 Weeks). | 1237 Participants |
| Placebo Ring | The Number of Participants That Experienced Grade 2, 3, 4 and Serious Adverse Events Over the Investigational Product Used Period (25 mg Dapivirine Administered in a Silicone Elastomer Vaginal Matrix Ring (DVR), Inserted Once Every 4 Weeks). | 1231 Participants |
Secondary
Acceptability of the DVR and Placebo Vaginal Ring
Questionnaires and qualitative data regarding the acceptability of use of a vaginal ring inserted once every 4 weeks over the trial period; Percentage of participants with positive response. Response of 'likely' or 'very likely' to the question: 'If in the future a vaginal ring was available that provided some protection against HIV, and it was similar to the one you used in this trial, how likely would you be to keep it inserted in your vagina every day?'
Time frame: 12 months per participant
Population: The Primary Safety Cohort (or ITT Cohort) included all eligible, randomized participants. Acceptability was reported for participant who provided responses to acceptability questionnaires.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dapivirine Vaginal Ring | Acceptability of the DVR and Placebo Vaginal Ring | 95.9 percentage of participants with data |
| Placebo Ring | Acceptability of the DVR and Placebo Vaginal Ring | 96.8 percentage of participants with data |
Secondary
Adherence to the Dapivirine Vaginal Ring.
Dapivirine residual levels in used rings and dapivirine plasma concentrations are two objective measures of adherence to DVR ring use. Adherence was defined as a dapivirine ring residual level \<=23.5 mg and dapivirine plasma level \>= 95 pg/mL.
Time frame: 12 months per participant
Population: Adherence is defined by a dapivirine residual level in returned used rings ≤ 23.5 mg and a dapivirine plasma concentration ≥ 95 pg/mL (if they are both available; otherwise categorisation was based on the available measurement. The objective measures (dapivirine residual levels in used rings and dapivirine plasma concentrations) used can only be determined for participants who used the active vaginal dapivirine ring.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Dapivirine Vaginal Ring | Adherence to the Dapivirine Vaginal Ring. | Month 28 | 263 participants with data |
| Dapivirine Vaginal Ring | Adherence to the Dapivirine Vaginal Ring. | Month 29 | 258 participants with data |
| Dapivirine Vaginal Ring | Adherence to the Dapivirine Vaginal Ring. | Month 30 | 251 participants with data |
| Dapivirine Vaginal Ring | Adherence to the Dapivirine Vaginal Ring. | Month 32 | 130 participants with data |
| Dapivirine Vaginal Ring | Adherence to the Dapivirine Vaginal Ring. | Month 33 | 120 participants with data |
| Dapivirine Vaginal Ring | Adherence to the Dapivirine Vaginal Ring. | Month 34 | 4 participants with data |
| Dapivirine Vaginal Ring | Adherence to the Dapivirine Vaginal Ring. | Month 31 | 133 participants with data |
| Dapivirine Vaginal Ring | Adherence to the Dapivirine Vaginal Ring. | Month 1 | 443 participants with data |
| Dapivirine Vaginal Ring | Adherence to the Dapivirine Vaginal Ring. | Month 2 | 460 participants with data |
| Dapivirine Vaginal Ring | Adherence to the Dapivirine Vaginal Ring. | Month 3 | 953 participants with data |
| Dapivirine Vaginal Ring | Adherence to the Dapivirine Vaginal Ring. | Month 4 | 537 participants with data |
| Dapivirine Vaginal Ring | Adherence to the Dapivirine Vaginal Ring. | Month 5 | 573 participants with data |
| Dapivirine Vaginal Ring | Adherence to the Dapivirine Vaginal Ring. | Month 6 | 963 participants with data |
| Dapivirine Vaginal Ring | Adherence to the Dapivirine Vaginal Ring. | Month 7 | 687 participants with data |
| Dapivirine Vaginal Ring | Adherence to the Dapivirine Vaginal Ring. | Month 8 | 699 participants with data |
| Dapivirine Vaginal Ring | Adherence to the Dapivirine Vaginal Ring. | Month 9 | 943 participants with data |
| Dapivirine Vaginal Ring | Adherence to the Dapivirine Vaginal Ring. | Month 10 | 830 participants with data |
| Dapivirine Vaginal Ring | Adherence to the Dapivirine Vaginal Ring. | Month 11 | 916 participants with data |
| Dapivirine Vaginal Ring | Adherence to the Dapivirine Vaginal Ring. | Month 12 | 922 participants with data |
| Dapivirine Vaginal Ring | Adherence to the Dapivirine Vaginal Ring. | Month 13 | 872 participants with data |
| Dapivirine Vaginal Ring | Adherence to the Dapivirine Vaginal Ring. | Month 14 | 858 participants with data |
| Dapivirine Vaginal Ring | Adherence to the Dapivirine Vaginal Ring. | Month 15 | 793 participants with data |
| Dapivirine Vaginal Ring | Adherence to the Dapivirine Vaginal Ring. | Month 16 | 704 participants with data |
| Dapivirine Vaginal Ring | Adherence to the Dapivirine Vaginal Ring. | Month 17 | 701 participants with data |
| Dapivirine Vaginal Ring | Adherence to the Dapivirine Vaginal Ring. | Month 18 | 675 participants with data |
| Dapivirine Vaginal Ring | Adherence to the Dapivirine Vaginal Ring. | Month 19 | 600 participants with data |
| Dapivirine Vaginal Ring | Adherence to the Dapivirine Vaginal Ring. | Month 20 | 598 participants with data |
| Dapivirine Vaginal Ring | Adherence to the Dapivirine Vaginal Ring. | Month 21 | 576 participants with data |
| Dapivirine Vaginal Ring | Adherence to the Dapivirine Vaginal Ring. | Month 22 | 499 participants with data |
| Dapivirine Vaginal Ring | Adherence to the Dapivirine Vaginal Ring. | Month 23 | 485 participants with data |
| Dapivirine Vaginal Ring | Adherence to the Dapivirine Vaginal Ring. | Month 24 | 471 participants with data |
| Dapivirine Vaginal Ring | Adherence to the Dapivirine Vaginal Ring. | Month 25 | 391 participants with data |
| Dapivirine Vaginal Ring | Adherence to the Dapivirine Vaginal Ring. | Month 26 | 384 participants with data |
| Dapivirine Vaginal Ring | Adherence to the Dapivirine Vaginal Ring. | Month 27 | 367 participants with data |
Secondary
Human Immunodeficiency Virus Type 1 Drug Resistance Mutations Among Participants Who Acquired HIV-1 Infection.
The analysis of HIV-1 drug resistance will be primarily descriptive in nature, and will depend on the pattern of resistance mutations observed in the HIV-1 seroconverters. The percentage of HIV-1 seroconverters with at least one HIV-1 drug resistant mutation will be presented overall, and by treatment arm, with corresponding 95% CIs.
Time frame: minimum of 12 months and a maximum of 14 months per participant
Population: The virology population included all ITT participants with seroconversion, excluding those who never received investigational product, or were retrospectively found to be HIV-1 RNA positive at enrollment (m-ITT) or were HIV-1 infected after discontinuation of ring use. Seroconversions among participants who were continued on open-label DVR-004 were included in the DVR-004 group, independent of initial randomization.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dapivirine Vaginal Ring | Human Immunodeficiency Virus Type 1 Drug Resistance Mutations Among Participants Who Acquired HIV-1 Infection. | 68 Participants |
| Placebo Ring | Human Immunodeficiency Virus Type 1 Drug Resistance Mutations Among Participants Who Acquired HIV-1 Infection. | 96 Participants |