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 safety and efficacy trial of a Dapivirine Vaginal Matrix Ring in healthy HIV-negative women.
Interventions
COMBINATION_PRODUCTPlacebo Vaginal Ring
Dapivirine Vaginal Ring containing 0.0 mg of dapivirine
COMBINATION_PRODUCTDapivirine Vaginal Ring, 25 mg
Dapivirine Vaginal Ring containing 25 mg of dapivirine
Sponsors
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
* Women \> 18 and \< 45 years of age, at screening, who can provide informed consent; * Available for all visits and consent to follow all procedures scheduled for the trial; * Self-reported sexually active (defined as an average of at least one penetrative penile-vaginal coital act per month for the last 3 months prior to screening); * HIV-negative as determined by the HIV algorithm applied at screening and enrolment; * On a stable form of contraception as defined within section 5.4 and willing to continue on stable contraception for the duration of the clinical trial, unless post-menopausal or surgically sterilised; * Asymptomatic for genital infections at the time of enrolment (if a woman is diagnosed with any clinically significant curable STI, she must have initiated treatment at least 1 week prior to enrolment and have completed the full course of treatment); * 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; * Willing to refrain from participation in another research trial using drugs, vaccines, medical devices, microbicides or oral pre-exposure prophylaxis investigational drugs for the duration of the IPM 027 trial.
Exclusion criteria
* Currently pregnant or last pregnancy within 3 months prior to screening or intends to become pregnant during trial participation; * Currently breast-feeding; * Non-therapeutic injection drug use in the 12 months prior to screening; * Participated in another research trial using drugs, medical devices, microbicides or oral pre-exposure prophylaxis agents within 60 days prior to screening; * Previously participated or currently participating in any HIV vaccine trial; * Untreated, clinically significant urogenital infections , e.g., urinary tract, or other sexually transmitted infections, or other gynaecological symptoms within 1 week prior to enrolment; * Has a Grade 2 or higher pelvic examination finding, according to the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events; Addendum 1 Female Genital Grading Table for Use in Microbicide Studies; * History of significant urogenital or uterine prolapse, undiagnosed vaginal bleeding, diagnosed chronic and/or recurrent vulvovaginal candidiasis, urethral obstruction, incontinence or urge incontinence; * Any gynaecological surgery within 90 days prior to screening; * Any Grade 1 or higher baseline aspartate aminotransferase (AST), alanine transaminase (ALT), or platelet count, and any Grade 2 or higher baseline haematology, chemistry or urinalysis laboratory value according to the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events; * Any history of anaphylaxis or severe allergy resulting in angioedema; or a history of sensitivity/allergy to latex or a silicone elastomer; * Any history of diabetes mellitus and chronic use of oral corticosteroid therapy; and any uncontrolled serious chronic or progressive disease; * Cervical cytology at screening that requires cryotherapy, biopsy or treatment (other than for infection). Women with Grade 1 cervical cytology findings 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); * Any condition(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 |
|---|---|---|
| HIV-1 Seroconversion According to Comprehensive HIV Testing Algorithm. | 24 months | HIV-1 seroconversion measured by rapid and specialised laboratory testing according to the comprehensive HIV testing algorithm. |
| All Adverse Events | 24 months | Self-reports, physical examination, gynaecological assessments, including pelvic/speculum examination, laboratory tests and other indicated investigations. All AEs will be reported, regardless of grade or relatedness. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Pregnancy in Each Trial Arm Over the IP Use Period; | 24 months | The percentage of participants with pregnancies in each treatment group. For each treatment group, the numerator will include the number of participants that had a positive urine pregnancy test during the trial period. |
| The Percentage of Women Who Report Adherence to the Use of the Vaginal Ring Inserted Once Every 4 Weeks Over the Trial Period; | 24 months | Questionnaires and qualitative data regarding sexual behaviour and adherence to the use of a vaginal ring inserted once every 4 weeks over the trial period. Dapivirine residual levels in used rings and dapivirine plasma concentrations are two objective measures of adherence to DVR ring use, |
| The Incidence Rate of HIV-2 Seroconversion. | 24 months | Rapid and specialised laboratory testing according to the comprehensive HIV testing algorithm in Appendix C of protocol. |
| The Percentage of Participants With HIV-1 Drug Resistance Mutations Among Participants Who Acquire HIV-1. | 24 months | 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 proportion 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. |
| The Percentage of Women Who Report the Use of the Vaginal Ring as Acceptable; | 24 months | Questionnaires and qualitative data regarding the acceptability of use of a vaginal ring inserted once every 4 weeks over the trial period; Number 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?' |
| The Incidence of Curable STIs | 24 months | The percentage of participants testing positive for any STI (gonorrhoea, chlamydia, trichomonas, syphilis) will be assessed. |
Countries
South Africa, Uganda
Participant flow
Recruitment details
Participants were screened between 27 March 2012 and 22 Oct 2014. The IPM 027 trial was originally designed with a sample size of approximately 1,650 participants, which was increased to approximately 1,950 participants according to the amended protocol (Protocol Version 1.0 Amendment 3.0, dated 12 September 2013). Participants were recruited and enrolled at 6 RCs in South Africa and 1 RC in Uganda. A total of 3,425 participants were screened, of whom 1,959 participants were enrolled.
Pre-assignment details
Participants who provided written informed consent at Screening Visit 1 were invited to undergo screening assessments for the trial. Participant screening was conducted over two scheduled Screening Visits with a maximum window period of 28 days between the two visits.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Vaginal Ring Vaginal Ring containing 0.0 mg Dapivirine
Placebo Vaginal Ring: Dapivirine Vaginal Ring containing 0.0 mg of dapivirine | 652 |
| Dapivirine Vaginal Ring Vaginal Ring containing 25mg of Dapivirine
Dapivirine Vaginal Ring, 25 mg: Dapivirine Vaginal Ring containing 25 mg of dapivirine | 1,307 |
| Total | 1,959 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 0 |
| Overall Study | Death | 1 | 2 |
| Overall Study | HIV seroconversion-related | 55 | 80 |
| Overall Study | inappropriate enrollment | 0 | 1 |
| Overall Study | Lost to Follow-up | 20 | 54 |
| Overall Study | Multiple Reasons | 3 | 1 |
| Overall Study | Non-compliance | 6 | 8 |
| Overall Study | not HIV seroconversion-related | 93 | 176 |
| Overall Study | Pregnancy | 13 | 29 |
| Overall Study | Withdrawal by Subject | 24 | 54 |
Baseline characteristics
| Characteristic | Placebo Vaginal Ring | Dapivirine Vaginal Ring | Total |
|---|---|---|---|
| Age, Continuous | 26.1 years STANDARD_DEVIATION 5.92 | 25.9 years STANDARD_DEVIATION 5.85 | 26.0 years STANDARD_DEVIATION 5.87 |
| BMI | 28.2 kg/(m^2) STANDARD_DEVIATION 6.8 | 28.1 kg/(m^2) STANDARD_DEVIATION 7.12 | 28.1 kg/(m^2) STANDARD_DEVIATION 7.01 |
| Education level primary education | 228 Participants | 384 Participants | 612 Participants |
| Education level secondary education | 371 Participants | 775 Participants | 1146 Participants |
| Education level tertiary education | 29 Participants | 90 Participants | 119 Participants |
| Education level unknown | 24 Participants | 58 Participants | 82 Participants |
| Has children | 601 Participants | 1190 Participants | 1791 Participants |
| Has main sex partner | 640 Participants | 1284 Participants | 1924 Participants |
| Marital status Divorced | 1 Participants | 2 Participants | 3 Participants |
| Marital status Legally separated | 7 Participants | 13 Participants | 20 Participants |
| Marital status Married | 63 Participants | 118 Participants | 181 Participants |
| Marital status Never married | 581 Participants | 1166 Participants | 1747 Participants |
| Marital status Widowed | 0 Participants | 8 Participants | 8 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 642 Participants | 1299 Participants | 1941 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 | 10 Participants | 8 Participants | 18 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment South Africa | 587 participants | 1175 participants | 1762 participants |
| Region of Enrollment Uganda | 65 participants | 132 participants | 197 participants |
| Sex: Female, Male Female | 652 Participants | 1307 Participants | 1959 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
| Usual number of vaginal sex act each month | 8.4 vaginal sex acts per month STANDARD_DEVIATION 10.46 | 8.1 vaginal sex acts per month STANDARD_DEVIATION 10.32 | 8.2 vaginal sex acts per month STANDARD_DEVIATION 10.37 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 3 / 652 | 2 / 1,306 |
| other Total, other adverse events | 561 / 652 | 1,147 / 1,306 |
| serious Total, serious adverse events | 9 / 652 | 41 / 1,306 |
Outcome results
Primary
All Adverse Events
Self-reports, physical examination, gynaecological assessments, including pelvic/speculum examination, laboratory tests and other indicated investigations. All AEs will be reported, regardless of grade or relatedness.
Time frame: 24 months
Population: The safety population included all participants who had been randomized to IP and used at least one DVR or placebo ring.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dapivirine Vaginal Ring | All Adverse Events | 1147 Participants |
| Placebo Vaginal Ring | All Adverse Events | 561 Participants |
Primary
HIV-1 Seroconversion According to Comprehensive HIV Testing Algorithm.
HIV-1 seroconversion measured by rapid and specialised laboratory testing according to the comprehensive HIV testing algorithm.
Time frame: 24 months
Population: This population consisted of all participants included in the ITT population (all randomised), excluding those who were not identified as HIV-seropositive at the Enrollment Visit, but who were later found to be already HIV-1 infected at enrollment through HIV-1 RNA PCR testing.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dapivirine Vaginal Ring | HIV-1 Seroconversion According to Comprehensive HIV Testing Algorithm. | 82 Participants |
| Placebo Vaginal Ring | HIV-1 Seroconversion According to Comprehensive HIV Testing Algorithm. | 61 Participants |
Secondary
Percentage of Participants With Pregnancy in Each Trial Arm Over the IP Use Period;
The percentage of participants with pregnancies in each treatment group. For each treatment group, the numerator will include the number of participants that had a positive urine pregnancy test during the trial period.
Time frame: 24 months
Population: The safety population included all participants who had been randomized to IP and used at least one DVR or placebo ring.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dapivirine Vaginal Ring | Percentage of Participants With Pregnancy in Each Trial Arm Over the IP Use Period; | 43 Participants |
| Placebo Vaginal Ring | Percentage of Participants With Pregnancy in Each Trial Arm Over the IP Use Period; | 20 Participants |
Secondary
The Incidence of Curable STIs
The percentage of participants testing positive for any STI (gonorrhoea, chlamydia, trichomonas, syphilis) will be assessed.
Time frame: 24 months
Population: The safety population included all participants who had been randomized to IP and used at least one DVR or placebo ring.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dapivirine Vaginal Ring | The Incidence of Curable STIs | 682 Participants |
| Placebo Vaginal Ring | The Incidence of Curable STIs | 315 Participants |
Secondary
The Incidence Rate of HIV-2 Seroconversion.
Rapid and specialised laboratory testing according to the comprehensive HIV testing algorithm in Appendix C of protocol.
Time frame: 24 months
Population: This population consisted of all participants included in the ITT population, excluding those who were not identified as HIV-seropositive at the Enrollment Visit, but who were later found to be already HIV-1 infected at enrollment through HIV-1 RNA PCR testing.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dapivirine Vaginal Ring | The Incidence Rate of HIV-2 Seroconversion. | 0 Participants |
| Placebo Vaginal Ring | The Incidence Rate of HIV-2 Seroconversion. | 0 Participants |
Secondary
The Percentage of Participants With HIV-1 Drug Resistance Mutations Among Participants Who Acquire HIV-1.
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 proportion 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: 24 months
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 | The Percentage of Participants With HIV-1 Drug Resistance Mutations Among Participants Who Acquire HIV-1. | 84 Participants |
| Placebo Vaginal Ring | The Percentage of Participants With HIV-1 Drug Resistance Mutations Among Participants Who Acquire HIV-1. | 58 Participants |
Secondary
The Percentage of Women Who Report Adherence to the Use of the Vaginal Ring Inserted Once Every 4 Weeks Over the Trial Period;
Questionnaires and qualitative data regarding sexual behaviour and adherence to the use of a vaginal ring inserted once every 4 weeks over the trial period. Dapivirine residual levels in used rings and dapivirine plasma concentrations are two objective measures of adherence to DVR ring use,
Time frame: 24 months
Population: 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 | The Percentage of Women Who Report Adherence to the Use of the Vaginal Ring Inserted Once Every 4 Weeks Over the Trial Period; | Week 76 | 84.0 percentage of participants with data |
| Dapivirine Vaginal Ring | The Percentage of Women Who Report Adherence to the Use of the Vaginal Ring Inserted Once Every 4 Weeks Over the Trial Period; | Week 4 | 77.1 percentage of participants with data |
| Dapivirine Vaginal Ring | The Percentage of Women Who Report Adherence to the Use of the Vaginal Ring Inserted Once Every 4 Weeks Over the Trial Period; | Week 8 | 76.5 percentage of participants with data |
| Dapivirine Vaginal Ring | The Percentage of Women Who Report Adherence to the Use of the Vaginal Ring Inserted Once Every 4 Weeks Over the Trial Period; | Week 12 | 75.0 percentage of participants with data |
| Dapivirine Vaginal Ring | The Percentage of Women Who Report Adherence to the Use of the Vaginal Ring Inserted Once Every 4 Weeks Over the Trial Period; | Week 16 | 74.9 percentage of participants with data |
| Dapivirine Vaginal Ring | The Percentage of Women Who Report Adherence to the Use of the Vaginal Ring Inserted Once Every 4 Weeks Over the Trial Period; | Week 20 | 73.7 percentage of participants with data |
| Dapivirine Vaginal Ring | The Percentage of Women Who Report Adherence to the Use of the Vaginal Ring Inserted Once Every 4 Weeks Over the Trial Period; | Week 24 | 73.9 percentage of participants with data |
| Dapivirine Vaginal Ring | The Percentage of Women Who Report Adherence to the Use of the Vaginal Ring Inserted Once Every 4 Weeks Over the Trial Period; | Week 28 | 73.4 percentage of participants with data |
| Dapivirine Vaginal Ring | The Percentage of Women Who Report Adherence to the Use of the Vaginal Ring Inserted Once Every 4 Weeks Over the Trial Period; | Week 32 | 73.5 percentage of participants with data |
| Dapivirine Vaginal Ring | The Percentage of Women Who Report Adherence to the Use of the Vaginal Ring Inserted Once Every 4 Weeks Over the Trial Period; | Week 36 | 74.9 percentage of participants with data |
| Dapivirine Vaginal Ring | The Percentage of Women Who Report Adherence to the Use of the Vaginal Ring Inserted Once Every 4 Weeks Over the Trial Period; | Week 40 | 76.1 percentage of participants with data |
| Dapivirine Vaginal Ring | The Percentage of Women Who Report Adherence to the Use of the Vaginal Ring Inserted Once Every 4 Weeks Over the Trial Period; | Week 44 | 76.3 percentage of participants with data |
| Dapivirine Vaginal Ring | The Percentage of Women Who Report Adherence to the Use of the Vaginal Ring Inserted Once Every 4 Weeks Over the Trial Period; | Week 48 | 77.4 percentage of participants with data |
| Dapivirine Vaginal Ring | The Percentage of Women Who Report Adherence to the Use of the Vaginal Ring Inserted Once Every 4 Weeks Over the Trial Period; | Week 52 | 78.5 percentage of participants with data |
| Dapivirine Vaginal Ring | The Percentage of Women Who Report Adherence to the Use of the Vaginal Ring Inserted Once Every 4 Weeks Over the Trial Period; | Week 56 | 78.9 percentage of participants with data |
| Dapivirine Vaginal Ring | The Percentage of Women Who Report Adherence to the Use of the Vaginal Ring Inserted Once Every 4 Weeks Over the Trial Period; | Week 60 | 81.1 percentage of participants with data |
| Dapivirine Vaginal Ring | The Percentage of Women Who Report Adherence to the Use of the Vaginal Ring Inserted Once Every 4 Weeks Over the Trial Period; | Week 64 | 82.7 percentage of participants with data |
| Dapivirine Vaginal Ring | The Percentage of Women Who Report Adherence to the Use of the Vaginal Ring Inserted Once Every 4 Weeks Over the Trial Period; | Week 68 | 85.0 percentage of participants with data |
| Dapivirine Vaginal Ring | The Percentage of Women Who Report Adherence to the Use of the Vaginal Ring Inserted Once Every 4 Weeks Over the Trial Period; | Week 72 | 83.9 percentage of participants with data |
| Dapivirine Vaginal Ring | The Percentage of Women Who Report Adherence to the Use of the Vaginal Ring Inserted Once Every 4 Weeks Over the Trial Period; | Week 80 | 81.4 percentage of participants with data |
| Dapivirine Vaginal Ring | The Percentage of Women Who Report Adherence to the Use of the Vaginal Ring Inserted Once Every 4 Weeks Over the Trial Period; | Week 84 | 81.1 percentage of participants with data |
| Dapivirine Vaginal Ring | The Percentage of Women Who Report Adherence to the Use of the Vaginal Ring Inserted Once Every 4 Weeks Over the Trial Period; | Week 88 | 81.5 percentage of participants with data |
| Dapivirine Vaginal Ring | The Percentage of Women Who Report Adherence to the Use of the Vaginal Ring Inserted Once Every 4 Weeks Over the Trial Period; | Week 92 | 81.6 percentage of participants with data |
| Dapivirine Vaginal Ring | The Percentage of Women Who Report Adherence to the Use of the Vaginal Ring Inserted Once Every 4 Weeks Over the Trial Period; | Week 96 | 83.1 percentage of participants with data |
| Dapivirine Vaginal Ring | The Percentage of Women Who Report Adherence to the Use of the Vaginal Ring Inserted Once Every 4 Weeks Over the Trial Period; | Week 100 | 82.6 percentage of participants with data |
| Dapivirine Vaginal Ring | The Percentage of Women Who Report Adherence to the Use of the Vaginal Ring Inserted Once Every 4 Weeks Over the Trial Period; | Week 104 | 80.1 percentage of participants with data |
Secondary
The Percentage of Women Who Report the Use of the Vaginal Ring as Acceptable;
Questionnaires and qualitative data regarding the acceptability of use of a vaginal ring inserted once every 4 weeks over the trial period; Number 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: 24 months
Population: This population consisted of all participants included in the ITT population, excluding those who were not identified as HIV-seropositive at the Enrollment Visit, but who were later found to be already HIV-1 infected at enrollment through HIV-1 RNA PCR testing.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Dapivirine Vaginal Ring | The Percentage of Women Who Report the Use of the Vaginal Ring as Acceptable; | Week 4 | 97.4 percentage of participants with data |
| Dapivirine Vaginal Ring | The Percentage of Women Who Report the Use of the Vaginal Ring as Acceptable; | Week 24 | 98.7 percentage of participants with data |
| Placebo Vaginal Ring | The Percentage of Women Who Report the Use of the Vaginal Ring as Acceptable; | Week 4 | 98.7 percentage of participants with data |
| Placebo Vaginal Ring | The Percentage of Women Who Report the Use of the Vaginal Ring as Acceptable; | Week 24 | 98.6 percentage of participants with data |