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A double-blind, randomized, placebo-controlled Phase I/II trial to evaluate the safety of dapivirine Gel 4759, 0.05% 2.5 g and dapivirine Gel 4789, 0.05% 2.5 g formulations as compared to the vaginal HEC-based Universal placebo gel, 2.5 g in healthy HIV-negative women
This was a double-blind, randomized, placebo-controlled trial, to be conducted over 10 months at five research centers in the USA among 180 healthy, sexually active women, to assess the safety and acceptability of dapivirine Gel 4759, 0.05% 2.5 g, and dapivirine Gel 4789, 0.05% 2.5 g, both vaginal microbicides containing dapivirine, compared to the vaginal HEC-based Universal placebo gel, 2.5 g, containing no active ingredient, used once daily for a period of 12 weeks.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| dapivirine gel 4789 | Active Comparator | will be applied by participants once daily for 12-weeks treatment period |
|
| dapivirine gel 4759 | Active Comparator | Will be applied by participants once daily for12-weeks treatment period |
|
| HEC-based placebo gel, 2.5g containing no Dapivirine | Placebo Comparator | Will be applied once daily for 12-weeks treatment period |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| dapivirine 4789 | Drug | dapivirine gel 4789, 0.05%, 2.5g applied once daily |
|
| Measure | Description | Time Frame |
|---|---|---|
| The Percentage of Women With the Composite Endpoint of Abnormal Safety Findings. | A composite endpoint was defined as the percentage of participants with any post-baseline abnormal finding from pelvic/speculum examination, colposcopy finding, STI diagnoses, laboratory test of DAIDS grade 3 or higher and any product-related AE. DAIDS severity grades are defined as follows: Grade 1 = mild Grade 2 = moderate Grade 3 = severe Grade 4 = potentially life-threatening Grade 5 = death | 12 weeks |
| Measure | Description | Time Frame |
|---|---|---|
| Changes in the Vaginal Flora | Cervicovaginal fluid specimens will be obtained to determine vaginal flora before first gel application and at Visits 3, 5, and 6. Appropriate statistical analyses incorporating repeated measures will be used to assess the changes in the vaginal flora in women using Dapivirine Gel 4759, 0.05% 2.5g, Dapivirine Gel 4789, 0.05% 2.5g or the vaginal HEC-based universal placebo gel, 2.5g. Nugent scores were used to assess changes in vaginal flora, and were categorized into three levels: (1) negative for BV (score: 0-3); (2) altered vaginal flora (score: 4-6); and (3) BV (score: 7-10). |
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Inclusion Criteria:
Women 18 to 40 years of age inclusive who can give written informed consent
Available for all visits and consent to follow all procedures scheduled for the trial
Healthy and self-reported sexually active
HIV-negative as determined by an HIV test at time of enrollment
Willing to be on a stable form of contraception
In the absence of the use of exogenous hormone(s), have a self-reported regular menstrual cycle
Upon pelvic/speculum examination and colposcopy at the enrollment visit, the cervix and vagina appear normal as determined by qualified research center staff
Asymptomatic for genital infections at the time of enrollment
Willing to refrain from use of vaginal products or objects for 14 days prior to enrollment and for the duration of the trial.
Documentation of no abnormality on Pap smear within 90 days prior to randomization;
Willing to answer acceptability and adherence questionnaires throughout the trial
Willing to refrain from participation in any other research trial for the duration of this trial
Willing to provide adequate locator information for trial retention purposes and be reachable per local standard procedures
Willing to abstain from all the following criteria beginning 48 hours prior to each trial visit:
Willing to abstain from all of the following for 3 days after biopsy procedures:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Dr Annalene Nel | International Partnership for Microbicides | Study Chair |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of Alabama at Birmingham, Alabama Microbicide Clinical Research Site (AMCRS) | Birmingham | Alabama | 35294 | United States | ||
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Approximately 180 women (35-50 per RC) were scheduled to be enrolled at 5 research centers in the USA. However, following IPM's decision to give priority to development of the dapivirine vaginal ring above that of dapivirine vaginal gel, the Sponsor decided to stop enrollment into IPM 020 trial after 128 participants were randomized. It was determined that the number of participants already enrolled were sufficient to allow for meaningful analysis of the data. Total trial duration was 18 months.
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| ID | Title | Description |
|---|---|---|
| FG000 | Dapivirine Gel 4789 | will be applied by participants once daily for 12-weeks treatment period dapivirine 4789: dapivirine gel 4789, 0.05%, 2.5g applied once daily |
| FG001 | Dapivirine Gel 4759 | Will be applied by participants once daily for12-weeks treatment period dapivirine gel 4759: dapivirine gel 4759, 0.05%, 2.5g applied once daily |
| FG002 | HEC-based Placebo Gel, 2.5g Containing no Dapivirine | Will be applied once daily for 12-weeks treatment period Drug placebo: HEC-based universal placebo gel, 2.5g applied once daily |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
Healthy, sexually active, HIV-negative women
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| ID | Title | Description |
|---|---|---|
| BG000 | Dapivirine Gel 4759 | Will be applied by participants once daily for12-weeks treatment period dapivirine gel 4759: dapivirine gel 4759, 0.05%, 2.5g applied once daily |
| BG001 | Dapivirine Gel 4789 |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | The Percentage of Women With the Composite Endpoint of Abnormal Safety Findings. | A composite endpoint was defined as the percentage of participants with any post-baseline abnormal finding from pelvic/speculum examination, colposcopy finding, STI diagnoses, laboratory test of DAIDS grade 3 or higher and any product-related AE. DAIDS severity grades are defined as follows: Grade 1 = mild Grade 2 = moderate Grade 3 = severe Grade 4 = potentially life-threatening Grade 5 = death | The ITT population included all trial participants who were randomized to one of the three treatment groups. | Posted | Count of Participants | Participants | 12 weeks |
|
Trial duration: 18 months The maximum period of gel exposure in all three treatment groups was 12 weeks.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Dapivirine Gel 4759 | Will be applied by participants once daily for12-weeks treatment period dapivirine gel 4759: dapivirine gel 4759, 0.05%, 2.5g applied once daily |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Cellulitis of the left breast | Reproductive system and breast disorders | MedDRA (10.0) | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Abdominal Pain | Gastrointestinal disorders | MedDRA (10.0) | Systematic Assessment |
Concluding a general trend in vaginal fluid data is, however, difficult as overall individual fluid levels for the two gel formulations were in the same range and differences based on median values were not consistent across visits.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr John Steytler | International Partnership for Microbicides | jsteytler@ipmglobal.org |
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| ID | Term |
|---|---|
| C481671 | Dapivirine |
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All enrolled participants will apply gel on a daily basis for 12 weeks, with clinical follow-up visits at weeks 2,4,8 and 12 to monitor safety and acceptability, and a final visit 4 weeks post gel discontinuation (Visit 6, week 16) Dapivirine concentration will be measured in blood and vaginal fluid and cervical tissue.
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Potential participants who provide inform consent will be invited to screen for the trial. All participants who consent to participate in the trial and meet specified inclusion/exclusion criteria will be invited to enrol. At enrolment women will be randomly assigned in a 1:1:1 ratio to one of three groups.
| dapivirine gel 4759 | Drug | dapivirine gel 4759, 0.05%, 2.5g applied once daily |
|
|
| Drug placebo | Drug | HEC-based universal placebo gel, 2.5g applied once daily |
|
|
| 16 weeks |
| The Distribution of Dapivirine Levels Observed in Plasma Samples at Each Specified Time Point | Dapivirine levels observed in plasma will be summarized using simple descriptive statistics. | 12 weeks |
| The Adherence to Once Daily Application of a Vaginal Microbicide Gel Over a 12-week Period in Healthy, Sexually Active, HIV-negative Women | Adherence is defined as the percentage of participants who used the gel each day of the preceding 14 days, based on participant self reports. | 12 weeks |
| Changes in the Vaginal pH | Cervicovaginal fluid specimens will be obtained to determine vaginal pH before first gel application and at screening, enrolment and visit 5 (week 12). Appropriate statistical analyses incorporating repeated measures will be used to assess the changes in the vaginal pH in women using Dapivirine Gel 4759, 0.05% 2.5g, Dapivirine Gel 4789, 0.05% 2.5g or the vaginal HEC-based universal placebo gel, 2.5g. | 12 weeks |
| The Distribution of Dapivirine Levels Observed in Vaginal Fluid at Each Specified Time Point. | The distribution of dapivirine levels observed in each type of sample will be summarized using simple descriptive statistics. In addition, the proportion of women with detectable dapivirine concentrations will be calculated for each type of sample at each collection time point. Exploratory analyses of dapivirine concentration data will also be performed to take into account information reported in a diary regarding menses and tampon use throughout the trial. | 12 weeks. Measured at 2, 4, and 8 weeks post-enrolment and at one of these at week 12; 24, 48, or 72 hours after gel discontinuation. (Participants were randomized to have vaginal fluid samples collected at one of these visits (5a, 5b, or 5c). |
| The Distribution of Dapivirine Levels Observed in Vaginal Tissue at Each Specified Time Point. | The distribution of dapivirine levels observed in vaginal tissue sample will be summarized using simple descriptive statistics. | 12 weeks. Measured at 2, 4, and 8 weeks post-enrolment and at one of these at week 12; 24, 48, or 72 hours after gel discontinuation. (Participants were randomized to have vaginal fluid samples collected at one of these visits (5a, 5b, or 5c). |
| Acceptability of Once Daily Application of a Vaginal Microbicide Gel Over a 12-week Period in Healthy, Sexually Active, HIV-negative Women | Acceptability was assessed as the percentage of participants at week 12 who were willing to use the gel every day if proven to prevent HIV. | 12 weeks |
| Harbor-UCLA Medical Center |
| Torrance |
| California |
| 90502 |
| United States |
| University of Illinois at Chicago | Chicago | Illinois | 60612 | United States |
| SNBL Clinical Pharmacology Center | Baltimore | Maryland | 21201 | United States |
| Albert Einstein College of Medicine | New York | New York | 10461 | United States |
| Adverse Event |
|
| Pregnancy |
|
| Not adherent |
|
| discontinued use of IP due to AE, but completed visits |
|
| IP dispensing error |
|
| not enough IP to complete trial due to IP dispending error |
|
| IP discontinued too long during BV treatment |
|
| lost 2 IP kits and did not have enough remaining to complete trial |
|
| participant did not attend clinic visit 6 (final visit) |
|
will be applied by participants once daily for 12-weeks treatment period
dapivirine 4789: dapivirine gel 4789, 0.05%, 2.5g applied once daily
| BG002 | HEC-based Placebo Gel, 2.5g Containing no Dapivirine | Will be applied once daily for 12-weeks treatment period Drug placebo: HEC-based universal placebo gel, 2.5g applied once daily |
| BG003 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| Married | Count of Participants | Participants |
|
| In a relationship with one partner, not married | Count of Participants | Participants |
|
| Cohabitating with main partner | Count of Participants | Participants |
|
| In a relationship with multiple partners | Count of Participants | Participants |
|
| Height | Mean | Standard Deviation | cm |
|
| Weight | Mean | Standard Deviation | kg |
|
| BMI | Mean | Standard Deviation | kg/(m^2) |
|
| OG001 | Dapivirine Gel 4789 | will be applied by participants once daily for 12-weeks treatment period dapivirine 4789: dapivirine gel 4789, 0.05%, 2.5g applied once daily |
| OG002 | HEC-based Placebo Gel, 2.5g Containing no Dapivirine | Will be applied once daily for 12-weeks treatment period Drug placebo: HEC-based universal placebo gel, 2.5g applied once daily |
|
|
| Secondary | Changes in the Vaginal Flora | Cervicovaginal fluid specimens will be obtained to determine vaginal flora before first gel application and at Visits 3, 5, and 6. Appropriate statistical analyses incorporating repeated measures will be used to assess the changes in the vaginal flora in women using Dapivirine Gel 4759, 0.05% 2.5g, Dapivirine Gel 4789, 0.05% 2.5g or the vaginal HEC-based universal placebo gel, 2.5g. Nugent scores were used to assess changes in vaginal flora, and were categorized into three levels: (1) negative for BV (score: 0-3); (2) altered vaginal flora (score: 4-6); and (3) BV (score: 7-10). | All participants who were assigned to a treatment group were analyzed as members of the group to which they were randomized, regardless of adherence to the planned course of treatment. Results are reported for participants who provided vaginal samples. | Posted | Number | percentage of participants with data | 16 weeks |
|
|
|
| Secondary | The Distribution of Dapivirine Levels Observed in Plasma Samples at Each Specified Time Point | Dapivirine levels observed in plasma will be summarized using simple descriptive statistics. | The PK analysis population included all participants who received at least one dose of the active IP and for whom at least one plasma, vaginal fluid or cervical tissue sample was taken. Results are provided for participants for whom samples were available. | Posted | Mean | Standard Deviation | picograms/mililiter | 12 weeks |
|
|
|
| Secondary | The Adherence to Once Daily Application of a Vaginal Microbicide Gel Over a 12-week Period in Healthy, Sexually Active, HIV-negative Women | Adherence is defined as the percentage of participants who used the gel each day of the preceding 14 days, based on participant self reports. | The ITT population included all trial participants who were randomized to one of the three treatment groups. Results are provided for participants who reported adherence information. | Posted | Number | percentage of participants with data | 12 weeks |
|
|
|
| Secondary | Changes in the Vaginal pH | Cervicovaginal fluid specimens will be obtained to determine vaginal pH before first gel application and at screening, enrolment and visit 5 (week 12). Appropriate statistical analyses incorporating repeated measures will be used to assess the changes in the vaginal pH in women using Dapivirine Gel 4759, 0.05% 2.5g, Dapivirine Gel 4789, 0.05% 2.5g or the vaginal HEC-based universal placebo gel, 2.5g. | All participants who were assigned to a treatment group were analyzed as members of the group to which they were randomized, regardless of adherence to the planned course of treatment. | Posted | Mean | Standard Deviation | Vaginal pH | 12 weeks |
|
|
|
| Secondary | The Distribution of Dapivirine Levels Observed in Vaginal Fluid at Each Specified Time Point. | The distribution of dapivirine levels observed in each type of sample will be summarized using simple descriptive statistics. In addition, the proportion of women with detectable dapivirine concentrations will be calculated for each type of sample at each collection time point. Exploratory analyses of dapivirine concentration data will also be performed to take into account information reported in a diary regarding menses and tampon use throughout the trial. | The PK analysis population included all participants who received at least one dose of the active IP and for whom at least one plasma, vaginal fluid or cervical tissue sample was taken. Results are provided for participants for whom samples were available. | Posted | Mean | Standard Deviation | nanogram/milliliter | 12 weeks. Measured at 2, 4, and 8 weeks post-enrolment and at one of these at week 12; 24, 48, or 72 hours after gel discontinuation. (Participants were randomized to have vaginal fluid samples collected at one of these visits (5a, 5b, or 5c). |
|
|
|
| Secondary | The Distribution of Dapivirine Levels Observed in Vaginal Tissue at Each Specified Time Point. | The distribution of dapivirine levels observed in vaginal tissue sample will be summarized using simple descriptive statistics. | The PK analysis population included all participants who received at least one dose of the active IP and for whom at least one plasma, vaginal fluid or cervical tissue sample was taken. | Posted | Mean | Standard Deviation | nanogram/gram | 12 weeks. Measured at 2, 4, and 8 weeks post-enrolment and at one of these at week 12; 24, 48, or 72 hours after gel discontinuation. (Participants were randomized to have vaginal fluid samples collected at one of these visits (5a, 5b, or 5c). |
|
|
|
| Secondary | Acceptability of Once Daily Application of a Vaginal Microbicide Gel Over a 12-week Period in Healthy, Sexually Active, HIV-negative Women | Acceptability was assessed as the percentage of participants at week 12 who were willing to use the gel every day if proven to prevent HIV. | The ITT population included all trial participants who were randomized to one of the three treatment groups. Results are reported for participants who provided questionnaire responses. | Posted | Count of Participants | Participants | 12 weeks |
|
|
|
| 0 |
| 43 |
| 1 |
| 43 |
| 30 |
| 43 |
| EG001 | Dapivirine Gel 4789 | will be applied by participants once daily for 12-weeks treatment period dapivirine 4789: dapivirine gel 4789, 0.05%, 2.5g applied once daily | 0 | 43 | 0 | 43 | 34 | 43 |
| EG002 | HEC-based Placebo Gel, 2.5g Containing no Dapivirine | Will be applied once daily for 12-weeks treatment period Drug placebo: HEC-based universal placebo gel, 2.5g applied once daily | 0 | 42 | 2 | 42 | 35 | 42 |
| Abdominal Pain | Gastrointestinal disorders | MedDRA (10.0) | Systematic Assessment |
|
| Asthma | Respiratory, thoracic and mediastinal disorders | MedDRA (10.0) | Systematic Assessment |
|
| Abdominal Pain Lower | Gastrointestinal disorders | MedDRA (10.0) | Systematic Assessment |
|
| Diarrhoea | Gastrointestinal disorders | MedDRA (10.0) | Systematic Assessment |
|
| Hypersensitivity | Immune system disorders | MedDRA (10.0) | Systematic Assessment |
|
| Chlamydial infection | Infections and infestations | MedDRA (10.0) | Systematic Assessment |
|
| Gonorrhoea | Infections and infestations | MedDRA (10.0) | Systematic Assessment |
|
| Nasopharyngitis | Infections and infestations | MedDRA (10.0) | Systematic Assessment |
|
| Sinusitis | Infections and infestations | MedDRA (10.0) | Systematic Assessment |
|
| Upper respiratory tract infection | Infections and infestations | MedDRA (10.0) | Systematic Assessment |
|
| Urinary tract infection | Infections and infestations | MedDRA (10.0) | Systematic Assessment |
|
| Vaginal candidiasis | Infections and infestations | MedDRA (10.0) | Systematic Assessment |
|
| Vaginitis bacterial | Infections and infestations | MedDRA (10.0) | Systematic Assessment |
|
| Vulvovaginal myotic infection | Infections and infestations | MedDRA (10.0) | Systematic Assessment |
|
| Haemoglobin decreased | Investigations | MedDRA (10.0) | Systematic Assessment |
|
| Muscle spasms | Musculoskeletal and connective tissue disorders | MedDRA (10.0) | Systematic Assessment |
|
| Headache | Nervous system disorders | MedDRA (10.0) | Systematic Assessment |
|
| Dysuria | Renal and urinary disorders | MedDRA (10.0) | Systematic Assessment |
|
| Adnexa uteri pain | Reproductive system and breast disorders | MedDRA (10.0) | Systematic Assessment |
|
| Cervix erythema | Reproductive system and breast disorders | MedDRA (10.0) | Systematic Assessment |
|
| Dysmenorrhoea | Reproductive system and breast disorders | MedDRA (10.0) | Systematic Assessment |
|
| Dyspareunia | Reproductive system and breast disorders | MedDRA (10.0) | Systematic Assessment |
|
| Menorrhagia | Reproductive system and breast disorders | MedDRA (10.0) | Systematic Assessment |
|
| Metrorrhagia | Reproductive system and breast disorders | MedDRA (10.0) | Systematic Assessment |
|
| Vaginal discharge | Reproductive system and breast disorders | MedDRA (10.0) | Systematic Assessment |
|
| Vulvovaginal discomfort | Reproductive system and breast disorders | MedDRA (10.0) | Systematic Assessment |
|
| Vulvovaginal pruritus | Reproductive system and breast disorders | MedDRA (10.0) | Systematic Assessment |
|
| Cough | Respiratory, thoracic and mediastinal disorders | MedDRA (10.0) | Systematic Assessment |
|
| Pharyngolaryngeal pain | Respiratory, thoracic and mediastinal disorders | MedDRA (10.0) | Systematic Assessment |
|
| Erythema | Skin and subcutaneous tissue disorders | MedDRA (10.0) | Systematic Assessment |
|
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| Week 0 : Altered Flora (4-6) |
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| Week 0 : Abnormal Flora (7 or more) |
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| Week 4 : Normal Flora (0-3) |
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| Week 4 : Altered Flora (4-6) |
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| Week 4 : Abnormal Flora (7 or more) |
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| Week 12: Normal Flora (0-3) |
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| Week 12: Altered Flora (4-6) |
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| Week 12: Abnormal Flora (7 or more) |
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| Week 16 (Follow-up after IP discontinuation): Normal Flora (0-3) |
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| Week 16 (Follow-up after IP discontinuation): Altered Flora (4-6) |
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| Week 16 (Follow-up after IP discontinuation): Abnormal Flora (7 or more) |
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| Week 4 |
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| Week 8 |
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| Week 12 |
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| Visit 5 (Week 12) |
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| Visit 3 (4 weeks post-enrolment) |
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| Visit 4 (8 weeks post-enrolment) |
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| Visit 5a (24 hours after gel discontinuation) |
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| Visit 5b (48 hours after gel discontinuation) |
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| Visit 5c (72 hours after gel discontinuation) |
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| Visit 5b (48 hours after gel discontinuation) |
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| Visit 5c (72 hours after gel discontinuation) |
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