HIV-I, Human Immunodeficiency Virus Type 1, Prophylaxis
Conditions
Keywords
Preexposure prophylaxis (PrEP), Prevention
Brief summary
This study will evaluate whether oral islatravir (ISL) is effective in preventing Human Immunodeficiency Virus Type 1 (HIV-1) infection in women at high-risk for HIV-1 infection. The study will compare oral ISL taken once a month with standard-of-care medication for prevention of HIV-1 infection, emtricitabine/tenofovir disoproxil (FTC/TDF), taken once per day. The primary hypothesis is that oral ISL is more effective than FTC/TDF at reducing the incidence rate per year of confirmed HIV-1 infections.
Detailed description
Based on laboratory findings of decreased lymphocyte and CD4+ T-cell counts across the islatravir program, dosing of blinded study intervention was halted on 13-Dec-2021 and screening and randomization of new participants was ended. Blinded assessments conducted prior to this date are designated as Study Part 1. During Study Part 2, participants from Part 1 have the option to receive daily open-label FTC/TDF while continuing in the study for safety monitoring. Study Part 3 was added to unblind each participant's Part 1 study intervention assignment, continue participants on FTC/TDF, and monitor safety.
Interventions
DRUGIslatravir
Oral 60 mg tablet administered once monthly during Part 1.
0 mg tablet administered once daily during Part 1.
DRUGFTC/TDF
Each tablet contains 200 mg emtricitabine and 245 mg of tenofovir disoproxil (equivalent to 300 mg tenofovir disoproxil fumarate or 201.22 mg tenofovir disproxil phosphate), administered orally once daily in Parts 1, 2, and 3.
DRUGPlacebo to ISL
0 mg tablet administered orally once monthly in Part 1.
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
TRIPLE (Subject, Caregiver, Investigator)
Masking description
In Study Part 1, a double-blinding technique with in-house blinding will be used. ISL and FTC/TDF will be packaged identically relative to their matching placebos so that blind is maintained. The participant, the investigator, and Sponsor personnel or delegate(s) who are involved in the study intervention administration or clinical evaluation of the participants are unaware of the intervention assignments. In Study Part 2, sponsor personnel not directly involved with blinded safety monitoring will be unblinded to participants' randomized study intervention in Part 1. In Study Part 3, participants, investigators, and all Sponsor personnel will be unblinded to the participants' original randomized study intervention group.
Eligibility
Sex/Gender
FEMALE
Age
16 Years to 45 Years
Healthy volunteers
Yes
Inclusion criteria
* Confirmed HIV-uninfected based on negative HIV-1/HIV-2 test results before randomization. * Sexually active (vaginal and/or anal sex) with a male sexual partner in the 30 days prior to screening. * High risk for HIV-1 infection. * Not pregnant or breastfeeding, and one of the following conditions applies: Not a woman of childbearing potential (WOCBP) or is a WOCBP and is using an acceptable contraceptive method during the intervention period and for at least 42 days after the last dose. * A WOCBP must have a negative pregnancy test within 24 hours prior to the first dose of study intervention.
Exclusion criteria
* Hypersensitivity or other contraindication to any of the components of the study interventions as determined by the investigator. * Findings of chronic hepatitis B virus (HBV) infection or past HBV. * Current or chronic history of liver disease. * History of malignancy within 5 years of screening except for adequately-treated basal cell or squamous cell skin cancer, or in situ cervical cancer. * Past or current use of cabotegravir, lenacapavir, or any other long-acting HIV prevention product. * Currently participating in or has participated in an interventional clinical study with an investigational compound or device, within 30 days prior to Day 1. * Expecting to conceive or donate eggs at any time during the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence Rate Per Year of Confirmed HIV-1 Infection Among Participants During Blinded Treatment +42 Days Post-Blind | Up to approximately 325 days | Incidence rate per year of confirmed HIV-1 infections is the number of participants with confirmed HIV-1 infections during the assessment period divided by the number of person-years in the arm. Data are based on participants with confirmed HIV-1 infection. The originally planned primary statistical analysis was removed via amendment when open-label treatment was initiated. |
| Number of Participants Who Experienced an Adverse Event (AE) During Blinded Treatment + 42 Days Post-Blind | Up to approximately 325 days | An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. The number of participants who experienced an AE will be reported for each treatment arm. |
| Number of Participants Who Discontinued Blinded Study Treatment Due to an AE | Up to 283 days | An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. The number of participants who discontinued blinded study treatment due to an AE will be reported for each treatment arm. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Incidence Rate Per Year During Blinded Treatment of Confirmed HIV-1 Infection Among ISL-Treated Participants | Up to approximately 237 days | Incidence rate per year of confirmed HIV-1 infections is the number of participants with confirmed HIV-1 infections during the assessment period divided by the number of person-years in the arm. Data are based on participants with confirmed HIV-1 infection. The originally planned secondary statistical analysis was removed via amendment when open-label treatment was initiated. |
Countries
South Africa, Uganda, United States
Contacts
STUDY_DIRECTORMedical Director
Merck Sharp & Dohme LLC
Participant flow
Pre-assignment details
One person mistakenly received study drug without being randomized. They are not included in Participant Flow or Baseline Characteristics because they were not enrolled in the study, but their adverse events are reported in the Adverse Events module because they received study drug.
Participants by arm
| Arm | Count |
|---|---|
| ISL QM ISL (islatravir) once monthly AND placebo to FTC/TDF (emtricitabine/tenofovir disoproxil) once daily. Following study-wide cessation of ISL administration, participants had the option to receive open-label FTC/TDF. Placebo was no longer administered once open label treatment began. | 362 |
| FTC/TDF QD FTC/TDF (TRUVADA™ or generic product emtricitabine/tenofovir disoproxil) administered once daily. Placebo to ISL (islatravir) administered once monthly. Following study-wide cessation of ISL administration, participants had the option to continue on open-label FTC/TDF. Placebo was no longer administered once open label treatment began. | 365 |
| Total | 727 |
Baseline characteristics
| Characteristic | FTC/TDF QD | Total | ISL QM |
|---|---|---|---|
| Age, Continuous | 26.1 Years STANDARD_DEVIATION 6.3 | 26.1 Years STANDARD_DEVIATION 6.2 | 26.0 Years STANDARD_DEVIATION 6.1 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 13 Participants | 24 Participants | 11 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 330 Participants | 659 Participants | 329 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 22 Participants | 44 Participants | 22 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 6 Participants | 11 Participants | 5 Participants |
| Race (NIH/OMB) Black or African American | 338 Participants | 672 Participants | 334 Participants |
| Race (NIH/OMB) More than one race | 4 Participants | 7 Participants | 3 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) White | 15 Participants | 34 Participants | 19 Participants |
| Sex: Female, Male Female | 365 Participants | 727 Participants | 362 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 364 | 0 / 343 | 0 / 366 | 0 / 345 | 0 / 1 |
| other Total, other adverse events | 145 / 362 | 292 / 343 | 210 / 365 | 284 / 345 | 0 / 1 |
| serious Total, serious adverse events | 4 / 362 | 13 / 343 | 2 / 365 | 23 / 345 | 0 / 1 |
Outcome results
Primary
Incidence Rate Per Year of Confirmed HIV-1 Infection Among Participants During Blinded Treatment +42 Days Post-Blind
Incidence rate per year of confirmed HIV-1 infections is the number of participants with confirmed HIV-1 infections during the assessment period divided by the number of person-years in the arm. Data are based on participants with confirmed HIV-1 infection. The originally planned primary statistical analysis was removed via amendment when open-label treatment was initiated.
Time frame: Up to approximately 325 days
Population: The analysis population includes all participants who were randomized and received at least 1 dose of study intervention and did not have confirmed HIV-1 infections prior to or at randomization.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ISL QM | Incidence Rate Per Year of Confirmed HIV-1 Infection Among Participants During Blinded Treatment +42 Days Post-Blind | 0.000 Percentage of Participants/Person-Year |
| FTC/TDF QD | Incidence Rate Per Year of Confirmed HIV-1 Infection Among Participants During Blinded Treatment +42 Days Post-Blind | 0.000 Percentage of Participants/Person-Year |
Primary
Number of Participants Who Discontinued Blinded Study Treatment Due to an AE
An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. The number of participants who discontinued blinded study treatment due to an AE will be reported for each treatment arm.
Time frame: Up to 283 days
Population: The analysis population includes all participants who were randomized and received at least 1 dose of study intervention.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| ISL QM | Number of Participants Who Discontinued Blinded Study Treatment Due to an AE | 2 Participants |
| FTC/TDF QD | Number of Participants Who Discontinued Blinded Study Treatment Due to an AE | 4 Participants |
Primary
Number of Participants Who Experienced an Adverse Event (AE) During Blinded Treatment + 42 Days Post-Blind
An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. The number of participants who experienced an AE will be reported for each treatment arm.
Time frame: Up to approximately 325 days
Population: The analysis population includes all participants who were randomized and received at least 1 dose of study intervention.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| ISL QM | Number of Participants Who Experienced an Adverse Event (AE) During Blinded Treatment + 42 Days Post-Blind | 198 Participants |
| FTC/TDF QD | Number of Participants Who Experienced an Adverse Event (AE) During Blinded Treatment + 42 Days Post-Blind | 255 Participants |
Secondary
Incidence Rate Per Year During Blinded Treatment of Confirmed HIV-1 Infection Among ISL-Treated Participants
Incidence rate per year of confirmed HIV-1 infections is the number of participants with confirmed HIV-1 infections during the assessment period divided by the number of person-years in the arm. Data are based on participants with confirmed HIV-1 infection. The originally planned secondary statistical analysis was removed via amendment when open-label treatment was initiated.
Time frame: Up to approximately 237 days
Population: The analysis population includes all participants who were randomized and received at least 1 dose of ISL and did not have confirmed HIV-1 infections prior to or at randomization.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ISL QM | Incidence Rate Per Year During Blinded Treatment of Confirmed HIV-1 Infection Among ISL-Treated Participants | 0.000 Percentage of Participants/Person-Year |