The LATITUDE Study: Long-Acting Therapy to Improve Treatment SUccess in Daily LifE
- Conditions
- HIV Infections
- Interventions
- Drug: Standard of Care (SOC) Oral ARTDrug: Oral RPVDrug: Oral CABDrug: RPV-LA Loading DoseDrug: CAB-LA Loading DoseDrug: RPV-LA Maintenance DoseDrug: CAB-LA Maintenance Dose
- Registration Number
- NCT03635788
- Brief Summary
The purpose of this study was to compare the efficacy, safety, and durability of two different strategies to treat participants with a history of sub-optimal adherence and control of their HIV infection: long-acting (LA) antiretroviral therapy (ART) and all-oral standard of care (SOC).
- Detailed Description
This study compared the efficacy, safety, and durability of two different strategies to treat participants with a history of sub-optimal adherence and control of their HIV infection: long-acting (LA) antiretroviral therapy (ART) with rilpivirine (RPV) LA and cabotegravir (CAB) LA versus all-oral standard of care (SOC).
As the study was originally designed, the study included four steps.
Step 1, Induction
Previously non-adherent individuals were enrolled and underwent a period (up to 24 weeks) of induction SOC ART regimen using conditional economic incentives (CEI). Participants who achieved virologic suppression criteria at or after Step 1, week 4, defined as: a) HIV-1 RNA ≤200 copies/mL or b) HIV-1 RNA of 201-399 copies/mL followed by HIV-1 RNA ≤200 copies/mL by Step 1, week 24, were eligible to enter Step 2.
Step 2, Randomization
Eligible participants were randomized at Step 2 entry in a 1:1 ratio to either of the two treatment arms:
Arm A (LA ART): A combination of oral RPV + oral CAB for 4 weeks (optional) followed by the LA ART Phase, consisting of a two-drug regimen using RPV-LA + CAB-LA Q4 weeks until the end of Step 2 (Table 5.2.1-2). The option to initiate LA ART at the Step 2 Randomization visit without oral RPV + oral CAB was at the discretion of the site investigator of Record (IoR) and participant (see section 2.1, Direct-to-Inject).
Arm B (SOC): Continuation of the SOC for 52 weeks.
Step 3, Continuation/Crossover
Arm A participants continued on RPV-LA + CAB-LA Q4 weeks for 52 weeks until the end of Step 3. Arm B participants (continuation of SOC) who achieved virologic suppression (HIV-1 RNA ≤200 copies/mL) at Step 2, week 48, or HIV-1 RNA of 201-399 copies/mL at Step 2, week 48, followed by HIV-1 RNA ≤200 copies/mL by Step 2, week 52, had the option to cross over at the end of Step 2 to oral RPV + oral CAB for 4 weeks (optional) followed by RPV-LA + CAB-LA every 4 weeks until the end of Step 3 (Table 5.2.1-3). Arm B participants who did not wish or were not eligible to cross over completed study follow-up at Step 2, week 52.
If RPV-LA + CAB-LA became available before a participant finished Step 3, and the participant chose to continue RPV-LA + CAB-LA as part of their clinical care, their follow-up in the study ended at the completion of Step 3. If for some reason the participant chose not to continue LA ART at the end of Step 3 or if LA ART was not available, the participant registered to Step 4 and was followed on locally sourced oral ARV for 52 weeks.
Step 4, Observation
Participants who registered to Step 4 were followed for up to 52 weeks on oral ART. In addition, any participant who received at least one dose of CAB-LA or RPV-LA at any step, and prematurely discontinued the LA ART prior to the end of Step 3, completed their respective Step (either Step 2 or 3) on study/off study treatment, and registered to Step 4 and were followed to complete 52 weeks total on oral ART after their last dose of any LA injectable.
If LA ART became available during follow-up in Step 4, and the participant and provider decided to restart LA ART, they were allowed to do so. In that case, the participants were not followed by the study after restarting LA ART.
On February 12, 2024, based on the interim efficacy results, Data Safety and Monitoring Board (DSMB) recommended stopping randomization to Step 2 and transitioning all eligible participants in Steps 1 and 2 to LA-ART. Per recommendations from DSMB, randomization into Step 2 stopped on February 16, 2024, leaving three steps in the current study protocol 4.0:
In Step 1, participants will receive a SOC oral induction regimen consisting of an ART regimen that involves at least 3 drugs for 24 weeks. Participants who achieve milestones will receive conditional economic incentives. With randomization into Step 2 ended, all eligible Step 1 participants will register to Step 3 at the completion of Step 1.
Participants who are currently on Step 2:
Eligible participants in Step 2 Arm A (already on RPV-LA + CAB-LA) will register to Step 3 and continue on this regimen until the end of Step 3 (52 weeks; See protocol for more information). This should happen at the next scheduled study visit after approval of Version 4.0.
Eligible participants in Step 2 Arm B (SOC arm) will register to Step 3 and switch to oral RPV + oral CAB for 4 weeks (optional; see protocol for more information) followed by RPV-LA + CAB-LA Q4 weeks until the end of Step 3 (52 weeks). This should happen at the next scheduled study visit after approval of Version 4.0.
Eligible participants will enter Step 4 and be followed up to 52 weeks on locally sourced oral ART.
Participants will be followed for up to a total of 180 weeks. Study visits, which will occur throughout the study, may include physical examinations; blood, urine, and hair collection; liver function tests; questionnaires; and an electrocardiogram (ECG).
NOTE: Data summarized in the primary analysis report were based on evaluations undertaken at visits conducted prior to the implementation of Protocol v4.0 which incorporated February 12, 2024 DSMB recommendations. Primary analyses were outlined in the A5359 primary Statistical Analysis Plan (SAP) version 6.0 (dated August 5, 2024) focusing on follow-up in Step 1 and Step 2.
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- All
- Target Recruitment
- 456
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Step 1 SOC Standard of Care (SOC) Oral ART In Step 1, participants received SOC oral ART regimen for up to 24 weeks. Step 2 Arm A: LA ART Oral RPV In Step 2, participants received oral RPV once daily and oral CAB once daily for 4 weeks (optional), followed by a RPV-LA loading dose and a CAB-LA loading dose, followed in 4 weeks by an RPV-LA maintenance dose and a CAB-LA maintenance dose every 4 weeks for 44 weeks. Step 2 Arm A: LA ART Oral CAB In Step 2, participants received oral RPV once daily and oral CAB once daily for 4 weeks (optional), followed by a RPV-LA loading dose and a CAB-LA loading dose, followed in 4 weeks by an RPV-LA maintenance dose and a CAB-LA maintenance dose every 4 weeks for 44 weeks. Step 2 Arm A: LA ART RPV-LA Loading Dose In Step 2, participants received oral RPV once daily and oral CAB once daily for 4 weeks (optional), followed by a RPV-LA loading dose and a CAB-LA loading dose, followed in 4 weeks by an RPV-LA maintenance dose and a CAB-LA maintenance dose every 4 weeks for 44 weeks. Step 2 Arm A: LA ART CAB-LA Loading Dose In Step 2, participants received oral RPV once daily and oral CAB once daily for 4 weeks (optional), followed by a RPV-LA loading dose and a CAB-LA loading dose, followed in 4 weeks by an RPV-LA maintenance dose and a CAB-LA maintenance dose every 4 weeks for 44 weeks. Step 2 Arm B: SOC Standard of Care (SOC) Oral ART In Step 2, participants continued SOC oral ART regimen for 52 weeks. Step 2 Arm A: LA ART RPV-LA Maintenance Dose In Step 2, participants received oral RPV once daily and oral CAB once daily for 4 weeks (optional), followed by a RPV-LA loading dose and a CAB-LA loading dose, followed in 4 weeks by an RPV-LA maintenance dose and a CAB-LA maintenance dose every 4 weeks for 44 weeks. Step 2 Arm A: LA ART CAB-LA Maintenance Dose In Step 2, participants received oral RPV once daily and oral CAB once daily for 4 weeks (optional), followed by a RPV-LA loading dose and a CAB-LA loading dose, followed in 4 weeks by an RPV-LA maintenance dose and a CAB-LA maintenance dose every 4 weeks for 44 weeks.
- Primary Outcome Measures
Name Time Method Cumulative Probability of Regimen Failure in Step 2 at Any Time Post Randomization and Week 48 Visit From Step 2 randomization to Step 2, Week 48 visit (up to 50 weeks) Regimen failure was defined as the occurrence of the earlier of the following two events
* virologic failure (defined as two consecutive HIV-1 RNA \>200 copies/mL after Step 2 randomization
* Permanent discontinuation of randomized study treatment prior to or at Week 48 visit
Cumulative probability was calculated by Kaplan-Meier method.
- Secondary Outcome Measures
Name Time Method Number of Participants With Virologic Non-success (>= 200 Copies/ml) From Step 2 randomization to Step 2, Week 48 (up to 50 weeks) Virologic non-success was defined by the US Food and Drug Administration (FDA) Snapshot algorithm
Percentage of Participants With Grade 1 or Higher Injection Site Reactions (ISR) During Step 2 Measured from Step 2 randomization through Step 2, Week 52 Summarized and tabulated by number of participants with at least 1 injection site reactions.
Severity Grade: 1 = Mild, 2 = Moderate, 3 = Severe, 4 = Life-Threatening, 5 = DeathCumulative Probability of Virologic Failure in Step 2 at Any Time Post Randomization to Week 48 Visit From Step 2 randomization to Step 2, Week 48 visit (up to 50 weeks) Virologic failure was defined as two consecutive HIV-1 RNA \>200 copies/mL after Step 2 randomization and up to Step 2 Week 48 visit, regardless of the time between them.
Cumulative probability was calculated by Kaplan-Meier method.Cumulative Probability of the Treatment-related Failure in Step 2 at Any Time Post Randomization to Week 48 Visit From after Step 2 randomization to Step 2, Week 48 (up to 50 weeks) Treatment-related failure was defined as the occurrence of the earlier of virologic failure or permanent Step 2 treatment discontinuation due to treatment-related adverse events.
Cumulative probability was calculated by Kaplan-Meier method.Number of Participants With Virologic Non-success (>= 50 Copies/ml) from Step 2 randomization to Step 2, Week 48 (up to 50 weeks) Virologic non-success was defined by the US Food and Drug Administration (FDA) Snapshot algorithm
Percentage of Participants With Plasma HIV-1 RNA Level Less Than 50 Copies/mL at Scheduled Study Visits on Steps 1 Measured from Step 1 entry through Step 1, Week 20 visit Summarized the percentage of participants with plasma HIV-1 RNA level less than 50 copies/mL by study visit
Percentage of Participants With Plasma HIV-1 RNA Level Less Than 200 Copies/mL at Scheduled Study Visits on Steps 1 Measured from Step 1 entry through Step 1, Week 20 visit Summarized the percentage of participants with plasma HIV-1 RNA level less than 200 copies/mL by study visit
Percentage of Participants With Plasma HIV-1 RNA Level Less Than 50 Copies/mL at Scheduled Study Visits on Steps 2 Measured from Step 2 entry through Step 2, Week 48 visit Summarized the percentage of participants with plasma HIV-1 RNA level less than 50 copies/mL by study visit, and randomized treatment.
Percentage of Participants With Plasma HIV-1 RNA Level Less Than 200 Copies/mL at Scheduled Study Visits on Steps 2 Measured from Step 2 entry through Step 2, Week 48 visit Summarized the percentage of participants with plasma HIV-1 RNA level less than 200 copies/mL by study visit, and randomized treatment.
Cumulative Probability of Discontinuation of Randomized Treatment in Step 2 Measured from Step 2 randomization through Step 2, Week 48 (up to 50 weeks) Permanent Step 2 treatment discontinuation was defined as premature discontinuation of randomized study treatment.
Cumulative probability was calculated by Kaplan-Meier method.Median Summary Score of HIV Treatment Satisfaction Questionnaire (HIVTSQ) in Step 2 HIVTSQ status was collected on both arms at Step 2 entry and Week 24, and also at Week 48 for those randomized to SOC. At Week 48, HIVTSQ change was collected for participants on the LA-ART arm. The questionnaire had 12 items rated using a 7-point Likert scale. Results were summarized as a total score that included 11 items, with the "pain/discomfort" item reported separately.
1. The HIVTSQ "status" measured participant satisfaction with their current treatment with individual item rated ranging from 0 ("very dissatisfied") to 6 ("very satisfied") and the total score ranging from 0 to 66, where higher scores indicated a greater level of satisfaction with their HIV-1 treatment.
2. The HIVTSQ "change" measured change in treatment satisfaction between a participant's previous and current treatment. The individual items were rated from -3 ("much less satisfied") to 3 ("much more satisfied") with a total score ranging from -33 to 33.Number of Participants With Missed or Delayed Injections for Participants Who Received LA ART in Step 2 Measured from Step 2 randomization through Step 2, Week 52 Delayed injection was defined as 36-56 days from the previous injection. Missed injection was defined as the duration from the previous injection was longer than 56 days.
Median of Summary Scores of HIV Treatment Adherence Self-Efficacy Scale in Step 1 Step 1 entry, Weeks 12 and 20. HIV Treatment Adherence Self-Efficacy Scale was a 12-item measure used to measure social and psychological determinants of adherence to ART among individuals living with HIV. The response scale to each individual item ranged from 0 ("cannot do at all") to 10 ("completely certain can do"). The total score reported was the average of all item scores, ranging from 0 to 10, with higher scores indicating higher adherence self-efficacy.
Median of Summary Scores of HIV Treatment Adherence Self-Efficacy Scale in Step 2 As Step 2 Week 0, Week 24 and Week 48 HIV Treatment Adherence Self-Efficacy Scale was a 12-item measure used to measure social and psychological determinants of adherence to ART among individuals living with HIV. The response scale to each individual item ranged from 0 ("cannot do at all") to 10 ("completely certain can do"). The total score reported was the average of all item scores, ranging from 0 to 10, with higher scores indicating higher adherence self-efficacy.
Number of Participants With New Drug-resistance Mutations in Participants With Virologic Failure in Step 2 Measured at Step 1 screening/entry and at the time of virologic failure in Step 2 Samples for HIV-1 resistance testing were collected at virologic failure confirmation visit. HIV-1 drug resistance mutations were determined using the IAS October/November 2022 Update of the Drug Resistance Mutations in HIV-1. New drug resistance mutations were defined as those detected at or after virologic failure which were not present at Step 1 screening/baseline.
Virologic failure defined as two consecutive HIV-1 RNA \> 200 copies/mL after Step 2 randomization, regardless of the time between them.Percentage of Participants Who Preferred Monthly Injections of Long-Acting HIV Treatment or Daily Oral HIV Treatment at Each Visit Step 2 week 48, premature treatment visit, and study discontinuation visit The Dichotomous Preference Questionnaire were:
1. Monthly injections of Long-Acting HIV Treatment
2. Daily oral HIVPercentage of Participants With Opinions About Conditional Economic Incentive (CEI) Withdrawal At Step 2 entry and Step 2, Week 8 The responses included: Not at all upset or disappointed, Not very upset or disappointed, Somewhat upset or disappointed, Extremely upset or disappointed, Undecided
Median of Average Total Score of Step 1 HIV Treatment Adherence Self-Efficacy Scale Score (HIV-ASES) Step 1 entry, Step 1 Weeks 12, and Step 1 Weeks 20 HIV-ASES was a 12-item measure used to measure social and psychological determinants of adherence to ART among individuals living with HIV. The response scale to each individual item ranged from 0 ("cannot do at all") to 10 ("completely certain can do"). The total score reported was the average of all item scores, ranging from 0 to 10, with higher scores indicating higher adherence self-efficacy.
Percentage of Participants With Missed Treatment Doses Among Participants Who Randomized to SOC Arm in Step 2 At Step 2 entry, Step 2 week 4, Step 2 week 8, step 2 week 16, step 2 week 24, step 2 week 36, Step 2 week 48, and Step 2 week 52 The outcome was defined as participants with at least one dose missed in the last 30 days at each visit
Trial Locations
- Locations (31)
University of Pittsburgh CRS
🇺🇸Pittsburgh, Pennsylvania, United States
Northwestern University CRS
🇺🇸Chicago, Illinois, United States
Brigham and Women's Hospital Therapeutics Clinical Research Site (BWH TCRS) CRS
🇺🇸Boston, Massachusetts, United States
Vanderbilt Therapeutics (VT) CRS
🇺🇸Nashville, Tennessee, United States
Columbia P&S CRS
🇺🇸New York, New York, United States
University of Colorado Hospital CRS
🇺🇸Aurora, Colorado, United States
University of Southern California CRS
🇺🇸Los Angeles, California, United States
UCLA CARE Center CRS
🇺🇸Los Angeles, California, United States
Alabama CRS
🇺🇸Birmingham, Alabama, United States
UCSD Antiviral Research Center CRS
🇺🇸San Diego, California, United States
Harbor-UCLA CRS
🇺🇸Torrance, California, United States
Ucsf Hiv/Aids Crs
🇺🇸San Francisco, California, United States
The Ponce de Leon Center CRS
🇺🇸Atlanta, Georgia, United States
Univ. of Florida Jacksonville NICHD CRS
🇺🇸Jacksonville, Florida, United States
Massachusetts General Hospital CRS (MGH CRS)
🇺🇸Boston, Massachusetts, United States
Johns Hopkins University CRS
🇺🇸Baltimore, Maryland, United States
Washington University Therapeutics (WT) CRS
🇺🇸Saint Louis, Missouri, United States
New Jersey Medical School Clinical Research Center CRS
🇺🇸Newark, New Jersey, United States
Jacobi Med. Ctr. Bronx NICHD CRS
🇺🇸Bronx, New York, United States
Weill Cornell Chelsea CRS
🇺🇸New York, New York, United States
Case Clinical Research Site
🇺🇸Cleveland, Ohio, United States
Weill Cornell Uptown CRS
🇺🇸New York, New York, United States
Ohio State University CRS
🇺🇸Columbus, Ohio, United States
Greensboro CRS
🇺🇸Greensboro, North Carolina, United States
Chapel Hill CRS
🇺🇸Chapel Hill, North Carolina, United States
SUNY Stony Brook NICHD CRS
🇺🇸Stony Brook, New York, United States
Cincinnati Clinical Research Site
🇺🇸Cincinnati, Ohio, United States
Houston AIDS Research Team CRS
🇺🇸Houston, Texas, United States
University of Washington AIDS CRS
🇺🇸Seattle, Washington, United States
Puerto Rico AIDS Clinical Trials Unit CRS
🇵🇷San Juan, Puerto Rico
Penn Therapeutics, CRS
🇺🇸Philadelphia, Pennsylvania, United States