Clinical trial NCT03635788: The LATITUDE Study: Long-Acting Therapy to Improve Treatment SUccess in Daily LifE
Official title: A Phase III Study to Evaluate Long-Acting Antiretroviral Therapy in Non-Adherent HIV-Infected Individuals
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: HIV Infections
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
Collaborators: name: ViiV Healthcare
First posted: 2018-08-17
Enrollment: 456
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: Step 1 Inclusion Criteria

HIV-1 infection, documented by any licensed rapid HIV test or HIV enzyme or chemiluminescence immunoassay (E/CIA) test kit at any time prior to study entry and confirmed by a licensed Western blot or a second antibody test by a method other than the initial rapid HIV and/or E/CIA, or by HIV-1 antigen, plasma HIV-1 RNA viral load.

NOTE: The term "licensed" referred to an FDA-approved kit, which was required for all IND studies.

WHO (World Health Organization) and CDC (Centers for Disease Control and Prevention) guidelines mandated that confirmation of the initial test result had to use a test that was different from the one used for the initial assessment. A reactive initial rapid test had to be confirmed by either another type of rapid assay or an E/CIA that was based on a different antigen preparation and/or different test principle (e.g., indirect versus competitive), or a Western blot or a plasma HIV-1 RNA viral load.

HIV-1 Plasma viral load (VL) greater than 200 copies/mL within 12 months prior to study entry by any US laboratory that had a Clinical Laboratory Improvement Amendments (CLIA) certification or its equivalent, unless the participant had been lost to clinical follow-up (see protocol for more information) and no viral load result was available within the last 12 months.

NOTE: Participants who satisfied non-adherence eligibility due to loss to clinical follow-up might not have had a viral load result available at the time of consideration for eligibility. Those participants could be screened and, regardless of their screening viral load result (either ≤ or \>200 copies/mL), they would have been eligible for study entry if they met all other inclusion/exclusion criteria.

Evidence of non-adherence to ART according to at least one of the following criteria:

Poor virologic response within 18 months prior to study entry (defined as less than 1 log10 decrease in HIV-1 RNA or HIV-1 RNA greater than 200 copies/mL at two time points at least 4 weeks apart) in individuals who had been prescribed ART for at least 6 consecutive months.

Lost to clinical follow-up within 18 months prior to study entry with ART non-adherence for greater than or equal to 6 consecutive months.

NOTE: Lost to clinical follow-up was defined as either no contact with the provider or missing greater than or equal to 1 appointment in a 6-month period. ART non-adherence was defined as a lapse in ART greater than or equal to 7 days (consecutive or non-consecutive), in the 6-month period where they were lost to clinical follow-up per participant report.

No evidence of any clinically relevant RPV or INSTI resistance-associated mutations (see protocol for more information) through commercially available genotypic (or phenotypic, if available) analyses from any laboratory that had a CLIA certification or equivalent within 60 days of study entry (see protocol for more information), nor history of such mutations on review of prior HIV-1 drug resistance tests by the site investigator. For participants in whom a screening HIV-1 conventional genotype could not be resulted by the testing laboratory, review of historical genotypes and treatment history by the IoR could be used to satisfy this criterion as indicated in the protocol.

Ability of site clinician, in conjunction with the participant, to construct an oral induction antiretroviral (ARV) regimen that had to include at least three ARVs of which at least two had to be predicted to be fully active. The regimen had to include PI/cobi and/or an INSTI based on screening and/or historic resistance testing.

Laboratory values obtained within 60 days prior to study entry by any laboratory that had a CLIA certification or its equivalent:

Hemoglobin greater than or equal to 9.0 g/dL

Absolute neutrophil count (ANC) greater than or equal to 600/mm\^3

Alanine aminotransferase (ALT) less than or equal to 3 x upper limit of normal (ULN)

Creatinine Clearance (CrCl) greater than or equal to 50 mL/min estimated by Chronic Kidney Disease Epidemiology Collaboration equation (CKD-Epi).

For participants of reproductive potential, a negative serum or urine pregnancy test with a sensitivity of less than or equal to 25 mIU/mL at screening. This was repeated again at study entry.

NOTE: Participants were considered to be NOT of reproductive potential if: 1) they had had amenorrhea for at least 12 consecutive months prior to study entry (i.e., who had had no menses within 12 months prior to study entry), and had a documented follicle-stimulating hormone (FSH) greater than 40 IU/mL; OR 2) an FSH level was not available, but they had had 24 consecutive months of amenorrhea (in the absence of medications known to induce amenorrhea); OR 3) they reported having undergone surgical sterilization (e.g., hysterectomy, or bilateral oophorectomy, or bilateral tubal ligation/hysteroscopic tubal occlusion).

Contraception Requirements

Participants of Reproductive Potential: Participants of reproductive potential, who were participating in sexual activity that could lead to pregnancy, had to agree to use at least one of the listed highly effective methods for contraception from 30 days prior to the first dose of study medication, while receiving the study drugs, and for 30 days after stopping oral medications, or the duration specified in the product label if receiving study drugs not supplied by the study, or 52 weeks after stopping RPV-LA or CAB-LA. Acceptable methods of contraception included:

Contraceptive subdermal implant

Intrauterine device or intrauterine system

Combined estrogen and progestogen oral contraceptive

Injectable progestogen

Contraceptive vaginal ring

Percutaneous contraceptive patches

Participants Who Were Not of Reproductive Potential: Participants who were not of reproductive potential were eligible to start study drugs without requiring the use of contraceptives. Any statement of self-reported sterility or that of her partner's had to be entered in the source documents.

NOTE A: Acceptable documentation of lack of reproductive potential was the participant's self-reported history of surgical sterilization, menopause, or male partner's azoospermia.

NOTE B: ALL participants in the study were to be counseled on safer sexual practices including the use and benefit/risk of effective barrier methods (e.g., male condom) and on the risk of HIV transmission to a partner without HIV.

Ability and willingness of participant or legal guardian/representative to provide written informed consent.

Step 1 Exclusion Criteria

Currently pregnant, planning to become pregnant during the study period, or currently breastfeeding.

Participants determined by the Site Investigator to have had a high risk of seizures, including participants with an unstable or poorly controlled seizure disorder.

NOTE: A participant with a prior history of seizure could have been considered for enrollment if the Investigator believed the risk of seizure recurrence was low. All cases of prior seizure history were to be discussed with the A5359 protocol leadership team (actg.leada5359@fstrf.org) prior to enrollment.

Advanced liver disease (as defined by any of the following: presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, or persistent jaundice), known biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones) OR history of liver cirrhosis.

Chronic Hepatitis C (HCV) with planned or anticipated use of anti-HCV therapy prior to the completion of Step 2.

History of or current active hepatitis B (HBV) infection defined as a positive HBV surface antigen test or any detectable HBV DNA in participants with isolated HBcAb and HBV DNA as follows:

Participants positive for HBsAg were excluded.

Participants negative for anti-HBs but positive for anti-HBc (negative HBsAg status) and any detectable HBV DNA were excluded.

NOTE: Participants positive for anti-HBc (negative HBsAg status) and positive for anti-HBs (past and/or current evidence) were immune to HBV and were not excluded. If prior documentation of immunity was available, repeat testing at screening was not required.

Current or anticipated need for chronic anti-coagulation therapy.

Unwilling to receive injections, or unable to receive gluteal injections.

Tattoo or other condition over the gluteus region, which could have interfered with the interpretation of injection site reaction.

Previous use of CAB.

Any acute or serious illness, within 7 days prior to entry, requiring systemic treatment and/or hospitalization that could have rendered the participant unable to receive study medication, in the opinion of the site investigator.

QTc greater than 450 ms using either Bazett or Fridericia method within 60 days prior to study entry: Whichever method was used at screening had to be used throughout the study period.

Any serious medical or psychiatric condition, which could have rendered the participant unable to receive study medication in the opinion of the site investigator.

Known allergy/sensitivity or any hypersensitivity to components of study drug(s) or their formulation.

Requirement for any medication that was prohibited with a study medication (refer to protocol-specific web page \[PSWP\]).

Step 2 Inclusion Criteria

Meeting virologic suppression criteria at or after Step 1, week 4, defined as:

1. HIV-1 RNA ≤200 copies/mL OR
2. HIV-1 RNA of 201-399 copies/mL followed by HIV-1 RNA ≤200 copies/mL by Step 1, week 24.

NOTE: The HIV-1 RNA viral load that was used to determine eligibility for randomization had to have been collected within 4 weeks (28 days) of the Step 2 randomization visit.

Step 2 Exclusion Criteria

Permanent discontinuation of study treatment for any reason during Step 1.

Participants who never started study treatment in Step 1 (see protocol for more information).

Step 3 Inclusion Criteria, Participants Registering from Step 1

Virologic suppression at or after Step 1, week 4, defined as:

1. HIV-1 RNA ≤200 copies/mL OR
2. HIV-1 RNA of 201-399 copies/mL followed by HIV-1 RNA ≤200 copies/mL by Step 1, week 24.

NOTE: The HIV-1 RNA viral load that was used to determine eligibility for Step 3 had to have been collected within 4 weeks (28 days) of the Step 3 registration visit.

Willingness to begin to receive LA ART.

Step 3 Exclusion Criteria, Participants Registering from Step 1

Permanent discontinuation of study treatment for any reason during Step 1.

Participants who never started study treatment in Step 1 (see protocol for more information).

Currently pregnant, planning to become pregnant during the study period, or currently breastfeeding.

Step 3 Inclusion Criteria, Participants Registering from Step 2

Willingness to continue LA ART (for those in Step 2 Arm A) or begin LA ART (for those in Step 2 Arm B).

Step 2 Arm B participants: HIV-1 RNA ≤200 copies/mL at the most recent Step 2 visit OR Confirmation of Virologic Failure visit.

NOTE: The HIV-1 RNA viral load that was used to determine eligibility for Step 3 had to have been collected within 4 weeks (28 days) of the Step 3 registration visit.

Step 3 Exclusion Criteria, Participants Registering from Step 2

Permanent discontinuation of study treatment (LA ART for Arm A and oral ART for Arm B) for any reason during Step 2.

Confirmed Virologic Failure during Step 2.

Step 2 Arm B Participants: Currently pregnant, planning to become pregnant during the study period, or currently breastfeeding.

NOTE: Step 2 Arm A participants who became pregnant and were permitted to continue on LA-ART could continue on that regimen in Step 3.

Step 4 Inclusion Criteria

Any participant who had received at least one dose of CAB-LA or RPV-LA AND did not have access to available LA ART through their provider, OR did not wish to continue LA ART.

Step 4 Exclusion Criteria

There were no exclusion criteria for Step 4.

Primary outcomes:
measure: Cumulative Probability of Regimen Failure in Step 2 at Any Time Post Randomization and Week 48 Visit
timeFrame: From Step 2 randomization to Step 2, Week 48 visit (up to 50 weeks)
Secondary outcomes:
measure: Cumulative Probability of Virologic Failure in Step 2 at Any Time Post Randomization to Week 48 Visit
timeFrame: From Step 2 randomization to Step 2, Week 48 visit (up to 50 weeks)
measure: Cumulative Probability of the Treatment-related Failure in Step 2 at Any Time Post Randomization to Week 48 Visit
timeFrame: From after Step 2 randomization to Step 2, Week 48 (up to 50 weeks)
measure: Number of Participants With Virologic Non-success (>= 50 Copies/ml)
timeFrame: from Step 2 randomization to Step 2, Week 48 (up to 50 weeks)
measure: Number of Participants With Virologic Non-success (>= 200 Copies/ml)
timeFrame: From Step 2 randomization to Step 2, Week 48 (up to 50 weeks)
measure: Percentage of Participants With Plasma HIV-1 RNA Level Less Than 50 Copies/mL at Scheduled Study Visits on Steps 1
timeFrame: Measured from Step 1 entry through Step 1, Week 20 visit
measure: Percentage of Participants With Plasma HIV-1 RNA Level Less Than 200 Copies/mL at Scheduled Study Visits on Steps 1
timeFrame: Measured from Step 1 entry through Step 1, Week 20 visit
measure: Percentage of Participants With Plasma HIV-1 RNA Level Less Than 50 Copies/mL at Scheduled Study Visits on Steps 2
timeFrame: Measured from Step 2 entry through Step 2, Week 48 visit
measure: Percentage of Participants With Plasma HIV-1 RNA Level Less Than 200 Copies/mL at Scheduled Study Visits on Steps 2
timeFrame: Measured from Step 2 entry through Step 2, Week 48 visit
measure: Cumulative Probability of Discontinuation of Randomized Treatment in Step 2
timeFrame: Measured from Step 2 randomization through Step 2, Week 48 (up to 50 weeks)
measure: Median Summary Score of HIV Treatment Satisfaction Questionnaire (HIVTSQ) in Step 2
timeFrame: 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.
measure: Number of Participants With Missed or Delayed Injections for Participants Who Received LA ART in Step 2
timeFrame: Measured from Step 2 randomization through Step 2, Week 52
measure: Median of Summary Scores of HIV Treatment Adherence Self-Efficacy Scale in Step 1
timeFrame: Step 1 entry, Weeks 12 and 20.
measure: Median of Summary Scores of HIV Treatment Adherence Self-Efficacy Scale in Step 2
timeFrame: As Step 2 Week 0, Week 24 and Week 48
measure: Number of Participants With New Drug-resistance Mutations in Participants With Virologic Failure in Step 2
timeFrame: Measured at Step 1 screening/entry and at the time of virologic failure in Step 2
measure: Percentage of Participants With Grade 1 or Higher Injection Site Reactions (ISR) During Step 2
timeFrame: Measured from Step 2 randomization through Step 2, Week 52
measure: Percentage of Participants Who Preferred Monthly Injections of Long-Acting HIV Treatment or Daily Oral HIV Treatment at Each Visit
timeFrame: Step 2 week 48, premature treatment visit, and study discontinuation visit
measure: Percentage of Participants With Opinions About Conditional Economic Incentive (CEI) Withdrawal
timeFrame: At Step 2 entry and Step 2, Week 8
measure: Median of Average Total Score of Step 1 HIV Treatment Adherence Self-Efficacy Scale Score (HIV-ASES)
timeFrame: Step 1 entry, Step 1 Weeks 12, and Step 1 Weeks 20
measure: Percentage of Participants With Missed Treatment Doses Among Participants Who Randomized to SOC Arm in Step 2
timeFrame: 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
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Alabama CRS
state: Alabama
city: Los Angeles
country: United States
facility: University of Southern California CRS
state: California
city: Los Angeles
country: United States
facility: UCLA CARE Center CRS
state: California
city: San Diego
country: United States
facility: UCSD Antiviral Research Center CRS
state: California
city: San Francisco
country: United States
facility: Ucsf Hiv/Aids Crs
state: California
city: Torrance
country: United States
facility: Harbor-UCLA CRS
state: California
city: Aurora
country: United States
facility: University of Colorado Hospital CRS
state: Colorado
city: Jacksonville
country: United States
facility: Univ. of Florida Jacksonville NICHD CRS
state: Florida
city: Atlanta
country: United States
facility: The Ponce de Leon Center CRS
state: Georgia
city: Chicago
country: United States
facility: Northwestern University CRS
state: Illinois
city: Baltimore
country: United States
facility: Johns Hopkins University CRS
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital CRS (MGH CRS)
state: Massachusetts
city: Boston
country: United States
facility: Brigham and Women's Hospital Therapeutics Clinical Research Site (BWH TCRS) CRS
state: Massachusetts
city: Saint Louis
country: United States
facility: Washington University Therapeutics (WT) CRS
state: Missouri
city: Newark
country: United States
facility: New Jersey Medical School Clinical Research Center CRS
state: New Jersey
city: Bronx
country: United States
facility: Jacobi Med. Ctr. Bronx NICHD CRS
state: New York
city: New York
country: United States
facility: Weill Cornell Chelsea CRS
state: New York
city: New York
country: United States
facility: Columbia P&S CRS
state: New York
city: New York
country: United States
facility: Weill Cornell Uptown CRS
state: New York
city: Stony Brook
country: United States
facility: SUNY Stony Brook NICHD CRS
state: New York
city: Chapel Hill
country: United States
facility: Chapel Hill CRS
state: North Carolina
city: Greensboro
country: United States
facility: Greensboro CRS
state: North Carolina
city: Cincinnati
country: United States
facility: Cincinnati Clinical Research Site
state: Ohio
city: Cleveland
country: United States
facility: Case Clinical Research Site
state: Ohio
city: Columbus
country: United States
facility: Ohio State University CRS
state: Ohio
city: Philadelphia
country: United States
facility: Penn Therapeutics, CRS
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh CRS
state: Pennsylvania
city: Nashville
country: United States
facility: Vanderbilt Therapeutics (VT) CRS
state: Tennessee
city: Houston
country: United States
facility: Houston AIDS Research Team CRS
state: Texas
city: Seattle
country: United States
facility: University of Washington AIDS CRS
state: Washington
city: San Juan
country: Puerto Rico
facility: Puerto Rico AIDS Clinical Trials Unit CRS
Study officials:
affiliation: Alabama CTU
name: Aadia Rana, M.D.
role: STUDY_CHAIR
References:
citation: Pluznik JA, Nijhawan AE, Spaulding AC. Does Anything Work? Improving HIV Care Engagement for Individuals Transitioning out of Correctional Settings. J Acquir Immune Defic Syndr. 2021 Mar 1;86(3):286-287. doi: 10.1097/QAI.0000000000002599. No abstract available.