The LATITUDE Study: Long-Acting Therapy to Improve Treatment SUccess in Daily LifE

• ClinicalTrials.gov Identifier: NCT03635788
• Recruitment Status: Recruiting
• First Posted: August 17, 2018
• Last Update Posted: December 15, 2023
• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Collaborator: ViiV Healthcare
• Information provided by (Responsible Party): National Institute of Allergy and Infectious Diseases (NIAID)

Tracking Information

• First Submitted Date: August 15, 2018
• First Posted Date: August 17, 2018
• Last Update Posted Date: December 15, 2023
• Actual Study Start Date: March 28, 2019
• Estimated Primary Completion Date: June 30, 2025 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: February 9, 2023)

Occurrence of regimen failure in Step 2 [ Time Frame: From after Step 2 randomization to Step 2, Week 48 ]

Regimen failure is defined as the occurrence of the first of the following two events at any time post randomization and Step 2, week 48, visit:

• Virologic failure (defined as confirmed HIV-1 RNA >200 copies/mL after Step 2 randomization)
• Permanent discontinuation of randomized study treatment

Original Primary Outcome Measures (submitted: August 15, 2018)

Time to regimen failure in Step 2 [ Time Frame: Measured through Step 2, Week 52 ]

Time will be measured from Step 2 randomization to the first of the following two events: virologic failure or permanent discontinuation of randomized study treatment

Current Secondary Outcome Measures (submitted: February 9, 2023)

• Occurrence of virologic failure in Step 2 at any time post randomization and week 48 visit [ Time Frame: from after Step 2 randomization to Step 2, Week 48 ]
  Virologic failure is defined as confirmed HIV-1 RNA greater than 200 copies/mL after Step 2 randomization
• Occurrence of the treatment-related failure in Step 2 at any time post randomization and week 48 visit [ Time Frame: from after Step 2 randomization to Step 2, Week 48 ]
  Time will be measured from the Step 2 randomization to the first of the following events: virologic failure or treatment discontinuation due to adverse event (AE)
• Number of participants with virologic non-success [ Time Frame: from after Step 2 randomization to Step 2, Week 48] ]
  Virologic non-success will be defined by the US Food and Drug Administration (FDA) Snapshot algorithm
• Number of participants with plasma HIV-1 RNA level less than 50 copies/mL and less than or equal to 200 copies/mL at scheduled study visits on Steps 1 and 2 [ Time Frame: Measured from Step 1 entry through Step 2, Week 52 ]
  Summarized and tabulated by Step, study visit, and randomized treatment
• Frequency of AEs during Steps 1 and 2 [ Time Frame: Measured from Step 1 entry through Step 2, Week 52 ]
  AEs will be graded based on the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), corrected Version 2.1, July 2017
• Occurrence of discontinuation of randomized treatment in Step 2 [ Time Frame: Measured from after Step 2 randomization through Step 2, Week 48 ]
  Time will be measured from Step 2 at any time post randomization to Step 2 week 48 visit
• Summary score of HIV Treatment Satisfaction Questionnaire (HIVTSQ) in Step 2 [ Time Frame: Step 2 randomization, Step 2 weeks 24 and 48 ]
  Summarized and tabulated by randomized treatments
• Frequency of missed or delayed injections for participants who received LA ART in Step 2 [ Time Frame: Measured from Step 2 randomization through Step 2, Week 52 ]
  Delayed injection is defined as 8 days beyond scheduled injection day.
• Summary scores of HIV Treatment Adherence Self-Efficacy Scale in Step 1 and Step 2 [ Time Frame: Measured from Step 1 through Step 2, Week 52 ]
  Summarized and tabulated by Step
• Frequency of new drug-resistance mutations in participants with virologic failure in Step 2 [ Time Frame: Measured from after Step 2 randomization through Step 2, Week 52 ]
  Summarized and tabulated by randomized treatment
• Frequency of Injection Site Reactions (ISR) during Step 2 [ Time Frame: Measured from Step 2 randomization through Step 2, Week 52 ]
  Summarized and tabulated by reaction site
• Summary of participant self-reported dichotomous preference questionnaire [ Time Frame: Step 2 week 48 ]
  Summarized and tabulated by randomized treatment

Original Secondary Outcome Measures (submitted: August 15, 2018)

• Time to virologic failure in Step 2 [ Time Frame: Measured through Step 2, Week 52 ]
  Virologic failure is defined as confirmed HIV-1 RNA greater than 200 copies/mL after Step 2 randomization
• Time to the treatment-related failure in Step 2 [ Time Frame: Measured through Step 2, Week 52 ]
  Time will be measured from the Step 2 randomization to the first of the following events: virologic failure or treatment discontinuation due to adverse event (AE)
• Number of participants with virologic success [ Time Frame: Measured through Step 2, Week 48 ]
  Virologic success will be defined by the US Food and Drug Administration (FDA) Snapshot algorithm
• Number of participants with plasma HIV-1 RNA level less than 50 copies/mL [ Time Frame: Measured through Step 2, Week 52 ]
• Frequency of AEs [ Time Frame: Measured through Step 2, Week 52 ]
  AEs will be graded based on the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), corrected Version 2.1, July 2017
• Time to discontinuation of randomized treatment in Step 2 [ Time Frame: Measured through Step 2, Week 52 ]
  Time will be measured from Step 2 randomization to the permanent discontinuation of randomized study treatment.
• Summary score of HIV Treatment Satisfaction Questionnaire (HIVTSQ) [ Time Frame: Measured through Step 2, Week 52 ]
• Pill count in Step 1 [ Time Frame: Measured through Step 1, Week 24 ]
• Pill count for participants who randomized to SOC arm in Step 2 [ Time Frame: Measured through Step 2, Week 52 ]
• Frequency of missed or delayed injections for participants who received LA ART in Step 2 [ Time Frame: Measured through Step 2, Week 52 ]
• Summary scores of HIV Treatment Adherence Self-Efficacy Scale [ Time Frame: Measured through Step 2, Week 52 ]
• Frequency of new drug-resistance mutations in participants with virologic failure in Step 2 [ Time Frame: Measured through Step 2, Week 52 ]
  Summarized and tabulated by randomized treatments
• Frequency of Injection Site Reactions (ISR) during Step 2 [ Time Frame: Measured through Step 2, Week 52 ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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
• Brief Summary: The purpose of this study is 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 will 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) with rilpivirine (RPV) LA and cabotegravir (CAB) LA versus all-oral standard of care (SOC).

The study includes four steps. 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.

In Step 2, eligible participants will be randomized to receive either oral RPV + oral CAB for 4 weeks (optional) followed by RPV-LA + CAB-LA every 4 weeks for until the end of step 3 or to continue on SOC for 52 weeks.

At the completion of Step 2, eligible participants randomized to SOC will have the option to register to Step 3 and receive LA ART, which includes oral RPV + oral CAB for 4 weeks (optional) followed by RPV-LA + CAB-LA every 4 weeks until the end of step 3. Participants already receiving RPV-LA + CAB-LA in Step 2 will continue on this regimen in Step 3 for 52 weeks.

Eligible participants will enter Step 4 and be followed for 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).

• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: HIV Infections

Intervention

• Drug: Standard of Care (SOC) Oral ART
  SOC oral ART regimen must include at least 3 drugs with 2 or more drugs predicted to be fully active, including a boosted protease inhibitor (PI) and/or an integrase strand transfer inhibitor (INSTI)
• Drug: Oral RPV
  RPV 25 mg tablets
  Other Name: Rilpivirine
• Drug: Oral CAB
  CAB 30 mg tablets
  Other Names:

  • Cabotegravir
  • GSK1265744
• Drug: RPV-LA Loading Dose
  900 mg administered as one 3 mL (900 mg) intramuscular injection in the gluteal muscle
  Other Name: Rilpivirine Long-Acting Injectable
• Drug: CAB-LA Loading Dose
  600 mg administered as one 3 mL (600 mg) intramuscular injection in the gluteal muscle
  Other Name: Cabotegravir Long-Acting Injectable
• Drug: RPV-LA Maintenance Dose
  600 mg administered as one 2 mL (600 mg) intramuscular injection in the gluteal muscle
  Other Name: Rilpivirine Long-Acting Injectable
• Drug: CAB-LA Maintenance Dose
  400 mg administered as one 2 mL (400 mg) intramuscular injection in the gluteal muscle
  Other Name: Cabotegravir Long-Acting Injectable

Study Arms

• Experimental: Arm A: LA ART
  In Step 1, participants will receive SOC oral ART regimen for up to 24 weeks. In Step 2, participants will receive 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. In Step 3, participants will receive a RPV-LA maintenance dose and a CAB-LA maintenance dose every 4 weeks until the end of Step 2. In Step 4, eligible participants will be followed until they complete 52 weeks on locally sourced oral ART.
  Interventions:

  • Drug: Standard of Care (SOC) Oral ART
  • Drug: Oral RPV
  • Drug: Oral CAB
  • Drug: RPV-LA Loading Dose
  • Drug: CAB-LA Loading Dose
  • Drug: RPV-LA Maintenance Dose
  • Drug: CAB-LA Maintenance Dose
• Active Comparator: Arm B: SOC Oral ART
  In Step 1, participants will receive SOC oral ART regimen for up to 24 weeks. In Step 2, participants will continue SOC oral ART regimen for 52 weeks. In Step 3, participants will receive 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 CAB-LA maintenance dose every 4 weeks until the end of Step 3. In Step 4, eligible participants will be followed until they complete 52 weeks on locally sourced oral ART.
  Interventions:

  • Drug: Standard of Care (SOC) Oral ART
  • Drug: Oral RPV
  • Drug: Oral CAB
  • Drug: RPV-LA Loading Dose
  • Drug: CAB-LA Loading Dose
  • Drug: RPV-LA Maintenance Dose
  • Drug: CAB-LA Maintenance Dose

• Publications *: 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.

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: August 15, 2018): 350
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: December 31, 2026
• Estimated Primary Completion Date: June 30, 2025 (Final data collection date for primary outcome measure)

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" refers to a FDA-approved kit, which is required for all IND studies.
• WHO (World Health Organization) and CDC (Centers for Disease Control and Prevention) guidelines mandate that confirmation of the initial test result must use a test that is different from the one used for the initial assessment. A reactive initial rapid test should be confirmed by either another type of rapid assay or an E/CIA that is 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 has a Clinical Laboratory Improvement Amendments (CLIA) certification or its equivalent, unless participant has been lost to clinical follow-up (see 4.1.3 NOTE) and no viral load result is available within the last 12 months

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 have 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 is defined as either no contact with provider or missed greater than or equal to 1 appointment in a 6-month period. ART non-adherence is 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 Manual of Procedures [MOPS] for list of exclusionary mutations) through commercially available genotypic (or phenotypic, if available) analyses from any laboratory that has 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 cannot be resulted by the testing laboratory, review of historical genotypes and treatment history by the IoR can be used to satisfy this criterion (see protocol for more information).
• Ability of site clinician, in conjunction with participant, to construct an oral induction antiretroviral (ARV) regimen that must include at least three ARVs of which at least two must be predicted to be fully active. The regimen must, 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 has 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, negative serum or urine pregnancy test with a sensitivity of less than or equal to 25 mIU/mL at screening. This will be repeated again at study entry.

• NOTE: Participants are considered to be NOT of reproductive potential if: 1) they have had amenorrhea for at least 12 consecutive months prior to study entry ((i.e., who have had no menses within 12 months prior to study entry), and have a documented follicle-stimulating hormone (FSH) greater than 40 IU/mL; OR 2) an FSH level is not available, but they have had 24 consecutive months of amenorrhea (in the absence of medications known to induce amenorrhea); OR 3) they report 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 are participating in sexual activity that could lead to pregnancy, must 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 include:

• Contraceptive subdermal implant
• Intrauterine device or intrauterine system
• Combined estrogen and progestogen oral contraceptive
• Injectable progestogen
• Contraceptive vaginal ring
• Percutaneous contraceptive patches
• Participants Who Are Not of Reproductive Potential: Participants who are not of reproductive potential are eligible to start study drugs without requiring the use of contraceptives. Any statement of self-reported sterility or that of her partner's must be entered in the source documents.
• NOTE A: Acceptable documentation of lack of reproductive potential is the participant's self-reported history of surgical sterilization, menopause, or male partner's azoospermia.
• NOTE B: ALL participants in the study should 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
• Age greater than or equal to 18 years.
• 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 a high risk of seizures, including participants with an unstable or poorly controlled seizure disorder.

• NOTE: A participant with a prior history of seizure may be considered for enrollment if the Investigator believes the risk of seizure recurrence is low. All cases of prior seizure history should 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 positive HBV surface antigen test or any detectable HBV DNA in participants with isolated HBcAb and HBV DNA as follows:

• Participants positive for HBsAg are excluded
• Participants negative for anti-HBs but positive for anti-HBc (negative HBsAg status) and any detectable HBV DNA are excluded
• NOTE: Participants positive for anti-HBc (negative HBsAg status) and positive for anti-HBs (past and/or current evidence) are immune to HBV and are not excluded. If prior documentation of immunity is available, repeat testing at screening is 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 gluteus region, which may interfere with 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 hospitalizationthat may render 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 is used at screening must be used throughout study period.
• Any serious medical or psychiatric condition, which may render 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 is 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 will be used to determine eligibility for randomization must 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

• Willingness to continue for those in Arm A or begin to receive LA ART for those in Arm B.
• Arm B participants: HIV-1 RNA less than 50 copies/mL at Step 2, week 48, or HIV-1 RNA of 50-399 copies/mL at Step 2, week 48, followed by HIV-1 RNA less than 50 copies/mL by Step 2, week 52.

Step 3 Exclusion Criteria

• Permanent discontinuation of study treatment for any reason during Step 2.
• Confirmed Virologic Failure during Step 2.
• (Only for Arm B in Step 2) Currently pregnant, planning to become pregnant during the study period, or currently breastfeeding.

Step 4 Inclusion Criteria

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

Step 4 Exclusion Criteria

• There are no exclusion criteria for Step 4.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Listed Location Countries: Puerto Rico, United States

Administrative Information

• NCT Number: NCT03635788
• Other Study ID Numbers: ACTG A5359; 30104 ( Registry Identifier: DAIDS-ES Registry Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: Individual participant data that underlie results in the publication, after deidentification.
• Supporting Materials: Study Protocol
• Supporting Materials: Statistical Analysis Plan (SAP)
• Time Frame: Beginning 3 months following publication and available throughout period of funding of the AIDS Clinical Trials Group by NIH.

Access Criteria

• With whom?

  • Researchers who provide a methodologically sound proposal for use of the data that is approved by the AIDS Clinical Trials Group.

• For what types of analyses?

  • To achieve aims in the proposal approved by the AIDS Clinical Trials Group.

• By what mechanism will data be made available?

  • Researchers may submit a request for access to data using the AIDS Clinical Trials Group "Data Request" form at: https://submit.mis.s-3.net/. Researchers of approved proposals will need to sign an AIDS Clinical Trials Group Data Use Agreement before receiving the data.

• Current Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
• Original Responsible Party: Same as current
• Current Study Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Original Study Sponsor: Same as current
• Collaborators: ViiV Healthcare

Investigators

• Study Chair: Aadia Rana, M.D.; Alabama CTU

• PRS Account: National Institute of Allergy and Infectious Diseases (NIAID)
• Verification Date: December 2023