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

HIV Infections Clinical Trial

Official title:

A Phase III Study to Evaluate Long-Acting Antiretroviral Therapy in Non-Adherent HIV-Infected Individuals

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03635788
• Other study ID #: ACTG A5359
• Secondary ID: 30104
• Status: Recruiting
• Phase: Phase 3
• Start date: March 28, 2019
• Est. completion date: December 31, 2026

Study information

• Verified date: December 2023
• Source: National Institute of Allergy and Infectious Diseases (NIAID)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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).

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 350
• Est. completion date: December 31, 2026
• Est. primary completion date: June 30, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• 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)
• Oral RPV
RPV 25 mg tablets
• Oral CAB
CAB 30 mg tablets
• RPV-LA Loading Dose
900 mg administered as one 3 mL (900 mg) intramuscular injection in the gluteal muscle
• CAB-LA Loading Dose
600 mg administered as one 3 mL (600 mg) intramuscular injection in the gluteal muscle
• RPV-LA Maintenance Dose
600 mg administered as one 2 mL (600 mg) intramuscular injection in the gluteal muscle
• CAB-LA Maintenance Dose
400 mg administered as one 2 mL (400 mg) intramuscular injection in the gluteal muscle

Locations

Country	Name	City	State
Puerto Rico	Puerto Rico AIDS Clinical Trials Unit CRS	San Juan
Puerto Rico	San Juan City Hosp. PR NICHD CRS	San Juan
United States	The Ponce de Leon Center CRS	Atlanta	Georgia
United States	University of Colorado Hospital CRS	Aurora	Colorado
United States	Johns Hopkins University CRS	Baltimore	Maryland
United States	Alabama CRS	Birmingham	Alabama
United States	Brigham and Women's Hospital Therapeutics Clinical Research Site (BWH TCRS) CRS	Boston	Massachusetts
United States	Massachusetts General Hospital CRS (MGH CRS)	Boston	Massachusetts
United States	Jacobi Med. Ctr. Bronx NICHD CRS	Bronx	New York
United States	Chapel Hill CRS	Chapel Hill	North Carolina
United States	Northwestern University CRS	Chicago	Illinois
United States	Rush University CRS	Chicago	Illinois
United States	Cincinnati Clinical Research Site	Cincinnati	Ohio
United States	Case Clinical Research Site	Cleveland	Ohio
United States	Ohio State University CRS	Columbus	Ohio
United States	Trinity Health and Wellness Center CRS	Dallas	Texas
United States	Greensboro CRS	Greensboro	North Carolina
United States	Houston AIDS Research Team CRS	Houston	Texas
United States	Univ. of Florida Jacksonville NICHD CRS	Jacksonville	Florida
United States	UCLA CARE Center CRS	Los Angeles	California
United States	University of Southern California CRS	Los Angeles	California
United States	Vanderbilt Therapeutics (VT) CRS	Nashville	Tennessee
United States	Columbia P&S CRS	New York	New York
United States	Weill Cornell Chelsea CRS	New York	New York
United States	Weill Cornell Uptown CRS	New York	New York
United States	New Jersey Medical School Clinical Research Center CRS	Newark	New Jersey
United States	Penn Therapeutics, CRS	Philadelphia	Pennsylvania
United States	University of Pittsburgh CRS	Pittsburgh	Pennsylvania
United States	The Miriam Hospital Clinical Research Site (TMH CRS) CRS	Providence	Rhode Island
United States	Washington University Therapeutics (WT) CRS	Saint Louis	Missouri
United States	UCSD Antiviral Research Center CRS	San Diego	California
United States	Ucsf Hiv/Aids Crs	San Francisco	California
United States	University of Washington AIDS CRS	Seattle	Washington
United States	SUNY Stony Brook NICHD CRS	Stony Brook	New York
United States	Harbor-UCLA CRS	Torrance	California

Sponsors (2)

Lead Sponsor	Collaborator
National Institute of Allergy and Infectious Diseases (NIAID)	ViiV Healthcare

Countries where clinical trial is conducted

United States,  Puerto Rico, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Occurrence of regimen failure in Step 2	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	From after Step 2 randomization to Step 2, Week 48
Secondary	Occurrence of virologic failure in Step 2 at any time post randomization and week 48 visit	Virologic failure is defined as confirmed HIV-1 RNA greater than 200 copies/mL after Step 2 randomization	from after Step 2 randomization to Step 2, Week 48
Secondary	Occurrence of the treatment-related failure in Step 2 at any time post randomization and week 48 visit	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)	from after Step 2 randomization to Step 2, Week 48
Secondary	Number of participants with virologic non-success	Virologic non-success will be defined by the US Food and Drug Administration (FDA) Snapshot algorithm	from after Step 2 randomization to Step 2, Week 48]
Secondary	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	Summarized and tabulated by Step, study visit, and randomized treatment	Measured from Step 1 entry through Step 2, Week 52
Secondary	Frequency of AEs during Steps 1 and 2	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	Measured from Step 1 entry through Step 2, Week 52
Secondary	Occurrence of discontinuation of randomized treatment in Step 2	Time will be measured from Step 2 at any time post randomization to Step 2 week 48 visit	Measured from after Step 2 randomization through Step 2, Week 48
Secondary	Summary score of HIV Treatment Satisfaction Questionnaire (HIVTSQ) in Step 2	Summarized and tabulated by randomized treatments	Step 2 randomization, Step 2 weeks 24 and 48
Secondary	Frequency of missed or delayed injections for participants who received LA ART in Step 2	Delayed injection is defined as 8 days beyond scheduled injection day.	Measured from Step 2 randomization through Step 2, Week 52
Secondary	Summary scores of HIV Treatment Adherence Self-Efficacy Scale in Step 1 and Step 2	Summarized and tabulated by Step	Measured from Step 1 through Step 2, Week 52
Secondary	Frequency of new drug-resistance mutations in participants with virologic failure in Step 2	Summarized and tabulated by randomized treatment	Measured from after Step 2 randomization through Step 2, Week 52
Secondary	Frequency of Injection Site Reactions (ISR) during Step 2	Summarized and tabulated by reaction site	Measured from Step 2 randomization through Step 2, Week 52
Secondary	Summary of participant self-reported dichotomous preference questionnaire	Summarized and tabulated by randomized treatment	Step 2 week 48