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

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ClinicalTrials.gov Identifier: NCT03635788
Recruitment Status : Recruiting
First Posted : August 17, 2018
Last Update Posted : October 8, 2019
Sponsor:
Collaborator:
ViiV
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)

Tracking Information
First Submitted Date  ICMJE August 15, 2018
First Posted Date  ICMJE August 17, 2018
Last Update Posted Date October 8, 2019
Actual Study Start Date  ICMJE March 28, 2019
Estimated Primary Completion Date September 1, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (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
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT03635788 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (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 ]
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE The LATITUDE Study: Long-Acting Therapy to Improve Treatment SUccess in Daily LifE
Official Title  ICMJE 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 at Weeks 2, 4, 8, 12, 16, and 20.

In Step 2, eligible participants will be randomized to receive either oral RPV + oral CAB for 4 weeks followed by RPV-LA + CAB-LA every 4 weeks for 48 weeks 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 followed by RPV-LA + CAB-LA every 4 weeks for 48 weeks. 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  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE HIV Infections
Intervention  ICMJE
  • 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  ICMJE
  • Experimental: Arm A: LA ART
    In Step 1, participants will receive SOC oral ART regimen for 24 weeks. In Step 2, participants will receive oral RPV once daily and oral CAB once daily for 4 weeks, followed by a RPV-LA loading dose and a CAB-LA loading dose, followed in 4 weeks by a 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 for 52 weeks. 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 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, followed by a RPV-LA loading dose and a CAB-LA loading dose, followed in 4 weeks by a RPV-LA maintenance dose and CAB-LA maintenance dose every 4 weeks for 44 weeks. 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 * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: August 15, 2018)
350
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE September 26, 2024
Estimated Primary Completion Date September 1, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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 60 days prior to study entry by any US laboratory that has a Clinical Laboratory Improvement Amendments (CLIA) certification or its equivalent.
  • 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 2 appointments 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 its equivalent within 60 days of study entry (see protocol for more information), nor history of such mutations on review of prior resistance tests by the site investigator. Genotypic analysis using proviral (i.e., archived) DNA is not allowed.
  • 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 Cockcroft-Gault
    • NOTE: A calculator for estimating the CrCl can be found at www.fstrf.org/ACTG/ccc.html.
  • For women 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: Female 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

    • Female Participants of Reproductive Potential: Female 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
    • Female Participants Who Are Not of Reproductive Potential: Women 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 woman'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 an uninfected partner.
  • 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.
  • 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.
  • Acute or serious illness requiring systemic treatment and/or hospitalization within 7 days prior to entry.
  • 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

  • HIV-1 RNA less than 50 copies/mL at Step 1, week 20, or HIV-1 RNA of 50-399 copies/mL at Step 1, week 20, followed by HIV-1 RNA less than 50 copies/mL by Step 1, week 24.

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.

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 commercially available LA ART,
  • OR does not wish to continue LA ART.

Step 4 Exclusion Criteria

  • There are no exclusion criteria for Step 4.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Listed Location Countries  ICMJE Puerto Rico,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03635788
Other Study ID Numbers  ICMJE 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  ICMJE
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://actgnetwork.org/about-actg/templates-and-forms. Researchers of approved proposals will need to sign an AIDS Clinical Trials Group Data Use Agreement before receiving the data.
Responsible Party National Institute of Allergy and Infectious Diseases (NIAID)
Study Sponsor  ICMJE National Institute of Allergy and Infectious Diseases (NIAID)
Collaborators  ICMJE ViiV
Investigators  ICMJE
Study Chair: Jose Castillo-Mancilla, M.D. University of Colorado Hospital CRS
Study Chair: Aadia Rana, M.D. Alabama CTU
PRS Account National Institute of Allergy and Infectious Diseases (NIAID)
Verification Date October 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP