Study to Evaluate the Efficacy, Safety, and Tolerability of Long-acting Intramuscular Cabotegravir and Rilpivirine for Maintenance of Virologic Suppression Following Switch From an Integrase Inhibitor in HIV-1 Infected Therapy Naive Participants
Condition: HIV Infections
MeSH terms: HIV Infections
Intervention: Cabotegravir (CAB) tablet; Rilpivirine (RPV) tablet; Cabotegravir - Injectable Suspension (CAB LA); Rilpivirine - Injectable Suspension (RPV LA); ABC/DTG/3TC STR - Tablet; DTG Tablet
Intervention description: It is a white oval shaped film coated 30 mg tablets for oral administration. CAB Tablet is composed of cabotegravir sodium, lactose monohydrate, microcrystalline cellulose, hypromellose, sodium starch glycolate, magnesium stearate, and white film-coat.; It is a 25 mg tablet with off-white, round, biconvex, film-coated and debossed on one side with "TMC" and the other side with "25". Each tablet contains RPV hydrochloride, and the inactive ingredients croscarmellose sodium, lactose monohydrate, magnesium stearate, polysorbate 20, povidone K30 and silicified microcrystalline cellulose.; It is a sterile white to slightly pink suspension containing 200 mg/mL of CAB as free acid for administration by intramuscular (IM) injection. Each vial is for single-dose use containing a withdrawable volume of 2.0 mL, and does not require dilution prior to administration. CAB LA is composed of cabotegravir free acid, polysorbate 20, polyethylene glycol 3350, mannitol, and water for injection.; It is a sterile white suspension containing 300 mg/mL of RPV as the free base. The route of administration is by intramuscular (IM) injection. Each vial contains a nominal fill of 2.0 mL, and does not require dilution prior to administration. RPV LA requires refrigeration and must be protected from light. RPV LA is composed of RPV free base, poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate, glucose monohydrate, sodium hydroxide, water for injection.; It is a purple, biconvex, oval, tablet debossed with "572 Tri" on one side, film-coated tablet contains abacavir sulphate equivalent to 600 mg of abacavir, dolutegravir sodium equivalent to 50 mg dolutegravir, and 300 mg of lamivudine. The inactive ABC/DTG/3TC tablet ingredients include D-mannitol, magnesium stearate, microcrystalline cellulose, povidone, and sodium starch glycolate.; It is a yellow, round, biconvex, 50 mg film-coated tablet debossed with "SV 572" on one side and "50" on the other side. Each tablet of DTG also contains the following inactive ingredients: D-mannitol, microcrystalline cellulose, povidone K29/32, sodium starch glycolate, and sodium stearyl fumarate.
Intervention MeSH terms: Rilpivirine; Cabotegravir
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 631.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Antiretroviral agent; Maintenance; rilpivirine; dolutegravir; TMC278; Triumeq; non-nucleoside reverse transcriptase inhibitor; once monthly, every 4 weeks, once daily; GSK1265744; CAB; Tivicay; Long-Acting Intramuscular rilpivirine; lamivudine; integrase inhibitor; Long-Acting Intramuscular Cabotegravir; ART naïve; cabotegravir; abacavir

Summary:

      The First Long-Acting Injectable Regimen (FLAIR) study is being conducted to establish if
      human immunodeficiency virus type-1 (HIV-1) infected adult participants whose virus is
      virologically suppressed on an integrase inhibitor single tablet regimen (INI STR) will
      remain suppressed after switching to a two-drug intramuscular (IM) long-acting (LA) regimen
      of cabotegravir (CAB) and rilpivirine (RPV). In this study, the INI STR will be limited to
      abacavir/dolutegravir/lamivudine (ABC/DTG/3TC). FLAIR is a Phase 3, multi-phase, randomized,
      open label, active-controlled, multicenter, parallel-group, non-inferiority study in HIV-1,
      anti-retroviral therapy (ART)-naïve adult participants. This study is designed to demonstrate
      the non-inferior antiviral activity of switching to a two drug CAB LA 400 mg + RPV LA 600 mg
      regimen every 4 weeks (Q4W: monthly) compared to remaining on ABC/DTG/3TC over 48 weeks (4
      weeks oral CAB + RPV, 44 weeks LA therapy). Participants who are HLA-B*5701 positive at
      Screening may enroll into the study and receive DTG plus a non-abacavir containing dual
      nucleoside reverse transcriptase inhibitor (NRTI) regimen. Eligible participants will enroll
      into the Induction Phase of the study and receive ABC/DTG/3TC for 20 weeks (Week [-20] to Day
      1). Participants who have an HIV 1 ribose nucleic acid (RNA) <50 copies per milliliter (c/mL)
      at Week (-4) will be randomized (1:1) into the Maintenance Phase at Day 1 to either continue
      ABC/DTG/3TC or to discontinue ABC/DTG/3TC and begin oral therapy with CAB 30 mg + RPV 25 mg
      once daily for approximately 4 Weeks, followed by monthly CAB LA + RPV LA injections from
      visit Week 4b until study completion or withdrawal. Participants who successfully complete
      Week 100 (without meeting study defined withdrawal criteria and who remain virologically
      suppressed through Week 96: HIV-1 RNA <50 c/mL) will be given the option to switch to the LA
      arm in the Extension Phase (using an optional oral lead-in with CAB + RPV) or be withdrawn
      from the study. Participants will continue to receive injections every 4 weeks during the
      Extension Phase until CAB LA and RPV LA are either locally approved and commercially
      available, the participant no longer derives clinical benefit, the participant meets a
      protocol-defined reason for discontinuation, or until development of either CAB LA or RPV LA
      is terminated.
    

Eligibility criteria:

        Inclusion Criteria: - HIV-1 infected, ART-naive men or women aged 18 years or greater at
        the time of signing the informed consent. - HIV-1 infection as documented by Screening
        plasma HIV-1 RNA >=1000 c/mL; - Antiretroviral-naive (<=10 days of prior therapy with any
        antiretroviral agent following a diagnosis of HIV-1 infection). Any previous exposure to an
        HIV integrase inhibitor or non-nucleoside reverse transcriptase inhibitor will be
        exclusionary. - Female Participants: A female participant is eligible to participate if she
        is not pregnant at Screening and first day of Induction Phase (as confirmed by a negative
        serum human chorionic gonadotrophin [hCG] test), not lactating, and at least one of the
        following conditions applies: Non-reproductive potential defined as: Pre-menopausal females
        with one of the following: Documented tubal ligation; Documented hysteroscopic tubal
        occlusion procedure with follow-up confirmation of bilateral tubal occlusion; Hysterectomy;
        Documented Bilateral Oophorectomy; Postmenopausal defined as 12 months of spontaneous
        amenorrhea [in questionable cases a blood sample with simultaneous follicle stimulating
        hormone (FSH) and estradiol levels consistent with menopause. Females on hormone
        replacement therapy (HRT) and whose menopausal status is in doubt will be required to use
        one of the highly effective contraception methods if they wish to continue their HRT during
        the study. Otherwise, they must discontinue HRT to allow confirmation of post-menopausal
        status prior to study enrolment. Reproductive potential and agrees to follow one of the
        options listed in the Modified List of Highly Effective Methods for Avoiding Pregnancy in
        Females of Reproductive Potential (FRP) from 30 days prior to the first dose of study
        medication, throughout the study, and for at least 30 days after discontinuation of all
        oral study medications and for at least 52 weeks after discontinuation of CAB LA and RPV
        LA. The investigator is responsible for ensuring that participants understand how to
        properly use these methods of contraception. 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. -
        Capable of giving signed informed consent which includes compliance with the requirements
        and restrictions listed in the consent form and in this protocol. - In France, a
        participant will be eligible for inclusion in this study only if either affiliated to or a
        beneficiary of a social security category.

        Exclusion Criteria: - Women who are pregnant, breastfeeding, or plan to become pregnant or
        breastfeed during the study. - Any evidence at Screening of an active Centers for Disease
        and Prevention Control (CDC) Stage 3 disease, except cutaneous Kaposi's sarcoma not
        requiring systemic therapy or historic or current cluster of differentiation4+ (CD4+) cell
        count <200 cells/ cubic millimeter (mm^3) are not exclusionary. - Participants with known
        moderate to severe hepatic impairment. - Any pre-existing physical or mental condition
        (including substance abuse disorder) which, in the opinion of the Investigator, may
        interfere with the participant's ability to comply with the dosing schedule and/or protocol
        evaluations or which may compromise the safety of the participant. - Participants
        determined by the Investigator to have a high risk of seizures, including participants with
        an unstable or poorly controlled seizure disorder. A participant with a prior history of
        seizure may be considered for enrolment if the Investigator believes the risk of seizure
        recurrence is low. All cases of prior seizure history should be discussed with the Medical
        Monitor prior to enrolment. - Participant who, in the investigator's judgment, poses a
        significant suicide risk. Participant's recent history of suicidal behavior and/or suicidal
        ideation should be considered when evaluating for suicide risk. - The participant has a
        tattoo or other dermatological condition overlying the gluteus region which may interfere
        with interpretation of injection site reactions. - Evidence of Hepatitis B virus (HBV)
        infection based on the results of testing at Screening for Hepatitis B surface antigen
        (HBsAg), Hepatitis B core antibody (anti HBc), Hepatitis B surface antibody (anti-HBs) and
        HBV dioxyribose nucleic acid (DNA) as follows: Participants positive for HBsAg are
        excluded; Participants negative for anti-HBs but positive for anti-HBc (negative HBsAg
        status) and positive for 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. - Asymptomatic individuals with chronic hepatitis C virus
        (HCV) infection will not be excluded, however Investigators must carefully assess if
        therapy specific for HCV infection is required; participants who are anticipated to require
        HCV treatment prior to Week 48 of the Maintenance Phase must be excluded. HCV treatment on
        study may be permitted post Week 48, following consultation with the Medical Monitor.
        Participants with HCV co-infection will be allowed entry into Phase 3 studies if: Liver
        enzymes meet entry criteria; HCV Disease has undergone appropriate work-up, HCV is not
        advanced, and will not require treatment prior to the Week 48 visit. Additional information
        (where available) on participants with HCV co-infection at screening should include results
        from any liver biopsy, fibroscan, ultrasound, or other fibrosis evaluation, history of
        cirrhosis or other decompensated liver disease, prior treatment, and timing/plan for HCV
        treatment. In the event that recent biopsy or imaging data is not available or is
        inconclusive, the Fib-4 score will be used to verify eligibility. A Fib-4 score > 3.25 is
        exclusionary; Fib-4 scores 1.45 - 3.25 requires Medical Monitor consultation. Fibrosis 4
        Score Formula: (Age x AST)/(Platelets x [square root of ALT]). - Unstable 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
        otherwise stable chronic liver disease per investigator assessment). - History of liver
        cirrhosis with or without hepatitis viral co-infection. - Ongoing or clinically relevant
        pancreatitis. - All participants will be screened for syphilis (rapid plasma reagin [RPR]).
        Participants with untreated syphilis infection, defined as a positive RPR without clear
        documentation of treatment, are excluded. Participants with a positive RPR test who have
        not been treated may be rescreened at least 30 days after completion of antibiotic
        treatment for syphilis. - Ongoing malignancy other than cutaneous Kaposi's sarcoma, basal
        cell carcinoma, or resected, non-invasive cutaneous squamous cell carcinoma, or cervical,
        anal or penile intraepithelial neoplasia; other localized malignancies require agreement
        between the investigator and the study Medical Monitor for inclusion of the participant
        prior to enrollment. - Any condition which, in the opinion of the Investigator, may
        interfere with the absorption, distribution, metabolism or excretion of the drug or render
        the participant unable to receive study medication. - History or presence of allergy or
        intolerance to the study drugs or their components or drugs of their class. In addition, if
        heparin is used during pharmacokinetic sampling (PK) sampling, participants with a history
        of sensitivity to heparin or heparin-induced thrombocytopenia must not be enrolled. -
        Current or anticipated need for chronic anti-coagulation. - Alanine aminotransferase (ALT)
        >=3 times upper limit normal (ULN). - Clinically significant cardiovascular disease, as
        defined by history/evidence of congestive heart failure, symptomatic arrhythmia,
        angina/ischemia, coronary artery bypass grafting (CABG) surgery or percutaneous
        transluminal coronary angioplasty (PTCA) or any clinically significant cardiac disease. -
        Exposure to an experimental drug and/or experimental vaccine within 28 days or 5 half-lives
        of the test agent, or twice the duration of the biological effect of the test agent,
        whichever is longer, prior to the first dose of investigational product (IP). - Treatment
        with any of the following agents within 28 days of Screening: radiation therapy; cytotoxic
        chemotherapeutic agents; tuberculosis (TB) therapy, with the exception of treatment of
        latent TB with isoniazid; Immunomodulators that alter immune responses (such as chronic
        systemic corticosteroids, interleukins, or interferons). Note: Participants using
        short-term (e.g. =<21 day) systemic corticosteroid treatment, topical, inhaled or
        intranasal corticosteroids are eligible for enrollment. - Treatment with an HIV-1
        immunotherapeutic vaccine within 90 days of Screening. - Treatment with any agent, except
        recognized ART as allowed above, with documented activity against HIV-1 within 28 days of
        the first dose of IP. - Use of medications which are associated with Torsades de Pointes -
        Any evidence of primary resistance to non-nuclease reverse transcriptase inhibitors
        (NNRTIs) (except for K103N which is allowed), or any known resistance to INIs from
        historical resistance test results. Note: re-tests of Screening genotypes are allowed only
        at the discretion of the study virologist. - Participants who are HLA-B*5701 positive and
        are unable to use an nuclease reverse transcriptase inhibitors (NRTI) backbone that does
        not contain abacavir (participants who are HLA-B*5701 positive may be enrolled if they use
        a NRTI backbone that does not contain abacavir; HLA-B*5701 positive participants may be
        excluded from the study if local provision of an alternate NRTI backbone is not possible).
        - Any verified Grade 4 laboratory abnormality. A single repeat test is allowed during the
        Screening Phase to verify a result. - Any acute laboratory abnormality at Screening, which,
        in the opinion of the Investigator, would preclude the participant's participation in the
        study of an investigational compound. - Participant has estimated creatinine clearance <50
        mL/min/1.73m^2 via the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI)
        equation. - Participants who are currently participating in or anticipate to be selected
        for any other interventional study.