Study Evaluating the Efficacy, Safety, and Tolerability of Switching to Long-acting Cabotegravir Plus Long-acting Rilpivirine From Current Antiretroviral Regimen in Virologically Suppressed HIV-1-infected Adults
Condition: Infection, Human Immunodeficiency Virus; HIV Infections
MeSH terms: Infections; Communicable Diseases; HIV Infections; Acquired Immunodeficiency Syndrome
Intervention: Cabotegravir (CAB) tablet; Rilpivirine (RPV) tablet; Cabotegravir - Injectable Suspension (CAB LA); Rilpivirine - Injectable Suspension (RPV LA); 2 NRTIs plus an INI, NNRTI, or PI
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.; Acceptable stable (initial or second) ARV regimens include 2 NRTIs plus:
INI with the exception of ABC/DTG/3TC (either the initial or second cART regimen)
NNRTI (either the initial or second cART regimen)
Boosted PI (or atazanavir [ATV] unboosted) (either the initial or second PI-based cART regimen)
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: 618.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Long-acting cabotegravir; Virologic failure; long-acting rilpivirine; Antiretroviral

Summary:

      The Antiretroviral Therapy as Long Acting Suppression (ATLAS) study is being conducted to
      establish if human immunodeficiency virus type-1 (HIV-1) infected adult subjects with current
      viral suppression on a regimen with 2 nucleoside reverse transcriptase inhibitors (NRTIs)
      plus a third agent, remain suppressed upon switching to a two-drug intramuscular (IM)
      long-acting (LA) regimen of cabotegravir (CAB) and rilpivirine (RPV). This is a Phase 3,
      multi-phase, randomized, open label, active-controlled, multicenter, parallel-group,
      non-inferiority study in HIV-1, antiretroviral therapy (ART)-adult subjects who are stably
      suppressed on a current antiretroviral (ARV) regimen. 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 with maintenance of current ARV regimen
      containing 2 NRTIs plus an INI, NNRTI, or a PI. Eligible subjects will be randomized (1:1)
      into the Maintenance Phase at Day 1 to either continue current ART or switch to initiate oral
      therapy with CAB 30 mg + RPV 25 mg once daily for 4 Weeks followed by Q4 weekly (monthly) CAB
      LA + RPV LA injections. Following the Maintenance phase at Week 52, subjects who were
      randomized to continue their current ART regimen will be given an option to switch to CAB LA
      + RPV LA injections. Those subjects would transition to LA dosing, beginning with 4 weeks
      oral CAB + RPV therapy at Week 52, and receive the first IM CAB LA + RPV LA injections at
      Week 56.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Aged 18 years or older (or ≥19 where required by local regulatory agencies), at the
             time of signing the informed consent.

          -  Must be on uninterrupted current regimen (either the initial or second ARV regimen)
             for at least 6 months prior to Screening. Any prior switch, defined as a change of a
             single drug or multiple drugs simultaneously, must have occurred due to
             tolerability/safety, access to medications, or convenience/simplification, and must
             NOT have been done for treatment failure (HIV-1 RNA ≥400 c/mL).

          -  Acceptable stable (initial or second) ARV regimens prior to Screening include 2 NRTIs
             plus: INI with the exception of ABC/DTG/3TC (either the initial or second cART
             regimen);NNRTI (either the initial or second cART regimen);Boosted PI (or atazanavir
             [ATV] unboosted) (must be either the initial cART regimen or one historical within
             class switch is permitted due to safety/tolerability) The addition, removal, or switch
             of a drug(s) that has been used to treat HIV based on antiretroviral properties of the
             drug constitutes a change in ART with the following limited exceptions: Historical
             changes in formulations of ART drugs or booster drugs will not constitute a change in
             ART regimen if the data support similar exposures and efficacy, and the change must
             have been at least 3 months prior to Screening; Historical perinatal use of an NRTI
             when given in addition to an ongoing HAART will not be considered a change in ART
             regimen; A change in dosing scheme of the same drug from twice daily to once daily
             will not be considered a change in ART regimen if data support similar exposures and
             efficacy.

          -  Documented evidence of at least two plasma HIV-1 RNA measurements <50 c/mL in the 12
             months prior to Screening: one within the 6 to 12 month window, and one within 6
             months prior to Screening;

          -  Plasma HIV-1 RNA <50 c/mL at Screening;

          -  A female subjects is eligible to participate if she is not pregnant (as confirmed by a
             negative serum human chorionic gonadotrophin (hCG) test at screen and a negative urine
             hCG test at Randomization), not lactating, and at least one of the following
             conditions applies:

               1. 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.

               2. Reproductive potential and agrees to 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, and
                  until 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 subjects understand how to
                  properly use these methods of contraception.

          -  Capable of giving signed informed consent which includes compliance with the
             requirements and restrictions listed in the consent form. Eligible subjects or their
             legal guardians (and next of kin when locally required), must sign a written Informed
             Consent Form before any protocol-specified assessments are conducted. Enrolment of
             subjects who are unable to provide direct informed consent is optional and will be
             based on local legal/regulatory requirements and site feasibility to conduct protocol
             procedures.

          -  Subjects enrolled in France must be affiliated to, or a beneficiary of, a social
             security category.

          -  All subjects participating in the study should be counselled 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.

        Exclusion Criteria:

          -  Within 6 months prior to Screening and after confirmed suppression to <50 c/mL on
             current ART regimen, any plasma HIV-1 RNA measurement ≥50 c/mL

          -  Within the 6 to 12 month window prior to Screening and after confirmed suppression to
             <50 c/mL, any plasma HIV-1 RNA measurement >200 c/mL, or 2 or more plasma HIV-1 RNA
             measurements ≥50 c/mL

          -  Any drug holiday during the window between initiating first HIV ART and 6 months prior
             to Screening, except for brief periods (less than 1 month) where all ART was stopped
             due to tolerability and/or safety concerns

          -  Any switch to a second line regimen, defined as change of a single drug or multiple
             drugs simultaneously, due to virologic failure to therapy (defined as a confirmed
             plasma HIV-1 RNA measurement ≥400 c/mL after initial suppression to <50 c/mL while on
             first line HIV therapy regimen)

          -  Abacavir/dolutegravir/lamivudine, (ABC/DTG/3TC) as current ART regimen

          -  A history of use of any regimen consisting of only single NNRTI therapy (even if only
             for peri-partum treatment), or only single or dual NRTI therapy prior to starting cART

          -  Subjects who are currently participating in or anticipate to be selected for any other
             interventional study

          -  Women who are pregnant, breastfeeding or plan to become pregnant or breastfeed during
             the study

          -  Any evidence of an active Center for Disease Control and Prevention (CDC) Stage 3
             disease [CDC, 2014], except cutaneous Kaposi's sarcoma not requiring systemic therapy
             and historical or current CD4 cell counts less than 200 cells/mm^3

          -  Subjects with moderate to severe hepatic impairment

          -  Any pre-existing physical or mental condition (including substance use disorder)
             which, in the opinion of the Investigator, may interfere with the subjects ability to
             comply with the dosing schedule and/or protocol evaluations or which may compromise
             the safety of the subject.

          -  Subjects determined by the Investigator to have a high risk of seizures, including
             subjects with an unstable or poorly controlled seizure disorder. A subject 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

          -  All subjects will be screened for syphilis (rapid plasma reagin [RPR]). Subjects with
             untreated syphilis infection, defined as a positive RPR without clear documentation of
             treatment, are excluded. Subjects with a serofast RPR result (persistence of a
             reactive nontreponemal syphilis test) despite history of adequate therapy and no
             evidence of re-exposure may enrol after consultation with the Medical Monitor.
             Subjects with a positive RPR test who have not been treated may be rescreened at least
             30 days after completion of antibiotic treatment for syphilis

          -  Subjects who, in the investigator's judgment, pose a significant suicide risk.
             Subject's recent history of suicidal behavior and/or suicidal ideation should be
             considered when evaluating for suicide risk

          -  The subject 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 DNA as follows:•Subjects
             positive for HBsAg are excluded;

          -  Subjects negative for anti-HBs but positive for anti-HBc (negative HBsAg status) and
             positive for HBV DNA are 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; subjects who are anticipated to require HCV treatment within 12
             months must be excluded. (HCV treatment on study may be permitted post Week 48,
             following consultation with the medical monitor) Subjects 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, and is not advanced, and will not require
             treatment prior to the Week 48 visit. Additional information (where available) on
             subjects 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 inconclusive, the
             Fib-4 score will be used to verify eligibility: 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 ( sqr [ ALT ])

          -  Unstable liver disease (as defined by any of the following: presence of
             ascites,encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric
             varices,or persistent jaundice or cirrhosis), 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

          -  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

          -  Ongoing malignancy other than cutaneous Kaposi's sarcoma, basal cell carcinoma, or
             resected, non-invasive cutaneous squamous cell carcinoma, or cervical intraepithelial
             neoplasia; other localized malignancies require agreement between the investigator and
             the Study medical monitor for inclusion of the subject prior to randomization

          -  Any condition which, in the opinion of the Investigator, may interfere with the
             absorption, distribution, metabolism or excretion of the study drugs or render the
             subject 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 PK sampling, subjects
             with a history of sensitivity to heparin or heparin-induced thrombocytopenia must not
             be enrolled

          -  Current or anticipated need for chronic anti-coagulation with the exception of the use
             of low dose acetylsalicylic acid (≤325mg).

          -  Any evidence of primary resistance based on the presence of any major known INI or
             NNRTI resistance-associated mutation, except for K103N, (International AIDS Society
             [IAS]-USA, 2015) by any historical resistance test result.

          -  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 subject's participation in the study of an
             investigational compound

          -  Subject has estimated creatine clearance <50mL/min per 1.73m^2 via CKDEPI Method

          -  Alanine aminotransferase (ALT) ≥3 × ULN Exposure to an experimental drug or
             experimental vaccine within either 30 days, 5 half-lives of the test agent, or twice
             the duration of the biological effect of the test agent, whichever is longer, prior to
             Day 1 of this study;

          -  Treatment with any of the following agents within 28 days of Screening: radiation
             therapy; cytotoxic chemotherapeutic agents; tuberculosis therapy with the exception of
             isoniazid (isonicotinylhydrazid,INH); anti-coagulation agents; Immunomodulators that
             alter immune responses such as chronic systemic corticosteroids, interleukins, or
             interferons. Note: Subjects using short term (e.g. ≤21 days) systemic corticosteroid
             treatment; topical, inhaled and intranasal corticosteroids are eligible for enrolment.

          -  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 study Day 1

          -  Use of medications which are associated with Torsade de Pointes.

          -  Current or prior history of etravirine (ETR)

          -  Current use of tipranavir/ritonavir or fosamprenavir/ritonavir

          -  Subjects receiving any prohibited medication and who are unwilling or unable to switch
             to an alternate medication.