Study to Identify and Determine Best Implementation Practices for Injectable Cabotegravir+Rilpivirine in the United States (US)
Condition: HIV Infections
MeSH terms: HIV Infections
Intervention: CAB LA+RPV LA
Intervention description: Subjects will receive one tablet of CAB 30 milligram(mg) + RPV 25 mg once daily from Day 1 for 1 month. During month 1, subjects will receive 600 mg of CAB LA injection+ 900 mg of RPV LA injection. Following Month 1, subjects will receive 400mg of CAB LA + 600mg of RPV LA at each subsequent injection.
Phase: Phase 3
Study type: Interventional
Primary purpose: Other
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 115.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Antiretroviral therapy, HIV infections, cabotegravir, rilpivirine, long-acting intramuscular injection,

Summary:

      Chronic human immunodeficiency virus (HIV) infection in adults continues to be characterized
      by increased development of resistant virus, increased transmission of resistant virus and
      issues associated with the long-term toxicity of anti-retroviral therapy (ART), despite
      advances in development of new ART, which provides extensive insight in management of
      HIV-infected individuals. Cabotegravir (CAB) is a potent integrase inhibitor (INI) and
      rilpivirine (RPV) is a potent non-nucleoside reverse transcriptase inhibitor (NNRTI). A
      two-drug regimen (DR)with CAB plus RPV long acting (LA) product offers many potential
      advantages over daily oral regimens including better tolerability, improved compliance,
      adherence, less likely to develop resistance, and overall treatment satisfaction in
      virologically suppressed subjects. This is a single-arm, open-label, multicenter, short term
      facilitation study to evaluate the effect of an implementation strategy on the degree of
      acceptability, appropriateness, feasibility, fidelity and sustainability of clinical
      practices to deliver the CAB+RPV LA regimen to HIV infected subjects and to also measure
      subject satisfaction by recording timeliness of visits, length of visit and their education.
      Approximately 135 subjects will be enrolled in the study and the total duration of the study
      will be approximately 52-weeks.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Be able to understand and comply with protocol requirements, instructions, and
             restrictions;

          -  Understand the long-term commitment to the study and be likely to complete the study
             as planned;

          -  Be considered appropriate candidates for participation in an investigative clinical
             trial with oral and intramuscularly injectable medications (e.g., no active substance
             use disorder, acute major organ disease, or planned long-term work assignments out of
             the country, etc.).

        All Participants eligible for enrolment in the study must meet all of the following
        criteria:

          -  Aged 18 years or older at the time of signing the informed consent.

          -  HIV-1 infected and must be on an active highly active antiretroviral therapy (HAART)
             (2 or 3 drug) 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 >=200 c/mL).

        Acceptable stable ARV regimens prior to Screening include 2 NRTIs plus:

        • INI (either the initial or second Combination antiretroviral therapy (cART) regimen)

          -  NNRTI (either the initial or second cART regimen)

          -  Boosted prediction interval (PI) (or atazanavir [ATV] unboosted) (must be either the
             initial cART regimen or one historical within class switch is permitted due to
             safety/tolerability)

          -  Any suppressed participants on a triple ART regimen for at least 6 months who had
             their regimen switched to a 2DR of dolutegravir (DTG)/RPV

             - Documented evidence of at least two plasma HIV-1 RNA measurements <50 c/mL in the 12
             months prior to Screening: at least one within 6 months prior to Screening;

               -  Plasma HIV-1 RNA <50 c/mL at Screening;

               -  A female participant is eligible to participate if she is not pregnant (as
                  confirmed by a negative urine human chorionic gonadotrophin (hCG) test at screen
                  and at Day 1), 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 (refer to laboratory reference ranges for confirmatory
             levels)]. 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.

             b. 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.

             - Capable of giving signed informed consent, which includes compliance with the
             requirements and restrictions listed in the consent form and in this protocol.
             Eligible participants 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 participants 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.

        Exclusion Criteria:

          -  Within 6 months prior to Screening, plasma HIV-1 RNA measurement >=50 c/mL;

          -  During the previous 12 months, any confirmed HIV-1 RNA measurement >=200 c/mL
             Exclusionary medical conditions

          -  Women who are pregnant, breastfeeding, or plan to become pregnant or breastfeed during
             the study

          -  Any evidence of a current Center for Disease Control and Prevention (CDC) Stage 3
             disease, except cutaneous Kaposi's sarcoma not requiring systemic therapy, and Cluster
             of Differentiation (CD4+) counts <200 cells/microliter are not exclusionary

          -  Any pre-existing physical or mental condition (including substance use 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.

          -  Participants who, in the investigator's judgment, pose 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 for
             Hepatitis B surface antigen (HBsAg), Hepatitis B core antibody (anti-HBc), Hepatitis B
             surface antibody (anti-HBs) and HBV Deoxyribonucleic 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.

          -  Participants who are anticipated to require HCV treatment within 12 months must be
             excluded. Asymptomatic individuals with chronic hepatitis C virus (HCV) infection will
             not be excluded; investigators must carefully assess if therapy specific for HCV
             infection is required. (HCV treatment on study may be permitted, following
             consultation and approval of the direct acting antiviral (DAA) drug based therapy
             being considered with the medical monitor).

          -  Participants with HCV co-infection will be allowed entry into this study if:

               -  Liver enzymes meet entry criteria

               -  HCV Disease has undergone appropriate work-up, and is not advanced. Additional
                  information (where available) on participants with HCV coinfection 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 participant prior to inclusion.

          -  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
             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.

          -  Current or anticipated need for chronic anti-coagulation with the exception of the use
             of low dose acetylsalicylic acid (<=325 milligram (mg) per day) or hereditary
             coagulation and platelet disorders such as haemophilia or Von Willebrand Disease.

          -  Corrected QT interval (QTc [Bazett]) >450 milli second (msec) or QTc (Bazett) >480
             msec for subjects with bundle branch block). Exclusionary Laboratory Values or
             Clinical Assessments (a single repeat to determine eligibility is allowed).

          -  Any evidence of primary resistance based on the presence of any major known INI or
             NNRTI resistance-associated mutation, except for K103N, (International acquired immune
             deficiency syndrome [AIDS] Society [IAS]-USA) by any historical resistance test
             result.

          -  ALT >=5 × Upper Limit Normal (ULN) or ALT >=3xULN and bilirubin >=1.5xULN (with >35%
             direct bilirubin) over the last 6 months.

          -  Any verified Grade 4 laboratory abnormality. A single repeat test is allowed during
             the Screening phase to verify a result.

          -  Participant has estimated creatinine clearance <50 mL/min/1.73meter^2 via the Chronic
             Kidney Disease Epidemiology Collaboration (CKD-EPI) equation.

        Concomitant Medications

          -  Exposure to an experimental drug or experimental vaccine within either 28 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 Day 1:

               -  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: Participants 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.

          -  Use of medications which are associated with Torsade de Pointes must be discussed with
             the Medical Monitor to determine eligibility.

          -  Subjects receiving any prohibited medication and who are unwilling or unable to switch
             to an alternate medication. Note: Any prohibited medications that decrease CAB or RPV
             concentrations should be discontinued for a minimum of four weeks or a minimum of
             three half-lives (whichever is longer) prior to the first dose and any other
             prohibited medications should be discontinued for a minimum of two weeks or a minimum
             of three half-lives (whichever is longer) prior to the first dose.