Phase 2b, Open-label, Multicenter, Rollover Study to Assess Antiviral Activity and Safety of Long-acting (LA) Cabotegravir (CAB) Plus LA Rilpivirine (RPV), Administered Every 2 Months (Q2M), in Human Immunodeficiency Virus (HIV)-Positive Participants From the LATTE Study
Condition: HIV Infections
MeSH terms: HIV Infections
Intervention: CAB LA; RPV LA; RPV; DTG
Intervention description: Administered CAB LA (600 mg) Q2M, as intramuscular injection.; Administered RPV LA (900 mg), Q2M, as intramuscular injection.; Oral dose of RPV 25 mg, administered once daily from Day 1 up to Month 12; Oral dose of DTG 50 mg administered once daily from Day 1 up to Month 12.
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Intervention model description: This is an Intervention Model, with parallel assignment, where the primary purpose of the study is, treatment, with 2 arms and no masking.
Masking: None (Open Label)
Masking description: This is an open-label study, thus no masking.
Enrollment: 97.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: HIV; Antiretroviral therapy; Maintenance; Long acting; LATTE

Summary:

      This study (POLAR), is designed to assess the antiviral activity and safety of CAB LA plus
      RPV LA, administered Q2M, in approximately 100 adult HIV-1 infected, antiretroviral therapy
      (ART) experienced participants. Participants will rollover from the NCT01641809 (LATTE)
      study, who have completed minimum duration of Week 312 and with demonstrated HIV-1
      ribonucleic acid (RNA) suppression (less than [<]50 copies (c) per milliliter [mL]), while
      receiving a two-drug regimen consisting of once-daily oral CAB at 30 milligram (mg) plus RPV
      at 25 mg. The participants will be offered the option to switch to the LA, intramuscular
      injections of CAB LA plus RPV LA, Q2M or the oral fixed dose combination (FDC) of
      dolutegravir (DTG) plus RPV, for the continued maintenance of HIV-1 RNA suppression, known as
      the Maintenance Phase (From Day 1 to Commercial Approval). Duration of study will vary from
      country to country, until regimen receives regulatory approval and becomes commercially
      available. The study plans to enroll approximately 100 participants. Any participant who
      receives at least one dose of CAB LA and/or RPV LA and discontinues the CAB LA plus RPV LA
      regimen for any reason will enter a 52-week Long-Term Follow-Up (LTFU) phase. Those
      participants must remain on suppressive highly active antiretroviral therapy (HAART) for at
      least 52 weeks after the last dose of CAB LA and or RPV LA.
    

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.

          -  A female participant is eligible to participate if she is not pregnant (as confirmed
             by a negative urine human chorionic gonadotrophin [hCG] test at Day 1), not lactating,
             and at least with one of following conditions:

             (a) Non-reproductive potential defined as: (i) Pre-menopausal females with one of the
             conditions as documented tubal ligation; Documented hysteroscopic tubal occlusion
             procedure with follow-up confirmation of bilateral tubal occlusion, Hysterectomy,
             Documented Bilateral Oophorectomy.

        (ii) 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, 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 the methods of contraception.

          -  Capable of giving signed informed consent.

          -  Must have been on oral CAB 30 mg plus RPV 25 mg regimen through at minimum Week 300 of
             the LATTE study as per LATTE protocol dosing requirements and until Day 1 of the POLAR
             study. Any disruptions in dosing during LATTE must be discussed with the Medical
             Monitor for a final determination of eligibility.

          -  Plasma HIV-1 RNA <50 c/mL at Week 300. If participant has plasma HIV-1 RNA >= 50 c/mL
             at Week 300 in LATTE, a single repeat to determine eligibility may be allowed ONLY
             after consultation with the medical monitor.

        Exclusion Criteria:

          -  During the last 6 months of participation in LATTE, consecutive (2 or more sequential)
             plasma HIV-1 RNA measurements >=50 c/mL.

          -  During the last 6 months of participation in LATTE, any HIV-1 RNA measurement >=200
             c/mL.

          -  Any evidence of a current Center for Disease Control and Prevention (CDC) Stage 3
             disease [CDC, 2014], except cutaneous Kaposi's sarcoma not requiring systemic therapy.

          -  Participants with moderate to severe hepatic impairment determined by Child-Pugh
             classification.

          -  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.

          -  Participants 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 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.

          -  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
             within 12 months must be excluded. (HCV treatment on study may be permitted, following
             consultation 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 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
             fibrosis- 4 (Fib-4) score will be used to verify eligibility where Fib-4 score >3.25
             is exclusionary; Fib-4 scores 1.45 - 3.25 requires Medical Monitor consultation where
             the Fibrosis 4 Score Formula: age multiplied by aspartate amino transferase (AST)
             divided by platelets multiplied by square of alanine aminotransferase (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 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
             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 (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 with the exception of the use
             of low dose acetylsalicylic acid (less than or equal to [<=]325 mg) or hereditary
             coagulation and platelet disorders such as hemophilia or Von Willebrand Disease.

          -  Corrected QT interval (QTc (Bazett)) >450 millisecond (msec) or QTc (Bazett) >480 msec
             for participants with bundle branch block.

          -  Any verified Grade 4 laboratory abnormality over the last 6 months in LATTE. A single
             repeat test is allowed to verify a result.

          -  Any acute laboratory abnormality over the last 6 months in LATTE, which, in the
             opinion of the investigator, would preclude the participant's participation in the
             study of an investigational compound.

          -  ALT>=5 times upper limit of normal (ULN) or ALT >= 3 times ULN and bilirubin >= 1.5
             times ULN (with >35 percent [%] direct bilirubin) over the last 6 months in LATTE.

          -  Exposure to an experimental drug (with the exception of those in the LATTE study
             including CAB and RPV) 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 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.

          -  Use of medications which are associated with Torsade de Pointes must be discussed with
             the Medical Monitor to determine eligibility.

          -  Participants receiving any prohibited medication and who are unwilling or unable to
             switch to an alternate medication.