Efficacy, Safety and Tolerability Study of Long-acting Cabotegravir Plus Long-acting Rilpivirine (CAB LA + RPV LA) in Human-immunodeficiency Virus-1 (HIV-1) Infected Adults

A Phase IIIb, Randomized, Multicenter, Parallel-group, Non-inferiority, Open-label Study Evaluating the Efficacy, Safety, and Tolerability of Long-acting Cabotegravir Plus Long-acting Rilpivirine Administered Every 8 Weeks or Every 4 Weeks in HIV-1-infected Adults Who Are Virologically Suppressed

This Antiretroviral Therapy as Long Acting Suppression every 2 Months (ATLAS-2M) study is designed to demonstrate the non-inferior antiviral activity and safety of CAB LA + RPV LA administered every 8 weeks (Q8W) compared to CAB LA + RPV LA administered every 4 weeks (Q4W) over a 48-week treatment period in approximately 1020 adult HIV-1 infected subjects. Subjects will be divided in 2 groups; Group 1 will include subjects receiving current anti-retroviral (ART) standard of care (SOC) therapy whereas group 2 will include subjects currently receiving CAB LA + RPV LA Q4W in ATLAS study. Subjects in both groups will be randomized to receive CAB LA + RPV LA Q4W or Q8W. The study will be carried out in 3 phases including screening phase, maintenance phase and extension phase. Subjects choosing not to enter the Extension phase can complete their study participation at the Week 100 visit and enter into the 52-week Long-Term Follow-Up (LTFU) Phase as required. A sub-study in the ATLAS-2M study will evaluate the pharmacokinetics, tolerability and efficacy of CAB and RPV long acting injections following intramuscular administration in the Vastus Lateralis Muscle (thigh) in HIV-infected Adult Participants who have received at least three years of Gluteal Injections in this ATLAS-2M Study.

Inclusion Criteria:

• Subjects who will 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 as an appropriate candidate 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.).
• Aged 18 years or older (or >=19 where required by local regulatory agencies), at the time of signing the informed consent.
• A female is eligible to participate if she is not pregnant (as confirmed by a negative serum human chorionic gonadotropin (hCG) test at screen and a negative urine hCG test at Randomization), 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 (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 enrollment.

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 these methods of contraception.

• Capable of giving signed informed consent. 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. Enrollment 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.
• Subjects receiving oral SOC treatment for HIV-1 (not participating in ATLAS Trial) must be on uninterrupted current regimen [either the initial or second anti-retroviral (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 copies/mL).
• For subjects receiving oral SOC treatment for HIV-1 (not participating in ATLAS Trial) Documented evidence of at least two plasma HIV-1 RNA measurements <50 copies/mL in the 12 months prior to Screening: one within the 6 to 12-month window, and one within 6 months prior to Screening.
• For subjects receiving oral SOC treatment for HIV-1 (not participating in ATLAS Trial): Plasma HIV-1 RNA <50 copies/mL at Screening
• Subjects transitioning from 201585 (ATLAS) must have been on CAB LA 400 milligram (mg) + RPV LA 600 mg Q4W or "Current ART" regimen through at minimum Week 52 of the ATLAS study as per ATLAS protocol dosing requirements and until Day 1 of the ATLAS-2M study. Any disruptions in dosing during ATLAS must be discussed with the Medical Monitor for a final determination of eligibility.
• For Participants transitioning from 201585 (ATLAS): plasma HIV-1 RNA <50 copies/mL at Screening Sub-study inclusion criteria
• Eligible participants must have been on CAB LA + RPV LA regimen for a minimum of 152 weeks while on the ATLAS-2M study.
• Plasma HIV-1 RNA <50 c/mL at Sub-Study Screening

Exclusion Criteria:

For subjects not transitioning from 201585 (ATLAS):

• Within 6 months prior to Screening, any plasma HIV-1 RNA measurement >=50 copies/mL
• Within the 6 to 12-month window prior to Screening, any plasma HIV-1 RNA measurement >200 copies/mL, or 2 or more plasma HIV-1 RNA measurements >=50 copies/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 >=200 copies/mL after initial suppression to <50 copies/mL while on first line HIV therapy regimen)
• A history of use of any regimen consisting of only mono or dual HIV-1 therapy (even if only for peri-partum treatment). Subjects who are currently participating in or anticipate to be selected for any other interventional study with the exception of the 201585 (ATLAS) study.

For Subjects transitioning from 201585 (ATLAS):

• During participation in ATLAS, consecutive (2 or more sequential) plasma HIV-1 RNA measurements >=50 copies/mL
• During participation in ATLAS, any HIV-1 RNA measurement >=200 copies/mL
• More than two total measurements of plasma HIV-1 RNA >=50 c/mL during participation in the ATLAS trial will require direct approval by the ATLAS-2M Medical Monitor and Study virologist for study participation.

For all subjects:

• 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 CD4+ counts <200 cells/µL are not exclusionary.
• 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 subject's 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 participants with an unstable or poorly controlled seizure disorder. A subject 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 Medical Monitor prior to enrollment.
• All subjects will be screened for syphilis (rapid plasma reagin [RPR]). Subjects with untreated secondary (late latent) or tertiary syphilis infection, defined as a positive RPR and a positive treponemal test without clear documentation of treatment, are excluded. Subjects with a false positive RPR (with negative treponemal test) or serofast RPR result (persistence of a reactive nontreponemal syphilis test despite history of adequate therapy and no evidence of re-exposure) may enroll after consultation with the Medical Monitor. Participants with primary syphilis or early latent secondary syphilis (acquired within the preceding year) who have a positive RPR test and have not been treated may be treated during the screening period and if completion of antibiotic treatment occurs during the screening period, may be allowed entry after consultation with the Medical Monitor. If antibiotic treatment cannot be completed before the screening window ends, subjects may be rescreened once following completion of antibiotic therapy for primary or early latent secondary 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 deoxyribonucleic acid (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. 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 within 12 months must be excluded. (HCV treatment on study may be permitted post Week 52, following consultation with the medical monitor).
• Subjects 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, and will not require treatment prior to the Week 52 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 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 ( square [ 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 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 (<=325 mg) or hereditary coagulation and platelet disorders such as hemophilia or Von Willebrand Disease.
• Any evidence of primary resistance based on the presence of any major known Integrase inhibitor (INI) or Non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance-associated mutation, except for K103N 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.
• Subjects has estimated creatine clearance <50mL/minute per 1.73 meter square (m^2) via Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) Method
• Alanine aminotransferase (ALT) >=3 × Upper limit of normal (ULN)
• Exposure to an experimental drug (with the exception of those in the ATLAS study including CAB, CAB LA, and RPV LA) 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 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 study Day 1. Treatment with acyclovir/valacyclovir is permitted.
• Use of medications which are associated with Torsade de Pointes.
• Current or prior history of etravirine (ETR) use.
• 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.
• Participation in other interventional studies or non-interventional studies that require any type of assessment outside the local standard of care practices is generally not permitted, however for eligible subjects in South Africa only, co-enrolment in the AIDS Clinical Trial Group ACTG interventional study (A5392) could be exceptionally permitted after review and approval by the Medical Monitor.

Sub-study exclusion criteria

• More than 1 plasma HIV-1 RNA measurement =>50 c/mL to <200 c/mL (virologic blip) within 24 weeks prior to sub-study Screening visit.
• Any Suspected Virologic Failure (HIV-RNA>200 c/mL)
• Participants planning to require oral bridging during participation in the ATLAS-2M sub-study
• Participant has a tattoo or any dermatological condition overlying the thigh region which may interfere with interpretation of injection site reactions
• 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