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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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HIV Infections

Intervention / Treatment
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* Drug: Cabotegravir Tablets
* Drug: Rilpivirine Tablets
* Drug: Cabotegravir Injectable Suspension
* Drug: Rilpivirine Injectable Suspension


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Two groups of subjects will be randomized to receive CAB LA + RPV LA Q4W, or CAB LA + RPV LA Q8W regimen
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Subjects in group 1 receiving study treatment once in 4 weeks<br>Group 1 will consist of subjects randomized from current ART SOC therapy. Subjects in group 1 will be randomized to receive CAB LA plus RPV LA Q4W via intramuscular (IM) route. All subjects will receive oral therapy with CAB 30 mg + RPV 25 mg once daily prior to randomization. | Drug: Cabotegravir Tablets<br>* CAB tablets are white to almost white oval shaped film coated 30 mg tablets for oral administration. CAB tablets are to be stored up to 30 degree Celsius and protected from moisture.<br>Drug: Rilpivirine Tablets<br>* RPV tablets are 25 mg tablets that are off-white, round, biconvex, film-coated and debossed on one side with TMC and the other side with 25. RPV tablets should be stored at 25 degree Celsius (excursions permitted to 15 degree-30 degree Celsius) and protected from light.<br>Drug: Cabotegravir Injectable Suspension<br>* CAB LA injectable suspension is a sterile white to slightly pink suspension containing 200 mg/mL of GSK1265744 as free acid for administration by IM injection. CAB LA injectable suspension is to be stored at up to 30 degree Celsius and should not be frozen.<br>Drug: Rilpivirine Injectable Suspension<br>* RPV LA injectable suspension is a sterile white suspension containing 300 mg/mL of RPV as the free base for administration by IM injection. RPV LA injectable suspension should be kept in the outer package and stored at 2-8 degree Celsius and should not be frozen. RPV LA should also be protected from light.<br>|
| Experimental: Subjects in group 1 receiving study treatment once in 8 weeks<br>Group 1 will consist of subjects randomized from current ART SOC therapy. Subjects in group 1 will be randomized to receive CAB LA plus RPV LA Q8W via IM route. All subjects will receive oral therapy with CAB 30 mg + RPV 25 mg once daily prior to randomization. | Drug: Cabotegravir Tablets<br>* CAB tablets are white to almost white oval shaped film coated 30 mg tablets for oral administration. CAB tablets are to be stored up to 30 degree Celsius and protected from moisture.<br>Drug: Rilpivirine Tablets<br>* RPV tablets are 25 mg tablets that are off-white, round, biconvex, film-coated and debossed on one side with TMC and the other side with 25. RPV tablets should be stored at 25 degree Celsius (excursions permitted to 15 degree-30 degree Celsius) and protected from light.<br>Drug: Cabotegravir Injectable Suspension<br>* CAB LA injectable suspension is a sterile white to slightly pink suspension containing 200 mg/mL of GSK1265744 as free acid for administration by IM injection. CAB LA injectable suspension is to be stored at up to 30 degree Celsius and should not be frozen.<br>Drug: Rilpivirine Injectable Suspension<br>* RPV LA injectable suspension is a sterile white suspension containing 300 mg/mL of RPV as the free base for administration by IM injection. RPV LA injectable suspension should be kept in the outer package and stored at 2-8 degree Celsius and should not be frozen. RPV LA should also be protected from light.<br>|
| Experimental: Subjects in group 2 receiving study treatment once in 4 weeks<br>Group 2 will consist of subjects currently receiving CAB LA + RPV LA Q4W in ATLAS study. Subjects in Group 2 will be randomized to continue CAB LA plus RPV LA Q4W administration via IM route. | Drug: Cabotegravir Injectable Suspension<br>* CAB LA injectable suspension is a sterile white to slightly pink suspension containing 200 mg/mL of GSK1265744 as free acid for administration by IM injection. CAB LA injectable suspension is to be stored at up to 30 degree Celsius and should not be frozen.<br>Drug: Rilpivirine Injectable Suspension<br>* RPV LA injectable suspension is a sterile white suspension containing 300 mg/mL of RPV as the free base for administration by IM injection. RPV LA injectable suspension should be kept in the outer package and stored at 2-8 degree Celsius and should not be frozen. RPV LA should also be protected from light.<br>|
| Experimental: Subjects in group 2 receiving study treatment once in 8 weeks<br>Group 2 will consist of subjects currently receiving CAB LA + RPV LA Q4W in ATLAS study. Subjects in Group 2 will be randomized to receive CAB LA plus RPV LA Q8W via IM route. | Drug: Cabotegravir Injectable Suspension<br>* CAB LA injectable suspension is a sterile white to slightly pink suspension containing 200 mg/mL of GSK1265744 as free acid for administration by IM injection. CAB LA injectable suspension is to be stored at up to 30 degree Celsius and should not be frozen.<br>Drug: Rilpivirine Injectable Suspension<br>* RPV LA injectable suspension is a sterile white suspension containing 300 mg/mL of RPV as the free base for administration by IM injection. RPV LA injectable suspension should be kept in the outer package and stored at 2-8 degree Celsius and should not be frozen. RPV LA should also be protected from light.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Plasma Human Immunodeficiency Virus-ribonucleic Acid (HIV-RNA) >=50 Copies Per Milliliter (c/mL) as Per Food and Drug Administration (FDA) Snapshot Algorithm at Week 48 | Percentage of participants with HIV-1 RNA >=50 c/mL as per FDA snapshot algorithm at Week 48 was assessed to demonstrate the non-inferior antiviral activity of CAB LA+RPV LA Q8W compared to CAB LA + RPV LA Q4W regimen over 48 weeks in HIV-1 infected ART experienced participants. The HIV-1 RNA >=50 c/mL per Snapshot algorithm was determined by the last on-treatment HIV-1 RNA measurement within the Week 48 analysis visit window. Intent-to-treat-Exposed (ITT-E) Population comprised of all randomized participants who received at least one dose of study treatment. Participants were assessed according to their randomized treatment, regardless of the treatment they received. | Week 48 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Plasma HIV-1 RNA <50 c/mL Using FDA Snapshot Algorithm at Week 48 | Percentage of participants with plasma HIV-1 RNA <50 c/mL at Week 48 using FDA Snapshot algorithm was assessed to demonstrate antiviral activity of CAB LA+RPV LA Q8W compared to CAB LA+ RPV LA Q4W. The HIV-1 RNA <50 c/mL per Snapshot algorithm was determined by last on-treatment HIV-1 RNA measurement within the analysis visit window. The 95% CIs were derived using normal approximation (Wald CI) | Week 48 | 
| Percentage of Participants With Plasma HIV-1 RNA <50 c/mL Using FDA Snapshot Algorithm at Week 24 | Percentage of participants with plasma HIV-1 RNA <50 c/mL at Week 48 using FDA Snapshot algorithm was assessed to demonstrate antiviral activity of CAB LA+RPV LA Q8W compared to CAB LA+ RPV LA Q4W. The HIV-1 RNA <50 c/mL per Snapshot algorithm was determined by last on-treatment HIV-1 RNA measurement within the analysis visit window. The 95% CIs were derived using normal approximation (Wald CI) | Week 24 | 
| Percentage of Participants With Protocol Defined Confirmed Virologic Failure (CVF) Through Weeks 24 and 48 | CVF was defined as rebound as indicated by two consecutive plasma HIV-1-RNA levels >=200 c/mL after prior suppression to <200 c/mL. Cumulative percentage of participants with protocol defined CVF up to Weeks 24 and 48 has been presented. | Weeks 24 and 48 | 
| Percentage of Participants With HIV-RNA >=50 c/mL as Per FDA Snapshot Algorithm at Week 24 | Percentage of participants with plasma HIV-1 RNA >=50 c/mL at Week 24 using FDA Snapshot algorithm was assessed to demonstrate antiviral activity of CAB LA+RPV LA Q8W compared to CAB LA+ RPV LA Q4W. The HIV-1 RNA >=50 c/mL per Snapshot algorithm was determined by the last on-treatment HIV-1 RNA measurement within the analysis visit window. The 95% CIs were derived using normal approximation (Wald CI). | Weeks 24 | 
| Absolute Values for HIV-1 RNA at Week 48 | Plasma samples were collected for quantitative analysis of HIV-1 RNA. Logarithm to base 10 (log10) values for plasma HIV-1 RNA has been presented. | Weeks 48 | 
| Change From Baseline Values for HIV-1 RNA at Week 48 | Plasma samples were collected for quantitative analysis of HIV-1 RNA. Baseline value is defined as latest pre-treatment assessment with a non-missing value, including those from unscheduled visits. Change from Baseline is defined as post-dose visit value minus Baseline value. Logarithm to base 10 values for plasma HIV-1 RNA has been presented. | Baseline (Day 1) and Week 48 | 
| Absolute Values for Cluster of Differentiation 4 Plus (CD4+) at Week 48 | Blood samples were collected and CD4+ cell count assessment by flow cytometry was carried out to evaluate the immunologic activity of CAB LA+RPV LA Q8W compared to CAB LA+RPV LA Q8W. | Week 48 | 
| Change From Baseline Values for CD4+ at Week 48 | Blood samples were collected and CD4+ cell count assessment by flow cytometry was carried out to evaluate the immunologic activity of CAB LA+RPV LA Q8W compared to CAB LA+RPV LA Q4W. Baseline value is defined as latest pre-treatment assessment with a non-missing value, including those from unscheduled visits. Change from Baseline is defined as post-dose visit value minus Baseline value. | Baseline (Day 1) and Week 48 | 
| Number of Participants With Non-serious Adverse Events (Non-SAEs >=5% Incidence) and Serious Adverse Events (SAEs)-Maintenance Phase | An adverse event is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study treatment, whether or not considered related to the study treatment. A SAE is defined as any untoward medical occurrence that, at any dose results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent disability/incapacity, is a congenital anomaly/birth defect, associated with liver injury and impaired liver function or any other situations as per medical or scientific judgement. Safety Population comprised of all randomized participants who received at least one dose of study treatment. Participants were assessed according to actual treatment received. | Up to Week 48 | 
| Number of Participants With Severity of Adverse Events-Maintenance Phase | Severity of adverse events were defined as per The Division of Acquired Immunodeficiency Syndrome (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS adverse events Grading Table). Severity grades for adverse events were as Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe), Grade 4 (Potentially life-threatening) and Grade 5 (all deaths related to an AE). | Up to Week 48 | 
| Number of Participants With Maximum Post-Baseline Chemistry Toxicities-Maintenance Phase | Clinical chemistry toxicities were graded as per the DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table)Blood samples were collected for the analysis of following clinical chemistry parameters: alanine aminotransferase (ALT), albumin, alkaline phosphate (ALP), aspartate aminotranferase (AST), bilirubin, carbon dioxide (CO2), cholesterol, creatinine kinase, creatinine, glomerular filtration rate (GFR) from creatinine adjusted for bovine serum albumin (BSA), glucose, hyperglycemia, hyperkalemia, hypernatremia, hypoglycemia, hypokalemia, hyponatremia, low density lipoprotein (LDL) calculation, lipase, phosphate, potassium, sodium and triglycerides. Severity grades were: Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe) and Grade 4 (Potentially life-threatening). | Up to Week 48 | 
| Number of Participants With Maximum Post-Baseline Hematology Toxicities-Maintenance Phase | The hematology toxicities were graded as per the DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table). Blood samples were collected for the analysis of following hematology parameters: hemoglobin, leukocytes, neutrophils and platelets. Severity grades were as Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe) and Grade 4 (Potentially life-threatening). | Up to Week 48 | 
| Percentage of Participants Who Discontinued Treatment Due to Adverse Events-Maintenance Phase | An adverse event is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study treatment, whether or not considered related to the study treatment. Percentage of participants with adverse events leading to withdrawal has been presented. | Up to Week 48 | 
| Change From Baseline in Clinical Chemistry Parameters: ALT, ALP, AST and Creatinine Kinase Over Time | Blood samples were collected for the analysis of clinical chemical parameters including ALT, ALP, AST and creatinine kinase. Baseline value is defined as latest pre-treatment assessment with a non-missing value, including those from unscheduled visits. Change from Baseline was defined as post-dose visit value minus Baseline value. | Baseline (Day 1) and Weeks 4, 8, 16, 24, 32, 40 and 48 | 
| Change From Baseline in Clinical Chemistry Parameter: Albumin Over Time | Blood samples were collected for the analysis of clinical chemistry parameter: albumin. Baseline value is defined as latest pre-treatment assessment with a non-missing value, including those from unscheduled visits. Change from Baseline was defined as post-dose visit value minus Baseline value. | Baseline (Day 1) and Weeks 4, 8, 16, 24, 32, 40 and 48 | 
| Change From Baseline in Clinical Chemistry Parameters: Bilirubin and Creatinine Over Time | Blood samples were collected for the analysis of clinical chemistry parameters: bilirubin and creatinine. Baseline value is defined as latest pre-treatment assessment with a non-missing value, including those from unscheduled visits. Change from Baseline was defined as post-dose visit value minus Baseline value. | Baseline (Day 1) and Weeks 4, 8, 16, 24, 32, 40 and 48 | 
| Change From Baseline in Clinical Chemistry Parameters: CO2, Chloride, Phosphate, Potassium, Sodium and Urea Over Time | Blood samples were collected for the analysis of clinical chemistry parameters: CO2, chloride, phosphate, potassium, sodium and urea. Baseline value is defined as latest pre-treatment assessment with a non-missing value, including those from unscheduled visits. Change from Baseline was defined as post-dose visit value minus Baseline value. | Baseline (Day 1) and Weeks 4, 8, 16, 24, 32, 40 and 48 | 
| Change From Baseline in Clinical Chemistry Parameters: Cholesterol, Glucose, Direct High Density Lipoprotein (HDL) Cholesterol, LDL Cholesterol Calculation and Triglycerides at Week 48 | Blood samples were collected for the analysis of clinical chemistry parameters: cholesterol, glucose, direct HDL cholesterol, LDL cholesterol calculation and triglycerides. Baseline value is defined as latest pre-treatment assessment with a non-missing value, including those from unscheduled visits. Change from Baseline was defined as post-dose visit value minus Baseline value. | Baseline (Day 1) and Week 48 | 
| Change From Baseline in Clinical Chemistry Parameter: GFR From Creatinine Adjusted Using Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) Over Time | Blood samples were collected for the analysis of clinical chemistry parameter: GFR from creatinine adjusted using CKD-EPI. Baseline value is defined as latest pre-treatment assessment with a non-missing value, including those from unscheduled visits. Change from Baseline was defined as post-dose visit value minus Baseline value. | Baseline (Day 1) and Weeks 4, 8, 16, 24, 32, 40 and 48 | 
| Change From Baseline in Clinical Chemistry Parameter: Lipase Over Time | Blood samples were collected for the analysis of clinical chemistry parameter: Lipase. Baseline value is defined as latest pre-treatment assessment with a non-missing value, including those from unscheduled visits. Change from Baseline was defined as post-dose visit value minus Baseline value. | Baseline (Day 1) and Weeks 4, 8, 16, 24, 32, 40 and 48 | 
| Change From Baseline in Hematology Parameters: Basophils, Eosinophils, Leukocytes, Lymphocytes, Monocytes, Neutrophils and Platelets Over Time | Blood samples were collected for the analysis of hematology parameters: basophils, eosinophils, leukocytes, lymphocytes, monocytes, neutrophils and platelets. Baseline value is defined as latest pre-treatment assessment with a non-missing value, including those from unscheduled visits. Change from Baseline was defined as post-dose visit value minus Baseline value. | Baseline (Day 1) and Weeks 4, 8, 16, 24, 32, 40 and 48 | 
| Change From Baseline in Hematology Parameter: Erythrocyte Mean Corpuscular Volume (MCV) Over Time | Blood samples were collected for the analysis of hematology parameter: erythrocyte MCV. Baseline value is defined as latest pre-treatment assessment with a non-missing value, including those from unscheduled visits. Change from Baseline was defined as post-dose visit value minus Baseline value. | Baseline (Day 1) and Weeks 4, 8, 16, 24, 32, 40 and 48 | 
| Change From Baseline in Hematology Parameter: Erythrocytes Over Time | Blood samples were collected for the analysis of hematology parameter: erythrocytes. Baseline value is defined as latest pre-treatment assessment with a non-missing value, including those from unscheduled visits. Change from Baseline was defined as post-dose visit value minus Baseline value. | Baseline (Day 1) and Weeks 4, 8, 16, 24, 32, 40 and 48 | 
| Change From Baseline in Hematology Parameter: Hematocrit Over Time | Blood samples were collected for the analysis of hematology parameter: hematocrit. Baseline value is defined as latest pre-treatment assessment with a non-missing value, including those from unscheduled visits. Change from Baseline was defined as post-dose visit value minus Baseline value. | Baseline (Day 1) and Weeks 4, 8, 16, 24, 32, 40 and 48 | 
| Change From Baseline in Hematology Parameter: Hemoglobin Over Time | Blood samples were collected for the analysis of hematology parameter: hemoglobin. Baseline value is defined as latest pre-treatment assessment with a non-missing value, including those from unscheduled visits. Change from Baseline was defined as post-dose visit value minus Baseline value. | Baseline (Day 1) and Weeks 4, 8, 16, 24, 32, 40 and 48 | 
| Number of Participants With Phenotypic Resistance- Maintenance Phase | Phenotypic resistance (PR) was analyzed in participants who met CVF criteria. PR for following Baseline third agent drugs: Integrase inhibitors(INI): bictegravir (BIC), CAB, dolutegravir (DTG), elvitegravir (EVG), raltegravir(RAL); non-nucleoside reverse transcriptase inhibitors(NNRTI): delavirdine(DLV), efavirenz(EFV), etravirine(ETR), nevirapine(NVP), RPV; nucleoside reverse transcriptase inhibitor (NRTI): lamivudine(3TC), abacavir(ABC), emtricitabine(FTC), tenofovir(TDF), zidovudine(ZDV), stavudine(d4T), didanosine(ddI) and protease inhibitors(PI): atazanavir(ATV), darunavir(DRV), fosamprenavir(FPV), indinavir(IDV), lopinavir(LPV), nelfinavir(NFV), ritonavir(RTV), saquinavir(SQV) and tipranavir (TPV) is presented. Phenotypic susceptibility was defined based on the fold change (FC) value: resistant (FC>clinical higher cutoff or biological cutoff), partially sensitive (FC<=clinical higher cutoff and > clinical lower cutoff), sensitive(FC<=clinical lower cutoff or biological cutoff) | Up to Week 48 analysis | 
| Number of Participants With Genotypic Resistance-Maintenance Phase | Genotypic resistance was analyzed in participants who met confirmed virologic withdrawal criteria. Genotypic Resistance data for the following Baseline third agent drugs, INI: BIC, DTG, EVG, RAL; NNRTI: DLV, EFV, ETR, NVP, RPV; NRTI: 3TC, ABC, FTC, TDF, ZDV, d4T, ddI and PI: ATV, ATV/ritonavir (r), DRV/r, FPV/r, IDV/r, LPV/r, NFV, RTV, SQV/r and TPV/r in participants meeting CVF criteria has been presented. | Up to Week 48 analysis | 
| Number of Participants With Their Treatment Preference as Assessed Using Preference Questionnaire at Week 48 Without (w/o) Prior Exposure to CAB+RPV-CAB 600 mg LA +RPV 900 mg LA Q8W Arm Only | Participants were administered the preference questionnaire which had 3 questions. For treatment preference, participants were required to provide their response to Question 1, which stated Based on your experience which HIV treatment do you prefer. The responses included 1) Injectable LA HIV treatment Q4W, 2) Injectable LA HIV Treatment Q8W (only select this answer if you received the 8-week injectable regimen of CAB LA + RPV LA during study), 3) Oral daily HIV treatment and 4) No preference. Oral daily HIV Treatment refers to the oral medication of CAB + RPV subjects received during the oral lead-in period. Number of participants without prior exposure to CAB+RPV who selected each of the responses based on their treatment preference is presented. | Week 48 | 
| Number of Participants With Their Treatment Preference as Assessed Using Preference Questionnaire at Week 48 With >=1 Weeks of Prior Exposure to CAB+RPV-CAB 600 mg LA +RPV 900 mg LA Q8W Arm Only | Participants were administered the preference questionnaire which had 3 questions. For treatment preference, participants were required to provide their response to Question 1, which stated Based on your experience which HIV treatment do you prefer. The responses included 1) Injectable LA HIV treatment Q4W, 2) Injectable LA HIV Treatment Q8W (only select this answer if you received the 8-week injectable regimen of CAB LA + RPV LA during study), 3) Oral daily HIV treatment and 4) No preference. Oral daily HIV Treatment refers to the oral medication of CAB + RPV subjects received during the oral lead-in period. Number of participants with >=1 weeks of prior exposure to CAB+RPV who selected each of the responses based on their treatment preference is presented. | Week 48 | 
| Number of Participants With Their Treatment Preference as Assessed Using Preference Questionnaire at Week 48-CAB 400 mg LA +RPV 600 mg LA Q4W Arm Only | Participants were administered the preference questionnaire which had 3 questions. For treatment preference, participants were required to provide their response to Question 1, which stated Based on your experience which HIV treatment do you prefer. The responses included 1) Injectable LA HIV treatment Q4W, 2) Injectable LA HIV Treatment Q8W (only select this answer if you received the 8-week injectable regimen of CAB LA + RPV LA during study), 3) Oral daily HIV treatment and 4) No preference. Oral daily HIV Treatment refers to the oral medication of CAB + RPV participants received during the oral lead-in period. Number of participants who selected each of the responses based on their treatment preference is presented. | Week 48 | 
| Change From Baseline in Life Satisfaction (LISAT) Using HIV/AIDs-targeted Quality of Life (HATQoL) Questionnaire in Participants With or Without Prior Exposure to CAB+RPV | The HATQoL questionnaire was used to assess the health related QoL (HRQoL). It comprises of three dimensions:LISAT, medication worries (MEDWO) and disclosure worries (DISWO). Total imputed value score for LISAT is calculated on a 0-100 scale using the formula: LISAT 100=[100 divided by (20 minus 4)]*(LISAT minus 4). A response of 5 in LISAT score shows satisfaction all of the time and 1 as none of the time. The higher the score, the greater satisfaction to life and the less worry. The transformed dimension score for each domain was summarized and analyzed. Last Observation Carried Forward (LOCF) was used as primary method of analysis. Data for participants without/with prior exposure to CAB+RPV (0 Weeks [without exposure] and >=1 Weeks [with exposure]) has been presented. Baseline value is defined as last available recorded value up to and including the Maintenance treatment start. Change from Baseline value is calculated as the value at the post-dose visit minus the Baseline value. | Baseline (Day 1) and Weeks 24 and 48 | 
| Change From Baseline in HIV Medication, MEDWO Using HATQoL Questionnaire in Participants With or Without Prior Exposure to CAB+RPV | The HATQoL questionnaire was used to assess the HRQoL. It comprises of three dimensions:LISAT, MEDWO and DISWO. The total imputed value score for MEDWO is calculated on a 0-100 scale using the formula: MEDWO 100=[100 divided by (25 minus 5)]*(MEDWO minus 5). A response of 1 in MEDWO score shows medication worries all of the time and 5 as none of the time. The higher the score, the greater satisfaction to life and the less worry. The transformed dimension score for each domain was summarized and analyzed. LOCF was used as primary method of analysis. Participants without/with prior exposure to CAB+RPV (0 Weeks [without exposure] and >=1 Weeks [with exposure]) has been presented. Baseline value is defined as last available recorded value up to and including the Maintenance treatment start. Change from Baseline value is calculated as the value at the post-dose visit minus the Baseline value. | Baseline (Day 1) and Weeks 24 and 48 | 
| Change From Baseline in DISWO Using HATQoL Questionnaire in Participants With or Without Prior Exposure to CAB+RPV | The HATQoL questionnaire was used to assess the HRQoL. It comprises of three dimensions:LISAT, MEDWO and DISWO. The total imputed value score for DISWO is calculated on a 0-100 scale using the formula: DISWO 100=[100 divided by (25 minus 5)]*(DISWO minus 5). A response of 1 in DISWO score shows disclosure worries all of the time and 5 as none of the time. The higher the score, the greater satisfaction to life and the less worry. The transformed dimension score for each domain was summarized and analyzed. LOCF was used as primary method of analysis. Participants without/with prior exposure to CAB+RPV (0 Weeks [without exposure] and >=1 Weeks [with exposure]) has been presented. Baseline value is defined as last available recorded value up to and including the Maintenance treatment start. Change from Baseline value is calculated as the value at the post-dose visit minus the Baseline value. | Baseline (Day 1) and Weeks 24 and 48 | 
| Change From Baseline in Total Treatment Satisfaction Score Using HIV Treatment Satisfaction Status Questionnaire (HIVTSQs) at Weeks 24 and 48 | The HIVTSQs treatment satisfaction questionnaire comprises of 1-12 questions and the total treatment satisfaction score is computed with items 1-11 and summed to produce a score with a possible range of 0 to 66. Higher scores represent greater treatment satisfaction as compared to the past few weeks. LOCF was used as primary method of analysis. Participants without/with prior exposure to CAB+RPV (0 Weeks [without exposure] and >=1 Weeks [with exposure]) has been presented. Baseline value is defined as last available recorded value up to and including the Maintenance treatment start. Change from Baseline value is calculated as the value at the post-dose visit minus the Baseline value. | Baseline (Day 1) and Weeks 24 and 48 | 
| Change From Baseline in Individual Item Scores Using HIVTSQs at Weeks 24 and 48 | HIVTSQs is a 12 item questionnaire. The individual item scores on HIVTSQs scale are rated as 6 (very satisfied, convenient, flexible, etc.) to 0 (very dissatisfied, inconvenient, inflexible, etc.). Higher scores represent greater satisfaction with each aspect of treatment. LOCF was used as primary method of analysis. Participants without/with prior exposure to CAB+RPV (0 Weeks [without exposure] and >=1 Weeks [with exposure]) has been presented. Baseline value is defined as last available recorded value up to and including the Maintenance treatment start. Change from Baseline value is calculated as the value at the post-dose visit minus the Baseline value. | Baseline (Day 1) and Weeks 24 and 48 | 
| Total Treatment Satisfaction Change Score Using HIV Treatment Satisfaction Change Questionnaire (HIVTSQc) at Week 48 | The HIVTSQc is a 1-12 items questionnaire. Each item is scored -3 to 3. Total treatment satisfaction change score is computed using items 1 to 11 and are summed to produce a score with a possible range of -33 to 33. Higher the score, greater the improvement in satisfaction with treatment; the lower the score, the greater the deterioration in satisfaction with treatment. A score of 0 represented no change. LOCF was used as primary method of analysis. Total treatment satisfaction change score for participants who entered the current study from Q4W arm of ATLAS (NCT number: NCT02951052) and from either standard of care (SOC) arms of ATLAS or the new SOC participants) has been presented. | Week 48 | 
| Change From Week 8 in Dimension Scores Using Perception of Injection (PIN) Questionnaire. | The PIN questionnaire explores bother of pain at injection site and injection site reactions (ISR), anxiety before and after injection, willingness to receive an HIV injectable treatment the following visit and satisfaction with mode of treatment administration of individuals receiving injection and perceptions of individuals associated with receiving injections. This measure contains 21 items that measure pain at injection site, local site reactions, impact on functioning and willingness to pursue injectable treatment outside of a clinical trial. Scores range from 1 to 5, and questions are phrased in such a way as to ensure that 1 always equated with the most favourable perception of vaccination, and 5 most unfavourable. Dimension scores include bother from ISR, leg movement, sleep and acceptability. Score of a domain is calculated as mean of all items within the domain. Higher scores represent worse perception of injection. LOCF was used as primary method of analysis. | Week 8 and Weeks 24 and 48 | 
| Change From Week 8 in Individual Item Scores (Anxiety Before, Pain, Satisfaction, Anxiety After and Willingness) Using Perception of Injection (PIN) Questionnaire. | The PIN questionnaire explores the bother of pain at the injection site and ISRs, anxiety before and after injection, willingness to receive an HIV injectable treatment the following visit and satisfaction with the mode of treatment administration of individuals receiving injection and perceptions of individuals associated with receiving injections. This measure contains 21 items that measure pain at injection site, local site reactions, impact on functioning and willingness to pursue injectable treatment outside of a clinical trial. The items in the scale are rated on a 5-point scale ranging from 1(very dissatisfied, extremely, etc.) to 5 (very satisfied, not at all, etc.). Lower scores represent worse perception of injection. LOCF was used as primary method of analysis. | Week 8 and Weeks 24 and 48 | 
| Change From Baseline in Treatment Acceptance a Using General Acceptance Dimension of the Chronic Treatment Acceptance (ACCEPT) Questionnaire in Participants With or Without Prior Exposure to CAB+RPV | The ACCEPT questionnaire is a generic medication acceptance measure assessing how participants weigh advantages and disadvantages of long-term medication.The questionnaire consists of 25 items that capture six dimensions.3 questions that focus on general acceptance of study medication were analyzed.Items on the scale are rated as 1-5 scores:1:not at all acceptable,2:not very acceptable,3:somewhat acceptable, 4:totally acceptable and 5:I don't know.Total score of the dimension is calculated as the mean of recoded items of the dimension and then linearly transformed to be on a scale from 0 to 100:Total Score=(mean of the recoded items in the dimension minus1)divided by2*100. LOCF was used as primary method of analysis. Data for participants without or with prior exposure has been presented. Baseline value is defined as last available value up to and including the Maintenance treatment. Change from Baseline value is calculated as the value at the post-dose visit minus the Baseline value. | Baseline (Day 1) and Weeks 24 and 48 | 
| Plasma Trough Concentration (Ctrough) for CAB LA Evaluable | Blood samples were collected at indicated time points for pharmacokinetic (PK) analysis of CAB LA. PK Population comprises of all participants who received CAB and / or RPV and underwent PK sampling during the study and provide at least 1 non-missing CAB and / or RPV plasma concentration value (Non-quantifiable [NQ] values will be considered as non-missing values). | Pre-dose at Weeks 4, 8, 16, 24, 32, 40 and 48 | 
| Plasma Ctrough for RPV LA Evaluable | Blood samples were collected at indicated time points for PK analysis of RPV LA. | Pre-dose at Weeks 4, 8, 16, 24, 32, 40 and 48 | 
| Area Under the Curve (AUC) for CAB LA | Blood samples were collected at indicated time points to analyze concentration in plasma for CAB LA. Participants who transitioned from ATLAS (201585 - NCT02951052) into this ATLAS-2M (207966) study had been treated with CAB + RPV for at least one year, were approaching steady state exposures, and were therefore excluded in order to focus the population analysis on those without prior exposure. | Predose at Weeks 4, 8, 13, 24, 32, 40, 48; 1 Week post-dose at Week 9 and 41 | 
| AUC for RPV LA | Blood samples were collected at indicated time points to analyze concentration in plasma for RPV LA. Participants who transitioned from ATLAS (201585 - NCT02951052) into this ATLAS-2M (207966) study had been treated with CAB + RPV for at least one year, were approaching steady state exposures, and were therefore excluded in order to focus the population analysis on those without prior exposure. | Predose at Weeks 4, 8, 13, 24, 32, 40, 48; 1 Week post-dose at Week 9 and 41 | 
| Maximum Concentration (Cmax) in Plasma for CAB LA Evaluable | Blood samples were collected at indicated time points to analyze Cmax in plasma for CAB LA. Participants who transitioned from ATLAS (201585 - NCT02951052) into this ATLAS-2M (207966) study had been treated with CAB + RPV for at least one year, were approaching steady state exposures, and were therefore excluded in order to focus the population analysis on those without prior exposure. | Predose at Weeks 4, 8, 13, 24, 32, 40, 48; 1 Week post-dose at Week 9 and 41 | 
| Cmax in Plasma for RPV LA Evaluable | Blood samples were collected at indicated time points to analyze Cmax in plasma for RPV LA. Participants who transitioned from ATLAS (201585 - NCT02951052) into this ATLAS-2M (207966) study had been treated with CAB + RPV for at least one year, were approaching steady state exposures, and were therefore excluded in order to focus the population analysis on those without prior exposure. | Predose at Weeks 4, 8, 13, 24, 32, 40, 48; 1 Week post-dose at Week 9 and 41 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Tolerability, Long acting Cabotegravir, Safety, HIV-1, Efficacy, ATLAS-2M, Long acting Rilpivirine