The First Long-Acting Injectable Regimen (FLAIR) study is being conducted to establish if human immunodeficiency virus type-1 (HIV-1) infected adult participants whose virus is virologically suppressed on an integrase inhibitor single tablet regimen (INI STR) will remain suppressed after switching to a two-drug intramuscular (IM) long-acting (LA) regimen of cabotegravir (CAB) and rilpivirine (RPV). In this study, the INI STR will be limited to abacavir/dolutegravir/lamivudine (ABC/DTG/3TC). FLAIR is a Phase 3, multi-phase, randomized, open label, active-controlled, multicenter, parallel-group, non-inferiority study in HIV-1, anti-retroviral therapy (ART)-naïve adult participants. This study is designed to demonstrate the non-inferior antiviral activity of switching to a two drug CAB LA 400 mg + RPV LA 600 mg regimen every 4 weeks (Q4W: monthly) compared to remaining on ABC/DTG/3TC over 48 weeks (4 weeks oral CAB + RPV, 44 weeks LA therapy). Participants who are HLA-B*5701 positive at Screening may enroll into the study and receive DTG plus a non-abacavir containing dual nucleoside reverse transcriptase inhibitor (NRTI) regimen. Eligible participants will enroll into the Induction Phase of the study and receive ABC/DTG/3TC for 20 weeks (Week [-20] to Day 1). Participants who have an HIV 1 ribose nucleic acid (RNA) <50 copies per milliliter (c/mL) at Week (-4) will be randomized (1:1) into the Maintenance Phase at Day 1 to either continue ABC/DTG/3TC or to discontinue ABC/DTG/3TC and begin oral therapy with CAB 30 mg + RPV 25 mg once daily for approximately 4 Weeks, followed by monthly CAB LA + RPV LA injections from visit Week 4b until study completion or withdrawal. Participants who successfully complete Week 100 (without meeting study defined withdrawal criteria and who remain virologically suppressed through Week 96: HIV-1 RNA <50 c/mL) will be given the option to switch to the LA arm in the Extension Phase (using an optional oral lead-in with CAB + RPV) or be withdrawn from the study. Participants will continue to receive injections every 4 weeks during the Extension Phase until CAB LA and RPV LA are either locally approved and commercially available, the participant no longer derives clinical benefit, the participant meets a protocol-defined reason for discontinuation, or until development of either CAB LA or RPV LA is terminated.
Name: Cabotegravir (CAB) tablet
Description: It is a white oval shaped film coated 30 mg tablets for oral administration. CAB Tablet is composed of cabotegravir sodium, lactose monohydrate, microcrystalline cellulose, hypromellose, sodium starch glycolate, magnesium stearate, and white film-coat.Type: DrugCAB LA + RPV LA every 4 weeks
Name: Rilpivirine (RPV) tablet
Description: It is a 25 mg tablet with off-white, round, biconvex, film-coated and debossed on one side with "TMC" and the other side with "25". Each tablet contains RPV hydrochloride, and the inactive ingredients croscarmellose sodium, lactose monohydrate, magnesium stearate, polysorbate 20, povidone K30 and silicified microcrystalline cellulose.Type: DrugCAB LA + RPV LA every 4 weeks
Name: Cabotegravir - Injectable Suspension (CAB LA)
Description: It is a sterile white to slightly pink suspension containing 200 mg/mL of CAB as free acid for administration by intramuscular (IM) injection. Each vial is for single-dose use containing a withdrawable volume of 2.0 mL, and does not require dilution prior to administration. CAB LA is composed of cabotegravir free acid, polysorbate 20, polyethylene glycol 3350, mannitol, and water for injection.Type: DrugCAB LA + RPV LA every 4 weeks
Name: Rilpivirine - Injectable Suspension (RPV LA)
Description: It is a sterile white suspension containing 300 mg/mL of RPV as the free base. The route of administration is by intramuscular (IM) injection. Each vial contains a nominal fill of 2.0 mL, and does not require dilution prior to administration. RPV LA requires refrigeration and must be protected from light. RPV LA is composed of RPV free base, poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate, glucose monohydrate, sodium hydroxide, water for injection.Type: DrugCAB LA + RPV LA every 4 weeks
Name: ABC/DTG/3TC STR - Tablet
Description: It is a purple, biconvex, oval, tablet debossed with "572 Tri" on one side, film-coated tablet contains abacavir sulphate equivalent to 600 mg of abacavir, dolutegravir sodium equivalent to 50 mg dolutegravir, and 300 mg of lamivudine. The inactive ABC/DTG/3TC tablet ingredients include D-mannitol, magnesium stearate, microcrystalline cellulose, povidone, and sodium starch glycolate.Type: DrugABC / DTG / 3TC (600 mg/50mg/300mg) once daily
Name: DTG Tablet
Description: It is a yellow, round, biconvex, 50 mg film-coated tablet debossed with "SV 572" on one side and "50" on the other side. Each tablet of DTG also contains the following inactive ingredients: D-mannitol, microcrystalline cellulose, povidone K29/32, sodium starch glycolate, and sodium stearyl fumarate.Type: DrugABC / DTG / 3TC (600 mg/50mg/300mg) once daily
Description: Virologic failure (HIV-1 RNA >= 50 c/mL) based on the FDA Snapshot algorithm for the Intent-to-Treat Exposed population (subjects randomized and receiving at least one dose of investigational product during the Maintenance Phase).
Measure: Proportion of participants with a 'virologic failure' endpoint as per Food and Drug Administration (FDA) Snapshot algorithm at Week 48 (Missing, Switch or Discontinuation = Failure, Intent-to-Treat Exposed [ITT-E] population). Time: Week 48Description: It will be assessed using the FDA Snapshot algorithm at Week 48 and is a key secondary endpoint.
Measure: Proportion of participants with Plasma HIV-1 RNA <50 c/mL at Week 48 Time: Week 48Description: It will be assessed using the FDA Snapshot algorithm at Week 96.
Measure: Proportion of participants with plasma HIV-1 RNA <50 c/mL at Week 96 Time: Week 96Description: It will be assessed using the FDA Snapshot algorithm at Week 48.
Measure: Proportion of participants with plasma HIV-1 RNA <200 c/mL at Week 48 Time: Week 48Description: It will be assessed using the FDA Snapshot algorithm at Week 96
Measure: Proportion of participants with plasma HIV-1 RNA <200 c/mL at Week 96 Time: Week 96Description: Proportion of participants with a virologic failure based on the FDA Snapshot algorithm for the Intent-to-Treat Exposed population (subjects randomized and receiving at least one dose of investigational product during the Maintenance Phase) will be assessed.
Measure: Proportion of participants with plasma HIV-1 RNA >=50 c/mL at Week 96 Time: Week 96Description: For the purposes of clinical management in this study, virologic failure is defined as any of the following: Non-response as indicated by a less than a 1.0 log10 c/mL decrease in plasma HIV-1 RNA after 4 weeks of starting the Induction Phase, which is subsequently confirmed, unless the plasma HIV-1 RNA is < 400 c/mL (Induction Phase criteria), Rebound as indicated by two consecutive plasma HIV-1 RNA that are > 0.5 log10 c/mL increase in plasma HIV-1 RNA from the nadir value on study, where the lowest HIV-1 RNA value is >=200 c/mL (Induction Phase criteria), Rebound as indicated by two consecutive plasma HIV-1 RNA levels >=200 c/mL after prior suppression to < 200 c/mL
Measure: Proportion of participants with confirmed virologic failure at Week 48 Time: Week 48Description: For the purposes of clinical management in this study, virologic failure is defined as any of the following: Non-response as indicated by a less than a 1.0 log10 c/mL decrease in plasma HIV-1 RNA after 4 weeks of starting the Induction Phase, which is subsequently confirmed, unless the plasma HIV-1 RNA is < 400 c/mL (Induction Phase criteria), Rebound as indicated by two consecutive plasma HIV-1 RNA that are > 0.5 log10 c/mL increase in plasma HIV-1 RNA from the nadir value on study, where the lowest HIV-1 RNA value is >=200 c/mL (Induction Phase criteria), Rebound as indicated by two consecutive plasma HIV-1 RNA levels >=200 c/mL after prior suppression to < 200 c/mL
Measure: Proportion of participants with confirmed virologic failure at Week 96 Time: Week 96Description: It will be analyzed overtime, including Week 48 and Week 96
Measure: Change from Baseline in plasma HIV-1 RNA Time: Baseline (Day 1) and up to Week 96Description: It will be analyzed overtime, including Week 48 and Week 96
Measure: Change from Baseline in CD4+ cell counts Time: Baseline (Day 1) and up to Week 96Description: It will be assessed overtime, including Week 48 and Week 96 (HIV-associated conditions, acquired immunodeficiency syndrome [AIDS] and death)
Measure: Number of participants with disease progression Time: Baseline (Day 1) and up to Week 96Description: An AE is any untoward medical occurrence in a clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Any untoward event resulting in death, life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, congenital anomaly/birth defect or any other situation according to medical or scientific judgement will be categorized as serious adverse event (SAE). Severity will be analyzed as mild, moderate and severe AEs. It will be assessed overtime, including Week 48 and Week 96.
Measure: Number of participants with adverse events (AEs), serious AEs (SAEs) and AEs by severity Time: Up to Week 96Description: It will be analyzed overtime, including Week 48 and Week 96
Measure: Number of participants with laboratory abnormalities Time: Up to Week 96Description: Laboratory parameters includes; 1. Hematology parameters-platelet count, red blood cell (RBC) count, white blood cell (WBC) count, hemoglobin, hematocrit, mean corpuscular volume, WBC differential (includes; neutrophils, lymphocytes, monocytes, eosinophils and basophils), 2. Clinical chemistry- blood urea nitrogen, creatinine, fasting glucose, sodium, potassium, chloride, total carbon dioxide, lipase, Aspartate aminotransferase , Alanine aminotransferase, alkaline phosphatase, phosphate, total bilirubin, albumin, creatine phosphokinase, creatinine clearance will be analyzed over time, including Week 48 and Week 96
Measure: Number of participants with abnormal change from Baseline in laboratory parameters. Time: Baseline (Day 1) and up to Week 96Description: Participants who discontinue treatment due to AEs will be analyzed overtime, including Week 48 and Week 96
Measure: Number of participants who discontinue treatment due to AEs Time: Up to Week 96Description: Genotypic and phenotypic resistance to treatments; CAB, RPV, and other on-study antiretroviral treatment (ART) over time, including Week 48 and Week 96
Measure: Number of participants with treatment emergent resistance Time: Up to Week 96Description: Fasting lipid panel includes; Total cholesterol, high density lipid (HDL) cholesterol, low density lipid (LDL) cholesterol and triglycerides will be analyzed over time, including Week 48 and Week 96
Measure: Change from Baseline in fasting lipids Time: Baseline (Day 1) and up to Week 96Description: Blood sample will be obtained from participants at the given time points. Pre dose sample will be collected at Weeks 4b, 5, 8, 12, 16, 20, 24, 28, 32, 36, 40, 41, 44, 48, 52, 56, 60, 96, 100 and 108 in IM arm and at 101 and 104a (direct to inject arm), week 104b (oral lead-in arm) for participants transitioning to CAB LA + RPV LA from ABC/DTG/3TC.
Measure: Plasma trough concentration (Ctrough) for CAB LA arm Time: Pre-dose at Weeks 4b, 5, 8, 12, 16, 20, 24, 28, 32, 36, 40, 41, 44, 48, 52, 56, 60, 96, 100, 101, 104a, 104b, 108.Description: Blood sample will be obtained from participants at the given time points. Pre dose sample will be collected at Weeks 4b, 5, 8, 12, 16, 20, 24, 28, 32, 36, 40, 41, 44, 48, 52, 56, 60, 96, 100 and 108 in IM arm and at 101 and 104a (direct to inject arm), week 104b (oral lead-in arm) for participants transitioning to CAB LA + RPV LA from ABC/DTG/3TC.
Measure: Plasma trough concentration (Ctrough) for RPV LA arm Time: Pre-dose at Weeks 4b, 5, 8, 12, 16, 20, 24, 28, 32, 36, 40, 41, 44, 48, 52, 56, 60, 96, 100, 101, 104a, 104b, 108.Description: Blood sample will be obtained to evaluate Cmax of CAB.
Measure: Maximum concentration (Cmax) in plasma for CAB LA arm Time: At anytime post-dose at Weeks 5, 41 and 101Description: Blood sample will be obtained to evaluate Cmax of RPV.
Measure: Maximum concentration (Cmax) in plasma for RPV LA arm Time: At anytime post-dose at Weeks 5, 41 and 101Description: Blood sample will be obtained from participants at the given time points. Pre dose sample will be collected at Weeks 4b, 5, 8, 12, 16, 20, 24, 28, 32, 36, 40, 41, 44, 48, 52, 56, 60, 96, 100 and 108 in IM arm and at 101 and 104a (direct to inject arm), week 104b (oral lead-in arm) for participants transitioning to CAB LA + RPV LA from ABC/DTG/3TC. Post-dose sample will be collected at Weeks 5, 41 and 101 in IM arm.
Measure: Plasma area under the concentration-time curve (AUC) for CAB LA arm Time: Pre-dose at Weeks 4b, 5, 8, 12, 16, 20, 24, 28, 32, 36, 40, 41, 44, 48, 52, 56, 60, 96, 100, 101, 104a, 104b, 108; At anytime post-dose at Weeks 5, 41 and 101Description: Blood sample will be obtained from participants at the given time points. Pre dose sample will be collected at Weeks 4b, 5, 8, 12, 16, 20, 24, 28, 32, 36, 40, 41, 44, 48, 52, 56, 60, 96, 100 and 108 in IM arm and at 101 and 104a (direct to inject arm), week 104b (oral lead-in arm) for participants transitioning to CAB LA + RPV LA from ABC/DTG/3TC. Post-dose sample will be collected at Weeks 5, 41 and 101 in IM arm.
Measure: Plasma area under the concentration-time curve (AUC) for RPV LA arm Time: Pre-dose at Weeks 4b, 5, 8, 12, 16, 20, 24, 28, 32, 36, 40, 41, 44, 48, 52, 56, 60, 96, 100, 101, 104a, 104b, 108; At anytime post-dose at Weeks 5, 41 and 101Description: The Perception of iNjection questionnaire (PIN) will be used to assess the following dimension scores: Bother of ISRs, Leg movement, Sleep, and Injection Acceptance. Additionally, individual PIN item scores will assess pain during injection, anxiety before and after injection, willingness to be injected in the future and overall satisfaction with mode of administration over time. PIN will be assessed at weeks 5, 41, 48, 96 (or Withdrawal).
Measure: Change from Week 5 in Dimension Scores Time: Week 5 and up to Week 96Description: The proportion of participants considering pain and local reactions following injection to be extremely or very acceptable based on the acceptability score after first injection and over time, and changes in the PIN acceptance score within the CAB LA + RPV LA arm over time will be assessed.
Measure: Proportion of participants considering pain and local reactions following injection to be extremely or very acceptable Time: Week 5 to Week 96Description: HR QoL will be assessed using the HIV/AIDS targeted quality of life questionnaire (HAT-QoL) short form at Baseline (Day 1), Week 24, Week 48, Week 96 (or Withdrawal).
Measure: Change from Baseline in health related quality of life (HR QoL) Time: Baseline (Day 1) and up to Week 96Description: The HIV Treatment Satisfaction Questionnaire-status-12 (HIVTSQs-12) will be used to assess the "Total Treatment Satisfaction" score and individual item scores of the HIV Treatment Satisfaction Questionnaire (status version) (HIVTSQs) at Week 4b, Week 24, Week 44, Week 96 (or Withdrawal). The change from baseline (Day 1) in HIVTSQs total score at Week 44 is a key secondary endpoint.
Measure: Change from Baseline in treatment satisfaction Time: Day 1 up to Week 96Description: Change in treatment satisfaction over time (using the HIVTSQ change version [HIVTSQc]) at Week 48 (or Withdrawal) will be assessed.
Measure: Change in treatment satisfaction at Week 48 Time: Baseline (Day 1) and up to Week 48Description: Overall health status will be assessed using the 12-item Short Form Survey (SF-12) at Day 1 and weeks 24, 48, 96 (or Withdrawal).
Measure: Change from Baseline in health status Time: Baseline (Day 1) and up to Week 96Description: Overall treatment acceptance to chronic therapy will be assessed using the "General Acceptance" dimension of the Chronic Treatment Acceptance (ACCEPT) questionnaire. It will be assessed at Day 1 and weeks 8, 24, 48, 96 (or Withdrawal).
Measure: Change from Baseline in treatment acceptance Time: Baseline (Day 1) and up to Week 96Description: Patient reported injection tolerability will be assessed using the Numeric Rating Scale (NRS) within the CAB LA + RPV LA arm. NRS will be assessed at weeks 4b, 5, 40, 41, and 96.
Measure: Change in tolerability of injection (for CAB LA + RPV LA) Time: Week 4b and up to Week 96Description: Demographic parameters and laboratory parameters will be evaluated as potential predictors of inter- and intra-participant variability for pharmacokinetic parameters. Number of subjects with identified potential predictors will be assessed.
Measure: Number of participants with potential predictors of inter- and intra-subject variability for pharmacokinetic parameters Time: Up to Week 96Description: Proportion of participants with HIV-1 RNA >= 50 c/mL at Week 124, with and without oral lead-in (FDA Snapshot algorithm, Extension Switch population) will be assessed.
Measure: Proportion of participants with HIV-1 RNA >= 50 c/mL at Week 124 in extension phase Time: Up to Week 124Description: Proportion of participants with plasma HIV-1 RNA <50 c/mL over time will be assessed.
Measure: Proportion of participants with plasma HIV-1 RNA <50 c/mL over time in extension phase Time: Up to Week 124Description: Proportion of participants with plasma HIV-1 RNA <200 c/mL over time will be assessed.
Measure: Proportion of participants with plasma HIV-1 RNA <200 c/mL over time in extension phase Time: Up to Week 124Description: Proportion of participants with confirmed virologic failure at Week 124 will be assessed.
Measure: Proportion of participants with confirmed virologic failure over time in extension phase Time: Up to Week 124Description: Genotypic and phenotypic resistance to treatments CAB and RPV will be assessed at Week 124.
Measure: Number of participants with treatment emergent genotypic and phenotypic resistance to CAB and RPV over time in extension phase Time: Up to Week 124Description: Change from Baseline in CD4+ cell counts will be assessed at Week 124.
Measure: Change from Baseline in CD4+ cell counts in extension phase Time: Up to Week 124Description: An AE is any untoward medical occurrence in a clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Any untoward event resulting in death, life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, congenital anomaly/birth defect or any other situation according to medical or scientific judgment will be categorized as SAE. Severity will be analyzed as mild, moderate and severe AEs.
Measure: Number of participants with AEs, SAEs and AEs by severity in extension phase Time: Up to Week 124Description: Number of participants with any laboratory abnormalities in extension phase will be assessed.
Measure: Number of participants with laboratory abnormalities in extension phase Time: Up to Week 124Description: Laboratory parameters includes; 1. Hematology parameters-platelet count, RBC count, WBC count, hemoglobin, hematocrit, mean corpuscular volume, WBC differential (includes; neutrophils, lymphocytes, monocytes, eosinophils and basophils), 2. Clinical chemistry- blood urea nitrogen, creatinine, fasting glucose, sodium, potassium, chloride, total carbon dioxide, lipase, Aspartate aminotransferase , Alanine aminotransferase, alkaline phosphatase, phosphate, total bilirubin, albumin, creatine phosphokinase, creatinine clearance will be analyzed.
Measure: Number of participants with abnormal change from Baseline in laboratory parameters in extension phase Time: Up to Week 124Description: Participants who discontinue treatment due to AEs will be analyzed up to Week 124.
Measure: Number of participants who discontinue treatment due to AEs in extension phase Time: Up to Week 124Description: It will be assessed for for participants switching from ABC/DTG/3TC in the Extension Phase (direct to inject without oral lead-in).
Measure: Plasma CAB and RPV concentrations in the Extension Phase (direct to inject without oral lead-in) Time: Weeks 100, 101 and 104aDescription: It will be assessed for participants switching from ABC/DTG/3TC in the Extension Phase (oral lead-in participants).
Measure: Plasma CAB and RPV concentrations in the Extension Phase (oral lead-in participants) Time: Week 104bAllocation: Randomized
Parallel Assignment
There is one SNP
- Treatment with any agent, except recognized ART as allowed above, with documented activity against HIV-1 within 28 days of the first dose of IP. - Use of medications which are associated with Torsades de Pointes - Any evidence of primary resistance to non-nuclease reverse transcriptase inhibitors (NNRTIs) (except for K103N which is allowed), or any known resistance to INIs from historical resistance test results. --- K103N ---