Clinical trial NCT02269917: Study to Evaluate Efficacy and Safety of Darunavir/Cobicistat/Emtricitabine/Tenofovir Alafenamide (D/C/F/TAF) Regimen Versus Boosted Protease Inhibitor (bPI) Along With Emtricitabine/Tenofovir Disoproxil Fumarate (FTC/TDF) Regimen in Virologically-Suppressed, HIV-1 Infected Participants
Official title: A Phase 3, Randomized, Active-controlled, Open-label Study to Evaluate the Efficacy, Safety and Tolerability of Switching to a Darunavir/ Cobicistat/ Emtricitabine/ Tenofovir Alafenamide (D/C/F/TAF) Once-daily Single-tablet Regimen Versus Continuing the Current Regimen Consisting of a Boosted Protease Inhibitor (bPI) Combined With Emtricitabine/Tenofovir Disoproxil Fumarate (FTC/TDF) in Virologically-suppressed, Human Immunodeficiency Virus Type 1 (HIV-1) Infected Subjects
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Human Immunodeficiency Virus Type 1
Keywords: Human Immunodeficiency Virus Type 1
Emerald
Darunavir
Cobicistat
Emtricitabine
Tenofovir Alafenamide
Lead sponsor: Janssen R&D Ireland
Sponsor class: INDUSTRY
First posted: 2014-10-21
Enrollment: 1149
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to demonstrate non-inferiority in efficacy while switching to a once-daily single-tablet regimen containing darunavir (DRV)/ cobicistat (COBI)/ emtricitabine (FTC)/ tenofovir alafenamide (TAF) (D/C/F/TAF tablet) relative to continuing the current regimen consisting of a boosted protease inhibitor (bPI) combined with tenofovir disoproxil fumarate (FTC/TDF) in virologically-suppressed (human immunodeficiency virus type 1 ribonucleic acid \[HIV-1 RNA\] concentrations less than \[\<\] 50 copies per milliliter \[copies/mL\]) HIV-1 infected participants.

Detailed description: This is a randomized (study medication assigned to participants by chance), active-controlled (study in which the experimental treatment or procedure is compared to a standard treatment or procedure), open-label (participants and researchers are aware about the treatment, participants are receiving), multicenter (when more than 1 hospital or medical school team work on a medical research study), study in virologically-suppressed, HIV-1 infected adult participants. The study will include a Screening Period of approximately 30 days (up to maximum 6 weeks), a controlled Treatment Period of 48 weeks, an Extension Phase of 48 weeks. All eligible participants will be randomly assigned to receive either current treatment regimen - a bPI (limited to DRV with low-dose ritonavir \[rtv\] or COBI, atazanavir \[ATV\] with rtv or COBI, or lopinavir \[LPV\] with rtv) combined with FTC/TDF, or experimental treatment regimen - D/C/F/TAF once-daily single-tablet for 48 weeks. After completion of week 48, participants assigned to the experimental treatment will continue with D/C/F/TAF in the extension phase up to week 96 . Participants who continued their current regimen will receive the experimental treatment (if all criteria are fulfilled) at week 52 up to week 96. As from Week 96, all participants will be given the option to continue D/C/F/TAF treatment, if they wish and if they continue to benefit from it until D/C/F/TAF becomes commercially available and is reimbursed, or can be accessed through another source in the country where he/she is living,or until the sponsor terminates clinical development. A bone investigation substudy will be performed at selected study sites, to assess bone biomarkers and energy x-ray absorptiometry (DXA) scans, in approximately 300 participants (200 in the D/C/F/TAF treatment arm versus 100 in the control arm) who provide informed consent for the substudy.

Eligibility criteria: Inclusion Criteria:

* Currently being treated with a stable antiretroviral (ARV) regimen consisting of a boosted protease inhibitor (limited to darunavir \[DRV\] or atazanavir with low-dose ritonavir \[rtv\] or cobicistat \[COBI\], or lopinavir with rtv) combined with emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) only, for at least 6 consecutive months preceding the Screening visit
* On-treatment plasma human immunodeficiency virus type 1 ribonucleic acid (HIV-1 RNA) concentrations less than (\<) 50 copies per milliliter (copies/mL) or HIV-1 RNA undetectable by a local HIV-1 RNA test between 12 and 2 months prior to the Screening visit and have HIV-1 RNA \<50 copies/mL at the Screening visit
* A single virologic elevation of greater than or equal to (\>=) 50 copies/mL after previously reaching viral suppression between 12 and 2 months prior to Screening is acceptable, provided a subsequent test prior to Screening was \<50 copies/mL
* Absence of history of failure on DRV treatment and absence of DRV resistance-associated mutations (RAMs), if documented historical genotypes are available
* Normal electrocardiogram (ECG) at Screening (or if abnormal, determined by the Investigator to be not clinically significant)

Exclusion Criteria:

* A new acquired immunodeficiency syndrome (AIDS) - defining condition diagnosed within the 30 days prior to Screening
* Proven or suspected acute hepatitis within 30 days prior to study entry
* Hepatitis C antibody positive; however, participants previously cured of hepatitis C virus (HCV) infection, with documented sustained virologic response, that is, undetectable HCV RNA 24 weeks after the last dose of HCV treatment, are allowed to participate
* Hepatitis B surface antigen (HBsAg) positive
* Participants with cirrhosis as diagnosed based on local practices

Primary outcomes:
measure: Percentage of Participants With Virologic Rebound (HIV-1 RNA >=50 Copies/mL) Cumulative Through Week 48
timeFrame: Through Week 48
Secondary outcomes:
measure: Percentage of Participants With Virologic Rebound (Plasma HIV-1 RNA >=20 Copies/mL) Cumulative Through 48 Weeks
timeFrame: Through 48 Weeks
measure: Percentage of Participants With Virologic Rebound (Plasma HIV-1 RNA >=200 Copies/mL) Cumulative Through 48 Weeks
timeFrame: Through 48 Weeks
measure: Percentage of Participants With Non-Virologic Rebound at Week 48 by Kaplan-Meier Estimates
timeFrame: Baseline up to Week 48
measure: Percentage of Participants Experiencing Grade 3 and 4 Adverse Events (AEs), Serious Adverse Events (SAEs), and Premature Discontinuation Due to AEs Through Week 48
timeFrame: Up to Week 48
measure: Change From Baseline in Serum Creatinine Levels at Weeks 24 and 48
timeFrame: Baseline and Weeks 24 and 48
measure: Change From Baseline in Estimated Glomerular Filtration Rate Based on Serum Creatinine (eGFRcr, by Cockcroft-Gault Formula [eGFRcg]) at Weeks 24 and 48
timeFrame: Baseline, Weeks 24 and 48
measure: Change From Baseline in Estimated Glomerular Filtration Rate Based on Serum Creatinine (eGFRcr, by Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI]) at Weeks 24 and 48
timeFrame: Baseline, Weeks 24 and 48
measure: Change From Baseline in Estimated Glomerular Filtration Rate Based on Serum Cystatin C (eGFRcyst, by Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI]) at Weeks 24 and 48
timeFrame: Baseline, Weeks 24 and 48
measure: Change From Baseline in Urine Albumin to Creatinine Ratio (UACR) and Urine Protein to Creatinine Ratio (UPCR) at Weeks 24 and 48
timeFrame: Baseline, Weeks 24 and 48
measure: Change From Baseline in Urine Retinol Binding Protein to Creatinine Ratio (URBPCR) and Urine Beta-2 Microglobulin to Creatinine Ratio (UB2MGCR) at Weeks 24 and 48
timeFrame: Baseline, Weeks 24 and 48
measure: Percent Change From Baseline in Urine Fractional Excretion of Phosphate (FEPO4) at Weeks 24 and 48
timeFrame: Baseline, Weeks 24 and 48
measure: Percentage of Participants With Virologic Response Based on HIV-1 RNA Less Than (<)20, <50, and <200 Copies/mL Threshold at Week 48 as Defined by the Food and Drug Administration (FDA) Snapshot Approach
timeFrame: Week 48
measure: Percentage of Participants With Virologic Response Based on HIV-1 RNA <20, <50, and <200 Copies/mL Threshold at Week 48 as Defined by the Time to Loss of Virologic Response (TLOVR) Algorithm
timeFrame: Week 48
measure: Change From Baseline in Cluster of Differentiation 4 Plus (CD4+) Cell Count at Weeks 24 and 48
timeFrame: Baseline, Weeks 24 and 48
measure: Percentage of Participants With Treatment Adherence of Greater Than (>)95 Percent (%) (Approach 1) Through Week 48
timeFrame: Through Week 48
measure: Percentage of Participants With Treatment Adherence of >95% (Approach 2) Through Week 48
timeFrame: Through Week 48
measure: Number of Participants With Resistance to Study Drug
timeFrame: Up to Week 48
measure: Predose (Trough) Plasma Concentration (C0h) of Darunavir
timeFrame: Predose at Weeks 2, 4, 8, 12, 24, 36, and 48
measure: Percent Change From Baseline in Serum Procollagen 1 N-Terminal Propeptide (P1NP) and Serum Collagen Type 1 Beta Carboxy Telopeptide (CTX) Levels at Weeks 24 and 48
timeFrame: Baseline, Weeks 24 and 48
measure: Percent Change From Baseline in Parathyroid Hormone (PTH) at Weeks 24 and 48
timeFrame: Baseline, Weeks 24 and 48
measure: Percent Change From Baseline in 25-hydroxy Vitamin D at Weeks 24 and 48
timeFrame: Baseline, Weeks 24 and 48
measure: Percent Change From Baseline in Spine and Hip Bone Mineral Density (BMD) at Weeks 24 and 48
timeFrame: Baseline, Weeks 24 and 48
measure: Change From Baseline in Bone Mineral Density (BMD) T-Score at Weeks 24 and 48
timeFrame: Baseline, Weeks 24 and 48
measure: Percentage of Participants With Virologic Rebound (HIV-1 RNA >=20 Copies/mL) Cumulative Through Week 96
timeFrame: Through Week 96 (D/C/F/TAF arm) and from Week 52 to Week 96 (Switch to D/C/F/TAF arm)
measure: Percentage of Participants With Virologic Rebound (HIV-1 RNA >=50 Copies/mL) Cumulative Through Week 96
timeFrame: Through Week 96 (D/C/F/TAF arm) and from Week 52 to Week 96 (Switch to D/C/F/TAF arm)
measure: Percentage of Participants With Virologic Rebound (HIV-1 RNA >=200 Copies/mL) Cumulative Through Week 96
timeFrame: Through Week 96 (D/C/F/TAF arm) and from Week 52 to Week 96 (Switch to D/C/F/TAF arm)
measure: Percentage of Participants With Non-Virologic Rebound at Week 96 by Kaplan-Meier Estimates
timeFrame: Baseline to Week 96 (D/C/F/TAF arm) and from Week 52 to Week 96 (Switch to D/C/F/TAF arm)
measure: Percentage of Participants With Virologic Response Based on HIV-1 RNA <20, <50, and <200 Copies/mL Threshold at Week 96 as Defined by the FDA Snapshot Approach
timeFrame: Week 96 (Comprising up to Week 96 for D/C/F/TAF and 44 weeks of D/C/F/TAF exposure [that is, from the switch to D/C/F/TAF at Week 52 up to Week 96])
measure: Percentage of Participants With Virologic Response Based on HIV-1 RNA <20, <50, and <200 Copies/mL Threshold at Week 96 as Defined by the TLOVR Algorithm
timeFrame: Week 96 (Comprising up to Week 96 for D/C/F/TAF and 44 weeks of D/C/F/TAF exposure [that is, from the switch to D/C/F/TAF at Week 52 up to Week 96])
measure: Percentage of Participants With Virologic Failure Based on HIV-1 RNA >=20, >=50, and >=200 Copies/mL Threshold at Week 96 as Defined by the FDA Snapshot Approach
timeFrame: Week 96 (Comprising up to Week 96 for D/C/F/TAF and 44 weeks of D/C/F/TAF exposure [that is, from the switch to D/C/F/TAF at Week 52 up to Week 96])
measure: Change From Reference in CD4+ Cell Count at Week 96
timeFrame: From Reference 1 to Week 96 for D/C/F/TAF+ F/TDF Group and Reference 2 to Week 96 for Switch to D/C/F/TAF (Comprising 44 weeks of D/C/F/TAF exposure [that is, from the switch to D/C/F/TAF at Week 52])
measure: Number of Participants With Resistance to Study Drug Through Week 96
timeFrame: Through Week 96 (D/C/F/TAF arm), up to Week 48 (Control arm) and from Week 52 to Week 96 (Switch to D/C/F/TAF arm)
measure: Percentage of Participants With Treatment Adherence of >95 (Approach 1) Through Week 96
timeFrame: Through Week 96 (D/C/F/TAF arm) and from Week 52 to Week 96 (Switch to D/C/F/TAF arm)
measure: Percentage of Participants With Treatment Adherence of >95% (Approach 2) Through Week 96
timeFrame: Through Week 96 (D/C/F/TAF arm) and from Week 52 to Week 96 (Switch to D/C/F/TAF arm)
measure: Percentage of Participants Experiencing Grade 3 and Grade 4 AEs, SAEs, and Premature Discontinuation Due to AEs Through Week 96
timeFrame: Through Week 96 (D/C/F/TAF arm) and from Week 52 to Week 96 (Switch to D/C/F/TAF arm)
measure: Change From Reference in Serum Creatinine Levels at Week 96
timeFrame: From Reference 1 to Week 96 for D/C/F/TAF+ F/TDF Group and Reference 2 to Week 96 for Switch to D/C/F/TAF
measure: Change From Reference in Estimated Glomerular Filtration Rate Based on Serum Creatinine (eGFRcr, by Cockcroft-Gault Formula [eGFRcg]) at Week 96
timeFrame: From Reference 1 to Week 96 for D/C/F/TAF+ F/TDF Group and Reference 2 to Week 96 for Switch to D/C/F/TAF
measure: Change From Reference in Estimated Glomerular Filtration Rate Based on Serum Creatinine (by CKD-EPI) at Week 96
timeFrame: From Reference 1 to Week 96 for D/C/F/TAF+ F/TDF Group and Reference 2 to Week 96 for Switch to D/C/F/TAF
measure: Change From Reference in Estimated Glomerular Filtration Rate Based on Serum Cystatin C (by CKD-EPI) at Week 96
timeFrame: From Reference 1 to Week 96 for D/C/F/TAF+ F/TDF Group and Reference 2 to Week 96 for Switch to D/C/F/TAF
measure: Change From Reference in UACR at Week 96
timeFrame: From Reference 1 to Week 96 for D/C/F/TAF+ F/TDF Group and Reference 2 to Week 96 for Switch to D/C/F/TAF
measure: Change From Reference in URBPCR at Week 96
timeFrame: From Reference 1 to Week 96 for D/C/F/TAF+ F/TDF Group and Reference 2 to Week 96 for Switch to D/C/F/TAF
measure: Change From Reference in UPCR at Week 96
timeFrame: From Reference 1 to Week 96 for D/C/F/TAF+ F/TDF Group and Reference 2 to Week 96 for Switch to D/C/F/TAF
measure: Change From Reference in UB2MGCR at Week 96
timeFrame: From Reference 1 to Week 96 for D/C/F/TAF+ F/TDF Group and Reference 2 to Week 96 for Switch to D/C/F/TAF
measure: Percent Change From Reference in FEPO4 at Week 96
timeFrame: From Reference 1 to Week 96 for D/C/F/TAF+ F/TDF Group and Reference 2 to Week 96 for Switch to D/C/F/TAF
measure: Percent Change From Reference in Levels of Serum P1NP at Week 96
timeFrame: From Reference 1 to Week 96 for D/C/F/TAF+ FTC/TDF Group and Reference 2 to Week 96 for Switch to D/C/F/TAF
measure: Percent Change From Reference in Levels of Serum CTX at Week 96
timeFrame: From Reference 1 to Week 96 for D/C/F/TAF+ FTC/TDF Group and Reference 2 to Week 96 for Switch to D/C/F/TAF
measure: Percent Change From Reference in Levels of PTH at Week 96
timeFrame: From Reference 1 to Week 96 for D/C/F/TAF+ FTC/TDF Group and Reference 2 to Week 96 for Switch to D/C/F/TAF
measure: Percent Change From Reference in Levels of 25-OH Vitamin D at Week 96
timeFrame: From Reference 1 to Week 96 for D/C/F/TAF+ FTC/TDF Group and Reference 2 to Week 96 for Switch to D/C/F/TAF
measure: Percent Change From Reference in Hip and Spine BMD at Week 96
timeFrame: From Reference 1 to Week 96 for D/C/F/TAF+ FTC/TDF Group and Reference 2 to Week 96 for Switch to D/C/F/TAF
measure: Change From Reference in BMD T-score of Hip and Spine at Week 96
timeFrame: From Reference 1 to Week 96 for D/C/F/TAF+ FTC/TDF Group and Reference 2 to Week 96 for Switch to D/C/F/TAF
measure: Percentage of Participants With Non-Virologic Rebound by Kaplan-Meier Estimates
timeFrame: Week 96 to end of extension (at every 6 months, up to 42 months)
measure: Percentage of Participants With Non-Treatment Failure by Kaplan-Meier Estimates
timeFrame: Week 96 to end of extension (up to 42 months)
measure: Percentage of Participants With HIV RNA <50, <20, <200 Copies/mL Post Week 96 to End of Extension
timeFrame: Week 96 to end of extension (up to 42 months)
measure: CD4+ Cell Count Post-Week 96 to End of Extension
timeFrame: Week 96 to end of extension (up to 42 months)
measure: Percentage of Participants With Treatment Adherence of >95% From Week 96 to End of Extension
timeFrame: Week 96 to end of extension (up to 42 months)
measure: Percentage of Participants Experiencing Grade 3 and 4 AEs, Serious Adverse Events (SAEs), and Premature Discontinuation Due to AEs Post-Week 96 to End of Extension
timeFrame: From Week 96 to end of extension (up to 42 months)
Other outcomes:
Locations:
city: Phoenix
country: United States
state: Arizona
city: Bakersfield
country: United States
state: California
city: Beverly Hills
country: United States
state: California
city: Long Beach
country: United States
state: California
city: Los Angeles
country: United States
state: California
city: San Diego
country: United States
state: California
city: San Francisco
country: United States
state: California
city: Washington
country: United States
state: District of Columbia
city: Fort Lauderdale
country: United States
state: Florida
city: Fort Pierce
country: United States
state: Florida
city: Orlando
country: United States
state: Florida
city: West Palm Beach
country: United States
state: Florida
city: Atlanta
country: United States
state: Georgia
city: Savannah
country: United States
state: Georgia
city: Chicago
country: United States
state: Illinois
city: Boston
country: United States
state: Massachusetts
city: Springfield
country: United States
state: Massachusetts
city: Berkley
country: United States
state: Michigan
city: Detroit
country: United States
state: Michigan
city: Minneapolis
country: United States
state: Minnesota
city: Kansas City
country: United States
state: Missouri
city: Saint Louis
country: United States
state: Missouri
city: Hillsborough
country: United States
state: New Jersey
city: Newark
country: United States
state: New Jersey
city: Somers Point
country: United States
state: New Jersey
city: Santa Fe
country: United States
state: New Mexico
city: New York
country: United States
state: New York
city: Chapel Hill
country: United States
state: North Carolina
city: Winston-Salem
country: United States
state: North Carolina
city: Cincinnati
country: United States
state: Ohio
city: Philadelphia
country: United States
state: Pennsylvania
city: Providence
country: United States
state: Rhode Island
city: Austin
country: United States
state: Texas
city: Dallas
country: United States
state: Texas
city: Fort Worth
country: United States
state: Texas
city: Houston
country: United States
state: Texas
city: Longview
country: United States
state: Texas
city: Seattle
country: United States
state: Washington
city: Antwerpen
country: Belgium
city: Brussels
country: Belgium
city: Bruxelles
country: Belgium
city: Gent
country: Belgium
city: Leuven
country: Belgium
city: Liège
country: Belgium
city: Edmonton
country: Canada
state: Alberta
city: Vancouver
country: Canada
state: British Columbia
city: Toronto
country: Canada
state: Ontario
city: Montreal
country: Canada
state: Quebec
city: Le Kremlin Bicetre
country: France
city: Lyon
country: France
city: Marseille
country: France
city: Montpellier
country: France
city: Nantes
country: France
city: Paris Cedex 10
country: France
city: Paris Cedex 12
country: France
city: Paris
country: France
city: Strasbourg Cedex
country: France
city: Tourcoing
country: France
city: Bydgoszcz
country: Poland
city: Chorzow
country: Poland
city: Lodz
country: Poland
city: Warszawa
country: Poland
city: Wroclaw
country: Poland
city: San Juan
country: Puerto Rico
city: Alicante
country: Spain
city: Badalona
country: Spain
city: Barcelona
country: Spain
city: Cordoba
country: Spain
city: Elche
country: Spain
city: Madrid
country: Spain
city: San Sebastian
country: Spain
city: Sevilla
country: Spain
city: Valencia
country: Spain
city: Göteborg
country: Sweden
city: Malmö
country: Sweden
city: Stockholm
country: Sweden
city: Basel
country: Switzerland
city: Bern
country: Switzerland
city: Zurich N/a
country: Switzerland
city: Brighton
country: United Kingdom
city: London
country: United Kingdom
city: Manchester
country: United Kingdom
Study officials:
affiliation: Janssen R&D Ireland
name: Janssen R&D Ireland Clinical Trial
role: STUDY_DIRECTOR
References:
citation: Ackaert O, McDougall D, Perez-Ruixo C, Perez-Ruixo JJ, Jezorwski J, Crauwels HM. Population Pharmacokinetic Analysis of Darunavir and Tenofovir Alafenamide in HIV-1-Infected Patients on the Darunavir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Single-Tablet Regimen (AMBER and EMERALD Studies). AAPS J. 2021 Jun 7;23(4):82. doi: 10.1208/s12248-021-00607-8.
citation: Huhn GD, Wilkin A, Mussini C, Spinner CD, Jezorwski J, El Ghazi M, Van Landuyt E, Lathouwers E, Brown K, Baugh B; AMBER and EMERALD study groups. Week 96 subgroup analyses of the phase 3, randomized AMBER and EMERALD trials evaluating the efficacy and safety of the once daily darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) single-tablet regimen in antiretroviral treatment (ART)-naive and -experienced, virologically-suppressed adults living with HIV-1. HIV Res Clin Pract. 2020 Dec;21(6):151-167. doi: 10.1080/25787489.2020.1844520. Epub 2021 Feb 2.
citation: Lathouwers E, Wong EY, Brown K, Baugh B, Ghys A, Jezorwski J, Mohsine EG, Van Landuyt E, Opsomer M, De Meyer S; AMBER and EMERALD Study Groups. Week 48 Resistance Analyses of the Once-Daily, Single-Tablet Regimen Darunavir/Cobicistat/Emtricitabine/Tenofovir Alafenamide (D/C/F/TAF) in Adults Living with HIV-1 from the Phase III Randomized AMBER and EMERALD Trials. AIDS Res Hum Retroviruses. 2020 Jan;36(1):48-57. doi: 10.1089/AID.2019.0111. Epub 2019 Oct 21.
citation: Huhn GD, Eron JJ, Girard PM, Orkin C, Molina JM, DeJesus E, Petrovic R, Luo D, Van Landuyt E, Lathouwers E, Nettles RE, Brown K, Wong EY. Darunavir/cobicistat/emtricitabine/tenofovir alafenamide in treatment-experienced, virologically suppressed patients with HIV-1: subgroup analyses of the phase 3 EMERALD study. AIDS Res Ther. 2019 Aug 29;16(1):23. doi: 10.1186/s12981-019-0235-1.
citation: Orkin C, Molina JM, Negredo E, Arribas JR, Gathe J, Eron JJ, Van Landuyt E, Lathouwers E, Hufkens V, Petrovic R, Vanveggel S, Opsomer M; EMERALD study group. Efficacy and safety of switching from boosted protease inhibitors plus emtricitabine and tenofovir disoproxil fumarate regimens to single-tablet darunavir, cobicistat, emtricitabine, and tenofovir alafenamide at 48 weeks in adults with virologically suppressed HIV-1 (EMERALD): a phase 3, randomised, non-inferiority trial. Lancet HIV. 2018 Jan;5(1):e23-e34. doi: 10.1016/S2352-3018(17)30179-0. Epub 2017 Oct 6.