A Phase III, Randomized, Multicenter, Parallel-group, Non-inferiority Study Evaluating the Efficacy, Safety, and Tolerability of Switching to Dolutegravir Plus Lamivudine in HIV-1 Infected Adults Who Are Virologically Suppressed

ViiV Healthcare1 site in 1 country743 target enrollmentJanuary 18, 2018

ConditionsHIV Infections

InterventionsDTG + 3TC TAF based regimen (TBR)

DrugsDTG + 3TC TAF based regimen (TBR)

Overview

Phase: Phase 3
Intervention: DTG + 3TC
Conditions: HIV Infections
Sponsor: ViiV Healthcare
Enrollment: 743
Locations: 1
Primary Endpoint: Percentage of Participants With Virologic Failure Endpoint as Per Food and Drug Administration (FDA) Snapshot Category at Week 48
Status: Completed
Last Updated: 2 years ago

Overview Investigators Eligibility Criteria Arms & Interventions Outcomes Sites Similar Trials

Overview

Brief Summary

The aim of the study is to establish if human immunodeficiency virus type 1 (HIV-1) infected adult participants with current virologic suppression on a >=3-drug tenofovir alafenamide (TAF) based regimen (TBR) remain suppressed upon switching to a two-drug regimen of dolutegravir (DTG) 50 milligram (mg) + lamivudine (3TC) 300 mg. This study will also provide important information regarding the safety and participant satisfaction with this two-drug regimen. The primary objective of this trial is to demonstrate the non-inferior antiviral activity of switching to DTG + 3TC once daily compared to continuation of TBR over 48 weeks in HIV-1 infected, antiretroviral therapy (ART)-experienced, virologically suppressed participants. This study also will characterize the long-term antiviral activity, tolerability and safety of DTG + 3TC compared to TBR through Week 144 and characterize the long-term antiviral activity, tolerability and safety of DTG + 3TC through Week 200.

This will be a 200-week, Phase III, randomized, open-label, active-controlled, multicenter, parallel- group study. The study will include a screening phase (up to 28 days), a randomized early switch phase (Day 1 up to Week 148), a randomized late switch phase (Week 148 up to Week 200), and a continuation phase (post Week 200). HIV-1 infected adults on stable TBR will be randomized 1:1 to switch to DTG + 3TC once daily for up to 200 weeks, or to continue their TBR for 148 weeks, at which time and if HIV-1 ribonucleic acid (RNA) <50 copies per milliliter (c/mL) at Week 144, these participants will switch to DTG + 3TC up to Week 200.

Registry

clinicaltrials.gov

Start Date

January 18, 2018

End Date

May 3, 2022

Last Updated

2 years ago

Study Type

Interventional

Study Design

Parallel

Sex

All

Investigators

Sponsor

ViiV Healthcare

Responsible Party

Sponsor

Eligibility Criteria

Inclusion Criteria

•Participant must be able to understand and comply with protocol requirements, instructions, and restrictions;
•Participant must be likely to complete the study as planned;
•Participant must be considered an appropriate candidate for participation in an investigative clinical trial with medication (example no active substance abuse, acute major organ disease, or planned long-term work assignments out of the country).
•Aged 18 years or older (or older where required by local regulatory agencies), at the time of signing the informed consent.
•HIV-1 infected men or women.
•Documented evidence of at least two plasma HIV-1 RNA measurements \<50 c/mL in the 12 months prior to Screening: one within the 6 to 12 month window, and one within 6 months prior to Screening.
•Plasma HIV-1 RNA \<50 c/mL at Screening.
•Must be on uninterrupted ART for at least 6 months prior to screening. Only the following regimens are allowed:
•Participant on a TAF-based regimen for at least 6 months as the initial regimen, or
•Participants who switched from a tenofovir disoproxil fumarate (TDF) first-regimen TAF, without any changes to the other drugs in their regimen, and have been on the TAF-based regimen for at least 3 months immediately prior to Screening i.e., the only switch made is from TDF to TAF. This switch must have occurred due to tolerability/safety, access to medications, or convenience/simplification, and must NOT have been done for suspected or established treatment failure. A switch from a PI boosted with ritonavir to the same PI boosted with cobicistat is allowed (and vice versa).

Exclusion Criteria

•Women who are breastfeeding or plan to become pregnant or breastfeed during the study.
•Any evidence of an active Centers for Disease Control and Prevention (CDC) Stage 3 disease, EXCEPT cutaneous Kaposi's sarcoma not requiring systemic therapy. Historical or current CD4 cell counts less than 200 cells/millimeter (mm)\^3 are NOT exclusionary.
•Participants with severe hepatic impairment (Class C) as determined by Child-Pugh classification.
•Unstable liver disease (as defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminaemia, oesophageal or gastric varices, or persistent jaundice), cirrhosis, known biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
•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 antigen antibody (anti-HBs) and HBV deoxyribonucleic acid (DNA) as follows: participants positive for HBsAg are excluded; participants negative for anti-HBs but positive for anti-HBc (negative HBsAg status) and positive for HBV DNA are excluded.
•Anticipated need for any hepatitis C virus (HCV) therapy during the first 48 weeks of the study, or anticipated need for HCV therapy based on interferon or for any drugs that have a potential for adverse drug-drug interactions with study treatment throughout the entire study period.
•Untreated syphilis infection (positive rapid plasma reagin \[RPR\] at Screening without clear documentation of treatment). Participants who are at least 7 days post completed treatment are eligible.
•History or presence of allergy or intolerance to the study drugs or their components or drugs of their class.
•Ongoing malignancy other than cutaneous Kaposi's sarcoma, basal cell carcinoma, or resected, non-invasive cutaneous squamous cell carcinoma, or cervical, anal or penile intraepithelial neoplasia.
•Participants who in the investigator's judgment, poses a significant suicidality risk.

Arms & Interventions

DTG + 3TC 50 mg/300 mg

Participants will receive a single tablet of a two-drug regimen of DTG 50 mg + 3TC 300 mg once daily from Day 1 through Week 200 (Early and Late Switch Phase).

Intervention: DTG + 3TC

TAF based regimen (TBR)

Participants will continue their TBR from Day 1 to Week 148 (Early Switch Phase), and eligible participants will switch to DTG + 3TC once daily from Week 148 to 200 (Late Switch Phase).

Intervention: TAF based regimen (TBR)

Outcomes

Primary Outcomes

Percentage of Participants With Virologic Failure Endpoint as Per Food and Drug Administration (FDA) Snapshot Category at Week 48

Time Frame: Week 48

Percentage of participants with virologic failure (plasma HIV-1 RNA \>=50 c/mL) was evaluated using FDA snapshot algorithm at Week 48. The Snapshot algorithm treated all participants without HIV-1 RNA data at the visit of interest (due to missing data or discontinuation of investigational product prior to the visit window) as non-responders, as well as participants who switch their concomitant antiretroviral therapy (ART) prior to the visit of interest. Intent-to-treat exposed (ITT-E) Population comprises of all randomized participants who received at least one dose of study treatment either DTG + 3TC or TBR. Participants were assessed according to the treatment to which the participant was randomized. Any participant receiving a treatment randomization number was considered to be randomized.

Secondary Outcomes

Change From Baseline in CD4+/CD8+ Cell Count Ratio at Weeks 24 and 48(Baseline (Day 1) and at Weeks 24 and 48)
Change From Baseline in CD4+/CD8+ Cell Count Ratio at Weeks 96 and 144(Baseline (Day 1) and at Weeks 96 and 144)
Percentage of Participants With Virologic Failure Endpoint as Per FDA Snapshot Category at Week 24(Week 24)
Percentage of Participants With Virologic Failure Endpoint as Per FDA Snapshot Category at Weeks 96, 144(Weeks 96 and 144)
Change From Baseline in CD4+ Cell Count at Weeks 24 and 48(Baseline (Day 1) and at Weeks 24 and 48)
Number of Participants With Disease Progression at Weeks 96 and 144(At Weeks 96 and 144)
Percentage of Participants With Plasma HIV-1 RNA <50 c/mL as Per Snapshot Algorithm at Weeks 96 and 144(Weeks 96 and 144)
Percentage of Participants With Plasma HIV-1 RNA <50 c/mL as Per Snapshot Algorithm at Week 48(Week 48)
Percentage of Participants With Plasma HIV-1 RNA <50 c/mL as Per Snapshot Algorithm at Week 24(Week 24)
Number of Participants Who Discontinued the Treatment Due to AEs: Up to Week 144(Up to Week 144)
Change From Baseline in Fasting Lipids at Weeks 24 and 48(Baseline (Day 1) and at weeks 24 and 48)
Number of Participants With Phenotypic Resistance: Up to Week 48(Up to Week 48)
Number of Participants With Phenotypic Resistance: Up to Week 144(Up to Week 144)
Number of Participants With Disease Progression at Weeks 24 and 48(At Weeks 24 and 48)
Number of Participants Randomized to TBR Arm Receiving TDF-based Regimen Who Discontinued the Treatment Due to AEs: Up to Week 48(Up to Week 48)
Number of Participants With Maximum Post-Baseline Emergent Hematology Toxicities: Up to Week 48(Up to Week 48)
Number of Participants With Maximum Post-Baseline Emergent Hematology Toxicities: Up to Week 144(Up to Week 144)
Change From Baseline in Renal Biomarkers- Urine Albumin/Creatinine (UA/C) Ratio and Urine Protein/Creatinine (UP/C) Ratio at Weeks 24 and 48(Baseline (Day 1) and at weeks 24 and 48)
Change From Baseline in Renal Biomarkers- Urine Beta-2 Microglobulin/Urine Creatinine Ratio at Weeks 24 and 48(Baseline (Day 1) and at weeks 24 and 48)
Change From Baseline in CD4+ Cell Count at Weeks 96 and 144(Baseline (Day 1) and at Weeks 96 and 144)
Number of Participants With Any SAEs and Common (>=2%) Non-SAEs: Up to Week 148(Up to Week 148)
Number of Participants With AEs by Their Severity Grades: Up to Week 48(Up to Week 48)
Number of Participants Randomized to TBR Arm Receiving TDF-based Regimen With AEs by Their Severity Grades: Up to Week 48(Up to Week 48)
Change From Baseline in Renal Biomarkers- UA/C Ratio and UP/C Ratio at Weeks 96 and 144(Baseline (Day 1) and at Weeks 96 and 144)
Number of Participants With Any Serious Adverse Events (SAEs) and Common (>=2%) Non-serious Adverse Events (Non-SAEs): Up to Week 48(Up to Week 48)
Number of Participants With Maximum Post-Baseline Emergent Clinical Chemistry Toxicities: Up to Week 48(Up to Week 48)
Number of Participants With Maximum Post-Baseline Emergent Clinical Chemistry Toxicities: Up to Week 144(Up to Week 144)
Change From Baseline in Renal Biomarkers- Urine Beta-2 Microglobulin/Urine Creatinine Ratio at Weeks 24 and 48 in Participants Randomized to TBR Arm Receiving TDF-based Regimen(Baseline (Day 1) and at weeks 24 and 48)
Number of Participants With Genotypic Resistance: Up to Week 144(Up to Week 144)
Number of Participants Randomized to TBR Arm Receiving TDF-based Regimen With Any SAEs and Common (>=2%) Non-SAEs: Up to Week 48(Up to Week 48)
Number of Participants With AEs by Their Severity Grades: Up to Week 144(Up to Week 144)
Number of Participants Who Discontinued the Treatment Due to AEs: Up to Week 48(Up to Week 48)
Number of Participants Randomized to TBR Arm Receiving TDF-based Regimen With Maximum Post-Baseline Emergent Hematology Toxicities: Up to Week 36(Up to Week 36)
Number of Participants Randomized to TBR Arm Receiving TDF-based Regimen With Maximum Post-Baseline Emergent Clinical Chemistry Toxicities: Up to Week 36(Up to Week 36)
Change From Baseline in Renal Biomarkers- UA/C Ratio and UP/C Ratio at Weeks 24 and 48 in Participants Randomized to TBR Receiving TDF-based Regimen(Baseline (Day 1) and at weeks 24 and 48)
Change From Baseline in Renal Biomarkers- Urine Beta-2 Microglobulin/Urine Creatinine Ratio at Weeks 96 and 144(Baseline (Day 1) and at Weeks 96 and 144)
Change From Baseline in Renal Biomarkers- Urine Phosphate at Weeks 24 and 48 in Participants Randomized to TBR Arm Receiving TDF-based Regimen(Baseline (Day 1) and at weeks 24 and 48)
Change From Baseline in Renal Biomarkers- Urine Phosphate at Weeks 96 and 144(Baseline (Day 1) and at Weeks 96 and 144)
Change From Baseline in Renal Biomarkers- Urine Retinol Binding Protein 4/Urine Creatinine at Weeks 24 and 48 in Participants Randomized to TBR Arm Receiving TDF-based Regimen(Baseline (Day 1) and at weeks 24 and 48)
Number of Participants With Genotypic Resistance: Up to Week 48(Up to Week 48)
Change From Baseline in Fasting Lipids at Weeks 24 and 48 in Participants Randomized to TBR Arm Receiving TDF-based Regimen(Baseline (Day 1) and at weeks 24 and 48)
Change From Baseline in Bone Biomarkers-serum Bone-specific ALP (Bone-ALP), Osteocalcin, Serum Procollagen 1 N-Terminal Propeptide (P1NP) and Serum Type 1 Collagen C-telopeptides (CTX-1) at Weeks 24 and 48(Baseline (Day 1) and at Weeks 24 and 48)
Change From Baseline in Bone Biomarkers-serum Bone-ALP, Osteocalcin, Serum P1NP and Serum Type 1 CTX-1 at Weeks 96 and 144(Baseline (Day 1) and at Weeks 96 and 144)
Change From Baseline in Renal Biomarkers- Urine Phosphate at Weeks 24 and 48(Baseline (Day 1) and at weeks 24 and 48)
Change From Baseline in Renal Biomarkers- Urine Retinol Binding Protein 4/Urine Creatinine at Weeks 24 and 48(Baseline (Day 1) and at weeks 24 and 48)
Change From Baseline in Renal Biomarkers- Urine Retinol Binding Protein 4/Urine Creatinine at Weeks 96 and 144(Baseline (Day 1) and at Weeks 96 and 144)
Change From Baseline in Fasting Lipids at Weeks 96 and 144(Baseline (Day 1) and at Weeks 96 and 144)
Change From Baseline in Bone Biomarkers-serum Bone-specific ALP (Bone-ALP), Osteocalcin, Serum P1NP and Serum CTX-1 in Participants Randomized to TBR Arm Receiving TDF-based Regimen at Weeks 24 and 48(Baseline (Day 1) and at Weeks 24 and 48)
Change From Baseline in Renal Biomarker- Serum Cystatin C at Weeks 96 and 144(Baseline (Day 1) and at Weeks 96 and 144)
Change From Baseline in Renal Biomarker- Serum Creatinine at Weeks 96 and 144(Baseline (Day 1) and at Weeks 96 and 144)
Change From Baseline in Bone Biomarker: Serum 25-hydroxyvitamin D at Weeks 24 and 48(Baseline (Day 1) and at Weeks 24 and 48)
Change From Baseline in Bone Biomarker: Serum 25-hydroxyvitamin D at Weeks 96 and 144(Baseline (Day 1) and at Weeks 96 and 144)
Change From Baseline in European Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L) Utility Score at Week 24 and 48(Baseline (Day 1) and at Weeks 24 and 48)
Change From Baseline in EQ-5D-5L Thermometer Scores at Week 24 and 48(Baseline (Day 1) and at Weeks 24 and 48)
Change From Baseline in EQ-5D-5L Thermometer Scores at Weeks 96 and 144(Baseline (Day 1) and at Weeks 96 and 144)
Change From Baseline in Bone Biomarker: Serum 25-hydroxyvitamin D at Weeks 24 and 48 in Participants Randomized to TBR Arm Receiving TDF-based Regimen(Baseline (Day 1) and at Weeks 24 and 48)
Change From Baseline in Renal Biomarker- Serum Cystatin C at Weeks 24 and 48 in Participants Randomized to TBR Arm Receiving TDF-based Regimen(Baseline (Day 1) and at Weeks 24 and 48)
Change From Baseline in Renal Biomarker- Serum Creatinine at Weeks 24 and 48(Baseline (Day 1) and at Weeks 24 and 48)
Change From Baseline in Renal Biomarker- Serum Creatinine at Weeks 24 and 48 in Participants Randomized to TBR Arm Receiving TDF-based Regimen(Baseline (Day 1) and at Weeks 24 and 48)
Change From Baseline in Renal Biomarker- Serum Cystatin C at Weeks 24 and 48(Baseline (Day 1) and at Weeks 24 and 48)
Change From Baseline in Renal Biomarker- Serum GFR From Cystatin C Adjusted Using CKD-EPI and Serum GFR From Creatinine Adjusted Using CKD-EPI at Weeks 96 and 144(Baseline (Day 1) and at Weeks 96 and 144)
Change From Baseline in EQ-5D-5L Utility Score at Weeks 96 and 144(Baseline (Day 1) and at Weeks 96 and 144)
Change From Baseline in Renal Biomarker- Serum GFR From Cystatin C Adjusted Using CKD-EPI and Serum GFR From Creatinine Adjusted Using CKD-EPI at Weeks 24 and 48(Baseline (Day 1) and at Weeks 24 and 48)
Change From Baseline in Renal Biomarker- Serum GFR From Cystatin C Adjusted Using CKD-EPI and Serum GFR From Creatinine Adjusted Using CKD-EPI at Weeks 24 and 48 in Participants Randomized to TBR Arm Receiving TDF-based Regimen(Baseline (Day 1) and at Weeks 24 and 48)