An Efficacy, Safety, and Tolerability Study Comparing Dolutegravir Plus Lamivudine With Dolutegravir Plus Tenofovir/Emtricitabine in Treatment naïve HIV Infected Subjects (Gemini 1)

• ClinicalTrials.gov Identifier: NCT02831673
• Recruitment Status: Active, not recruiting
• First Posted: July 13, 2016
• Results First Posted: April 18, 2019
• Last Update Posted: December 17, 2020
• Sponsor: ViiV Healthcare
• Collaborators: PPD; GlaxoSmithKline
• Information provided by (Responsible Party): ViiV Healthcare

Tracking Information

• First Submitted Date: July 8, 2016
• First Posted Date: July 13, 2016
• Results First Submitted Date: March 26, 2019
• Results First Posted Date: April 18, 2019
• Last Update Posted Date: December 17, 2020
• Actual Study Start Date: July 21, 2016
• Actual Primary Completion Date: March 29, 2018 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: March 26, 2019)

Percentage of Participants With Plasma Human Immunodeficiency Virus Type 1 (HIV-1) Ribonucleic Acid (RNA) <50 Copies/mL (c/mL) at Week 48 [ Time Frame: Week 48 ]

Percentage of participants with HIV-1 RNA<50 c/mL was obtained using Food and Drug Administration (FDA) Snapshot algorithm. 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. This endpoint was analyzed using a stratified analysis with Cochran-Mantel-Haenszel (CMH) weights. Intent-To-Treat Exposed (ITT-E) Population was used which comprised of all randomized participants who receive at least one dose of study treatment.

Original Primary Outcome Measures (submitted: July 8, 2016)

Percentage of subjects with plasma HIV 1 RNA <50 copies/milliliter at Week 48 [ Time Frame: Week 48 ]

The proportion of responders (HIV-1 RNA <50 copies/mL) among randomized subjects who received at least one dose of study medication (ITT-E population) will be assessed at Week 48 according to the FDA's Snapshot algorithm.

Current Secondary Outcome Measures (submitted: March 26, 2019)

• Percentage of Participants With Plasma HIV-1 RNA <50 c/mL at Week 24 [ Time Frame: Week 24 ]
  Percentage of participants with HIV-1 RNA<50 c/mL was obtained using FDA Snapshot algorithm. 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 ART prior to the visit of interest. This endpoint was analyzed using a stratified analysis with Cochran-Mantel-Haenszel weights.
• Time to Viral Suppression (HIV-1 RNA <50 c/mL) [ Time Frame: Up to Week 48 ]
  Time of viral suppression is defined as the first viral load value <50 c/mL. Nonparametric Kaplan-Meier method was performed. Participants who withdrew for any reason without being suppressed were censored at date of withdrawal. Participants who have not been withdrawn and have not had viral suppression at time of the analysis were censored at last viral load date. Confidence Interval (CI) was estimated using the Brookmeyer-Crowley method. Median along with interquartile range (first Quartile and third Quartile) have been presented.
• CD4+ Cell Counts at Weeks 24 and 48 [ Time Frame: Weeks 24 and 48 ]
  CD4+ cells are type of white blood cells that fight infection and as HIV infection progresses, the number of these cells declines. Blood samples were collected at specified time points to assess CD4+. It was evaluated by flow cytometry.
• Changes From Baseline in CD4+ Cell Counts at Week 24 and 48 [ Time Frame: Baseline (Day 1) and Weeks 24, 48 ]
  CD4+ cells are type of white blood cells that fight infection and as HIV infection progresses, the number of these cells declines. Blood samples were collected at specified time points to assess CD4+. It was evaluated by flow cytometry. Baseline value is defined as the the latest pre-dose assessment (Day 1). Change from Baseline was defined as post-dose visit value minus Baseline value. Adjusted mean and standard error has been presented. Adjusted mean is the estimated mean change from Baseline at each visit in each arm calculated from a repeated measures model adjusting for the following covariates/factors: treatment, visit, Baseline plasma HIV-1 RNA (factor), Baseline CD4+ cell count, treatment and visit interaction, and Baseline CD4+ cell count and visit interaction, with visit as the repeated factor.
• Number of Participants With HIV-1 Disease Progression [ Time Frame: Up to Week 48 ]
  HIV-associated conditions were recorded during the study and was assessed according to the 2014 Centers for Disease Control and Prevention (CDC) Classification System for HIV Infection in Adults. Disease progression summarize participants who had HIV infection stage 3 associated conditions or death. Indicators of clinical disease progression were defined as: CDC Category Stage 1 at enrolment to Stage 3 event; CDC Category Stage 2 at enrolment to Stage 3 event; CDC Category Stage 3 at enrolment to New Stage 3 Event; CDC Category Stage 1, 2 or 3 at enrolment to Death.
• Number of Participants With Treatment-emergent Genotypic Resistance [ Time Frame: Up to Week 48 ]
  Number of participants, who meet confirmed virologic withdrawal (CVW) criteria, with treatment emergent phenotypic resistance to Integrase strand transfer inhibitor (INSTI) and/or Nucleoside reverse transcriptase inhibitor (NRTI) was summarized. The Viral Genotypic Population comprised of all participants in the ITT-E population who have available on-treatment genotypic resistance data.
• Number of Participants With Treatment-emergent Phenotypic Resistance [ Time Frame: Up to Week 48 ]
  Number of participants, who meet CVW criteria, with treatment emergent phenotypic resistance to INSTI and/or NRTI were summarized. Assessment of antiviral activity of anti-retroviral therapy (ART) using phenotypic test results was interpreted through a proprietary algorithm (from Monogram Biosciences) and provides the overall susceptibility of the drug. Partially sensitive and resistant calls were considered resistant in this analysis. Number of participants with phenotype at time of CVW by phenotypic cut-off at or prior to Week 48 have been presented. The Viral Phenotypic Population comprised of all participants in the ITT-E population who have available on-treatment phenotypic resistance data.
• Number of Participants With Any Adverse Event (AE) and Serious AE (SAE) [ Time Frame: Up to Week 48 ]
  An AE is any untoward medical occurrence in a clinical investigation participant, 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, any other situation according to medical or scientific judgment that may not be immediately life-threatening or result in death or hospitalization but may jeopardize the participant or may require medical or surgical intervention or event associated with liver injury and impaired liver function were categorized as SAE. Safety Population was used which comprised of all participants who received at least one dose of study treatment.
• Number of Participants With AEs by Their Severity Grades [ Time Frame: Up to Week 48 ]
  An AE is any untoward medical occurrence in a clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Adverse events were evaluated by the investigator and graded according to the Division of Acquired Immunodeficiency Syndrome (DAIDS) toxicity scales from Grade 1 to 5 (1=Mild, 2=Moderate, 3=Severe, 4=Potentially life threatening, 5=Death). The higher the grade, the more severe the symptoms. Number of participants with adverse events by maximum grade have been presented.
• Number of Participants With Any Drug Related AEs and Drug Related AEs by Maximum Grade [ Time Frame: Up to Week 48 ]
  An AE is any untoward medical occurrence in a clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Adverse events were evaluated by the investigator and graded according to the DAIDS toxicity scales from Grade 1 to 5 (1=Mild, 2=Moderate, 3=Severe, 4=Potentially life threatening, 5=Death). The higher the grade, the more severe the symptoms. Number of participants with drug related AEs and drug related AEs by maximum grade have been presented.
• Number of Participants With Maximum Post-Baseline Emergent Hematology Toxicities [ Time Frame: Up to Week 48 ]
  Blood samples were collected up to Week 48 for assessment of hematology parameters to assess any abnormality per toxicity scales for platelet count, neutrophils, hemoglobin. Any abnormality was graded according to DAIDS toxicity scales from Grade 1 to 4 (1=Mild, 2=Moderate, 3=Severe, 4=Potentially life threatening). The higher the grade, the more severe the symptoms. Only those participants with maximum post-Baseline emergent hematology toxicities in any of the hematology parameters have been presented.
• Number of Participants With Maximum Post-Baseline Emergent Chemistry Toxicities [ Time Frame: Up to Week 48 ]
  Blood samples were collected up to Week 48 for assessment of Alanine Aminotransferase (ALT), Aspartate aminotransferase (AST), Creatinine, Glucose, Potassium, Sodium, Chloride, Calcium, Total carbon dioxide (CO2), Alkaline phosphatase (ALP), Phosphate, Total bilirubin, Total protein, Albumin, Creatine phosphokinase (CPK), Creatinine clearance,Glomerular filtration rate (GFR), Total cholesterol, High density lipoprotein (HDL), Low density lipoprotein (LDL), Triglyceride and Lipase. Any abnormality was graded according to DAIDS toxicity scales from Grade 1 to 4 (1=Mild, 2=Moderate, 3=Severe, 4=Potentially life threatening). The higher the grade, the more severe the symptoms. Only those participants with maximum post-Baseline emergent chemistry toxicities in any of the chemistry parameters have been presented.
• Number of Participants Who Discontinue Treatment Due to AEs Over Weeks 24, 48 [ Time Frame: Up to Week 48 ]
  An AE is any untoward medical occurrence in a clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Data cut-off dates for analysis at Week 24 and Week 48 were 19-Jan-2018 and 22-May-2018 respectively. Number of participants who discontinued treatment due to AEs have been reported.
• Change From Baseline in Renal Biomarkers-Serum Cystatin C and Serum Retinol Binding Protein (RBP) at Weeks 24, 48 [ Time Frame: Baseline and at Weeks 24, 48 ]
  Blood and/or urine were collected to perform evaluation of renal inflammation biomarkers which included Serum Cystatin C and Serum Retinol Binding Protein (RBP). Baseline value is the latest pre-dose assessment. Change from Baseline was defined as post-dose visit value minus Baseline value. Adjusted mean and standard error is presented. Adjusted mean is the estimated mean change from baseline at each visit in each arm calculated from a repeated measures model adjusting for: treatment, visit, baseline plasma HIV-1 RNA (factor), baseline CD4+ cell count (factor), age, sex (factor), race (factor), presence of diabetes mellitus (factor), presence of hypertension (factor), baseline biomarker value, treatment and visit interaction, and baseline biomarker value and visit interaction; with visit as the repeated factor.
• Change From Baseline in Renal Biomarkers-Serum GFR From Cystatin C Adjusted Using Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) and Serum or Plasma GFR From Creatinine Adjusted Using CKD-EPI at Weeks 24, 48 [ Time Frame: Baseline and at Weeks 24, 48 ]
  Blood and/or urine were collected to perform evaluation of renal inflammation biomarkers which included Serum GFR from cystatin C adjusted using CKD-EPI (GFR-cystatin C adjusted)and Serum or Plasma GFR from creatinine adjusted using CKD-EPI. Baseline value is the latest pre-dose assessment. Change from Baseline was defined as post-dose visit value minus Baseline value. Adjusted mean and standard error is presented. Adjusted mean is the estimated mean change from baseline at each visit in each arm calculated from a repeated measures model adjusting for: treatment, visit, baseline plasma HIV-1 RNA (factor), baseline CD4+ cell count (factor), age, sex (factor), race (factor), presence of diabetes mellitus (factor), presence of hypertension (factor), baseline biomarker value, treatment and visit interaction, and baseline biomarker value and visit interaction; with visit as the repeated factor.
• Change From Baseline in Renal Biomarker-Serum or Plasma Creatinine at Weeks 24, 48 [ Time Frame: Baseline and at Weeks 24, 48 ]
  Blood and/or urine were collected to perform evaluation of renal inflammation biomarker which included Serum or Plasma Creatinine. Baseline value is defined as the latest pre-dose assessment. Change from Baseline was calculated as post-dose visit value minus Baseline value. Adjusted mean and standard error is presented. Adjusted mean is the estimated mean change from baseline at each visit in each arm calculated from a repeated measures model adjusting for: treatment, visit, baseline plasma HIV-1 RNA (factor), baseline CD4+ cell count (factor), age, sex (factor), race (factor), presence of diabetes mellitus (factor), presence of hypertension (factor), baseline biomarker value, treatment and visit interaction, and baseline biomarker value and visit interaction; with visit as the repeated factor.
• Ratio to Baseline in Renal Biomarkers-Urine and Serum Beta-2 Microglobulin (B2M), Urine Albumin/Creatinine, Urine B2M/Urine Creatinine, Urine Phosphate, Urine Protein/Creatinine, Urine RBP 4 and Urine RBP 4/Urine Creatinine at Weeks 24, 48 [ Time Frame: Baseline and at Weeks 24, 48 ]
  Blood and/or urine were collected to perform evaluation of renal inflammation biomarkers which included Urine and Serum B2M, Urine Albumin/Creatinine, Urine B2M/Urine Creatinine, Urine Phosphate, Urine Protein/Creatinine, Urine RBP 4 and Urine RBP 4/Urine Creatinine. Baseline value is defined as the latest pre-dose assessment. Ratio to Baseline was calculated as ratio of post-dose visit value over Baseline value. Statistical analysis of changes from baseline were performed on log-transformed data. Results were transformed back via exponential transformation such that treatment comparisons are assessed via odds ratios. Estimated ratio of geometric means (each visit over Baseline) and 95% confidence interval (CI) have been presented.
• Change From Baseline in Bone Biomarkers-Serum Bone Specific Alkaline Phosphatase (Bone-ALP), Serum Osteocalcin, Serum Procollagen 1 N-Terminal Propeptide (PINP) and Serum Type I Collagen C-Telopeptides (CTX-1) at Weeks 24, 48 [ Time Frame: Baseline and at Weeks 24, 48 ]
  Blood samples were collected to perform evaluation of bone biomarkers which included bone-ALP, Serum Osteocalcin, PINP and CTX-1. Baseline value is defined as the latest pre-dose assessment. Change from Baseline was calculated as post-dose visit value minus Baseline value. Adjusted mean and standard error is presented. Adjusted mean is the estimated mean change from baseline at each visit in each arm calculated from a repeated measures model adjusting for: treatment, visit, baseline plasma HIV-1 RNA (factor), baseline CD4+ cell count (factor), age, sex (factor), race (factor), BMI (factor), smoking status (factor), current Vitamin D use (factor), baseline biomarker value, treatment and visit interaction, and baseline biomarker value and visit interaction; with visit as the repeated factor.
• Change From Baseline in Bone Biomarker-Serum Vitamin D at Weeks 24, 48 [ Time Frame: Baseline and at Weeks 24, 48 ]
  Blood samples were collected to perform evaluation of bone biomarker serum vitamin D. Baseline value is defined as the latest pre-dose assessment. Change from Baseline was calculated as post-dose visit value minus Baseline value. Adjusted mean and standard error is presented. Adjusted mean is the estimated mean change from baseline at each visit in each arm calculated from a repeated measures model adjusting for: treatment, visit, baseline plasma HIV-1 RNA (factor), baseline CD4+ cell count (factor), age, sex (factor), race (factor), BMI (factor), smoking status (factor), current Vitamin D use (factor), baseline biomarker value, treatment and visit interaction, and baseline biomarker value and visit interaction; with visit as the repeated factor.
• Percentage Change From Baseline in Fasting Lipids-Serum or Plasma Cholesterol, Serum or Plasma HDL Cholesterol (Direct), Serum or Plasma LDL Cholesterol (Calculated or Direct) and Serum or Plasma Triglycerides at Weeks 24, 48 [ Time Frame: Baseline (Day 1) and at Weeks 24, 48 ]
  Blood samples were collected to perform evaluation of fasting lipids which included Serum or Plasma Cholesterol, Serum or Plasma HDL Cholesterol (Direct), Serum or Plasma LDL Cholesterol (Calculated or Direct) and Serum or Plasma Triglycerides. Baseline value is defined as the latest pre-dose assessment (Day 1). Percentage change from Baseline was calculated as 100 multiplied by ([post-dose visit value minus Baseline value] divided by Baseline value).
• Percentage Change From Baseline in Fasting Lipid-Serum or Plasma Total Cholesterol/HDL Cholesterol Ratio at Weeks 24, 48 [ Time Frame: Baseline (Day 1) and at Weeks 24, 48 ]
  Blood samples were collected to perform evaluation of fasting lipid-Serum or Plasma Total Cholesterol/HDL Cholesterol Ratio. Baseline value is the latest pre-dose assessment (Day 1). Percentage change from Baseline was calculated as 100 multiplied by ([post-dose visit value minus Baseline value] divided by Baseline value).
• Percentage of Participants With Grade 2 or Greater Laboratory Abnormalities in Fasting LDL Cholesterol by Weeks 24, 48 [ Time Frame: Up to Week 48 ]
  Blood samples were collected to perform evaluation of fasting LDL cholesterol. Any abnormalities were evaluated by the investigator and graded according to DAIDS toxicity scales from Grade 1 to 4 (1=Mild, 2=Moderate, 3=Severe, 4=Potentially life threatening). The higher the grade, the more severe the symptoms. Percentage of participants with Grade 2 or greater laboratory abnormalities in fasting LDL cholesterol by Weeks 24 and 48 have been presented. Participants without any post-Baseline fasting LDL cholesterol value prior to Week 48 or those who had Baseline lipids-lowering agents are not included. Lipid Last Observation Carried Forward (LOCF) data was used such that the last available fasted, on-treatment lipid value prior to the initiation of a lipid-lowering agent was used in place of future observed values.
• Percentage of Participants by Subgroups (by Age, Gender, Baseline CD4+ Cell Count, Baseline HIV-1 RNA, Race) With Plasma HIV-1 RNA <50 c/mL at Week 24 [ Time Frame: Week 24 ]
  Percentage of participants by subgroups (by age, gender, Baseline CD4+ cell count, Baseline HIV-1 RNA, race) with HIV-1 RNA<50 c/mL was obtained using FDA Snapshot algorithm. 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 ART prior to the visit of interest. Data was presented by subgroups: age (<35, 35 to <50, >=50 years); gender (males and females), Baseline CD4+ cell count (<=200, >200), Baseline HIV-1 RNA (<=100000, >100000) and Race (White, African American/African H., Asian, Other).
• Percentage of Participants by Subgroups (by Age, Gender, Baseline CD4+ Cell Count Baseline HIV-1 RNA, Race) With Plasma HIV-1 RNA <50 c/mL at Week 48 [ Time Frame: Week 48 ]
  Percentage of participants by subgroups (by age, gender, Baseline CD4+ cell count, Baseline HIV-1 RNA, race) with HIV-1 RNA<50 c/mL was obtained using FDA Snapshot algorithm. 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 ART prior to the visit of interest. Data was presented by subgroups: age (<35, 35 to <50, >=50 years); gender (males and females), Baseline CD4+ cell count (<=200, >200), Baseline HIV-1 RNA (<=100000, >100000) and Race (White, African American/African H., Asian, Other).
• Changes From Baseline in CD4+ Cell Counts at Week 48 by Subgroups [ Time Frame: Baseline (Day 1) and Week 48 ]
  CD4+ cells are type of white blood cells that fight infection and as HIV infection progresses, the number of these cells declines. Blood samples were collected at specified time points to assess CD4+. It was evaluated by flow cytometry. Baseline value is the latest pre-dose assessment (Day 1). Change from Baseline was defined as post-dose visit value minus Baseline value. Adjusted mean and standard error is presented for subgroups (Baseline plasma HIV-1 RNA, Baseline CD4+ cell count, Age group, Gender and race). For each subgroup, adjusted mean is the estimated mean change from Baseline in each arm calculated from Analysis of Covariance (ANCOVA) model adjusting for the following covariates/factors: treatment, Baseline plasma HIV-1 RNA (factor), Baseline CD4+ cell count, subgroup, and treatment and relevant subgroup interaction. For CD4+ cell count subgroup, Baseline CD4+ cell count group is included as a factor only.
• Changes From Baseline in CD4+ Cell Counts at Week 24 by Subgroups [ Time Frame: Baseline (Day 1) and Week 24 ]
  CD4+ cells are type of white blood cells that fight infection and as HIV infection progresses, the number of these cells declines. Blood samples were collected at specified time points to assess CD4+. It was evaluated by flow cytometry. Baseline value is the latest pre-dose assessment (Day 1). Change from Baseline was defined as post-dose visit value minus Baseline value. Adjusted mean and standard error is presented for subgroups (Baseline plasma HIV-1 RNA, Baseline CD4+ cell count, Age, Gender, and race). For each subgroup, adjusted mean is the estimated mean change from Baseline in each arm calculated from ANCOVA model adjusting for the following covariates/factors: treatment, Baseline plasma HIV-1 RNA (factor), Baseline CD4+ cell count, subgroup, and treatment and relevant subgroup interaction. For CD4+ cell count subgroup, Baseline CD4+ cell count group is included as a factor only.
• Change From Baseline in EuroQol - 5 Dimensions - 5 Levels (EQ-5D-5L) Utility Score at Weeks 4, 24, 48 [ Time Frame: Baseline and Weeks 4, 24, 48 ]
  EQ-5D-5L questionnaire provides a profile of participant function and a global health state rating. The five-item measure has 1 question assessing each of 5 dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression and 5 levels for each dimension including 1=no problems, 2=slight problems, 3=moderate problems, 4=severe problems and 5=extreme problems. The health state is defined by combining the levels of answers from each of the 5 questions. Each health state is referred to in terms of a 5 digit code. Health state 5 digit code is translated into utility score, which is valued up to 1 (perfect health) with lower values meaning worse state. EQ-5D-5L utility score ranges from -0.281 to 1. Higher scores indicate better health. Baseline was the latest pre-dose assessment and change from Baseline=post-dose value minus Baseline value.
• Change From Baseline in EuroQol - 5 Dimensions - 5 Levels (EQ-5D-5L) Thermometer Scores at Weeks 4, 24 48 [ Time Frame: Baseline (Day 1) and Weeks 4, 24, 48 ]
  EQ-5D-5L questionnaire provides a profile of participant function and a global health state rating. The five-item measure has one question assessing each of five dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression and 5 levels for each dimension including 1=no problems, 2=slight problems, 3=moderate problems, 4=severe problems and 5=extreme problems. EQ-5D-5L included EQ visual Analogue scale (EQ VAS) 'Thermometer' which provided Self-rated current health status. Score ranges from 0 (worst imaginable health state) to 100 (best imaginable health state). MMRM was run on the LOCF dataset, using the observed margins (OM) option. Baseline was the latest pre-dose assessment value and change from Baseline=post-dose value minus Baseline value.

Original Secondary Outcome Measures (submitted: July 8, 2016)

• Percentage of subjects with plasma HIV 1 RNA <50 copies/milliliter at Weeks 24, 96, and 144 [ Time Frame: Week 24, 96, and 144 ]
  The proportion of responders (HIV-1 RNA <50 copies/mL) among randomized subjects in the ITT-E population will be assessed at Weeks 24, 96 and 144 according to the FDA's Snapshot algorithm
• Time to viral suppression (HIV 1 RNA <50 copies/milliliter) over time [ Time Frame: Up to Week 144 ]
  Time to HIV-1 RNA <50 copies/mL
• Absolute values in CD4+ cell counts at Weeks 24, 48, 96 and 144 [ Time Frame: Weeks 24, 48, 96 and 144 ]
  Blood samples will be collected for assessment of lymphocytes by flow cytometry
• Changes from Baseline in CD4+ cell counts at Weeks 24, 48, 96 and 144 [ Time Frame: Baseline (Day 1), Weeks 24, 48, 96 and 144 ]
  Blood samples will be collected for assessment of lymphocytes by flow cytometry
• Number of subjects with disease progression (HIV associated conditions, acquired immunodeficiency syndrome, and death) over time [ Time Frame: Up to Week 144 ]
  Antiviral and immunological activity evaluated by incidence of disease progression (HIV-associated conditions, Acquired immune deficiency syndrome and death) over time
• Incidence of treatment-emergent genotypic resistance to DTG and 3TC or TDF/FTC in subjects meeting confirmed virologic withdrawal criteria [ Time Frame: Up to Week 148 and then every 12 week post Week 148 (assessed Upto a maximum of 3.5 years) ]
  Viral genotype for both Baseline samples and from samples collected at the time of meeting a virologic withdrawal criterion may be analysed
• Number of subjects with adverse events and serious adverse events over time [ Time Frame: Up to end of study (Approximately 7 years) ]
  Serious adverse event (SAE) is any untoward medical occurrence that, at any dose can result in death, or is life threatening or requires hospitalisation or prolongation of existing hospitalization or results in disability/incapacity or is a congenital anomaly/birth defect or is associated with liver injury and impaired liver function. An adverse event (AE) can be any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product.
• Incidence of treatment-emergent phenotypic resistance to DTG and 3TC or TDF/FTC in subjects meeting confirmed virologic withdrawal criteria [ Time Frame: Up to end of study (Approximately 7 years) ]
  Viral phenotype for both Baseline samples and from samples collected at the time of meeting a virologic withdrawal criterion may be analysed
• Number of subjects with adverse events (AEs), severity of AEs and treatment discontinuations due to AEs over time [ Time Frame: Up to end of study (Approximately 7 years)Baseline and up to Week 144 ]
  Safety and tolerability of DTG + 3TC will be compared to DTG + TDF/FTC over time. An AE is any untoward medical occurrence in a patient or clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.
• Change from Baseline in renal biomarkers [ Time Frame: Baseline (Day 1), Weeks 24, 48, 96 and 144 ]
  Safety will be assessed in terms of biomarkers. Blood and urine samples will be collected for renal biomarker assessments.
• Change from Baseline in bone biomarkers [ Time Frame: Baseline (Day 1), Weeks 24, 48, 96 and 144 ]
  Safety will be assessed in terms of biomarkers. Blood samples will be collected for bone biomarker assessments
• Change from Baseline in fasting lipids [ Time Frame: Baseline (Day 1), Weeks 24, 48, 96 and 144 ]
  Samples for lipid measurements will be obtained in a fasted state. Effects of DTG + 3TC on fasting lipids will be compared to DTG + TDF/FTC.
• Number of subjects with Grade 2 or greater laboratory abnormalities in fasting low density lipoprotein cholesterol over time [ Time Frame: Weeks 24, 48, 96 and 144 ]
  Samples for lipid measurements will be obtained in a fasted state. Grade 2 or 3 low density lipoprotein cholesterol (as per Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events).
• Percentage of subjects with plasma HIV 1 RNA <50 c/mL by subgroups based on age, gender, Baseline CD4+ cell count [ Time Frame: Weeks 24, 48, 96 and 144 ]
  Impact of age, gender, Baseline CD4+ cell count on antiviral activity of DTG + 3TC compared to DTG + TDF/FTC
• Change from Baseline in CD4+ cell count by patient subgroups based on age, gender, Baseline CD4+ cell count [ Time Frame: Baseline (Day 1), Weeks 24, 48, 96 and 144 ]
  Impact of age, gender, Baseline CD4+ cell count on immunological activity of DTG + 3TC compared to DTG + TDF/FTC
• Change from Baseline in health related quality of life [ Time Frame: Baseline (Day 1), Weeks 4, 24, 48, 96 and 144 ]
  The European quality of life 5 dimensions 5 levels (EQ-5D-5L), is a self-reported scale that provides a profile of patient function (including mobility, self care, usual activities, pain/discomfort, and anxiety/depression) and a global health state rating.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: An Efficacy, Safety, and Tolerability Study Comparing Dolutegravir Plus Lamivudine With Dolutegravir Plus Tenofovir/Emtricitabine in Treatment naïve HIV Infected Subjects (Gemini 1)
• Official Title: A Phase III, Randomised, Double Blind, Multicentre, Parallel Group, Non Inferiority Study Evaluating the Efficacy, Safety, and Tolerability of Dolutegravir Plus Lamivudine Compared to Dolutegravir Plus Tenofovir/Emtricitabine in Human Immunodeficiency Virus 1 Infected Treatment naïve Adults
• Brief Summary: This study will compare safety, efficacy, and tolerability of a two drug regimen of dolutegravir (DTG) plus (+) lamivudine (3TC) administered once daily with DTG plus two nucleoside reverse transcriptase inhibitors (Tenofovir [TDF]/Emtricitabine [FTC] fixed dose combination [FDC]) administered once daily in human immunodeficiency virus (HIV) 1 infected adult subjects that have not previously received antiretroviral therapy. The study is designed to demonstrate the non-inferior antiviral activity of DTG plus 3TC regimen to that of DTG plus TDF/FTC FDC and will characterise the long term antiviral activity, tolerability and safety of DTG plus 3TC through Week 148. Approximately, 700 subjects will be randomised 1:1 to receive DTG + 3TC or DTG + TDF/FTC FDC. Subjects will be stratified by screening HIV 1 ribonucleotide nucleic acid (RNA) levels and by screening CD4+ (cluster of differentiation 4) cell count.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment

Condition

• Infection, Human Immunodeficiency Virus
• HIV Infections

Intervention

• Drug: Dolutegravir (DTG)
  DTG is available as 50 mg white, round, biconvex, film coated tablet debossed on one side with 'SV 572' and on the other side with '50'. The tablets are packaged into high density polyethylene (HDPE) bottles with induction seals and child resistant closures. Each 45 ml bottle contains 30 tablets and a desiccant. DTG 50 mg tablet will be orally administered once daily with or without food upto 148 weeks.
• Drug: Lamivudine (3TC)
  Lamivudine is available as swedish orange, 'AA' sized elongated double blind HPMC capsules containing 300 mg lamivudine to visually match overencapsulated TDF/FTC FDC tablet. The capsules are packaged into HDPE bottles with induction seals and child resistant closures. Each 150 mL bottle contains 30 capsules and a desiccant. Overencapsulated 3TC 300 mg tablet will be orally administered once daily with or without food upto 96 weeks. From Week 96 to Week 148, lamivudine will be dispensed as 300 mg white, diamond shaped, scored, film coated tablets debossed with 'GX CJ7' on both sides, packed in over labelled HDPE bottles with child-resistant closures each containing 30 tablets.
• Drug: Tenofovir disoproxil fumarate/Emtricitabine (TDF/FTC FDC)
  Tenofovir disoproxil fumarate and Emtricitabine are available as swedish orange, 'AA' sized elongated double blind HPMC capsules containing 300 mg TDF and 200 mg FTC to visually match overencapsulated 3TC tablet. The capsules are packaged into HDPE bottles with induction seals and child resistant closures. Each 150 mL bottle contains 30 capsules and a desiccant. Overencapsulated tenofovir disoproxil fumarate/emtricitabine tablet will be orally administered once daily with or without food upto 96 weeks. From Week 96 to Week 148, tenofovir disoproxil fumarate/emtricitabine will be dispensed as 300/200 mg white, blue, capsule shaped, film coated tablets debossed with 'GILEAD' on one side and '701' on another side, packed in overlabelled HDPE bottles with polypropylene childresistant closures each containing 30 tablets and a desiccant.

Study Arms

• Experimental: DTG + 3TC (50 mg+300 mg)
  Eligible subjects will receive one 50 mg tablet of DTG plus one overencapsulated 300 mg 3TC tablet orally once daily upto 96 weeks; thereafter will receive DTG plus 3TC tablet upto Week 148 and will continue to receive this schedule until (i) DTG and 3TC are both locally approved for use as part of a dual regimen, and the single entities of DTG and 3TC are available to patients (e.g. through public health services), or (ii) the DTG/3TC FDC tablet, if required by local regulations, is available, , or (iii) the subject no longer derives clinical benefit, or (iv) the subject meets a protocol defined reason for discontinuation, or (v) development of the DTG plus 3TC dual regimen is terminated.
  Interventions:

  • Drug: Dolutegravir (DTG)
  • Drug: Lamivudine (3TC)
• Active Comparator: DTG + TDF/FTC FDC (50 mg+300/200 mg)
  Eligible subjects will receive one 50 mg tablet of DTG plus one overencapsulated TDF/ FTC FDC (300/200 mg) tablet orally once daily upto 96 weeks; thereafter will receive DTG plus TDF/FTC FDC tablets upto Week 148 (open-label randomised phase).
  Interventions:

  • Drug: Dolutegravir (DTG)
  • Drug: Tenofovir disoproxil fumarate/Emtricitabine (TDF/FTC FDC)

• Publications *: Cahn P, Madero JS, Arribas JR, Antinori A, Ortiz R, Clarke AE, Hung CC, Rockstroh JK, Girard PM, Sievers J, Man C, Currie A, Underwood M, Tenorio AR, Pappa K, Wynne B, Fettiplace A, Gartland M, Aboud M, Smith K; GEMINI Study Team. Dolutegravir plus lamivudine versus dolutegravir plus tenofovir disoproxil fumarate and emtricitabine in antiretroviral-naive adults with HIV-1 infection (GEMINI-1 and GEMINI-2): week 48 results from two multicentre, double-blind, randomised, non-inferiority, phase 3 trials. Lancet. 2019 Jan 12;393(10167):143-155. doi: 10.1016/S0140-6736(18)32462-0. Epub 2018 Nov 9. Erratum in: Lancet. 2018 Nov 28;:.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: April 16, 2018): 719
• Original Estimated Enrollment (submitted: July 8, 2016): 700
• Estimated Study Completion Date: March 4, 2024
• Actual Primary Completion Date: March 29, 2018 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Must be an HIV 1 infected adult >=18 years of age (or older, if required by local regulations) at the time of signing the informed consent

• An eligible female subject should not be pregnant (as confirmed by a negative serum human chorionic gonadotrophin (hCG) test at Screening and negative urine test at Baseline), not lactating, and at least one of the following conditions applies

  • Non reproductive premenopausal women are those that have undergone documented tubal ligation or documented hysteroscopic tubal occlusion procedure with follow up confirmation of bilateral tubal occlusion or documented bilateral oophorectomy or hysterectomy
  • Non reproductive premenopausal women are those with 12 months of spontaneous amenorrhea and >=45 years of age
  • Women with reproductive potential agree to follow one of the protocol-defined methods for avoiding pregnancy
• Should have screening plasma HIV 1 RNA levels of 1000 c/mL to <=100,000 c/mL. If an independent review of accumulated data from other clinical trials investigating the DTG plus 3TC dual regimen is supportive of the DTG plus 3TC treatment regimen, enrolment will be opened to subjects with Screening plasma HIV 1 RNA of 1000 c/mL to <=500,000 c/mL
• Subject should be antiretroviral naïve (defined as <=10 days of prior therapy with any antiretroviral agent following a diagnosis of HIV 1 infection). Subjects who received HIV post exposure prophylaxis (PEP) or pre exposure prophylaxis (PrEP) in the past are allowed as long as the last PEP/PrEP dose was >1 year from HIV diagnosis or there is documented HIV seronegativity between the last prophylactic dose and the date of HIV diagnosis
• Subject or the subject's legal representative capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the consent form and the protocol
• Subjects enrolled in France: a subject will be eligible for inclusion in this study only if either affiliated to or a beneficiary of a social security category

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 (CDC, 2014), except cutaneous Kaposi's sarcoma not requiring systemic therapy and historical or current CD4 cell counts less than 200 cells/mm^3
• Subjects 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 or HBV surface antibody (anti-HBs or HBsAb) based on:

Subjects positive for HBV surface antigen (HBsAg) at screening will be excluded Subjects negative for HBV core antibody (anti HBs) but positive for anti HBc (negative HBsAg status) and positive for HBV deoxyribose nucleic acid (DNA) will be excluded; however, subjects positive for anti HBc (negative HBsAg status) and positive for anti HBs (past and/or current evidence) are immune to HBV and will not be excluded

• Anticipated need for any hepatitis B virus (HCV) therapy during the first 48 weeks of the study and for HCV therapy based on interferon or any drugs that have a potential for adverse drug:drug interactions with study treatment throughout the entire study period
• Untreated syphilis infection positive RPR at Screening without clear documentation of treatment. Subjects who are at least 14 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; other localised malignancies require agreement between the investigator and the Study Medical Monitor for inclusion of the subject
• Subjects who in the Investigator's judgment, poses a significant suicidality risk. Recent history of suicidal behaviour and/or suicidal ideation may be considered as evidence of serious suicide risk
• Treatment with an HIV 1 immunotherapeutic vaccine within 90 days of Screening

• Treatment with any of the following agents within 28 days of Screening:

  • Radiation therapy,
  • Cytotoxic chemotherapeutic agents,
  • Any systemic immune suppressant
• Treatment with any agent, except recognised ART as allowed above, with documented activity against HIV 1 in vitro within 28 days of first dose of study treatment
• Exposure to an experimental drug or experimental vaccine within either 28 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 the first dose of study treatment
• Subjects enrolled in France: the subject has participated in any study using an investigational drug during the previous 60 days or 5 half lives, or twice the duration of the biological effect of the experimental drug or vaccine, whichever is longer, prior to screening for the study or the subject will participate simultaneously in another clinical study
• Any evidence of pre existing viral resistance based on the presence of any major resistance associated mutation in the Screening result or, if known, in any historical resistance test result
• Any verified Grade 4 laboratory abnormality. A single repeat test is allowed during the Screening period 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
• Alanine aminotransferase (ALT) >=5 times the upper limit of normal (ULN) or ALT >=3xULN and bilirubin >=1.5xULN (with >35% direct bilirubin)
• Creatinine clearance of <50 mL/min per 1.73 m^2 via the chronic kidney disease epidemiology collaboration (CKD EPI) method

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Argentina, Australia, Belgium, Canada, France, Germany, Italy, Korea, Republic of, Mexico, Netherlands, Portugal, Romania, Russian Federation, South Africa, Spain, Taiwan, United Kingdom, United States

Administrative Information

• NCT Number: NCT02831673
• Other Study ID Numbers: 204861; 2015-004418-95 ( EudraCT Number )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: ViiV Healthcare
• Study Sponsor: ViiV Healthcare

Collaborators

• PPD
• GlaxoSmithKline

Investigators

• Study Director: GSK Clinical Trials; ViiV Healthcare

• PRS Account: ViiV Healthcare
• Verification Date: December 2020