Comparative Efficacy and Safety Study of Dolutegravir and Lopinavir/Ritonavir in Second-line Treatment

A Phase 3b, Randomized, Open-label Study of the Antiviral Activity and Safety of Dolutegravir Compared to Lopinavir/Ritonavir Both Administered With Dual Nucleoside Reverse Transcriptase Inhibitor Therapy in HIV-1 Infected Adult Subjects With Treatment Failure on First Line Therapy

For treatment of human immunodeficiency virus type 1(HIV-1), publicly funded programmes tend to follow World Health Organization (WHO) guidelines to use a non-nucleoside reverse transcriptase inhibitor (NNRTI) combined with two nucleoside reverse transcriptase inhibitors (NRTIs) for first-line antiretroviral therapy (ART); however, there is a need for further data on the best treatment options for people with HIV-1 who have virological failure with this first-line regimen. The number of patients failing on their first-line regimen is increasing thereby requiring a switch to second-line treatment to reduce accumulation of drug-resistance mutations, disease progression, HIV transmission, and death. WHO guidelines recommend second-line antiretroviral therapy for adults consisting of two NRTIs + a ritonavir-boosted protease inhibitor (PI); atazanavir (ATV) plus ritonavir (RTV) or lopinavir (LPV)/RTV are the preferred boosted PI options. This study is conducted to demonstrate non-inferior antiviral activity at 48 weeks of a dolutegravir (DTG) containing regimen compared to a WHO-recommended standard of care regimen for second line treatment, LPV/RTV + two NRTIs, in HIV-1 infected patients failing first line therapy. This study comprises of a Screening Phase (approximately 28 to 42 days), a Randomized Phase (Day 1 to Week 48 plus a 4-week treatment extension), and a Continuation Phase. Approximately 612 subjects will be randomized 1:1 to receive DTG 50 milligram (mg) once daily or LPV/RTV (800/200 mg once daily or 400/100 mg twice daily, in accordance with investigator decision and local label), each added to an investigator selected background regimen of two NRTIs at least one of which needs to be fully active based on viral resistance testing at Screening. Subjects randomized to the LPV/RTV arm will either (i) continue receiving LPV/RTV and complete the study after the 4-week treatment extension at Week 52, or (ii) switch to the DTG arm prior to study completion at Week 52 and continue to have access to DTG in the Continuation Phase. Subjects randomized to receive DTG who successfully complete 52 weeks of treatment and subjects originally randomized to receive LPV/RTV but switched to DTG prior to Week 52 will continue to have access to DTG until it is either locally approved and commercial supplies are available to patients or the patient no longer derives clinical benefit, or the patient meets a protocol-defined reason for discontinuation.

Study Overview

• Status: Completed
• Conditions: HIV Infections
• Intervention / Treatment: Drug: DTG; Drug: Two NRTIs; Drug: LPV/RTV

• Study Type: Interventional
• Enrollment (Actual): 627
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina, 1141
    • GSK Investigational Site
  • Buenos Aires, Argentina, C1221ADC
    • GSK Investigational Site
  • Ciudad Autónoma de Buenos Aires, Argentina, C1426ABP
    • GSK Investigational Site
  • Córdoba, Argentina, 5000
    • GSK Investigational Site
  • Buenos Aires
    • Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina, C1405CKC
      • GSK Investigational Site
    • Ciudad de Buenos Aires, Buenos Aires, Argentina, C1202ABB
      • GSK Investigational Site
  • Santa Fe
    • Rosario, Santa Fe, Argentina, 2000
      • GSK Investigational Site
• Brazil
  • Rio de Janeiro, Brazil, 21045900
    • GSK Investigational Site
  • São Paulo, Brazil, 04121-000
    • GSK Investigational Site
  • Bahía
    • Salvador, Bahía, Brazil, 40110-010
      • GSK Investigational Site
  • São Paulo
    • Sao Paulo, São Paulo, Brazil, 01246-090
      • GSK Investigational Site
• Chile
  • Santiago, Chile, 8360159
    • GSK Investigational Site
  • Región Metro De Santiago
    • Puente Alto - Santiago, Región Metro De Santiago, Chile, 8207257
      • GSK Investigational Site
    • Santiago, Región Metro De Santiago, Chile, 8330074
      • GSK Investigational Site
    • Santiago, Región Metro De Santiago, Chile, 8900088
      • GSK Investigational Site
• China
  • Beijing, China, 100015
    • GSK Investigational Site
  • Beijing, China, 100069
    • GSK Investigational Site
  • Shanghai, China, 201508
    • GSK Investigational Site
  • Guangdong
    • Guangzhou, Guangdong, China, 510060
      • GSK Investigational Site
• Colombia
  • Bogota, Colombia, 5600520
    • GSK Investigational Site
  • Bogota, Colombia, 111311
    • GSK Investigational Site
• Kenya
  • Nairobi, Kenya, 00100
    • GSK Investigational Site
• Mexico
  • Distrito Federal, Mexico, 06470
    • GSK Investigational Site
  • Mexico, Mexico, 14000
    • GSK Investigational Site
  • Mexico City, Mexico, 03720
    • GSK Investigational Site
  • Jalisco
    • Guadalajara, Jalisco, Mexico, 44280
      • GSK Investigational Site
• Peru
  • Callao, Peru, Callao 02
    • GSK Investigational Site
  • Lima, Peru, 1
    • GSK Investigational Site
  • Lima, Peru, Lima 31
    • GSK Investigational Site
  • Lima, Peru, 32
    • GSK Investigational Site
• Romania
  • Bucharest, Romania, 021105
    • GSK Investigational Site
  • Bucharest, Romania, 030303
    • GSK Investigational Site
  • Cluj-Napoca, Romania, 400348
    • GSK Investigational Site
  • Constanta, Romania, 900708
    • GSK Investigational Site
  • Targu Mures, Romania, 540394
    • GSK Investigational Site
• Russian Federation
  • Barnaul, Russian Federation, 656010
    • GSK Investigational Site
  • Ekaterinburg, Russian Federation, 620149
    • GSK Investigational Site
  • Kazan, Russian Federation, 420061
    • GSK Investigational Site
  • Kemerovo, Russian Federation, 650056
    • GSK Investigational Site
  • Krasnodar, Russian Federation, 350015
    • GSK Investigational Site
  • Moscow, Russian Federation, 129110
    • GSK Investigational Site
  • Moscow, Russian Federation, 105275
    • GSK Investigational Site
  • Smolensk, Russian Federation, 214006
    • GSK Investigational Site
  • St. Petersburg, Russian Federation, 190103
    • GSK Investigational Site
  • Toliyatti, Russian Federation, 445846
    • GSK Investigational Site
• South Africa
  • Bloemfontein, South Africa, 9301
    • GSK Investigational Site
  • Durban, South Africa, 4001
    • GSK Investigational Site
  • Observatory, Cape Town, South Africa, 7925
    • GSK Investigational Site
  • Westdene, South Africa, 2092
    • GSK Investigational Site
  • Gauteng
    • Soweto, Gauteng, South Africa, 2013
      • GSK Investigational Site
• Thailand
  • Bangkok, Thailand, 10330
    • GSK Investigational Site
  • Chiang Mai, Thailand, 50200
    • GSK Investigational Site
  • Khon Kaen, Thailand, 40002
    • GSK Investigational Site
  • Nonthaburi, Thailand, 11000
    • GSK Investigational Site
  • Ratchatewi, Thailand, 10400
    • GSK Investigational Site
• Ukraine
  • Kyiv, Ukraine, 03115
    • GSK Investigational Site
  • Odessa, Ukraine, 65031
    • GSK Investigational Site
  • Vinnytsia, Ukraine, 21021
    • GSK Investigational Site
  • Zaporizhzhya, Ukraine, 69006
    • GSK Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• HIV-1 infected subjects >=18 years of age.
• A female subject may be eligible to enter and participate in the study if she:

is of non-childbearing potential defined as either post-menopausal (12 months of spontaneous amenorrhea and >=45 years of age) or physically incapable of becoming pregnant with documented tubal ligation, hysterectomy, or bilateral oophorectomy or, is of child-bearing potential, with a negative pregnancy test at both Screening and Day 1 and agrees to use one of the protocol-defined methods of contraception to avoid pregnancy throughout the study and for at least 2 weeks after discontinuation of all study medication.

• HIV-1 infection as documented by HIV-1 RNA >=400 c/mL at Screening.
• Subject has been on a first-line treatment regimen consisting of an NNRTI plus two NRTIs for at least 6 months and is currently experiencing virologic failure to this first-line regimen defined as two consecutive (>=7 days apart) HIV-1 RNA results of >=400 c/mL.
• Subjects must receive at least one fully active agent within the dual-NRTI background regimen for second line treatment. Fully active is defined by the Screening genotypic resistance report of the central laboratory (or a laboratory contracted by the central laboratory) showing no evidence of full or of partial resistance for a given NRTI which will be taken on study.
• Subject is PI-naïve and Integrase inhibitor (INI)-naïve, defined as no prior or current exposure to any PI or INI.
• Subject or the subject's legal representative is willing and able to understand and provide signed and dated written informed consent prior to screening.

Exclusion Criteria:

• Women who are breastfeeding.
• Any evidence of an active Centers for Disease Control and Prevention (CDC) Category C disease Exceptions include cutaneous Kaposi's sarcoma not requiring systemic therapy and historic or current CD4+ cell levels <200 cells per cubic millimeter
• 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).
• Anticipated need for hepatitis C virus (HCV) therapy during the Randomized Phase of the study.
• 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 intraepithelial neoplasia; other localized 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 behavior 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, systemically administered immunomodulators.
• Treatment with any agent, other than licensed ART as allowed above with documented activity against HIV-1 in vitro/vivo within 28 days of first dose of IP. The exception is use of entecavir, in appropriate clinical situations, for treatment of hepatitis B [e.g. prior intolerance to Tenofovir (TDF), viral resistance to lamivudine (3TC) / Emtricitabine (FTC)] after discussion and agreement between the investigator and the medical monitor.
• 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 IP.
• Any evidence of primary viral resistance to PIs or INIs based on the presence of any major resistance-associated mutation.
• The subject's virus does not yield results using genotype at Screening (assay data is essential for eligibility determination).
• Any verified Grade 4 laboratory abnormality, with the exception of Grade 4 triglycerides. 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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: DTG arm; Subjects will receive one oral tablet of 50 mg DTG once daily plus two NRTIs selected by the investigator	Drug: DTG; DTG is supplied as 50 mg tablets; Drug: Two NRTIs; Investigators will choose a dual NRTI background regimen for each subject . In consultation with the medical monitor, 3TC may be added as a third NRTI to a dual-NRTI background regimen in subjects with chronic HBV infection and evidence of HIV resistance to 3TC
Active Comparator: LPV/RTV arm; Subjects will receive four oral tablets of200/50 mg LPV/RTV once daily or two oral tablets of 200/50 mg LPV/RTV twice daily plus two NRTIs selected by the investigator	Drug: Two NRTIs; Investigators will choose a dual NRTI background regimen for each subject . In consultation with the medical monitor, 3TC may be added as a third NRTI to a dual-NRTI background regimen in subjects with chronic HBV infection and evidence of HIV resistance to 3TC; Drug: LPV/RTV; LPV/RTV is supplied as the LPV/RTV oral tablet, which contains 200 mg of LPV and 50 mg of RTV

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Plasma HIV-1 Ribonucleic Acid (RNA) <50 Copies Per Milliliter (c/mL) at Week 48	Percentage of participants with plasma HIV 1 RNA <50 c/mL at Week 48 using the Food and Drug Administration (FDA) snapshot algorithm was assessed to demonstrate the non-inferior activity of DTG plus 2 NRTI's compared to LPV/RTV plus 2 NRTI's. Analysis was performed on Intent-to-treat exposed (ITT-E) Population, which comprised of all randomized participants who received at least one dose of study medication. Percentage values are rounded off.	Week 48

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants Without Virologic or Tolerability Failure at Week 24 and Week 48	Virologic or tolerability failure was defined as treatment-related discontinuation (meeting confirmed virologic withdrawal criteria, treatment-related adverse event, safety stopping criteria, and lack of efficacy). Percentage of participants without virologic failure by Week 24 and Week 48 have been presented. Participants who did not met the protocol defined confirmed virologic withdrawal criteria and are ongoing in the study, or who had discontinued for non-treatment related reasons were censored.	Week 24 and Week 48
Time to Viral Suppression at Week 48	Viral suppression was defined as HIV-1 RNA <50 c/mL. Time to viral suppression was analyzed and median and interquartile range has been presented.	Week 48
Percentage of Participants With Plasma HIV-1 RNA <50 c/mL at Week 24	Percentage of participants with plasma HIV 1 RNA <50 c/mL at Week 24 using the FDA snapshot algorithm was assessed to demonstrate the non-inferior activity of DTG plus 2 NRTI's compared to LPV/RTV plus 2 NRTI's. Percentage values are rounded off.	Week 24
Percentage of Participants With Plasma HIV-1 RNA <400 c/mL at Weeks 24 and 48	Percentage of participants with plasma HIV 1 RNA <400 c/mL at Week 24 and 48 using the FDA snapshot algorithm were evaluated. Percentage values are rounded off.	Week 24 and Week 48
Change From Baseline in Helper-inducer T-lymphocyte Having Surface Antigen Cluster of Differentiation (CD4+) Cell Count at Weeks 24 and 48	Blood was collected and CD4+ cell count assessment was carried out at indicated time points to evaluate the immunological activity of DTG compared to LPV/RTV. Baseline was defined as the latest pre-dose assessment value. Change from Baseline was calculated as post-dose visit value minus Baseline value.	Baseline (Day 1, Pre-dose), Week 24 and Week 48
Number of Participants With Disease Progression-Randomized + Continuation Phase	Disease progression included HIV-associated conditions, acquired immune deficiency syndrome (AIDS) and death. Number of participants with disease progression to Centers for Disease Control and Prevention (CDC) class C or death have been presented.	Up to Week 348
Number of Participants With Treatment-emergent Genotypic Resistance-Randomized Phase	Number of participants, who met confirmed virologic withdrawal (CVW) criteria with paired Baseline and time of CVW resistance data with treatment emergent genotypic resistance to Integrase strand transfer inhibitor (INSTI), NRTI, Protease inhibitor (PI) were summarized. Viral Genotypic Population comprised of all participants in the ITT-E population with available On-treatment genotypic resistance data at the time confirmed virologic withdrawal criterion was met during Randomized Phase.	Up to Week 52
Number of Participants With Treatment-emergent Genotypic Resistance-Continuation Phase	Number of participants, who met confirmed virologic withdrawal criteria with paired Baseline and time of CVW resistance data, with treatment emergent genotypic resistance to Integrase strand transfer inhibitor (INSTI), NRTI, Protease inhibitor (PI) were summarized. Analysis was performed on Viral Genotypic Continuation Population which comprised all participants in the ITT-E- Continuation Population with available on-treatment genotypic resistance data in the Continuation Phase.	Up to Week 295
Number of Participants With Fold Change in Treatment-emergent Phenotypic Resistance From Baseline-Randomized Phase	Number of participants with fold change in treatment-emergent phenotypic resistance from Baseline to DTG, LPV/RTV was counted to assess the development of viral resistance. Baseline was defined as the latest pre-dose assessment value. Change from Baseline was calculated as post-dose visit value minus Baseline value. Change in grade 0 to >2 from Baseline is presented. Analysis was performed on viral phenotypic Population, which comprised of all participants in the ITT-E Population with available On-treatment phenotypic resistance data at the time confirmed virologic withdrawal criterion is met during Randomized Phase.	Baseline (Day 1, Pre-dose) and up to Week 52
Number of Participants With Fold Change in Treatment-emergent Phenotypic Resistance From Baseline-Continuation Phase	Number of participants with fold change in treatment-emergent phenotypic resistance from Baseline to DTG was counted to assess the development of viral resistance. Baseline was defined as the latest pre-dose assessment value. Change from Baseline was calculated as post-dose visit value minus Baseline value. Change in grade 0 to >2 from Baseline is presented. Analysis was performed on Viral Phenotypic Continuation Population which comprises all participants in the ITT-E- Continuation Population with available on-treatment phenotypic resistance data in the Continuation Phase.	Baseline (Day 1, Pre-dose) and up to Week 295
Number of Participants With Non-serious Adverse Events (AEs) With >=2% Frequency Threshold and Serious Adverse Events (SAEs)-Randomized Phase	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. SAE is defined as any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, or is a congenital anomaly/birth defect, other situations as per medical or scientific judgment and is associated with liver injury or impaired liver function. Safety Population was used which comprised of all participants who received at least one dose of study treatment. Adverse events which were not Serious were considered as Non-Serious adverse events.	Up to Week 52
Number of Participants With Non-serious AEs With >=2% Frequency Threshold and SAEs-Continuation Phase	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. SAE is defined as any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, or is a congenital anomaly/birth defect, other situations as per medical or scientific judgment and is associated with liver injury or impaired liver function. Adverse events which were not Serious were considered as non-serious AEs.	Up to Week 295
Number of Participants With Non-serious AEs With >=2% Frequency Threshold and SAEs-Randomized + Continuation Phase	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. SAE is defined as any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, or is a congenital anomaly/birth defect, other situations as per medical or scientific judgment and is associated with liver injury or impaired liver function. Adverse events which were not Serious were considered as non-serious AEs.	Up to Week 348
Change From Baseline in Glucose, Chloride, Carbon-di-oxide (CO2), Potassium, Phosphate, Sodium, Urea, Cholesterol, High Density Lipoprotein (HDL) Cholesterol, Low Density Lipoprotein (LDL) Cholesterol and Triglycerides	Blood samples were collected from participants to evaluate clinical chemistry parameters including glucose, chloride, carbon-di-oxide (CO2), potassium, phosphate, sodium, urea, cholesterol, high density lipoprotein (HDL) cholesterol, low density lipoprotein (LDL) cholesterol and triglycerides. Lipid parameters were evaluated in fasting condition. Change from Baseline in clinical chemistry parameters at Weeks 4, 8, 16, 24, 36, 48, 52 are presented. Baseline was defined as the latest pre-dose assessment value. Change from Baseline was calculated as post-Baseline visit values minus Baseline value.	Baseline (Day 1, Pre-dose), Week 4, Week 8, Week 16, Week 24, Week 36, Week 48 and Week 52
Change From Baseline in Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Creatine Kinase Values	Blood samples were collected from participants to evaluate clinical chemistry parameters including ALP, ALT, AST and creatine kinase. Change from Baseline in clinical chemistry parameters at Weeks 4, 8, 16, 24, 36, 48, 52 are presented. Baseline was defined as the latest pre-dose assessment value. Change from Baseline was calculated as post-Baseline visit values minus Baseline value.	Baseline (Day 1, Pre-dose), Week 4, Week 8, Week 16, Week 24, Week 36, Week 48 and Week 52
Change From Baseline in Albumin Values	Blood samples were collected from participants to evaluate clinical chemistry parameter including albumin. Change from Baseline in clinical chemistry parameters at Weeks 4, 8, 16, 24, 36, 48, 52 are presented. Baseline was defined as the latest pre-dose assessment value. Change from Baseline was calculated as post-Baseline visit values minus Baseline value.	Baseline (Day 1, Pre-dose), Week 4, Week 8, Week 16, Week 24, Week 36, Week 48 and Week 52
Change From Baseline in Creatinine and Bilirubin Values	Blood samples were collected from participants to evaluate clinical chemistry parameters including creatinine and bilirubin. Change from Baseline in clinical chemistry parameters at Weeks 4, 8, 16, 24, 36, 48, 52 are presented. Baseline was defined as the latest pre-dose assessment value. Change from Baseline was calculated as post-Baseline visit values minus Baseline value.	Baseline (Day 1, Pre-dose), Week 4, Week 8, Week 16, Week 24, Week 36, Week 48 and Week 52
Change From Baseline in Lipase Values	Blood samples were collected from participants to evaluate clinical chemistry parameter including lipase. Change from Baseline in lipase at Weeks 4, 8, 16, 24, 36, 48, 52 are presented. Baseline was defined as the latest pre-dose assessment value. Change from Baseline was calculated as post-Baseline visit values minus Baseline value.	Baseline (Day 1, Pre-dose), Week 4, Week 8, Week 16, Week 24, Week 36, Week 48 and Week 52
Number of Participants With Clinical Chemistry Toxicities -Randomized Phase	Number of participants with clinical chemistry toxicities has been presented. Toxicities were based on the Division of AIDS (DAIDS) grading system. Grade 1=Mild, Grade 2= Moderate, Grade 3= Severe, Grade 4= Potentially life-threatening. Higher the grade, more severe the symptoms. Lipids and glucose parameters were summarized on fasting data. Data has been reported for clinical chemistry parameters including serum glucose, ALT, Albumin, ALP, AST, Bilirubin, CO2, Creatine kinase, LDL cholesterol calculation, LDL cholesterol direct, Lipase, Phosphate, Potassium, Sodium, Cholesterol, Creatinine and Serum Triglycerides.	Up to Week 52
Number of Participants With Clinical Chemistry Toxicities-Continuation Phase	Number of participants with clinical chemistry toxicities has been presented. Toxicities were based on the Division of AIDS (DAIDS) grading system. Grade 1=Mild, Grade 2= Moderate, Grade 3= Severe, Grade 4= Potentially life-threatening. Higher the grade, more severe the symptoms. Lipids and glucose parameters were summarized on fasting data. Data has been reported for clinical chemistry parameters including serum glucose, ALT, Albumin, ALP, AST, Bilirubin, CO2, Creatine kinase, LDL cholesterol calculation, LDL cholesterol direct, Lipase, Phosphate, Potassium, Sodium, Cholesterol, Creatinine and Serum Triglycerides.	Up to Week 295
Change From Baseline in Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils, Platelets and Leukocytes	Blood samples were collected from participants to evaluate clinical hematology parameters including basophils, eosinophils, lymphocytes, monocytes, neutrophils, platelets and leukocytes. Change from Baseline in clinical hematology parameters at Weeks 4, 8, 16, 24, 36, 48, 52 are presented. Baseline was defined as the latest pre-dose assessment value. Change from Baseline was calculated as post-Baseline visit values minus Baseline value.	Baseline (Day 1, Pre-dose), Week 4, Week 8, Week 16, Week 24, Week 36, Week 48 and Week 52
Change From Baseline in Hematocrit Values	Blood samples were collected from participants to evaluate clinical hematology parameter including hematocrit. Change from Baseline in hematocrit values at Weeks 4, 8, 16, 24, 36, 48, 52 are presented. Baseline was defined as the latest pre-dose assessment value. Change from Baseline was calculated as post-Baseline visit values minus Baseline value.	Baseline (Day 1, Pre-dose), Week 4, Week 8, Week 16, Week 24, Week 36, Week 48 and and Week 52
Change From Baseline in Hemoglobin Values	Blood samples were collected from participants to evaluate clinical hematology parameter including hemoglobin. Change from Baseline in hemoglobin values at Weeks 4, 8, 16, 24, 36, 48, 52 are presented. Baseline was defined as the latest pre-dose assessment value. Change from Baseline was calculated as post-Baseline visit values minus Baseline value.	Baseline (Day 1, Pre-dose), Week 4, Week 8, Week 16, Week 24, Week 36, Week 48 and Week 52
Change From Baseline in Mean Corpuscular Volume (MCV)	Blood samples were collected from participants to evaluate clinical hematology parameter including MCV. Change from Baseline in MCV values at Weeks 4, 8, 16, 24, 36, 48, 52 are presented. Baseline was defined as the latest pre-dose assessment value. Change from Baseline was calculated as post-Baseline visit values minus Baseline value.	Baseline (Day 1, Pre-dose), Week 4, Week 8, Week 16, Week 24, Week 36, Week 48 and and Week 52
Change From Baseline in Erythrocyte Values	Blood samples were collected from participants to evaluate clinical hematology parameter including erythrocyte. Change from Baseline in erythrocyte values at Weeks 4, 8, 16, 24, 36, 48, 52 are presented. Baseline was defined as the latest pre-dose assessment value. Change from Baseline was calculated as post-Baseline visit values minus Baseline value.	Baseline (Day 1, Pre-dose), Week 4, Week 8, Week 16, Week 24, Week 36, Week 48 and up to Week 52
Number of Participants With Hematology Toxicities -Randomized Phase	Number of participants with hematology toxicities has been presented. Toxicities were based on the Division of AIDS (DAIDS) grading system. Grade 1=Mild, Grade 2= Moderate, Grade 3= Severe, Grade 4= Potentially life-threatening. Higher the grade, more severe the symptoms. Data has been reported for hematology parameters including Hemoglobin, Leukocytes, Neutrophils and Platelets.	Up to Week 52
Number of Participants With Hematology Toxicities-Continuation Phase	Number of participants with hematology toxicities has been presented. Toxicities were based on the Division of AIDS (DAIDS) grading system. Grade 1=Mild, Grade 2= Moderate, Grade 3= Severe, Grade 4= Potentially life-threatening. Higher the grade, more severe the symptoms. Data has been reported for hematology parameters including Hemoglobin, Leukocytes, Neutrophils and Platelets.	Up to Week 295
Number of Participants Who Discontinued Treatment Due to AEs-Randomized Phase	Number of participants who discontinued study treatment due to AEs or SAEs were summarized.	Up to Week 52
Number of Participants Who Discontinued Treatment Due to AEs-Continuation Phase	Number of participants who discontinued study treatment due to AEs were summarized.	Up to Week 295
Change From Baseline in Fasting LDL Cholesterol at Week 24 and Week 48	Blood samples were collected from participants in fasting state to evaluate LDL cholesterol. Baseline was defined as the latest pre-dose assessment value. Change from Baseline was calculated as post-Baseline visit values minus Baseline value. Analysis was performed using multiple imputation with missing at random assumption. Only participants available at the time of evaluation were analyzed.	Baseline (Day 1, Pre-dose), Week 24 and Week 48
Change From Baseline in Fasting Total Cholesterol/HDL Cholesterol Ratio	Blood samples were collected from participants in fasting state to evaluate total cholesterol/HDL cholesterol ratio. Baseline was defined as the latest pre-dose assessment value. Change from Baseline was calculated as post-Baseline visit values minus Baseline value. Only participants available at the time of evaluation were analyzed. Analysis was performed using multiple imputation with missing at random assumption.	Baseline (Day 1, Pre-dose), Week 24 and Week 48
Number of Participants With Maximum Post-Baseline Emergent Grade 2 or Greater Laboratory Abnormalities in Fasting LDL Cholesterol	Blood samples were collected from participants in fasting state at indicated time-points to evaluate LDL cholesterol. Baseline was defined as the latest pre-dose assessment value. Change from Baseline was calculated as post-Baseline visit values minus Baseline value. Number of participants who experienced maximum grade 2 or greater toxicity post-Baseline in fasting LDL cholesterol was summarized. Participants were graded using the Division of AIDS Table for Grading Severity of Adult and Pediatric Adverse Events. Grade 1=mild; grade 2=moderate; grade 3=severe; grade 4=potentially life-threatening. Higher the grade, more severe the symptoms.	Up to Week 48
Number of Participants With Maximum Post-Baseline Emergent Grade 2 or Greater Drug-related Diarrhea	Number of participants who experienced maximum grade 2 or greater toxicity post-Baseline in drug-related diarrhea was summarized. Baseline was defined as the latest pre-dose assessment value. Change from Baseline was calculated as post-Baseline visit values minus Baseline value. Participants were graded using the Division of AIDS Table for Grading Severity of Adult and Pediatric Adverse Events. Grade 1=mild; grade 2=moderate; grade 3=severe; grade 4=potentially life-threatening. Higher the grade, more severe the symptoms.	Week 24 and Week 48
Change From Baseline in Gastrointestinal Symptom Rating Scale (GSRS) Score	The GSRS is a disease-specific instrument of 15 items combined into five symptom clusters depicting Reflux, Abdominal pain, Indigestion, Diarrhea and Constipation. The scale ranges from 1= no discomfort to 7= very severe discomfort for each symptom cluster. Higher scores show greater severity of symptoms. Baseline was defined as the latest pre-dose assessment value. Change from Baseline was calculated as post-Baseline visit values minus Baseline value. The analysis was performed using Last Observation Carried Forward (LOCF) dataset. In the LOCF dataset, missing values were carried forward from the previous, non-missing available on-treatment assessment.	Baseline (Day 1, Pre-dose), Week 4, Week 24, Week 48
Change From Baseline in Treatment Satisfaction, Using the HIV-Treatment Satisfaction Questionnaire (HIVTSQ) Score	The HIVTSQ is a self-reported scales that measure overall satisfaction with treatment. The score ranges from 0-10. The higher the score, the greater the improvement in treatment satisfaction as compared to the past few weeks. A smaller score represents a decline in treatment satisfaction compared to the past few weeks. Baseline was defined as the latest pre-dose assessment value. Change from Baseline was calculated as post-Baseline visit values minus Baseline value. The analysis was performed using LOCF dataset. In the LOCF dataset, missing values were carried forward from the previous, non-missing available on-treatment assessment.	Baseline (Day 1, Pre-dose), Week 4, Week 24, Week 48
Number of Participants Showing Adherence With Treatment, Using the Morisky 8-Item Medication Adherence Scale (MMAS-8)	Treatment compliance was evaluated through MMAS-8. It is an eight-item self-reported measure of medication-taking behavior. The score ranges from 0-8 where scores of 8 indicate high or near perfect adherence, and scores of less than 6 indicate poor or inadequate adherence on the MMAS-8 scale. Number of participants showing low, medium and high adherence to treatment are presented. Low adherence is a score 0-5.75, medium adherence is a score of 6-7.75 and high adherence is a score of 8. The analysis was performed using LOCF dataset. In the LOCF dataset, missing values were carried forward from the previous, non-missing available on-treatment assessment.	Baseline (Day 1, Pre-dose), Week 4, Week 24 and Week 48

Collaborators and Investigators

• Sponsor: ViiV Healthcare
• Collaborators: GlaxoSmithKline

Publications and helpful links

General Publications

• Aboud M, Kaplan R, Lombaard J, Zhang F, Hidalgo JA, Mamedova E, Losso MH, Chetchotisakd P, Brites C, Sievers J, Brown D, Hopking J, Underwood M, Nascimento MC, Punekar Y, Gartland M, Smith K. Dolutegravir versus ritonavir-boosted lopinavir both with dual nucleoside reverse transcriptase inhibitor therapy in adults with HIV-1 infection in whom first-line therapy has failed (DAWNING): an open-label, non-inferiority, phase 3b trial. Lancet Infect Dis. 2019 Mar;19(3):253-264. doi: 10.1016/S1473-3099(19)30036-2. Epub 2019 Feb 4.
• Underwood M, Horton J, Nangle K, Hopking J, Smith K, Aboud M, Wynne B, Sievers J, Stewart EL, Wang R. Integrase Inhibitor Resistance Mechanisms and Structural Characteristics in Antiretroviral Therapy-Experienced, Integrase Inhibitor-Naive Adults with HIV-1 Infection Treated with Dolutegravir plus Two Nucleoside Reverse Transcriptase Inhibitors in the DAWNING Study. Antimicrob Agents Chemother. 2022 Jan 18;66(1):e0164321. doi: 10.1128/AAC.01643-21. Epub 2021 Oct 25.

Study record dates

Study Major Dates

• Study Start (Actual): December 11, 2014
• Primary Completion (Actual): August 2, 2017
• Study Completion (Actual): February 14, 2022

Study Registration Dates

• First Submitted: August 25, 2014
• First Submitted That Met QC Criteria: August 25, 2014
• First Posted (Estimate): August 28, 2014

Study Record Updates

• Last Update Posted (Actual): March 13, 2023
• Last Update Submitted That Met QC Criteria: February 9, 2023
• Last Verified: January 1, 2023

More Information

Terms related to this study

• Keywords: HIV-1; integrase inhibitor; dolutegravir; lopinavir/ritonavir; non-inferiority; second-line treatment; antiretroviral therapy-experienced
• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immunologic Deficiency Syndromes; Immune System Diseases; HIV Infections
• Other Study ID Numbers: 200304; 2014-001057-17 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Qualified researchers may request access to anonymized individual patient-level data (IPD) and related study documents of the eligible studies via the Data Sharing Portal. Details on ViiV's data sharing criteria can be found at: https://viivhealthcare.com/about-viiv/corporate-ethics-compliance/commitment-to-data-transparency/
• IPD Sharing Time Frame: Anonymized IPD is made available within 6 months of publication of primary, key secondary and safety results for studies in product with approved indication(s) or terminated asset(s) across all indications.
• IPD Sharing Access Criteria: Anonymized IPD is shared with researchers whose proposals are approved by an Independent Review Panel and after a Data Sharing Agreement is in place. Access is provided for an initial period of 12 months but an extension may be granted, when justified, for up to 6 months.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No