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

Primary Purpose

HIV Infections

Status

Completed

Phase

Phase 3

Locations

International

Study Type

Interventional

Intervention

DTG

LPV/RTV

Two NRTIs

About this trial

This is an interventional treatment trial for HIV Infections focused on measuring integrase inhibitor, non-inferiority, dolutegravir, lopinavir/ritonavir, second-line treatment, HIV-1, antiretroviral therapy-experienced

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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)

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

DTG arm

LPV/RTV arm

Arm Description

Subjects will receive one oral tablet of 50 mg DTG once daily plus two NRTIs selected by the investigator

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

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Number of Participants With Clinical Chemistry Toxicities-Continuation Phase

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.

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.

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.

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.

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.

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.

Number of Participants With Hematology Toxicities-Continuation Phase

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.

Number of Participants Who Discontinued Treatment Due to AEs-Continuation Phase

Number of participants who discontinued study treatment due to AEs were summarized.

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.

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.

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.

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.

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.

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.

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.

Full Information

NCT ID

NCT02227238

First Posted

August 25, 2014

Last Updated

February 9, 2023

Sponsor

ViiV Healthcare

Collaborators

GlaxoSmithKline

1. Study Identification

Unique Protocol Identification Number

NCT02227238

Brief Title

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

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

January 2023

Overall Recruitment Status

Completed

Study Start Date

December 11, 2014 (Actual)

Primary Completion Date

August 2, 2017 (Actual)

Study Completion Date

February 14, 2022 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

ViiV Healthcare

Collaborators

GlaxoSmithKline

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

HIV Infections

Keywords

integrase inhibitor, non-inferiority, dolutegravir, lopinavir/ritonavir, second-line treatment, HIV-1, antiretroviral therapy-experienced

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 3

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Randomized

Enrollment

627 (Actual)

8. Arms, Groups, and Interventions

Arm Title

DTG arm

Arm Type

Experimental

Arm Description

Subjects will receive one oral tablet of 50 mg DTG once daily plus two NRTIs selected by the investigator

Arm Title

LPV/RTV arm

Arm Type

Active Comparator

Arm Description

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

Intervention Type

Drug

Intervention Name(s)

DTG

Intervention Description

DTG is supplied as 50 mg tablets

Intervention Type

Drug

Intervention Name(s)

LPV/RTV

Intervention Description

LPV/RTV is supplied as the LPV/RTV oral tablet, which contains 200 mg of LPV and 50 mg of RTV

Intervention Type

Drug

Intervention Name(s)

Two NRTIs

Intervention Description

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

Primary Outcome Measure Information:

Title

Percentage of Participants With Plasma HIV-1 Ribonucleic Acid (RNA) <50 Copies Per Milliliter (c/mL) at Week 48

Description

Time Frame

Week 48

Secondary Outcome Measure Information:

Title

Percentage of Participants With Plasma HIV-1 RNA <50 c/mL at Week 24

Description

Time Frame

Week 24

Title

Percentage of Participants With Plasma HIV-1 RNA <400 c/mL at Weeks 24 and 48

Description

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.

Time Frame

Week 24 and Week 48

Title

Percentage of Participants Without Virologic or Tolerability Failure at Week 24 and Week 48

Description

Time Frame

Week 24 and Week 48

Title

Time to Viral Suppression at Week 48

Description

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.

Time Frame

Week 48

Title

Change From Baseline in Helper-inducer T-lymphocyte Having Surface Antigen Cluster of Differentiation (CD4+) Cell Count at Weeks 24 and 48

Description

Time Frame

Baseline (Day 1, Pre-dose), Week 24 and Week 48

Title

Number of Participants With Disease Progression-Randomized + Continuation Phase

Description

Time Frame

Up to Week 348

Title

Number of Participants With Treatment-emergent Genotypic Resistance-Randomized Phase

Description

Time Frame

Up to Week 52

Title

Number of Participants With Treatment-emergent Genotypic Resistance-Continuation Phase

Description

Time Frame

Up to Week 295

Title

Number of Participants With Fold Change in Treatment-emergent Phenotypic Resistance From Baseline-Randomized Phase

Description

Time Frame

Baseline (Day 1, Pre-dose) and up to Week 52

Title

Number of Participants With Fold Change in Treatment-emergent Phenotypic Resistance From Baseline-Continuation Phase

Description

Time Frame

Baseline (Day 1, Pre-dose) and up to Week 295

Title

Number of Participants With Non-serious Adverse Events (AEs) With >=2% Frequency Threshold and Serious Adverse Events (SAEs)-Randomized Phase

Description

Time Frame

Up to Week 52

Title

Number of Participants With Non-serious AEs With >=2% Frequency Threshold and SAEs-Continuation Phase

Description

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.

Time Frame

Up to Week 295

Title

Number of Participants With Non-serious AEs With >=2% Frequency Threshold and SAEs-Randomized + Continuation Phase

Description

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.

Time Frame

Up to Week 348

Title

Description

Time Frame

Baseline (Day 1, Pre-dose), Week 4, Week 8, Week 16, Week 24, Week 36, Week 48 and Week 52

Title

Change From Baseline in Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Creatine Kinase Values

Description

Time Frame

Baseline (Day 1, Pre-dose), Week 4, Week 8, Week 16, Week 24, Week 36, Week 48 and Week 52

Title

Change From Baseline in Albumin Values

Description

Time Frame

Baseline (Day 1, Pre-dose), Week 4, Week 8, Week 16, Week 24, Week 36, Week 48 and Week 52

Title

Change From Baseline in Creatinine and Bilirubin Values

Description

Time Frame

Baseline (Day 1, Pre-dose), Week 4, Week 8, Week 16, Week 24, Week 36, Week 48 and Week 52

Title

Change From Baseline in Lipase Values

Description

Time Frame

Baseline (Day 1, Pre-dose), Week 4, Week 8, Week 16, Week 24, Week 36, Week 48 and Week 52

Title

Number of Participants With Clinical Chemistry Toxicities -Randomized Phase

Description

Time Frame

Up to Week 52

Title

Number of Participants With Clinical Chemistry Toxicities-Continuation Phase

Description

Time Frame

Up to Week 295

Title

Change From Baseline in Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils, Platelets and Leukocytes

Description

Time Frame

Baseline (Day 1, Pre-dose), Week 4, Week 8, Week 16, Week 24, Week 36, Week 48 and Week 52

Title

Change From Baseline in Hematocrit Values

Description

Time Frame

Baseline (Day 1, Pre-dose), Week 4, Week 8, Week 16, Week 24, Week 36, Week 48 and and Week 52

Title

Change From Baseline in Hemoglobin Values

Description

Time Frame

Baseline (Day 1, Pre-dose), Week 4, Week 8, Week 16, Week 24, Week 36, Week 48 and Week 52

Title

Change From Baseline in Mean Corpuscular Volume (MCV)

Description

Time Frame

Baseline (Day 1, Pre-dose), Week 4, Week 8, Week 16, Week 24, Week 36, Week 48 and and Week 52

Title

Change From Baseline in Erythrocyte Values

Description

Time Frame

Baseline (Day 1, Pre-dose), Week 4, Week 8, Week 16, Week 24, Week 36, Week 48 and up to Week 52

Title

Number of Participants With Hematology Toxicities -Randomized Phase

Description

Time Frame

Up to Week 52

Title

Number of Participants With Hematology Toxicities-Continuation Phase

Description

Time Frame

Up to Week 295

Title

Number of Participants Who Discontinued Treatment Due to AEs-Randomized Phase

Description

Number of participants who discontinued study treatment due to AEs or SAEs were summarized.

Time Frame

Up to Week 52

Title

Number of Participants Who Discontinued Treatment Due to AEs-Continuation Phase

Description

Number of participants who discontinued study treatment due to AEs were summarized.

Time Frame

Up to Week 295

Title

Change From Baseline in Fasting LDL Cholesterol at Week 24 and Week 48

Description

Time Frame

Baseline (Day 1, Pre-dose), Week 24 and Week 48

Title

Change From Baseline in Fasting Total Cholesterol/HDL Cholesterol Ratio

Description

Time Frame

Baseline (Day 1, Pre-dose), Week 24 and Week 48

Title

Number of Participants With Maximum Post-Baseline Emergent Grade 2 or Greater Laboratory Abnormalities in Fasting LDL Cholesterol

Description

Time Frame

Up to Week 48

Title

Number of Participants With Maximum Post-Baseline Emergent Grade 2 or Greater Drug-related Diarrhea

Description

Time Frame

Week 24 and Week 48

Title

Change From Baseline in Gastrointestinal Symptom Rating Scale (GSRS) Score

Description

Time Frame

Baseline (Day 1, Pre-dose), Week 4, Week 24, Week 48

Title

Change From Baseline in Treatment Satisfaction, Using the HIV-Treatment Satisfaction Questionnaire (HIVTSQ) Score

Description

Time Frame

Baseline (Day 1, Pre-dose), Week 4, Week 24, Week 48

Title

Number of Participants Showing Adherence With Treatment, Using the Morisky 8-Item Medication Adherence Scale (MMAS-8)

Description

Time Frame

Baseline (Day 1, Pre-dose), Week 4, Week 24 and Week 48

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

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)

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

GSK Clinical Trials

Organizational Affiliation

ViiV Healthcare

Official's Role

Study Director

Facility Information:

Facility Name

GSK Investigational Site

City

Ciudad Autónoma de Buenos Aires

State/Province

Buenos Aires

ZIP/Postal Code

C1405CKC

Country

Argentina

Facility Name

GSK Investigational Site

City

Ciudad de Buenos Aires

State/Province

Buenos Aires

ZIP/Postal Code

C1202ABB

Country

Argentina

Facility Name

GSK Investigational Site

City

Rosario

State/Province

Santa Fe

ZIP/Postal Code

2000

Country

Argentina

Facility Name

GSK Investigational Site

City

Buenos Aires

ZIP/Postal Code

1141

Country

Argentina

Facility Name

GSK Investigational Site

City

Buenos Aires

ZIP/Postal Code

C1221ADC

Country

Argentina

Facility Name

GSK Investigational Site

City

Ciudad Autónoma de Buenos Aires

ZIP/Postal Code

C1426ABP

Country

Argentina

Facility Name

GSK Investigational Site

City

Córdoba

ZIP/Postal Code

5000

Country

Argentina

Facility Name

GSK Investigational Site

City

Salvador

State/Province

Bahía

ZIP/Postal Code

40110-010

Country

Brazil

Facility Name

GSK Investigational Site

City

Sao Paulo

State/Province

São Paulo

ZIP/Postal Code

01246-090

Country

Brazil

Facility Name

GSK Investigational Site

City

Rio de Janeiro

ZIP/Postal Code

21045900

Country

Brazil

Facility Name

GSK Investigational Site

City

São Paulo

ZIP/Postal Code

04121-000

Country

Brazil

Facility Name

GSK Investigational Site

City

Puente Alto - Santiago

State/Province

Región Metro De Santiago

ZIP/Postal Code

8207257

Country

Chile

Facility Name

GSK Investigational Site

City

Santiago

State/Province

Región Metro De Santiago

ZIP/Postal Code

8330074

Country

Chile

Facility Name

GSK Investigational Site

City

Santiago

State/Province

Región Metro De Santiago

ZIP/Postal Code

8900088

Country

Chile

Facility Name

GSK Investigational Site

City

Santiago

ZIP/Postal Code

8360159

Country

Chile

Facility Name

GSK Investigational Site

City

Guangzhou

State/Province

Guangdong

ZIP/Postal Code

510060

Country

China

Facility Name

GSK Investigational Site

City

Beijing

ZIP/Postal Code

100015

Country

China

Facility Name

GSK Investigational Site

City

Beijing

ZIP/Postal Code

100069

Country

China

Facility Name

GSK Investigational Site

City

Shanghai

ZIP/Postal Code

201508

Country

China

Facility Name

GSK Investigational Site

City

Bogota

ZIP/Postal Code

111311

Country

Colombia

Facility Name

GSK Investigational Site

City

Bogota

ZIP/Postal Code

5600520

Country

Colombia

Facility Name

GSK Investigational Site

City

Nairobi

ZIP/Postal Code

00100

Country

Kenya

Facility Name

GSK Investigational Site

City

Guadalajara

State/Province

Jalisco

ZIP/Postal Code

44280

Country

Mexico

Facility Name

GSK Investigational Site

City

Distrito Federal

ZIP/Postal Code

06470

Country

Mexico

Facility Name

GSK Investigational Site

City

Mexico City

ZIP/Postal Code

03720

Country

Mexico

Facility Name

GSK Investigational Site

City

Mexico

ZIP/Postal Code

14000

Country

Mexico

Facility Name

GSK Investigational Site

City

Callao

ZIP/Postal Code

Callao 02

Country

Peru

Facility Name

GSK Investigational Site

City

Lima

ZIP/Postal Code

Country

Peru

Facility Name

GSK Investigational Site

City

Lima

ZIP/Postal Code

Country

Peru

Facility Name

GSK Investigational Site

City

Lima

ZIP/Postal Code

Lima 31

Country

Peru

Facility Name

GSK Investigational Site

City

Bucharest

ZIP/Postal Code

021105

Country

Romania

Facility Name

GSK Investigational Site

City

Bucharest

ZIP/Postal Code

030303

Country

Romania

Facility Name

GSK Investigational Site

City

Cluj-Napoca

ZIP/Postal Code

400348

Country

Romania

Facility Name

GSK Investigational Site

City

Constanta

ZIP/Postal Code

900708

Country

Romania

Facility Name

GSK Investigational Site

City

Targu Mures

ZIP/Postal Code

540394

Country

Romania

Facility Name

GSK Investigational Site

City

Barnaul

ZIP/Postal Code

656010

Country

Russian Federation

Facility Name

GSK Investigational Site

City

Ekaterinburg

ZIP/Postal Code

620149

Country

Russian Federation

Facility Name

GSK Investigational Site

City

Kazan

ZIP/Postal Code

420061

Country

Russian Federation

Facility Name

GSK Investigational Site

City

Kemerovo

ZIP/Postal Code

650056

Country

Russian Federation

Facility Name

GSK Investigational Site

City

Krasnodar

ZIP/Postal Code

350015

Country

Russian Federation

Facility Name

GSK Investigational Site

City

Moscow

ZIP/Postal Code

105275

Country

Russian Federation

Facility Name

GSK Investigational Site

City

Moscow

ZIP/Postal Code

129110

Country

Russian Federation

Facility Name

GSK Investigational Site

City

Smolensk

ZIP/Postal Code

214006

Country

Russian Federation

Facility Name

GSK Investigational Site

City

St. Petersburg

ZIP/Postal Code

190103

Country

Russian Federation

Facility Name

GSK Investigational Site

City

Toliyatti

ZIP/Postal Code

445846

Country

Russian Federation

Facility Name

GSK Investigational Site

City

Soweto

State/Province

Gauteng

ZIP/Postal Code

2013

Country

South Africa

Facility Name

GSK Investigational Site

City

Bloemfontein

ZIP/Postal Code

9301

Country

South Africa

Facility Name

GSK Investigational Site

City

Durban

ZIP/Postal Code

4001

Country

South Africa

Facility Name

GSK Investigational Site

City

Observatory, Cape Town

ZIP/Postal Code

7925

Country

South Africa

Facility Name

GSK Investigational Site

City

Westdene

ZIP/Postal Code

2092

Country

South Africa

Facility Name

GSK Investigational Site

City

Bangkok

ZIP/Postal Code

10330

Country

Thailand

Facility Name

GSK Investigational Site

City

Chiang Mai

ZIP/Postal Code

50200

Country

Thailand

Facility Name

GSK Investigational Site

City

Khon Kaen

ZIP/Postal Code

40002

Country

Thailand

Facility Name

GSK Investigational Site

City

Nonthaburi

ZIP/Postal Code

11000

Country

Thailand

Facility Name

GSK Investigational Site

City

Ratchatewi

ZIP/Postal Code

10400

Country

Thailand

Facility Name

GSK Investigational Site

City

Kyiv

ZIP/Postal Code

03115

Country

Ukraine

Facility Name

GSK Investigational Site

City

Odessa

ZIP/Postal Code

65031

Country

Ukraine

Facility Name

GSK Investigational Site

City

Vinnytsia

ZIP/Postal Code

21021

Country

Ukraine

Facility Name

GSK Investigational Site

City

Zaporizhzhya

ZIP/Postal Code

69006

Country

Ukraine

12. IPD Sharing Statement

Plan to Share IPD

Yes

IPD Sharing 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 URL

https://viivhealthcare.com/about-viiv/corporate-ethics-compliance/commitment-to-data-transparency/

Citations:

PubMed Identifier

30732940

Citation

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.

Results Reference

background

PubMed Identifier

34694877

Citation

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. Erratum In: Antimicrob Agents Chemother. 2023 Mar 16;67(3):e0032622.

Results Reference

background

Learn more about this trial

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

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

HIV Infections

About this trial

Eligibility Criteria

Sites / Locations

Arms of the Study

Arm 1

Arm 2

Outcomes

Primary Outcome Measures

Secondary Outcome Measures

Full Information

1. Study Identification

2. Study Status

3. Sponsor/Collaborators

4. Oversight

5. Study Description

6. Conditions and Keywords

7. Study Design

8. Arms, Groups, and Interventions

10. Eligibility

12. IPD Sharing Statement

Learn more about this trial