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

NCT ID: NCT02227238

Last Updated: 2023-03-13

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 627 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2014-12-11
• Study Completion Date: 2022-02-14

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.

Conditions

HIV Infections

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

DTG arm

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

Group Type: EXPERIMENTAL

DTG

Intervention Type: DRUG

DTG is supplied as 50 mg tablets

Two NRTIs

Intervention Type: DRUG

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

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

Group Type: ACTIVE_COMPARATOR

LPV/RTV

Intervention Type: DRUG

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

Two NRTIs

Intervention Type: DRUG

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

Interventions

DTG

DTG is supplied as 50 mg tablets

Intervention Type: DRUG

LPV/RTV

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

Intervention Type: 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

Intervention Type: DRUG

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)

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

GlaxoSmithKline

INDUSTRY

Sponsor Role: collaborator

ViiV Healthcare

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

GSK Clinical Trials

Role: STUDY_DIRECTOR

ViiV Healthcare

Locations

GSK Investigational Site

Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina

GSK Investigational Site

Ciudad de Buenos Aires, Buenos Aires, Argentina

GSK Investigational Site

Rosario, Santa Fe Province, Argentina

GSK Investigational Site

Buenos Aires, , Argentina

GSK Investigational Site

Buenos Aires, , Argentina

GSK Investigational Site

Buenos Aires, , Argentina

GSK Investigational Site

Córdoba, , Argentina

GSK Investigational Site

Salvador, Estado de Bahia, Brazil

GSK Investigational Site

São Paulo, São Paulo, Brazil

GSK Investigational Site

Rio de Janeiro, , Brazil

GSK Investigational Site

São Paulo, , Brazil

GSK Investigational Site

Puente Alto - Santiago, Región Metro de Santiago, Chile

GSK Investigational Site

Santiago, Región Metro de Santiago, Chile

GSK Investigational Site

Santiago, Región Metro de Santiago, Chile

GSK Investigational Site

Santiago, , Chile

GSK Investigational Site

Guangzhou, Guangdong, China

GSK Investigational Site

Beijing, , China

GSK Investigational Site

Beijing, , China

GSK Investigational Site

Shanghai, , China

GSK Investigational Site

Bogotá, , Colombia

GSK Investigational Site

Bogotá, , Colombia

GSK Investigational Site

Nairobi, , Kenya

GSK Investigational Site

Guadalajara, Jalisco, Mexico

GSK Investigational Site

Distrito Federal, , Mexico

GSK Investigational Site

Mexico City, , Mexico

GSK Investigational Site

México, , Mexico

GSK Investigational Site

Callao, , Peru

GSK Investigational Site

Lima, , Peru

GSK Investigational Site

Lima, , Peru

GSK Investigational Site

Lima, , Peru

GSK Investigational Site

Bucharest, , Romania

GSK Investigational Site

Bucharest, , Romania

GSK Investigational Site

Cluj-Napoca, , Romania

GSK Investigational Site

Constanța, , Romania

GSK Investigational Site

Târgu Mureş, , Romania

GSK Investigational Site

Barnaul, , Russia

GSK Investigational Site

Kazan', , Russia

GSK Investigational Site

Kemerovo, , Russia

GSK Investigational Site

Krasnodar, , Russia

GSK Investigational Site

Moscow, , Russia

GSK Investigational Site

Moscow, , Russia

GSK Investigational Site

Saint Petersburg, , Russia

GSK Investigational Site

Smolensk, , Russia

GSK Investigational Site

Toliyatti, , Russia

GSK Investigational Site

Yekaterinburg, , Russia

GSK Investigational Site

Soweto, Gauteng, South Africa

GSK Investigational Site

Bloemfontein, , South Africa

GSK Investigational Site

Durban, , South Africa

GSK Investigational Site

Observatory, Cape Town, , South Africa

GSK Investigational Site

Westdene, , South Africa

GSK Investigational Site

Bangkok, , Thailand

GSK Investigational Site

Chiang Mai, , Thailand

GSK Investigational Site

Khon Kaen, , Thailand

GSK Investigational Site

Nonthaburi, , Thailand

GSK Investigational Site

Ratchatewi, , Thailand

GSK Investigational Site

Kyiv, , Ukraine

GSK Investigational Site

Odesa, , Ukraine

GSK Investigational Site

Vinnytsia, , Ukraine

GSK Investigational Site

Zaporizhzhya, , Ukraine

Countries

Argentina; Brazil; Chile; China; Colombia; Kenya; Mexico; Peru; Romania; Russia; South Africa; Thailand; Ukraine

References

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.

Reference Type: BACKGROUND

PMID: 30732940 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 34694877 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

2014-001057-17

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

200304

Identifier Type: -

Identifier Source: org_study_id