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

NCT02227238 | Completed Phase 3 Results DMC

• 2 other identifiers: 2003042014-001057-17
• Study Type: interventional
• Target: 627
• Locations: 13 countries
• Sites: 59

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

Keywords

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

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (36)

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

  Week 24

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

  Week 24 and Week 48

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

  Week 24 and Week 48

• Time to Viral Suppression at Week 48

  Week 48

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

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

Study Arms (2)

DTG arm

EXPERIMENTAL

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

Drug: DTG; Drug: Two NRTIs

LPV/RTV arm

ACTIVE COMPARATOR

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: LPV/RTV; Drug: Two NRTIs

Interventions

DTG DRUG

DTG is supplied as 50 mg tablets

DTG arm

LPV/RTV DRUG

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

LPV/RTV arm

Two NRTIs 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

DTG arm; LPV/RTV arm

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.
• 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.

Sponsors & Collaborators

• ViiV Healthcare: lead
• GlaxoSmithKline: collaborator

Study Sites (59)

GSK Investigational Site

Ciudad Autónoma de Buenos Aires, Buenos Aires, C1405CKC, Argentina

Location

GSK Investigational Site

Ciudad de Buenos Aires, Buenos Aires, C1202ABB, Argentina

Location

GSK Investigational Site

Rosario, Santa Fe Province, 2000, Argentina

Location

GSK Investigational Site

Buenos Aires, 1141, Argentina

Location

GSK Investigational Site

Buenos Aires, C1221ADC, Argentina

Location

GSK Investigational Site

Buenos Aires, C1426ABP, Argentina

Location

GSK Investigational Site

Córdoba, 5000, Argentina

Location

GSK Investigational Site

Salvador, Estado de Bahia, 40110-010, Brazil

Location

GSK Investigational Site

São Paulo, São Paulo, 01246-090, Brazil

Location

GSK Investigational Site

Rio de Janeiro, 21045900, Brazil

Location

GSK Investigational Site

São Paulo, 04121-000, Brazil

Location

GSK Investigational Site

Puente Alto - Santiago, Región Metro de Santiago, 8207257, Chile

Location

GSK Investigational Site

Santiago, Región Metro de Santiago, 8330074, Chile

Location

GSK Investigational Site

Santiago, Región Metro de Santiago, 8900088, Chile

Location

GSK Investigational Site

Santiago, 8360159, Chile

Location

GSK Investigational Site

Guangzhou, Guangdong, 510060, China

Location

GSK Investigational Site

Beijing, 100015, China

Location

GSK Investigational Site

Beijing, 100069, China

Location

GSK Investigational Site

Shanghai, 201508, China

Location

GSK Investigational Site

Bogotá, 111311, Colombia

Location

GSK Investigational Site

Bogotá, 5600520, Colombia

Location

GSK Investigational Site

Nairobi, 00100, Kenya

Location

GSK Investigational Site

Guadalajara, Jalisco, 44280, Mexico

Location

GSK Investigational Site

Distrito Federal, 06470, Mexico

Location

GSK Investigational Site

Mexico City, 03720, Mexico

Location

GSK Investigational Site

México, 14000, Mexico

Location

GSK Investigational Site

Callao, Callao 02, Peru

Location

GSK Investigational Site

Lima, 1, Peru

Location

GSK Investigational Site

Lima, 32, Peru

Location

GSK Investigational Site

Lima, Lima 31, Peru

Location

GSK Investigational Site

Bucharest, 021105, Romania

Location

GSK Investigational Site

Bucharest, 030303, Romania

Location

GSK Investigational Site

Cluj-Napoca, 400348, Romania

Location

GSK Investigational Site

Constanța, 900708, Romania

Location

GSK Investigational Site

Târgu Mureş, 540394, Romania

Location

GSK Investigational Site

Barnaul, 656010, Russia

Location

GSK Investigational Site

Kazan', 420061, Russia

Location

GSK Investigational Site

Kemerovo, 650056, Russia

Location

GSK Investigational Site

Krasnodar, 350015, Russia

Location

GSK Investigational Site

Moscow, 105275, Russia

Location

GSK Investigational Site

Moscow, 129110, Russia

Location

GSK Investigational Site

Saint Petersburg, 190103, Russia

Location

GSK Investigational Site

Smolensk, 214006, Russia

Location

GSK Investigational Site

Toliyatti, 445846, Russia

Location

GSK Investigational Site

Yekaterinburg, 620149, Russia

Location

GSK Investigational Site

Soweto, Gauteng, 2013, South Africa

Location

GSK Investigational Site

Bloemfontein, 9301, South Africa

Location

GSK Investigational Site

Durban, 4001, South Africa

Location

GSK Investigational Site

Observatory, Cape Town, 7925, South Africa

Location

GSK Investigational Site

Westdene, 2092, South Africa

Location

GSK Investigational Site

Bangkok, 10330, Thailand

Location

GSK Investigational Site

Chiang Mai, 50200, Thailand

Location

GSK Investigational Site

Khon Kaen, 40002, Thailand

Location

GSK Investigational Site

Nonthaburi, 11000, Thailand

Location

GSK Investigational Site

Ratchatewi, 10400, Thailand

Location

GSK Investigational Site

Kyiv, 03115, Ukraine

Location

GSK Investigational Site

Odesa, 65031, Ukraine

Location

GSK Investigational Site

Vinnytsia, 21021, Ukraine

Location

GSK Investigational Site

Zaporizhzhya, 69006, Ukraine

Location

Related Publications (2)

• 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.

  PMID: 30732940 BACKGROUND

• 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.

  PMID: 34694877 BACKGROUND

MeSH Terms

Conditions

HIV Infections

Condition Hierarchy (Ancestors)

Blood-Borne Infections; Communicable Diseases; Infections; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Genital Diseases; Urogenital Diseases; Immunologic Deficiency Syndromes; Immune System Diseases

Results Point of Contact

• Title: GSK Response Center
• Organization: ViiV Healthcare

GSKClinicalSupportHD@gsk.com

866-435-7343

Study Officials

• GSK Clinical Trials

  ViiV Healthcare

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 25, 2014
• First Posted: August 28, 2014
• Study Start: December 11, 2014
• Primary Completion: August 2, 2017
• Study Completion: February 14, 2022
• Last Updated: March 13, 2023
• Results First Posted: July 12, 2019

Record last verified: 2023-01

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• 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.
• 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.

Locations

CO (2); BR (4); PE (4); RU (10); UA (4); RO (5); CN (4); KE (1); CL (4); AR (7); ME (4); TH (5); ZA (5)