Clinical trial NCT02227238: 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
Overall status: COMPLETED
Phase: PHASE3
Conditions: HIV Infections
Keywords: integrase inhibitor
non-inferiority
dolutegravir
lopinavir/ritonavir
second-line treatment
HIV-1
antiretroviral therapy-experienced
Lead sponsor: ViiV Healthcare
Sponsor class: INDUSTRY
Collaborators: name: GlaxoSmithKline
First posted: 2014-08-28
Enrollment: 627
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


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)

Primary outcomes:
measure: Percentage of Participants With Plasma HIV-1 Ribonucleic Acid (RNA) <50 Copies Per Milliliter (c/mL) at Week 48
timeFrame: Week 48
Secondary outcomes:
measure: Percentage of Participants With Plasma HIV-1 RNA <50 c/mL at Week 24
timeFrame: Week 24
measure: Percentage of Participants With Plasma HIV-1 RNA <400 c/mL at Weeks 24 and 48
timeFrame: Week 24 and Week 48
measure: Percentage of Participants Without Virologic or Tolerability Failure at Week 24 and Week 48
timeFrame: Week 24 and Week 48
measure: Time to Viral Suppression at Week 48
timeFrame: Week 48
measure: Change From Baseline in Helper-inducer T-lymphocyte Having Surface Antigen Cluster of Differentiation (CD4+) Cell Count at Weeks 24 and 48
timeFrame: Baseline (Day 1, Pre-dose), Week 24 and Week 48
measure: Number of Participants With Disease Progression-Randomized + Continuation Phase
timeFrame: Up to Week 348
measure: Number of Participants With Treatment-emergent Genotypic Resistance-Randomized Phase
timeFrame: Up to Week 52
measure: Number of Participants With Treatment-emergent Genotypic Resistance-Continuation Phase
timeFrame: Up to Week 295
measure: Number of Participants With Fold Change in Treatment-emergent Phenotypic Resistance From Baseline-Randomized Phase
timeFrame: Baseline (Day 1, Pre-dose) and up to Week 52
measure: Number of Participants With Fold Change in Treatment-emergent Phenotypic Resistance From Baseline-Continuation Phase
timeFrame: Baseline (Day 1, Pre-dose) and up to Week 295
measure: Number of Participants With Non-serious Adverse Events (AEs) With >=2% Frequency Threshold and Serious Adverse Events (SAEs)-Randomized Phase
timeFrame: Up to Week 52
measure: Number of Participants With Non-serious AEs With >=2% Frequency Threshold and SAEs-Continuation Phase
timeFrame: Up to Week 295
measure: Number of Participants With Non-serious AEs With >=2% Frequency Threshold and SAEs-Randomized + Continuation Phase
timeFrame: Up to Week 348
measure: 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
timeFrame: Baseline (Day 1, Pre-dose), Week 4, Week 8, Week 16, Week 24, Week 36, Week 48 and Week 52
measure: Change From Baseline in Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Creatine Kinase Values
timeFrame: Baseline (Day 1, Pre-dose), Week 4, Week 8, Week 16, Week 24, Week 36, Week 48 and Week 52
measure: Change From Baseline in Albumin Values
timeFrame: Baseline (Day 1, Pre-dose), Week 4, Week 8, Week 16, Week 24, Week 36, Week 48 and Week 52
measure: Change From Baseline in Creatinine and Bilirubin Values
timeFrame: Baseline (Day 1, Pre-dose), Week 4, Week 8, Week 16, Week 24, Week 36, Week 48 and Week 52
measure: Change From Baseline in Lipase Values
timeFrame: Baseline (Day 1, Pre-dose), Week 4, Week 8, Week 16, Week 24, Week 36, Week 48 and Week 52
measure: Number of Participants With Clinical Chemistry Toxicities -Randomized Phase
timeFrame: Up to Week 52
measure: Number of Participants With Clinical Chemistry Toxicities-Continuation Phase
timeFrame: Up to Week 295
measure: Change From Baseline in Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils, Platelets and Leukocytes
timeFrame: Baseline (Day 1, Pre-dose), Week 4, Week 8, Week 16, Week 24, Week 36, Week 48 and Week 52
measure: Change From Baseline in Hematocrit Values
timeFrame: Baseline (Day 1, Pre-dose), Week 4, Week 8, Week 16, Week 24, Week 36, Week 48 and and Week 52
measure: Change From Baseline in Hemoglobin Values
timeFrame: Baseline (Day 1, Pre-dose), Week 4, Week 8, Week 16, Week 24, Week 36, Week 48 and Week 52
measure: Change From Baseline in Mean Corpuscular Volume (MCV)
timeFrame: Baseline (Day 1, Pre-dose), Week 4, Week 8, Week 16, Week 24, Week 36, Week 48 and and Week 52
measure: Change From Baseline in Erythrocyte Values
timeFrame: Baseline (Day 1, Pre-dose), Week 4, Week 8, Week 16, Week 24, Week 36, Week 48 and up to Week 52
measure: Number of Participants With Hematology Toxicities -Randomized Phase
timeFrame: Up to Week 52
measure: Number of Participants With Hematology Toxicities-Continuation Phase
timeFrame: Up to Week 295
measure: Number of Participants Who Discontinued Treatment Due to AEs-Randomized Phase
timeFrame: Up to Week 52
measure: Number of Participants Who Discontinued Treatment Due to AEs-Continuation Phase
timeFrame: Up to Week 295
measure: Change From Baseline in Fasting LDL Cholesterol at Week 24 and Week 48
timeFrame: Baseline (Day 1, Pre-dose), Week 24 and Week 48
measure: Change From Baseline in Fasting Total Cholesterol/HDL Cholesterol Ratio
timeFrame: Baseline (Day 1, Pre-dose), Week 24 and Week 48
measure: Number of Participants With Maximum Post-Baseline Emergent Grade 2 or Greater Laboratory Abnormalities in Fasting LDL Cholesterol
timeFrame: Up to Week 48
measure: Number of Participants With Maximum Post-Baseline Emergent Grade 2 or Greater Drug-related Diarrhea
timeFrame: Week 24 and Week 48
measure: Change From Baseline in Gastrointestinal Symptom Rating Scale (GSRS) Score
timeFrame: Baseline (Day 1, Pre-dose), Week 4, Week 24, Week 48
measure: Change From Baseline in Treatment Satisfaction, Using the HIV-Treatment Satisfaction Questionnaire (HIVTSQ) Score
timeFrame: Baseline (Day 1, Pre-dose), Week 4, Week 24, Week 48
measure: Number of Participants Showing Adherence With Treatment, Using the Morisky 8-Item Medication Adherence Scale (MMAS-8)
timeFrame: Baseline (Day 1, Pre-dose), Week 4, Week 24 and Week 48
Other outcomes:
Locations:
city: Ciudad Autónoma de Buenos Aires
country: Argentina
facility: GSK Investigational Site
state: Buenos Aires
city: Ciudad de Buenos Aires
country: Argentina
facility: GSK Investigational Site
state: Buenos Aires
city: Rosario
country: Argentina
facility: GSK Investigational Site
state: Santa Fe
city: Buenos Aires
country: Argentina
facility: GSK Investigational Site
city: Buenos Aires
country: Argentina
facility: GSK Investigational Site
city: Ciudad Autónoma de Buenos Aires
country: Argentina
facility: GSK Investigational Site
city: Córdoba
country: Argentina
facility: GSK Investigational Site
city: Salvador
country: Brazil
facility: GSK Investigational Site
state: Bahía
city: Sao Paulo
country: Brazil
facility: GSK Investigational Site
state: São Paulo
city: Rio de Janeiro
country: Brazil
facility: GSK Investigational Site
city: São Paulo
country: Brazil
facility: GSK Investigational Site
city: Puente Alto - Santiago
country: Chile
facility: GSK Investigational Site
state: Región Metro De Santiago
city: Santiago
country: Chile
facility: GSK Investigational Site
state: Región Metro De Santiago
city: Santiago
country: Chile
facility: GSK Investigational Site
state: Región Metro De Santiago
city: Santiago
country: Chile
facility: GSK Investigational Site
city: Guangzhou
country: China
facility: GSK Investigational Site
state: Guangdong
city: Beijing
country: China
facility: GSK Investigational Site
city: Beijing
country: China
facility: GSK Investigational Site
city: Shanghai
country: China
facility: GSK Investigational Site
city: Bogota
country: Colombia
facility: GSK Investigational Site
city: Bogota
country: Colombia
facility: GSK Investigational Site
city: Nairobi
country: Kenya
facility: GSK Investigational Site
city: Guadalajara
country: Mexico
facility: GSK Investigational Site
state: Jalisco
city: Distrito Federal
country: Mexico
facility: GSK Investigational Site
city: Mexico City
country: Mexico
facility: GSK Investigational Site
city: Mexico
country: Mexico
facility: GSK Investigational Site
city: Callao
country: Peru
facility: GSK Investigational Site
city: Lima
country: Peru
facility: GSK Investigational Site
city: Lima
country: Peru
facility: GSK Investigational Site
city: Lima
country: Peru
facility: GSK Investigational Site
city: Bucharest
country: Romania
facility: GSK Investigational Site
city: Bucharest
country: Romania
facility: GSK Investigational Site
city: Cluj-Napoca
country: Romania
facility: GSK Investigational Site
city: Constanta
country: Romania
facility: GSK Investigational Site
city: Targu Mures
country: Romania
facility: GSK Investigational Site
city: Barnaul
country: Russian Federation
facility: GSK Investigational Site
city: Ekaterinburg
country: Russian Federation
facility: GSK Investigational Site
city: Kazan
country: Russian Federation
facility: GSK Investigational Site
city: Kemerovo
country: Russian Federation
facility: GSK Investigational Site
city: Krasnodar
country: Russian Federation
facility: GSK Investigational Site
city: Moscow
country: Russian Federation
facility: GSK Investigational Site
city: Moscow
country: Russian Federation
facility: GSK Investigational Site
city: Smolensk
country: Russian Federation
facility: GSK Investigational Site
city: St. Petersburg
country: Russian Federation
facility: GSK Investigational Site
city: Toliyatti
country: Russian Federation
facility: GSK Investigational Site
city: Soweto
country: South Africa
facility: GSK Investigational Site
state: Gauteng
city: Bloemfontein
country: South Africa
facility: GSK Investigational Site
city: Durban
country: South Africa
facility: GSK Investigational Site
city: Observatory, Cape Town
country: South Africa
facility: GSK Investigational Site
city: Westdene
country: South Africa
facility: GSK Investigational Site
city: Bangkok
country: Thailand
facility: GSK Investigational Site
city: Chiang Mai
country: Thailand
facility: GSK Investigational Site
city: Khon Kaen
country: Thailand
facility: GSK Investigational Site
city: Nonthaburi
country: Thailand
facility: GSK Investigational Site
city: Ratchatewi
country: Thailand
facility: GSK Investigational Site
city: Kyiv
country: Ukraine
facility: GSK Investigational Site
city: Odessa
country: Ukraine
facility: GSK Investigational Site
city: Vinnytsia
country: Ukraine
facility: GSK Investigational Site
city: Zaporizhzhya
country: Ukraine
facility: GSK Investigational Site
Study officials:
affiliation: ViiV Healthcare
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
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.
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.