A Clinical Trial of GSK3640254 + Dolutegravir (DTG) in Human Immunodeficiency Virus-1 Infected Treatment-naive Adults

Study Overview
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Brief Summary
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The purpose of this study was to evaluate the efficacy of GSK3640254 + DTG relative to lamivudine (3TC) + DTG in treatment-naïve adult participants living with human immunodeficiency virus (HIV)-1. The participants were randomized to one of the three doses of blinded GSK3640254 (100, 150, or 200 milligrams [mgs]) or a reference arm of blinded 3TC-each in combination with open label DTG.

Official Title
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A Phase IIb, Randomized, Double-blind, Parallel-group Study to Assess the Efficacy, Safety, Tolerability, and Resistance Profile of GSK3640254 in Combination With Dolutegravir Compared to Dolutegravir Plus Lamivudine in HIV-1 Infected, Treatment-naïve Adults

Conditions
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HIV Infections

Intervention / Treatment
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* Drug: GSK3640254
* Drug: Dolutegravir
* Drug: Lamivudine capsules
* Drug: Lamivudine tablets


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Treatment-naive, defined as no anti-retrovirals (ARVs) (in combination or monotherapy) received after a known diagnosis of HIV-1 infection. Documented HIV infection and Screening plasma HIV-1 RNA greater than or equal to (>=)1000 c/mL. Screening CD4+ T-cell count >=250 cells per millimeter^3 (cells/cubic millimeter). Body weight >=50.0 kilograms (kg) (110 pounds [lbs.]) for men and >=45.0 kg (99 lbs.) for women and body mass index (BMI) >18.5 kilograms per meter^2 (kg/meter square). Calculations will utilize sex assigned at birth. Exclusion Criteria: Any evidence of an active Centers for Disease Control and Prevention (CDC) Stage 3 disease [CDC, 2014], except cutaneous Kaposi's sarcoma not requiring systemic therapy. Presence of primary HIV infection, evidenced by acute retroviral syndrome (example [e.g.], fever, malaise, fatigue, etc.) and/or evidence of recent (within 3 months) documented viremia without antibody production and/or evidence of recent (within 3 months) documented seroconversion. Unstable liver disease (as defined by any of the following: presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, or persistent jaundice or cirrhosis), known biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones or otherwise stable chronic liver disease per investigator assessment); History of ongoing or clinically relevant hepatitis within the previous 6 months. Any history of significant underlying psychiatric disorder. Any history of major depressive disorder with or without suicidal features, or anxiety disorders, that required medical intervention (pharmacologic or not) such as hospitalization or other inpatient treatment and/or chronic (>6 months) outpatient treatment. A pre-existing condition, in the opinion of the Investigator or Medical Monitor, that could interfere with normal gastrointestinal anatomy or motility (e.g., gastroesophageal reflux disease [GERD], gastric ulcers, gastritis, inflammatory bowel disease), hepatic and/or renal function, or with the absorption, metabolism, and/or excretion of the study interventions or render the participant unable to take oral study treatment. Familial or personal history of long QT syndrome or sudden cardiac death. Active treatment for a viral infection other than HIV-1, such as Hepatitis B, with an agent that is active against HIV-1 (were known to be infected with HIV-1 after treatment for Hepatitis B was completed). Participants who require concomitant medications known to be associated with a prolonged corrected QT (QTc) interval. Exposure to an experimental drug, human blood product, monoclonal antibody, or vaccine (which does not have emergency, conditional, or standard market authorization) within 28 days prior to the first dose of study treatment.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: This is a randomized, parallel-group study.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: GSK3640254 100 mg + Dolutegravir (DTG) 50 mg<br>Participants with human immunodeficiency virus type 1 (HIV-1) orally received low dose (100 mg) GSK3640254 tablet blinded and 50 mg DTG unblinded. Each participant received one tablet per day of each intervention up to Week 24. | Drug: GSK3640254<br>* GSK3640254 was available as 25 mg or 100 mg tablets administered orally.<br>Drug: Dolutegravir<br>* DTG was available as 50 mg tablets administered orally.<br>|
| Experimental: GSK3640254 150 mg + DTG 50 mg<br>Participants with HIV-1 orally received medium dose (150 mg) GSK3640254 tablet blinded and 50 mg DTG unblinded. Each participant received one tablet per day of each intervention up to Week 24. | Drug: GSK3640254<br>* GSK3640254 was available as 25 mg or 100 mg tablets administered orally.<br>Drug: Dolutegravir<br>* DTG was available as 50 mg tablets administered orally.<br>|
| Experimental: GSK3640254 200 mg + DTG 50 mg<br>Participants with HIV-1 orally received high dose (200 mg) GSK3640254 tablet blinded and 50 mg DTG unblinded. Each participant received one tablet per day of each intervention up to Week 24. | Drug: GSK3640254<br>* GSK3640254 was available as 25 mg or 100 mg tablets administered orally.<br>Drug: Dolutegravir<br>* DTG was available as 50 mg tablets administered orally.<br>|
| Active Comparator: DTG 50 mg + Lamivudine (3TC) 300 mg<br>Participants with HIV-1 orally received unblinded 50 mg DTG one tablet and blinded 300 mg 3TC. Each participant received one capsule per day of each intervention up to Week 24. | Drug: Dolutegravir<br>* DTG was available as 50 mg tablets administered orally.<br>Drug: Lamivudine capsules<br>* 3TC was available as 300 mg capsules administered orally as a blinded treatment.<br>Drug: Lamivudine tablets<br>* 3TC was available as 300 mg tablets administered orally as an unblinded treatment.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Plasma HIV-1 Ribonucleic Acid (RNA) Less Than (<)50 Copies Per Milliliter (c/mL) at Week 24 | Percentage of participants with plasma HIV-1 RNA <50 c/mL at Week 24 using the Food and Drug Administration (FDA) snapshot algorithm was assessed to evaluate the antiviral activity in HIV-1 infected ART (anti-retroviral therapy)-naïve participants. | At Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Absolute Values of HIV-1 RNA Through Week 24 | Plasma samples were collected for quantitative analysis of HIV-1 RNA. Logarithm to base 10 (log 10) values for plasma HIV-1 RNA has been presented. Baseline is defined as the latest non-missing value prior to first dose of treatment according to date and time including unscheduled visits. | At Baseline (Day 1) and Week 24 | 
| Change From Baseline in HIV-1 RNA Through Week 24 | Plasma samples were collected for quantitative analysis of HIV-1 RNA. Logarithm to base 10 (log 10) values for plasma HIV-1 RNA has been presented. Change from Baseline is defined as post-dose visit value minus Baseline value. | At Week 24 compared to baseline (Day 1) | 
| Absolute Values of Cluster of Differentiation 4+ (CD4+) T-cell Counts Through Week 24 | Blood samples were collected and CD4+ cell count assessment by flow cytometry was carried out to evaluate the immunologic activity. Baseline is defined as the latest non-missing value prior to first dose of treatment according to date and time including unscheduled visits. | At Baseline (Day 1) and Week 24 | 
| Change From Baseline in CD4+ T-cell Counts Through Week 24 | Blood samples were collected and CD4+ cell count assessment was carried out to evaluate the immunologic activity. Change from Baseline is defined as post-dose visit value minus Baseline value. | At Week 24 compared to baseline (Day 1) | 
| Number of Participants With Serious Adverse Events (SAEs) and Deaths, up to End of Continued Access to Treatment Post-study Termination (Day 478) | An SAE is defined as any serious adverse event that, at any dose results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity and is a congenital anomaly/birth defect. The study was terminated by the sponsor after primary analysis (at week 24). Adverse event data were collected up to end of continued access to treatment post-study termination (Day 478). | From Day 1 up to end of continued access to treatment post-study termination (Day 478) | 
| Number of Participants With Adverse Events (AEs) Leading to Discontinuation, up to End of Continued Access to Treatment Post-study Termination (Day 478) | Number of participants who discontinued treatment due to AEs are presented. The study was terminated by the sponsor after primary analysis (at week 24). Adverse event data were collected up to end of continued access to treatment post-study termination (Day 478). | From Day 1 up to end of continued access to treatment post-study termination (Day 478) | 
| Number of Participants With Adverse Events of Special Interest (AESIs), up to End of Continued Access to Treatment Post-study Termination (Day 478) | AEs of special interest (AESIs) included AEs related to QT prolongation, gastrointestinal (GI) intolerability/toxicity, psychiatric events, nervous system disorders, skin and subcutaneous tissue disorders and cardiac disorders. The study was terminated by the sponsor after primary analysis (at week 24). Adverse event data were collected up to end of continued access to treatment post-study termination (Day 478). | From Day 1 up to end of continued access to treatment post-study termination (Day 478) | 
| Number of Participants Who Develop Genotypic Resistance up to Week 24 | Blood samples were collected for drug resistance testing to assess the development of viral resistance to GSK3640254 through Week 24. New mutations were tabulated by drug class: integrase strand transfer inhibitor (INSTI), non-nucleoside reverse transcriptase inhibitor (NNRTI), nucleoside reverse transcriptase inhibitor (NRTI) and protease inhibitor (PI). Protocol-Defined Virologic Failure (PDVF) was defined as having virologic non-response (HIV-1 RNA <1.0 log10 c/mL reduction from baseline and <200 copies/mL by Week 12, confirmed levels >=200 c/mL at or after Week 24 and plasma HIV-1 RNA <= 50 c/mL from testing on Week 24, virologic rebound (confirmed HIV-1 RNA >=200 copies/mL after confirmed consecutive HIV-1 RNA <50 copies/mL). | From Day 1 up to Week 24 | 
| Number of Participants Who Develop Phenotypic Resistance up to Week 24 | Blood samples were collected for drug resistance testing to assess the development of viral resistance to GSK3640254 and other on-study Anti-Retroviral Therapy (ART) in participants experiencing virologic failure through Week 24. Only plasma HIV-1 RNA values determined by the central laboratory were used to assess virologic failure. PDVF was defined as having virologic non-response (HIV-1 RNA <1.0 log10 c/mL reduction from baseline and <200 copies/mL by Week 12, confirmed levels >=200 c/mL at or after Week 24 and plasma HIV-1 RNA <= 50 c/mL from testing on Week 24, virologic rebound (confirmed HIV-1 RNA >=200 copies/mL after confirmed consecutive HIV-1 RNA <50 copies/mL). | From Day 1 up to Week 24 | 
| Trough Concentration (Ctrough) of GSK3640254 at Weeks 2, 4, 8, 12 and 24 | Trough concentration (Ctrough) is the concentration reached by a drug immediately before the next dose is administered. This was determined to assess the steady-state exposure of GSK3640254 when given in combination with DTG. | At Weeks 2, 4, 8, 12 (PRE DOSE), 12 (2-6HR POST DOSE), 24 (PRE DOSE), 24 (2-6HR POST DOSE) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Human immunodeficiency virus-1, GSK3640254, Dolutegravir, Lamivudine, Treatment-naive