A Dose-Range Finding Clinical Trial Study in Human Immunodeficiency Virus (HIV-1) Infected Treatment-Naive Adults

Study Overview
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Brief Summary
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This is a phase 2b, randomized, multicenter, parallel group, partially blind (to GSK3640254 doses [100, 150 and 200 milligrams {mg}]), active controlled clinical trial. It will aim to investigate the safety, efficacy and dose-response of GSK3640254 compared to dolutegravir (DTG), each given in combination with 2 Nucleoside Reverse Transcriptase Inhibitors (NRTIs) (abacavir/lamivudine [ABC/3TC] or emtricitabine/tenofovir alafenamide [FTC/TAF])

Official Title
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A Phase IIb, Randomized, Partially Blind, Active Controlled, Dose-range Finding Study of GSK3640254 Compared to a Reference Arm of Dolutegravir, Each in Combination With Nucleoside Reverse Transcriptase Inhibitors, in HIV-1 Infected Antiretroviral Treatment-naive Adults

Conditions
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HIV Infections

Intervention / Treatment
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* Drug: GSK3640254
* Drug: ABC/3TC
* Drug: FTC/TAF
* Drug: Dolutegravir
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants must be 18 years of age inclusive, at the time of signing the informed consent. Treatment-naive, defined as no anti-retrovirals (ARVs) (in combination or monotherapy) received after the diagnosis of HIV-1 infection (for example [e.g.], use of Pre-exposure prophylaxis [PreP] meets inclusion. Documented HIV infection and Screening plasma HIV-1 RNA greater than or equal to (>=)1000 c/mL. Screening CD4+ T-cell count >=250 cells/mm^3. Antiviral susceptibility to the NRTI backbone selected should be demonstrated Body weight >=50.0 kilograms (kg) (110 pounds [lbs]) for men and >=45.0 kg (99 lbs) for women and body mass index (BMI) greater than (>)18.5 kg/meter square (m^2).Calculations will utilize sex assigned at birth Participants who are male at birth and participants who are female at birth. Participants who are female at birth: Contraceptive use by participant who are female at birth should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. • A participant who is female at birth is eligible to participate if they are not pregnant or breastfeeding, and one of the following conditions applies: Is a participant of non-childbearing potential (PONCBP) Or is a POCBP and using an acceptable contraceptive method during the study intervention period (at a minimum until after the last dose of study intervention). Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol. For participants enrolled in France: a participant will be eligible for inclusion in this study only if either affiliated to or a beneficiary of a social security category. Exclusion criteria: Any evidence of an active Center for Disease Control and Prevention (CDC) Stage 3 disease, except cutaneous Kaposi's sarcoma not requiring systemic therapy. Ongoing malignancy other than cutaneous Kaposi's sarcoma, basal cell carcinoma, or resected, non-invasive cutaneous squamous cell carcinoma, or cervical, anal or penile intraepithelial neoplasia. Presence of primary HIV-1 infection, evidenced by acute retroviral syndrome (e.g., fever, malaise, fatigue) and/or evidence of recent (within 3 months) documented viremia without antibody production and/or evidence of recent (within 3 months) documented seroconversion. Known history of liver cirrhosis with or without viral hepatitis co-infection. 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. History of drug or other allergy that, in the opinion of the Investigator or Medical Monitor, contraindicates their participation. Any history of significant underlying psychiatric disorder, in the opinion of the Investigator or ViiV Medical Monitor, including but not limited to schizophrenia, bipolar disorder with or without psychotic symptoms, other psychotic disorders, or schizotypal (personality) disorder or a clinical assessment of suicidality based on the responses on the Columbia-Suicide Severity Rating Scale (eCSSRS). 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. Any pre-existing physical or other psychiatric condition (including alcohol or drug abuse), which, in the opinion of the Investigator or ViiV Medical Monitor (with or without psychiatric evaluation), could interfere with the participant's ability to comply with the dosing schedule and protocol evaluations or which might compromise the safety of the participant. A pre-existing condition, in the opinion of the Investigator or ViiV 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 drugs or render the participant unable to take oral study treatment. Myocardial infarction in the past 3 months. Familial or personal history of long QT syndrome or sudden cardiac death. Medical history, current or historical, of significant cardiac arrhythmias or Electrocardiogram (ECG) findings which, in the opinion of the Investigator or ViiV Medical Monitor, will interfere with the safety of the participant. 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). 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, any systemic immune suppressant. Participants receiving any protocol-prohibited medication and who are unwilling or unable to switch to an alternate medication. Participants who are unwilling to stop any medications as required by the local lab test for Helicobacter (H.) pylori. Participants who require concomitant medications known to be associated with a prolonged Corrected QT interval (QTc). 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. Current enrollment or past participation within the last 30 days before signing of consent in any other clinical study involving an investigational study intervention (including an investigational Coronavirus Disease (COVID) vaccine) or any other type of medical research. Any evidence of viral resistance based on the NRTI backbone selected. Historical evidence (prior to study screening period) of the presence of resistance- associated mutations gag A364V or A364A/V. Creatinine Clearance <50 mL/minute. Alanine aminotransferase (ALT) >=3 times upper limit of normal (ULN) or ALT >=2 times ULN and total bilirubin >=1.5 times ULN. Evidence of Hepatitis B virus (HBV) infection based on the results of testing for Hepatitis B surface antigen (HBsAg), Hepatitis B core antibody (anti-HBc), Hepatitis B surface antibody (anti-HBs) and reflex HBV deoxyribonucleic acid (DNA) as follows: Participants positive for HBsAg are excluded; Participants negative for anti-HBs but positive for anti-HBc (negative HBsAg status) and positive for HBV DNA on reflex testing are excluded. Positive Hepatitis C antibody test result at Screening and positive on reflex to Hepatitis C RNA. Positive test results for H. pylori; Known or suspected active COVID-19 infection or contact with an individual with known COVID-19, within 14 days of study enrollment Untreated syphilis infection (positive rapid plasma reagin [RPR] at Screening) without documentation of treatment. Presence of moderate-to-severe hepatic impairment (Class B or C) as determined by Child-Pugh classification. Any acute laboratory abnormality at Screening, which, in the opinion of the investigator or ViiV Medical Monitor, would preclude participation in the study of an investigational compound. Urine Drug Screen positive (showing presence of): Amphetamines, Barbiturates, Cocaine, 3,4-Methyl enedioxy methamphetamine (MDMA) or Phencyclidine, or non-prescribed opiates, oxycodone, benzodiazepines, methadone, methamphetamines or tricyclic antidepressants. Any clinically relevant Grade 4 laboratory abnormality at Screen, including results for creatine phosphokinase (CPK) and lipid abnormalities that lack a compelling explanation from the Investigator. Where participation in the study would result in donation of blood or blood products in excess of 500 mL within 28 days. Exposure to more than 4 new investigational drugs or vaccines (exclusive of a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) potential indication within 12 months prior to the first dosing day; Treatment with radiation therapy or cytotoxic chemotherapeutic agents or any systemic immunosuppressive agent within 30 days of study drug administration or anticipated need for such treatment within the study; ECG Heart Rate <50 beats per minute (bpm) or >100 bpm, or QT duration corrected for heart rate by Fridericia's formula (QTcF) >450 milliseconds (msec). For Portugal only: HIV-2 infection (either determined by prior testing, medical history, or obtained locally during the Screening window).

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, multicenter, parallel group study.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Blinded GSK3640254 100 mg + GSK3640254 matching placebo + Open Label ABC/3TC or FTC/TAF<br> | Drug: GSK3640254<br>* GSK3640254 will be available as a 25 mg and 100 mg tablets to be administered via oral route.<br>Drug: ABC/3TC<br>* ABC/3TC will be available as abacavir 600 mg/lamivudine 300 mg tablet to be administered via oral route.<br>Drug: FTC/TAF<br>* FTC/TAF will be available as emtricitabine 200 mg/tenofovir alafenamide 25 mg tablet to be administered via oral route.<br>Drug: Placebo<br>* Placebo matching GSK3640254 will be administered in the form of tablets via oral route.<br>|
| Experimental: Blinded GSK3640254 150 mg + Open Label ABC/3TC or FTC/TAF<br> | Drug: GSK3640254<br>* GSK3640254 will be available as a 25 mg and 100 mg tablets to be administered via oral route.<br>Drug: ABC/3TC<br>* ABC/3TC will be available as abacavir 600 mg/lamivudine 300 mg tablet to be administered via oral route.<br>Drug: FTC/TAF<br>* FTC/TAF will be available as emtricitabine 200 mg/tenofovir alafenamide 25 mg tablet to be administered via oral route.<br>|
| Experimental: Blinded GSK3640254 200 mg + GSK3640254 matching placebo + Open Label ABC/3TC or FTC/TAF<br> | Drug: GSK3640254<br>* GSK3640254 will be available as a 25 mg and 100 mg tablets to be administered via oral route.<br>Drug: ABC/3TC<br>* ABC/3TC will be available as abacavir 600 mg/lamivudine 300 mg tablet to be administered via oral route.<br>Drug: FTC/TAF<br>* FTC/TAF will be available as emtricitabine 200 mg/tenofovir alafenamide 25 mg tablet to be administered via oral route.<br>Drug: Placebo<br>* Placebo matching GSK3640254 will be administered in the form of tablets via oral route.<br>|
| Active Comparator: Open Label DTG + Open Label ABC/3TC or FTC/TAF<br> | Drug: ABC/3TC<br>* ABC/3TC will be available as abacavir 600 mg/lamivudine 300 mg tablet to be administered via oral route.<br>Drug: FTC/TAF<br>* FTC/TAF will be available as emtricitabine 200 mg/tenofovir alafenamide 25 mg tablet to be administered via oral route.<br>Drug: Dolutegravir<br>* Dolutegravir will be available as a 50 mg tablet to be administered via oral route.<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 was assessed using the Food and Drug Administration (FDA) snapshot algorithm to demonstrate the antiviral activity of GSK3640254 given in combination with either ABC/3TC or FTC/TAF compared to the reference treatment of DTG given in combination with either ABC/3TC or FTC/TAF. | At Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Plasma HIV-1 RNA <50 c/mL at Week 48 | Percentage of participants with plasma HIV-1 RNA <50 c/mL at week 48 was assessed using the FDA snapshot algorithm to demonstrate the antiviral activity of GSK3640254 given in combination with either ABC/3TC or FTC/TAF compared to the reference treatment of DTG given in combination with either ABC/3TC or FTC/TAF. | At Week 48 | 
| Percentage of Participants With Plasma HIV-1 RNA <50 c/mL at Week 96 | Percentage of participants with plasma HIV-1 RNA <50 c/mL at week 96 will be assessed using the FDA snapshot algorithm to demonstrate the antiviral activity of GSK3640254 given in combination with either ABC/3TC or FTC/TAF compared to the reference treatment of DTG given in combination with either ABC/3TC or FTC/TAF. | At Week 96 | 
| Absolute Values of HIV-1 RNA at Weeks 24 and 48 | Plasma samples were collected for quantitative analysis of HIV-1 RNA. Logarithm to base 10 (log10) values for plasma HIV-1 RNA have been presented. Baseline was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. | Baseline (Day 1) and at Weeks 24 and 48 | 
| Absolute Values of HIV-1 RNA at Week 96 | Plasma samples will be collected for quantitative analysis of HIV-1 RNA. Logarithm to base 10 (log10) values for plasma HIV-1 RNA will be presented. Baseline will be defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. | Baseline (Day 1) and at Week 96 | 
| Change From Baseline in Plasma HIV-1 RNA at Weeks 24 and 48 | Plasma samples were collected for quantitative analysis of HIV-1 RNA. log10 values for plasma HIV-1 RNA have been presented. Baseline was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. Change from Baseline is defined as post-dose visit value minus Baseline value. | Baseline (Day 1) and at Weeks 24 and 48 | 
| Change From Baseline in Plasma HIV-1 RNA at Week 96 | Plasma samples will be collected for quantitative analysis of HIV-1 RNA. log10 values for plasma HIV-1 RNA will be presented. Baseline will be defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. Change from Baseline will be defined as post-dose visit value minus Baseline value. | Baseline (Day 1) and at Week 96 | 
| Absolute Values of Cluster of Differentiation 4 Plus (CD4+) Cell Counts at Weeks 24 and 48 | Blood samples were collected and CD4+ cell count was assessed using flow cytometry. Baseline was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. | Baseline (Day 1) and at Weeks 24 and 48 | 
| Absolute Values of Cluster of Differentiation 4 Plus (CD4+) Cell Counts at Week 96 | Blood samples will be collected and CD4+ cell count will be assessed using flow cytometry. Baseline will be defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. | Baseline (Day 1) and at Week 96 | 
| Change From Baseline in CD4+ Cell Counts at Weeks 24 and 48 | Blood samples were collected and CD4+ cell count was assessed using flow cytometry. Baseline was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. Change from Baseline is defined as post-dose visit value minus Baseline value. | Baseline (Day 1) and at Weeks 24 and 48 | 
| Change From Baseline in CD4+ Cell Counts at Week 96 | Blood samples will be collected and CD4+ cell count will be assessed using flow cytometry. Baseline will be defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. Change from Baseline will be defined as post-dose visit value minus Baseline value. | Baseline (Day 1) and at Week 96 | 
| Number of Participants With Serious Adverse Events (SAEs) and Deaths Through Weeks 24 and 48 | 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, is a congenital anomaly/birth defect, or any other situation according to medical or scientific judgment. | Up to Weeks 24 and 48 | 
| Number of Participants With Serious Adverse Events (SAEs) and Deaths Through Week 96 | An SAE will be 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, is a congenital anomaly/birth defect, or any other situation according to medical or scientific judgment. | Up to Week 96 | 
| Number of Participants With Adverse Events (AEs) Leading to Treatment Discontinuation Through Weeks 24 and 48 | An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study intervention, whether or not considered related to the study intervention. Number of participants who discontinued study treatment due to AEs are presented. | Up to Weeks 24 and 48 | 
| Number of Participants With Adverse Events (AEs) Leading to Treatment Discontinuation Through Week 96 | An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study intervention, whether or not considered related to the study intervention. Number of participants who discontinue study treatment due to AEs will be presented. | Up to Week 96 | 
| Number of Participants With AEs Based on Maximum Severity Grades at Weeks 24 and 48 | An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study intervention, whether or not considered related to the study intervention. The severity of AEs was defined as per the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table) Version 2.1 and was categorized into grades as following: Grade 1 - mild, Grade 2 - moderate, Grade 3 - severe, Grade 4 - Potentially life threatening and Grade 5 - Fatal. Higher grade indicates more severe condition. Number of participants with adverse events by maximum grade have been presented. | At Weeks 24 and 48 | 
| Number of Participants With AEs Based on Maximum Severity Grades at Week 96 | An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study intervention, whether or not considered related to the study intervention. The severity of AEs will be defined as per the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table) Version 2.1 and will be categorized into grades as following: Grade 1 - mild, Grade 2 - moderate, Grade 3 - severe, Grade 4 - Potentially life threatening and Grade 5 - Fatal. Higher grade will indicate more severe condition. Number of participants with adverse events by maximum grade will be presented. | At Week 96 | 
| Number of Participants With AEs of Special Interest (AESI) (Gastrointestinal (GI), Nervous System, and Psychiatric AEs) Through Weeks 24 and 48 | An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study intervention, whether or not considered related to the study intervention. Number of participants with AESI (gastrointestinal (GI), nervous system, and psychiatric AEs) are presented. | At Weeks 24 and 48 | 
| Number of Participants With AEs of Special Interest (AESI) (Gastrointestinal (GI), Nervous System, and Psychiatric AEs) Through Week 96 | An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study intervention, whether or not considered related to the study intervention. Number of participants with AESI (gastrointestinal (GI), nervous system, and psychiatric AEs) will be presented. | At Week 96 | 
| Number of Participants With Genotypic Resistance | Plasma samples were collected for resistance testing. Genotypic testing was conducted in participants meeting protocol-defined virologic failure (PDVF) criteria. Baseline was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. Only those participants with data available at specified time points have been analyzed. | Baseline (Day 1) and at Weeks 24 and 48 | 
| Number of Participants With Genotypic Resistance - Week 96 | Plasma samples will be collected for resistance testing. Genotypic testing will be conducted in participants meeting protocol-defined virologic failure (PDVF) criteria. Baseline will be defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. | Baseline (Day 1) and at Week 96 | 
| Number of Participants With Phenotypic Resistance | Plasma samples were collected for resistance testing. Phenotypic testing was conducted in participants meeting PDVF criteria. Baseline was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. | Baseline (Day 1) and at Weeks 24 and 48 | 
| Number of Participants With Phenotypic Resistance - Week 96 | Plasma samples will be collected for resistance testing. Phenotypic testing will be conducted in participants meeting PDVF criteria. Baseline will be defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. | Baseline (Day 1) and at Week 96 | 
| Observed Plasma Concentration at the End of the Dosing Interval (Ctau) of GSK3640254 at Steady State - Week 2 | Blood samples were collected at indicated time points for pharmacokinetic (PK) analysis of GSK3640254. Observed plasma concentration at the end of the dosing interval was determined directly from the concentration-time data. | Pre-dose, 1, 2, 3, 3.5, 4, 4.5, 5, 6, 10, and 24 hours post-dose at Week 2 | 
| Observed Plasma Concentration at the End of the Dosing Interval (Ctau) of GSK3640254 at Steady State - Weeks 24 and 48 | Blood samples were collected at indicated time points for pharmacokinetic (PK) analysis of GSK3640254. Observed plasma concentration at the end of the dosing interval was determined directly from the concentration-time data. | At Weeks 24 and 48 | 
| Area Under the Plasma Drug Concentration-time Curve From Pre-dose to the End of the Dosing Interval (AUC [0-tau]) of GSK3640254 at Steady State | Blood samples were collected at indicated time points for PK analysis of GSK3640254. | Pre-dose, 1, 2, 3, 3.5, 4, 4.5, 5, 6, 10, and 24 hours post-dose at Week 2 | 
| Maximum Observed Concentration (Cmax) of GSK3640254 at Steady State | Blood samples were collected at indicated time points for PK analysis of GSK3640254. | Pre-dose, 1, 2, 3, 3.5, 4, 4.5, 5, 6, 10, and 24 hours post-dose at Week 2 | 
| Observed Pre-dose Plasma Concentration (C0) of GSK3640254 at Steady State | Blood samples were collected at indicated time points for PK analysis of GSK3640254. Observed pre-dose plasma concentration was determined directly from the concentration-time data. | Pre-dose, 1, 2, 3, 3.5, 4, 4.5, 5, 6, 10, and 24 hours post-dose at Week 2 | 
| Time to Cmax (Tmax) of GSK3640254 at Steady State | Blood samples were collected at indicated time points for PK analysis of GSK3640254. Tmax was determined directly from the concentration-time data. | Pre-dose, 1, 2, 3, 3.5, 4, 4.5, 5, 6, 10, and 24 hours post-dose at Week 2 | 
| Steady State Oral Clearance (CLt/F) of GSK3640254 | Blood samples were collected at indicated time points for PK analysis of GSK3640254. | Pre-dose, 1, 2, 3, 3.5, 4, 4.5, 5, 6, 10, and 24 hours post-dose at Week 2 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HIV infection, GSK3640254, Nucleoside Reverse Transcriptase Inhibitor, Dolutegravir, Abacavir (ABC)/Lamivudine (3TC), Emtricitabine (FTC)/tenofovir alafenamide (TAF), Maturation Inhibitor