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

Phase 2

Terminated

• Conditions: HIV Infections
• Interventions: Drug: GSK3640254; Drug: ABC/3TC; Drug: FTC/TAF; Drug: Dolutegravir; Drug: Placebo

• Registration Number: NCT04493216
• Lead Sponsor: ViiV Healthcare

Brief Summary

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 aims 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 \[FTC/TAF\]).

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2020-07-10
• Study First Submitted QC: 2020-07-27
• Study First Posted: 2020-07-30
• Study Start: 2020-11-18
• Primary Completion: 2022-09-05
• Study Completion: 2023-05-29
• Results First Submitted: 2023-09-05
• Results First Submitted QC: 2023-10-26
• Results First Posted: 2023-11-18
• Status Verified: 2024-05
• Last Update Submitted: 2024-05-29
• Last Update Posted: 2024-06-26

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 161

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 utilized 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 was female at birth was eligible to participate if they were not pregnant or breastfeeding, and one of the following conditions applies:

  • Was a participant of non-childbearing potential (PONCBP)
  • Or was 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 was 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:

  1. Participants positive for HBsAg were excluded;
  2. Participants negative for anti-HBs but positive for anti-HBc (negative HBsAg status) and positive for HBV DNA on reflex testing were 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).

Exclusion Criteria

Not provided

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
GSK3640254 150 mg + ABC/3TC or FTC/TAF	GSK3640254	Participants with HIV-1, orally received 150 mg (one 100 mg tablet + two 25 mg tablets per day) of GSK3640254 in a blinded setting. Open label dual NRTI background therapies were given as one tablet per day combination of 600 mg ABC / 300 mg 3TC OR 200 mg FTC / 25 mg TAF orally.
GSK3640254 100 mg+ Placebo+ ABC/3TC or FTC/TAF	ABC/3TC	Participants with human immunodeficiency virus type 1 (HIV-1), orally received one 100 mg tablet per day of GSK3640254 and two tablets per day of matching placebo in a blinded setting. Open label dual NRTI background therapies were given as one tablet per day of 600 mg abacavir (ABC) / 300 mg lamivudine (3TC) OR 200 mg emtricitabine (FTC) / 25 mg tenofovir alafenamide (TAF) orally.
GSK3640254 100 mg+ Placebo+ ABC/3TC or FTC/TAF	FTC/TAF	Participants with human immunodeficiency virus type 1 (HIV-1), orally received one 100 mg tablet per day of GSK3640254 and two tablets per day of matching placebo in a blinded setting. Open label dual NRTI background therapies were given as one tablet per day of 600 mg abacavir (ABC) / 300 mg lamivudine (3TC) OR 200 mg emtricitabine (FTC) / 25 mg tenofovir alafenamide (TAF) orally.
GSK3640254 100 mg+ Placebo+ ABC/3TC or FTC/TAF	Placebo	Participants with human immunodeficiency virus type 1 (HIV-1), orally received one 100 mg tablet per day of GSK3640254 and two tablets per day of matching placebo in a blinded setting. Open label dual NRTI background therapies were given as one tablet per day of 600 mg abacavir (ABC) / 300 mg lamivudine (3TC) OR 200 mg emtricitabine (FTC) / 25 mg tenofovir alafenamide (TAF) orally.
GSK3640254 150 mg + ABC/3TC or FTC/TAF	ABC/3TC	Participants with HIV-1, orally received 150 mg (one 100 mg tablet + two 25 mg tablets per day) of GSK3640254 in a blinded setting. Open label dual NRTI background therapies were given as one tablet per day combination of 600 mg ABC / 300 mg 3TC OR 200 mg FTC / 25 mg TAF orally.
GSK3640254 150 mg + ABC/3TC or FTC/TAF	FTC/TAF	Participants with HIV-1, orally received 150 mg (one 100 mg tablet + two 25 mg tablets per day) of GSK3640254 in a blinded setting. Open label dual NRTI background therapies were given as one tablet per day combination of 600 mg ABC / 300 mg 3TC OR 200 mg FTC / 25 mg TAF orally.
GSK3640254 200 mg+ Placebo+ ABC/3TC or FTC/TAF	GSK3640254	Participants with HIV-1, orally received two 100 mg tablets (200 mg) per day of GSK3640254 and one tablet per day of matching placebo in a blinded setting. Open label dual NRTI background therapies were given as one tablet per day combination of 600 mg ABC / 300 mg 3TC OR 200 mg FTC / 25 mg TAF orally.
GSK3640254 200 mg+ Placebo+ ABC/3TC or FTC/TAF	ABC/3TC	Participants with HIV-1, orally received two 100 mg tablets (200 mg) per day of GSK3640254 and one tablet per day of matching placebo in a blinded setting. Open label dual NRTI background therapies were given as one tablet per day combination of 600 mg ABC / 300 mg 3TC OR 200 mg FTC / 25 mg TAF orally.
GSK3640254 200 mg+ Placebo+ ABC/3TC or FTC/TAF	FTC/TAF	Participants with HIV-1, orally received two 100 mg tablets (200 mg) per day of GSK3640254 and one tablet per day of matching placebo in a blinded setting. Open label dual NRTI background therapies were given as one tablet per day combination of 600 mg ABC / 300 mg 3TC OR 200 mg FTC / 25 mg TAF orally.
GSK3640254 200 mg+ Placebo+ ABC/3TC or FTC/TAF	Placebo	Participants with HIV-1, orally received two 100 mg tablets (200 mg) per day of GSK3640254 and one tablet per day of matching placebo in a blinded setting. Open label dual NRTI background therapies were given as one tablet per day combination of 600 mg ABC / 300 mg 3TC OR 200 mg FTC / 25 mg TAF orally.
Dolutegravir (DTG) 50 mg + ABC/3TC or FTC/TAF	ABC/3TC	Participants with HIV-1, orally received one 50 mg tablet per day of DTG in an open label setting. Open label dual NRTI background therapies were given as one tablet per day combination of 600 mg ABC / 300 mg 3TC OR 200 mg FTC / 25 mg TAF orally.
Dolutegravir (DTG) 50 mg + ABC/3TC or FTC/TAF	FTC/TAF	Participants with HIV-1, orally received one 50 mg tablet per day of DTG in an open label setting. Open label dual NRTI background therapies were given as one tablet per day combination of 600 mg ABC / 300 mg 3TC OR 200 mg FTC / 25 mg TAF orally.
GSK3640254 100 mg+ Placebo+ ABC/3TC or FTC/TAF	GSK3640254	Participants with human immunodeficiency virus type 1 (HIV-1), orally received one 100 mg tablet per day of GSK3640254 and two tablets per day of matching placebo in a blinded setting. Open label dual NRTI background therapies were given as one tablet per day of 600 mg abacavir (ABC) / 300 mg lamivudine (3TC) OR 200 mg emtricitabine (FTC) / 25 mg tenofovir alafenamide (TAF) orally.
Dolutegravir (DTG) 50 mg + ABC/3TC or FTC/TAF	Dolutegravir	Participants with HIV-1, orally received one 50 mg tablet per day of DTG in an open label setting. Open label dual NRTI background therapies were given as one tablet per day combination of 600 mg ABC / 300 mg 3TC OR 200 mg FTC / 25 mg TAF orally.

Primary Outcome Measures

Name	Time	Method
Percentage of Participants With Plasma HIV-1 Ribonucleic Acid (RNA) Less Than (<)50 Copies Per Milliliter (c/mL) at Week 24	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.

Secondary Outcome Measures

Name	Time	Method
Absolute Values of HIV-1 RNA at Weeks 24 and 48	Baseline (Day 1) and 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.
Absolute Values of Cluster of Differentiation 4 Plus (CD4+) Cell Counts at Weeks 24 and 48	Baseline (Day 1) and 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 in CD4+ Cell Counts at Weeks 24 and 48	Baseline (Day 1) and 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.
Percentage of Participants With Plasma HIV-1 RNA <50 c/mL at Week 48	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.
Change From Baseline in Plasma HIV-1 RNA at Weeks 24 and 48	Baseline (Day 1) and 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.
Number of Participants With Serious Adverse Events (SAEs) and Deaths	From Day 1 up to end of continued access to treatment post-study termination (Day 922)	An SAE was defined as any serious adverse event that, at any dose resulted in death, was life threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect, or any other situation according to medical or scientific judgment.
Number of Participants With Adverse Events (AEs) Leading to Treatment Discontinuation	From Day 1 up to end of continued access to treatment post-study termination (Day 922)	An AE was 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.
Number of Participants With AEs Based on Maximum Severity Grades	From Day 1 up to end of continued access to treatment post-study termination (Day 922)	An AE was 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 Genotypic Resistance	Baseline (Day 1) and at Weeks 24 and 48	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.
Number of Participants With AEs of Special Interest (AESI)	From Day 1 up to end of continued access to treatment post-study termination (Day 922)	An AE was 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.
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	Pre-dose, 1, 2, 3, 3.5, 4, 4.5, 5, 6, 10, and 24 hours post-dose at Week 2	Blood samples were collected at indicated time points for PK analysis of GSK3640254.
Number of Participants With Phenotypic Resistance	Baseline (Day 1) and at Weeks 24 and 48	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.
Observed Plasma Concentration at the End of the Dosing Interval (Ctau) of GSK3640254 at Steady State - Weeks 24 and 48	At 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.
Observed Plasma Concentration at the End of the Dosing Interval (Ctau) of GSK3640254 at Steady State - Week 2	Pre-dose, 1, 2, 3, 3.5, 4, 4.5, 5, 6, 10, and 24 hours post-dose at 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.
Maximum Observed Concentration (Cmax) of GSK3640254 at Steady State	Pre-dose, 1, 2, 3, 3.5, 4, 4.5, 5, 6, 10, and 24 hours post-dose at Week 2	Blood samples were collected at indicated time points for PK analysis of GSK3640254.
Observed Pre-dose Plasma Concentration (C0) of GSK3640254 at Steady State	Pre-dose, 1, 2, 3, 3.5, 4, 4.5, 5, 6, 10, and 24 hours post-dose at Week 2	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.
Time to Cmax (Tmax) of GSK3640254 at Steady State	Pre-dose, 1, 2, 3, 3.5, 4, 4.5, 5, 6, 10, and 24 hours post-dose at Week 2	Blood samples were collected at indicated time points for PK analysis of GSK3640254. Tmax was determined directly from the concentration-time data.
Steady State Oral Clearance (CLt/F) of GSK3640254	Pre-dose, 1, 2, 3, 3.5, 4, 4.5, 5, 6, 10, and 24 hours post-dose at Week 2	Blood samples were collected at indicated time points for PK analysis of GSK3640254.

Trial Locations

Locations (1)

GSK Investigational Site; 🇨🇭 Zuerich, Switzerland