Clinical trial NCT04493216: A Dose-Range Finding Clinical Trial Study in Human Immunodeficiency Virus (HIV-1) Infected Treatment-Naive Adults
Official title: 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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: HIV Infections
Keywords: HIV infection
GSK3640254
Nucleoside Reverse Transcriptase Inhibitor
Dolutegravir
Abacavir (ABC)/Lamivudine (3TC)
Emtricitabine (FTC)/tenofovir alafenamide (TAF)
Maturation Inhibitor
Lead sponsor: ViiV Healthcare
Sponsor class: INDUSTRY
First posted: 2020-07-30
Enrollment: 161
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: This is a randomized, multicenter, parallel group study.
Primary purpose: TREATMENT

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 \[FTC/TAF\]).


Eligibility criteria: 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).

Primary outcomes:
measure: Percentage of Participants With Plasma HIV-1 Ribonucleic Acid (RNA) Less Than (<)50 Copies Per Milliliter (c/mL) at Week 24
timeFrame: At Week 24
Secondary outcomes:
measure: Percentage of Participants With Plasma HIV-1 RNA <50 c/mL at Week 48
timeFrame: At Week 48
measure: Absolute Values of HIV-1 RNA at Weeks 24 and 48
timeFrame: Baseline (Day 1) and at Weeks 24 and 48
measure: Change From Baseline in Plasma HIV-1 RNA at Weeks 24 and 48
timeFrame: Baseline (Day 1) and at Weeks 24 and 48
measure: Absolute Values of Cluster of Differentiation 4 Plus (CD4+) Cell Counts at Weeks 24 and 48
timeFrame: Baseline (Day 1) and at Weeks 24 and 48
measure: Change From Baseline in CD4+ Cell Counts at Weeks 24 and 48
timeFrame: Baseline (Day 1) and at Weeks 24 and 48
measure: Number of Participants With Serious Adverse Events (SAEs) and Deaths
timeFrame: From Day 1 up to end of continued access to treatment post-study termination (Day 922)
measure: Number of Participants With Adverse Events (AEs) Leading to Treatment Discontinuation
timeFrame: From Day 1 up to end of continued access to treatment post-study termination (Day 922)
measure: Number of Participants With AEs Based on Maximum Severity Grades
timeFrame: From Day 1 up to end of continued access to treatment post-study termination (Day 922)
measure: Number of Participants With AEs of Special Interest (AESI)
timeFrame: From Day 1 up to end of continued access to treatment post-study termination (Day 922)
measure: Number of Participants With Genotypic Resistance
timeFrame: Baseline (Day 1) and at Weeks 24 and 48
measure: Number of Participants With Phenotypic Resistance
timeFrame: Baseline (Day 1) and at Weeks 24 and 48
measure: Observed Plasma Concentration at the End of the Dosing Interval (Ctau) of GSK3640254 at Steady State - Week 2
timeFrame: Pre-dose, 1, 2, 3, 3.5, 4, 4.5, 5, 6, 10, and 24 hours post-dose at Week 2
measure: Observed Plasma Concentration at the End of the Dosing Interval (Ctau) of GSK3640254 at Steady State - Weeks 24 and 48
timeFrame: At Weeks 24 and 48
measure: 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
timeFrame: Pre-dose, 1, 2, 3, 3.5, 4, 4.5, 5, 6, 10, and 24 hours post-dose at Week 2
measure: Maximum Observed Concentration (Cmax) of GSK3640254 at Steady State
timeFrame: Pre-dose, 1, 2, 3, 3.5, 4, 4.5, 5, 6, 10, and 24 hours post-dose at Week 2
measure: Observed Pre-dose Plasma Concentration (C0) of GSK3640254 at Steady State
timeFrame: Pre-dose, 1, 2, 3, 3.5, 4, 4.5, 5, 6, 10, and 24 hours post-dose at Week 2
measure: Time to Cmax (Tmax) of GSK3640254 at Steady State
timeFrame: Pre-dose, 1, 2, 3, 3.5, 4, 4.5, 5, 6, 10, and 24 hours post-dose at Week 2
measure: Steady State Oral Clearance (CLt/F) of GSK3640254
timeFrame: Pre-dose, 1, 2, 3, 3.5, 4, 4.5, 5, 6, 10, and 24 hours post-dose at Week 2
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: GSK Investigational Site
state: California
city: Fort Pierce
country: United States
facility: GSK Investigational Site
state: Florida
city: Orlando
country: United States
facility: GSK Investigational Site
state: Florida
city: Orlando
country: United States
facility: GSK Investigational Site
state: Florida
city: Berkley
country: United States
facility: GSK Investigational Site
state: Michigan
city: Jackson
country: United States
facility: GSK Investigational Site
state: Mississippi
city: Omaha
country: United States
facility: GSK Investigational Site
state: Nebraska
city: Cincinnati
country: United States
facility: GSK Investigational Site
state: Ohio
city: Dallas
country: United States
facility: GSK Investigational Site
state: Texas
city: Ciudad Autonoma de Buenos Aires
country: Argentina
facility: GSK Investigational Site
state: Buenos Aires
city: Ciudad Autonoma de Buenos Aires
country: Argentina
facility: GSK Investigational Site
state: Buenos Aires
city: Ciudad Autonoma de Buenos Aires
country: Argentina
facility: GSK Investigational Site
state: Buenos Aires
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: Buenos Aires
country: Argentina
facility: GSK Investigational Site
city: Buenos Aires
country: Argentina
facility: GSK Investigational Site
city: San Juan
country: Argentina
facility: GSK Investigational Site
city: Ottawa
country: Canada
facility: GSK Investigational Site
state: Ontario
city: Montreal
country: Canada
facility: GSK Investigational Site
state: Quebec
city: Montreal
country: Canada
facility: GSK Investigational Site
state: Quebec
city: Montreal
country: Canada
facility: GSK Investigational Site
state: Quebec
city: Marseille
country: France
facility: GSK Investigational Site
city: Paris
country: France
facility: GSK Investigational Site
city: Tourcoing cedex
country: France
facility: GSK Investigational Site
city: Muenchen
country: Germany
facility: GSK Investigational Site
state: Bayern
city: Bochum
country: Germany
facility: GSK Investigational Site
state: Nordrhein-Westfalen
city: Koeln
country: Germany
facility: GSK Investigational Site
state: Nordrhein-Westfalen
city: Roma
country: Italy
facility: GSK Investigational Site
state: Lazio
city: Milano
country: Italy
facility: GSK Investigational Site
state: Lombardia
city: Milano
country: Italy
facility: GSK Investigational Site
state: Lombardia
city: Torino
country: Italy
facility: GSK Investigational Site
state: Piemonte
city: Brescia
country: Italy
facility: GSK Investigational Site
city: Milano
country: Italy
facility: GSK Investigational Site
city: Almada
country: Portugal
facility: GSK Investigational Site
city: Aveiro
country: Portugal
facility: GSK Investigational Site
city: Porto
country: Portugal
facility: GSK Investigational Site
city: Porto
country: Portugal
facility: GSK Investigational Site
city: Kazan
country: Russian Federation
facility: GSK Investigational Site
city: Saint-Petersburg
country: Russian Federation
facility: GSK Investigational Site
city: Samara
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: Johannesburg
country: South Africa
facility: GSK Investigational Site
state: Gauteng
city: Wentworth
country: South Africa
facility: GSK Investigational Site
state: KwaZulu- Natal
city: Observatory, Cape Town
country: South Africa
facility: GSK Investigational Site
city: Vosloorus Ext 2
country: South Africa
facility: GSK Investigational Site
city: Alicante
country: Spain
facility: GSK Investigational Site
city: Badalona, Barcelona
country: Spain
facility: GSK Investigational Site
city: Barcelona
country: Spain
facility: GSK Investigational Site
city: Barcelona
country: Spain
facility: GSK Investigational Site
city: L'Hospitalet de Llobregat
country: Spain
facility: GSK Investigational Site
city: La Coruña
country: Spain
facility: GSK Investigational Site
city: Madrid
country: Spain
facility: GSK Investigational Site
city: Madrid
country: Spain
facility: GSK Investigational Site
city: Madrid
country: Spain
facility: GSK Investigational Site
city: Madrid
country: Spain
facility: GSK Investigational Site
city: Malaga
country: Spain
facility: GSK Investigational Site
city: Marbella
country: Spain
facility: GSK Investigational Site
city: Murcia
country: Spain
facility: GSK Investigational Site
city: Palma de Mallorca
country: Spain
facility: GSK Investigational Site
city: Sevilla
country: Spain
facility: GSK Investigational Site
city: Sevilla
country: Spain
facility: GSK Investigational Site
city: Valencia
country: Spain
facility: GSK Investigational Site
city: Valencia
country: Spain
facility: GSK Investigational Site
city: Zuerich
country: Switzerland
facility: GSK Investigational Site
Study officials:
affiliation: ViiV Healthcare
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Spinner CD, Felizarta F, Rizzardini G, Philibert P, Mitha E, Domingo P, Stephan CJ, DeGrosky M, Bainbridge V, Zhan J, Dumitrescu TP, Jeffrey JL, Xu J, Halliday F, Gan J, Johnson M, Gartland M, Joshi SR, Lataillade M. Phase IIa Proof-of-Concept Evaluation of the Antiviral Efficacy, Safety, Tolerability, and Pharmacokinetics of the Next-Generation Maturation Inhibitor GSK3640254. Clin Infect Dis. 2022 Sep 14;75(5):786-794. doi: 10.1093/cid/ciab1065.