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

• ClinicalTrials.gov Identifier: NCT04900038
• Recruitment Status: Terminated
• First Posted: May 25, 2021
• Results First Posted: December 14, 2023
• Last Update Posted: December 14, 2023
• Sponsor: ViiV Healthcare
• Collaborator: Syneos Health
• Information provided by (Responsible Party): ViiV Healthcare

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
HIV Infections	Drug: GSK3640254; Drug: Dolutegravir; Drug: Lamivudine capsules; Drug: Lamivudine tablets	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 85 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: This is a randomized, parallel-group study.
• Masking: Double (Participant, Investigator)
• Masking Description: The dose level of GSK3640254 in each of the treatment arms containing GSK3640254 was blinded to the research participants and all study personnel during the study through the Week 24 primary endpoint.
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: August 18, 2021
• Actual Primary Completion Date: November 22, 2022
• Actual Study Completion Date: May 11, 2023

Arms and Interventions

Arm	Intervention/treatment
Experimental: GSK3640254 100 mg + Dolutegravir (DTG) 50 mg; 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; GSK3640254 was available as 25 mg or 100 mg tablets administered orally.; Drug: Dolutegravir; DTG was available as 50 mg tablets administered orally.
Experimental: GSK3640254 150 mg + DTG 50 mg; 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; GSK3640254 was available as 25 mg or 100 mg tablets administered orally.; Drug: Dolutegravir; DTG was available as 50 mg tablets administered orally.
Experimental: GSK3640254 200 mg + DTG 50 mg; 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; GSK3640254 was available as 25 mg or 100 mg tablets administered orally.; Drug: Dolutegravir; DTG was available as 50 mg tablets administered orally.
Active Comparator: DTG 50 mg + Lamivudine (3TC) 300 mg; 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; DTG was available as 50 mg tablets administered orally.; Drug: Lamivudine capsules; 3TC was available as 300 mg capsules administered orally as a blinded treatment.; Drug: Lamivudine tablets; 3TC was available as 300 mg tablets administered orally as an unblinded treatment.

Outcome Measures

Primary Outcome Measures :

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

Secondary Outcome Measures :

1. Absolute Values of HIV-1 RNA Through Week 24 [ Time Frame: At Baseline (Day 1) and 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.
2. Change From Baseline in HIV-1 RNA Through Week 24 [ Time Frame: At Week 24 compared to baseline (Day 1) ]
   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.
3. Absolute Values of Cluster of Differentiation 4+ (CD4+) T-cell Counts Through Week 24 [ Time Frame: At Baseline (Day 1) and 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.
4. Change From Baseline in CD4+ T-cell Counts Through Week 24 [ Time Frame: At Week 24 compared to baseline (Day 1) ]
   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.
5. Number of Participants With Serious Adverse Events (SAEs) and Deaths, up to End of Continued Access to Treatment Post-study Termination (Day 478) [ Time Frame: From Day 1 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).

6. Number of Participants With Adverse Events (AEs) Leading to Discontinuation, up to End of Continued Access to Treatment Post-study Termination (Day 478) [ Time Frame: From Day 1 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).
7. Number of Participants With Adverse Events of Special Interest (AESIs), up to End of Continued Access to Treatment Post-study Termination (Day 478) [ Time Frame: From Day 1 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).

8. Number of Participants Who Develop Genotypic Resistance up to Week 24 [ Time Frame: From Day 1 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).

9. Number of Participants Who Develop Phenotypic Resistance up to Week 24 [ Time Frame: From Day 1 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).
10. Trough Concentration (Ctrough) of GSK3640254 at Weeks 2, 4, 8, 12 and 24 [ Time Frame: At Weeks 2, 4, 8, 12 (PRE DOSE), 12 (2-6HR POST DOSE), 24 (PRE DOSE), 24 (2-6HR POST DOSE) ]
    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.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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.

Contacts and Locations

Locations

United States, California

GSK Investigational Site

Bakersfield, California, United States, 93301

GSK Investigational Site

Palm Springs, California, United States, 92262

United States, Colorado

GSK Investigational Site

Denver, Colorado, United States, 80246

United States, Florida

GSK Investigational Site

Fort Pierce, Florida, United States, 34982

GSK Investigational Site

Miami, Florida, United States, 33140

GSK Investigational Site

Orlando, Florida, United States, 32806

United States, Missouri

GSK Investigational Site

Kansas City, Missouri, United States, 64111

United States, Nebraska

GSK Investigational Site

Omaha, Nebraska, United States, 68198

Argentina

GSK Investigational Site

Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina, C1405CKC

GSK Investigational Site

Buenos Aires, Argentina, C1202ABB

GSK Investigational Site

Buenos Aires, Argentina, C1425AGC

Canada, Quebec

GSK Investigational Site

Montreal, Quebec, Canada, H2L 4E9

GSK Investigational Site

Montreal, Quebec, Canada, H2L 4P9

France

GSK Investigational Site

Paris, France, 75012

GSK Investigational Site

Tourcoing cedex, France, 59208

Germany

GSK Investigational Site

Frankfurt, Hessen, Germany, 60596

GSK Investigational Site

Koeln, Nordrhein-Westfalen, Germany, 50668

GSK Investigational Site

Berlin, Germany, 10787

GSK Investigational Site

Hamburg, Germany, 20146

Italy

GSK Investigational Site

Bergamo, Lombardia, Italy, 24127

GSK Investigational Site

Milano, Lombardia, Italy, 20127

Portugal

GSK Investigational Site

Porto, Portugal, 4369-004

GSK Investigational Site

Vila Nova de Gaia, Portugal, 4434-502

Puerto Rico

GSK Investigational Site

San Juan, Puerto Rico, 00909

South Africa

GSK Investigational Site

Durban, South Africa, 4091

GSK Investigational Site

Johannesburg, South Africa, 2113

GSK Investigational Site

Parow, South Africa, 7505

GSK Investigational Site

Vosloorus Ext 2, South Africa, 1475

Spain

GSK Investigational Site

Barcelona, Spain, 08036

GSK Investigational Site

Barcelona, Spain, 08907

GSK Investigational Site

Barcelona, Spain, 8003

GSK Investigational Site

Bilbao, Spain, 48013

GSK Investigational Site

Elche, Spain, ?03203

GSK Investigational Site

La Laguna-Tenerife, Spain, 38320

GSK Investigational Site

Madrid, Spain, 28007

GSK Investigational Site

Madrid, Spain, 28031

GSK Investigational Site

Madrid, Spain, 28040

GSK Investigational Site

Madrid, Spain, 28041

GSK Investigational Site

Madrid, Spain, 28046

GSK Investigational Site

Murcia, Spain, 30120

GSK Investigational Site

Palma de Mallorca, Spain, 07198

GSK Investigational Site

Sant Boi de Llobregat, Spain, 08830

GSK Investigational Site

Valencia, Spain, 46026

GSK Investigational Site

Vigo, Spain, 36312

Sponsors and Collaborators

ViiV Healthcare

Syneos Health

Investigators

• Study Director: GSK Clinical Trials; ViiV Healthcare

  Study Documents (Full-Text)

Documents provided by ViiV Healthcare:

Study Protocol  [PDF] August 11, 2022

Statistical Analysis Plan  [PDF] May 19, 2023

More Information

• Responsible Party: ViiV Healthcare
• ClinicalTrials.gov Identifier: NCT04900038
• Other Study ID Numbers: 212483
• First Posted: May 25, 2021
• Results First Posted: December 14, 2023
• Last Update Posted: December 14, 2023
• Last Verified: November 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: IPD for this study will be made available via the Clinical Study Data Request site.
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Clinical Study Report (CSR)
• Time Frame: IPD will be made available within 6 months of publishing the results of the primary endpoints, a key secondary endpoints and safety data of the study.
• Access Criteria: Access is provided after a research proposal is submitted and has received approval from the Independent Review Panel and after a Data Sharing Agreement is in place. Access is provided for an initial period of 12 months but an extension can be granted, when justified, for up to another 12 months.
• URL: http://clinicalstudydatarequest.com

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by ViiV Healthcare:

Human immunodeficiency virus-1; GSK3640254; Dolutegravir; Lamivudine; Treatment-naive

Additional relevant MeSH terms:

HIV Infections; Blood-Borne Infections; Communicable Diseases; Infections; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Genital Diseases; Urogenital Diseases; Immunologic Deficiency Syndromes; Immune System Diseases; Lamivudine; Dolutegravir; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Antiviral Agents; Anti-Infective Agents; Anti-HIV Agents; Anti-Retroviral Agents; HIV Integrase Inhibitors; Integrase Inhibitors