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

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ClinicalTrials.gov Identifier: NCT04493216
Recruitment Status : Recruiting
First Posted : July 30, 2020
Last Update Posted : October 5, 2021
Sponsor:
Information provided by (Responsible Party):
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 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])

Condition or disease Intervention/treatment Phase
HIV Infections Drug: GSK3640254 Drug: ABC/3TC Drug: FTC/TAF Drug: Dolutegravir Drug: Placebo Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 150 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: This is a randomized, multicenter, parallel group study.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: The study treatment assignments will not be blinded (GSK3640254 versus Dolutegravir control arm). However, the dose level of GSK3640254 in each of the treatment arms containing GSK3640254 will be blinded to the research participants and all study personnel during the study. The Sponsor personnel will also remain blinded until the database lock for the Week 24 analysis.
Primary Purpose: Treatment
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
Actual Study Start Date : November 18, 2020
Estimated Primary Completion Date : October 10, 2022
Estimated Study Completion Date : December 13, 2028

Resource links provided by the National Library of Medicine

MedlinePlus related topics: HIV/AIDS

Arm Intervention/treatment
Experimental: Blinded GSK3640254 100 mg + GSK3640254 matching placebo + Open Label ABC/3TC or FTC/TAF Drug: GSK3640254
GSK3640254 will be available as a 25 mg and 100 mg tablets to be administered via oral route.

Drug: ABC/3TC
ABC/3TC will be available as abacavir 600 mg/lamivudine 300 mg tablet to be administered via oral route.

Drug: FTC/TAF
FTC/TAF will be available as emtricitabine 200 mg/tenofovir alafenamide 25 mg tablet to be administered via oral route.

Drug: Placebo
Placebo matching GSK3640254 will be administered in the form of tablets via oral route.

Experimental: Blinded GSK3640254 150 mg + Open Label ABC/3TC or FTC/TAF Drug: GSK3640254
GSK3640254 will be available as a 25 mg and 100 mg tablets to be administered via oral route.

Drug: ABC/3TC
ABC/3TC will be available as abacavir 600 mg/lamivudine 300 mg tablet to be administered via oral route.

Drug: FTC/TAF
FTC/TAF will be available as emtricitabine 200 mg/tenofovir alafenamide 25 mg tablet to be administered via oral route.

Experimental: Blinded GSK3640254 200 mg + GSK3640254 matching placebo + Open Label ABC/3TC or FTC/TAF Drug: GSK3640254
GSK3640254 will be available as a 25 mg and 100 mg tablets to be administered via oral route.

Drug: ABC/3TC
ABC/3TC will be available as abacavir 600 mg/lamivudine 300 mg tablet to be administered via oral route.

Drug: FTC/TAF
FTC/TAF will be available as emtricitabine 200 mg/tenofovir alafenamide 25 mg tablet to be administered via oral route.

Drug: Placebo
Placebo matching GSK3640254 will be administered in the form of tablets via oral route.

Active Comparator: Open Label DTG + Open Label ABC/3TC or FTC/TAF Drug: ABC/3TC
ABC/3TC will be available as abacavir 600 mg/lamivudine 300 mg tablet to be administered via oral route.

Drug: FTC/TAF
FTC/TAF will be available as emtricitabine 200 mg/tenofovir alafenamide 25 mg tablet to be administered via oral route.

Drug: Dolutegravir
Dolutegravir will be available as a 50 mg tablet to be administered via oral route.




Primary Outcome Measures :
  1. Proportion of participants with plasma HIV-1 ribonucleic acid (RNA) <50 copies per milliliter (c/mL) at Week 24 [ Time Frame: At Week 24 ]

Secondary Outcome Measures :
  1. Proportion of participants with plasma HIV-1 RNA <50 c/mL at Weeks 48 and 96 [ Time Frame: At Weeks 48 and 96 ]
  2. Absolute values of HIV-1 RNA at Weeks 24, 48 and 96 [ Time Frame: At Weeks 24, 48 and 96 ]
  3. Change from Baseline in plasma HIV-1 RNA at Weeks 24, 48 and 96 (c/mL) [ Time Frame: Baseline and at Weeks 24, 48 and 96 ]
  4. Absolute values of Cluster of differentiation 4 plus (CD4+) cell counts at Weeks 24, 48 and 96 [ Time Frame: At Weeks 24, 48 and 96 ]
  5. Change from Baseline in CD4+ cell counts at Weeks 24, 48 and 96 (Cells per cubic millimeters [cells/mm^3]) [ Time Frame: Baseline and at Weeks 24, 48 and 96 ]
  6. Number of participants with Adverse events (AEs), serious adverse events (SAEs), Deaths and adverse events (AEs) leading to treatment discontinuation at Weeks 24, 48 and 96 [ Time Frame: At Weeks 24, 48 and 96 ]
  7. Severity of AEs at Weeks 24, 48 and 96 [ Time Frame: At Weeks 24, 48 and 96 ]
  8. Number of participants who develop phenotypic and genotypic resistance resistance at Weeks 24, 48 and 96 [ Time Frame: At Weeks 24, 48 and 96 ]
  9. Maximum observed concentration (Cmax) of GSK3640254 at steady state at Weeks 24 and 48 [ Time Frame: At Weeks 24 and 48 ]
  10. AUC over the dosing interval (AUC [0-tau]) of GSK3640254 at Weeks 24 and 48 [ Time Frame: At Weeks 24 and 48 ]
  11. Plasma concentration at the end of the dosing (Ctau) of GSK3640254 at steady state at Weeks 24 and 48 [ Time Frame: At Weeks 24 and 48 ]


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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 >=300 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:

    1. Participants positive for HBsAg are excluded;
    2. 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), ALT, 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).
  • To assess any potential impact on participant eligibility with regard to safety, the Investigator must refer to the investigator's brochure (IB) and supplements, approved product labels, and/or local prescribing information for detailed information regarding warnings, precautions, contraindications, AEs, drug interactions, and other significant data pertaining to the study interventions.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04493216


Contacts
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Contact: US GSK Clinical Trials Call Center 877-379-3718 GSKClinicalSupportHD@gsk.com
Contact: EU GSK Clinical Trials Call Center +44 (0) 20 89904466 GSKClinicalSupportHD@gsk.com

Locations
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Sponsors and Collaborators
ViiV Healthcare
Investigators
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Study Director: GSK Clinical Trials ViiV Healthcare
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Responsible Party: ViiV Healthcare
ClinicalTrials.gov Identifier: NCT04493216    
Other Study ID Numbers: 208379
First Posted: July 30, 2020    Key Record Dates
Last Update Posted: October 5, 2021
Last Verified: October 2021
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, 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

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by ViiV Healthcare:
HIV infection
GSK3640254
Nucleoside Reverse Transcriptase Inhibitor
Dolutegravir
Abacavir (ABC)/Lamivudine (3TC)
Emtricitabine (FTC)/tenofovir alafenamide (TAF)
Maturation Inhibitor
Additional relevant MeSH terms:
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HIV Infections
Infections
Blood-Borne Infections
Communicable Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Immunologic Deficiency Syndromes
Immune System Diseases
Dolutegravir
HIV Integrase Inhibitors
Integrase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-HIV Agents
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents