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

Sponsor

ViiV Healthcare (Industry)

Overall Status

Active, not recruiting

CT.gov ID

NCT04493216

Collaborator

(none)

150

Enrollment

Locations

Arms

95.1

Anticipated Duration (Months)

2.3

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This is a phase 2b, randomized, multicenter, parallel group, partially blind (to GSK3640254 doses [100, 150 and 200 milligrams ]), 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

Study Design

Study Type:

Interventional

Anticipated Enrollment :

150 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

This is a randomized, multicenter, parallel group study.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 :

Nov 18, 2020

Anticipated Primary Completion Date :

Sep 5, 2022

Anticipated Study Completion Date :

Oct 23, 2028

Arms and Interventions

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.

Outcome Measures

Primary Outcome Measures

Proportion of participants with plasma HIV-1 ribonucleic acid (RNA) <50 copies per milliliter (c/mL) at Week 24 [At Week 24]

Secondary Outcome Measures

Proportion of participants with plasma HIV-1 RNA <50 c/mL at Weeks 48 and 96 [At Weeks 48 and 96]
Absolute values of HIV-1 RNA at Weeks 24, 48 and 96 [At Weeks 24, 48 and 96]
Change from Baseline in plasma HIV-1 RNA at Weeks 24, 48 and 96 (c/mL) [Baseline and at Weeks 24, 48 and 96]
Absolute values of Cluster of differentiation 4 plus (CD4+) cell counts at Weeks 24, 48 and 96 [At Weeks 24, 48 and 96]
Change from Baseline in CD4+ cell counts at Weeks 24, 48 and 96 (Cells per cubic millimeters [cells/mm^3]) [Baseline and at Weeks 24, 48 and 96]
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 [At Weeks 24, 48 and 96]
Severity of AEs at Weeks 24, 48 and 96 [At Weeks 24, 48 and 96]
Number of participants who develop phenotypic and genotypic resistance resistance at Weeks 24, 48 and 96 [At Weeks 24, 48 and 96]
Maximum observed concentration (Cmax) of GSK3640254 at steady state at Weeks 24 and 48 [At Weeks 24 and 48]
AUC over the dosing interval (AUC [0-tau]) of GSK3640254 at Weeks 24 and 48 [At Weeks 24 and 48]
Plasma concentration at the end of the dosing (Ctau) of GSK3640254 at steady state at Weeks 24 and 48 [At Weeks 24 and 48]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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).

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	GSK Investigational Site	Los Angeles	California	United States	90027
2	GSK Investigational Site	Fort Pierce	Florida	United States	34982
3	GSK Investigational Site	Orlando	Florida	United States	32803
4	GSK Investigational Site	Orlando	Florida	United States	32806
5	GSK Investigational Site	Berkley	Michigan	United States	48072
6	GSK Investigational Site	Jackson	Mississippi	United States	39216-4505
7	GSK Investigational Site	Omaha	Nebraska	United States	68198
8	GSK Investigational Site	Cincinnati	Ohio	United States	45267-0405
9	GSK Investigational Site	Dallas	Texas	United States	75246
10	GSK Investigational Site	Ciudad Autonoma de Buenos Aires	Buenos Aires	Argentina	C1128AAF
11	GSK Investigational Site	Ciudad Autonoma de Buenos Aires	Buenos Aires	Argentina	C1207AAP
12	GSK Investigational Site	Ciudad Autonoma de Buenos Aires	Buenos Aires	Argentina	C1425AGC
13	GSK Investigational Site	Ciudad Autonoma de Buenos Aires	Buenos Aires	Argentina	C1425AWK
14	GSK Investigational Site	Ciudad Autónoma de Buenos Aires	Buenos Aires	Argentina	C1405CKC
15	GSK Investigational Site	Ciudad de Buenos Aires	Buenos Aires	Argentina	C1202ABB
16	GSK Investigational Site	Buenos Aires		Argentina	1141
17	GSK Investigational Site	San Juan		Argentina	5400
18	GSK Investigational Site	Ottawa	Ontario	Canada	K1H 8L6
19	GSK Investigational Site	Toronto	Ontario	Canada	M5B 1W8
20	GSK Investigational Site	Montreal	Quebec	Canada	H2L 4E9
21	GSK Investigational Site	Montreal	Quebec	Canada	H2L 4P9
22	GSK Investigational Site	Montreal	Quebec	Canada	H4A 3J1
23	GSK Investigational Site	Marseille		France	13003
24	GSK Investigational Site	Paris		France	75018
25	GSK Investigational Site	Tourcoing cedex		France	59208
26	GSK Investigational Site	Muenchen	Bayern	Germany	81675
27	GSK Investigational Site	Bochum	Nordrhein-Westfalen	Germany	44787
28	GSK Investigational Site	Koeln	Nordrhein-Westfalen	Germany	50674
29	GSK Investigational Site	Roma	Lazio	Italy	00149
30	GSK Investigational Site	Milano	Lombardia	Italy	20127
31	GSK Investigational Site	Milano	Lombardia	Italy	20157
32	GSK Investigational Site	Torino	Piemonte	Italy	10149
33	GSK Investigational Site	Brescia		Italy	25123
34	GSK Investigational Site	Milano		Italy	20157
35	GSK Investigational Site	Almada		Portugal	2801-951
36	GSK Investigational Site	Aveiro		Portugal	3814-501
37	GSK Investigational Site	Porto		Portugal	4099-001
38	GSK Investigational Site	Porto		Portugal	4200-319
39	GSK Investigational Site	Kazan		Russian Federation	420061
40	GSK Investigational Site	Saint-Petersburg		Russian Federation	191167
41	GSK Investigational Site	Samara		Russian Federation	443029
42	GSK Investigational Site	Smolensk		Russian Federation	214006
43	GSK Investigational Site	St. Petersburg		Russian Federation	190103
44	GSK Investigational Site	Johannesburg	Gauteng	South Africa	2113
45	GSK Investigational Site	Wentworth	KwaZulu- Natal	South Africa	4052
46	GSK Investigational Site	Observatory, Cape Town		South Africa	7925
47	GSK Investigational Site	Vosloorus Ext 2		South Africa	1475
48	GSK Investigational Site	Alicante		Spain	03010
49	GSK Investigational Site	Badalona, Barcelona		Spain	8916
50	GSK Investigational Site	Barcelona		Spain	08025
51	GSK Investigational Site	Barcelona		Spain	08035
52	GSK Investigational Site	L'Hospitalet de Llobregat		Spain	08907
53	GSK Investigational Site	La Coruña		Spain	15006
54	GSK Investigational Site	Madrid		Spain	28006
55	GSK Investigational Site	Madrid		Spain	28034
56	GSK Investigational Site	Madrid		Spain	28040
57	GSK Investigational Site	Madrid		Spain	28046
58	GSK Investigational Site	Malaga		Spain	29010
59	GSK Investigational Site	Marbella		Spain	29600
60	GSK Investigational Site	Murcia		Spain	30003
61	GSK Investigational Site	Palma de Mallorca		Spain	07010
62	GSK Investigational Site	Sevilla		Spain	41013
63	GSK Investigational Site	Sevilla		Spain	41014
64	GSK Investigational Site	Valencia		Spain	46010
65	GSK Investigational Site	Valencia		Spain	46014
66	GSK Investigational Site	Zuerich		Switzerland	8091