Clinical trial NCT05585307: Study of Novel Antiretrovirals in Participants With HIV-1
Official title: An Umbrella Phase 1b, Open-label, Multi-Cohort Study to Evaluate Safety, Pharmacokinetics, and Antiviral Activity of Novel Antiretrovirals in Participants With HIV-1
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: HIV-1-infection
Lead sponsor: Gilead Sciences
Sponsor class: INDUSTRY
First posted: 2022-10-18
Enrollment: 49
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: The Substudies were conducted in parallel. However, the cohorts within the Substudies received drug assignment sequentially.
Primary purpose: TREATMENT

Brief summary: Master protocol: The goal of this master clinical trial study is to learn how novel antiretrovirals (medicines that stop the virus from multiplying) affect the human immunodeficiency virus-1 (HIV-1) infection in people living with HIV (PWH).

Substudy-01 (GS-US-544-5905-01) will evaluate bavtavirine in PWH.

Substudy-02 (GS-US-544-5905-02) will evaluate GS-1720 in PWH.

Substudy-03 (GS-US-544-5905-03) will evaluate GS-6212 in PWH.

Detailed description: This umbrella study will begin with a substudy of bavtavirine (Substudy-01), and later substudies GS-1720 (Substudy-02) and GS-6212 (Substudy-03) will be added. Substudies evaluating additional study drugs will be added in a staggered manner when relevant nonclinical and/or clinical data become available.

* Substudy-01 enrollment closed, actual enrollment is 13.
* Substudy-02 enrollment closed, actual enrollment is 28.
* Substudy-03 enrollment closed, actual enrollment is 8.

Eligibility criteria: Key Inclusion Criteria:

All Substudies:

* Plasma human immunodeficiency virus-1 (HIV-1) ribonucleic acid (RNA) ≥ 5000 copies/mL but ≤ 400,000 copies/mL at screening.
* Cluster of differentiation 4 (CD4) cell count \> 200 cells/mm\^3 at screening.
* Antiretroviral (ARV) treatment-naive or treatment-experienced but naive to the investigational ARV drug class being investigated in the given substudy and have not received any ARV within 12 weeks of screening, including medications received for pre-exposure prophylaxis (PrEP) or postexposure prophylaxis (PEP) (note that current or prior receipt of long acting (LA) parenteral ARVs such as monoclonal antibodies (mAbs) targeting HIV-1, injectable cabotegravir (CAB), or injectable rilpivirine (RPV) is exclusionary).
* Have adequate renal function (estimated glomerular filtration rate (eGFR) ≥ 70 mL/min/1.73 m\^2)
* No clinically significant abnormalities in electrocardiogram (ECG) at screening.

Substudy-01, Substudy-02, and Substudy-03:

* Participants in substudy-01 should be willing to initiate a non-NNRTI based SOC ART on Day 11.
* Participants in substudy-02 and Substudy-03 should be willing to initiate any SOC ART on Day 11.
* Willing and able to comply with meal requirements on dosing days.

Key Exclusion Criteria:

All Substudies:

* Known historical genotypic or phenotypic resistance to 4 major ARV classes (nucleoside reverse transcriptase inhibitor (NRTI), nonnucleoside reverse transcriptase inhibitor (NNRTI), protease inhibitor (PI), integrase strand-transfer inhibitor (INSTI)).
* History of an AIDS-defining condition including present at the time of screening.
* Active, serious infections (other than HIV-1) requiring therapy and including active tuberculosis infection \< 30 days prior to randomization.
* History of or current clinical decompensated liver cirrhosis (eg, ascites, encephalopathy, or variceal bleeding).
* Any other serious or active clinical condition or prior therapy that, in the opinion of the investigator, would make the individual unsuitable for the study or unable to comply with dosing requirements.
* Hepatitis C virus (HCV) antibody positive and detectable HCV RNA.
* Chronic hepatitis B virus (HBV) infection, as determined by either:

  * Positive HBV surface antigen and negative HBV surface antibody, regardless of HBV core antibody status, at the screening visit, or
  * Positive HBV core antibody and negative HBV surface antibody, regardless of HBV surface antigen status, at the screening visit.
* Hepatic transaminases (aspartate aminotransferase (AST) or alanine aminotransferase (ALT)) \> 5 x upper limit of normal (ULN).
* Current alcohol or substance use judged by the investigator to potentially interfere with individual study compliance.
* Positive serum pregnancy test at screening or a positive pregnancy test prior to Day 1.
* Individuals with plan to breastfeed during the study period including the protocol-defined follow-up period.
* Requirement for ongoing therapy with or prior use of any prohibited medications listed in the protocol. Any prescription medications or over the counter medications, including herbal products, within 28 days prior to start of study drug dosing must be reviewed and approved by the sponsor, with the exception of vitamins and/or acetaminophen and/or ibuprofen.
* Any current or prior receipt of LA parenteral ARVs such as mAbs targeting HIV-1, injectable CAB, or injectable RPV, for treatment or prophylaxis (PrEP, PEP).

Substudy-01, Substudy-02, Substudy-03:

* Requirement for ongoing therapy with any prohibited medications listed in protocol.

Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Primary outcomes:
measure: Substudies 01, 02 and 03: Change From Baseline in Plasma Human Immunodeficiency Virus (HIV)-1 Ribonucleic Acid (RNA) (log10 Copies/mL) at Day 11 Relative to Historical Placebo Data
timeFrame: Baseline, Day 11
Secondary outcomes:
measure: Substudies 01, 02 and 03: Change From Baseline in Plasma HIV-1 RNA (log10 Copies/mL) at Day 8 Relative to Historical Placebo Data
timeFrame: Baseline, Day 8
measure: Substudies 01, 02 and 03: Percentage of Participants With Treatment-emergent Adverse Events (TEAEs)
timeFrame: First dose up to last dose (Substudy 01: Up to Day 39; Substudy 02: Up to Day 60; Substudy 03: Up to Day 25)
measure: Substudies 01, 02 and 03: Percentage of Participants With Graded Laboratory Abnormalities
timeFrame: First dose up to last dose (Substudy 01: Up to Day 39; Substudy 02: Up to Day 60; Substudy 03: Up to Day 25)
measure: Substudy 01: Pharmacokinetic (PK) Parameter: Cmax of Bavtavirine
timeFrame: Cohorts 1, 2 and 3 (Day 1: Predose, 0.5, 1, 2, 3, 4, 5, 6, 8, and 12 hours postdose); Cohort 3: Day 2: Predose, 0.5, 1, 2, 3, 4, 5, 6, and 8 hours postdose
measure: Substudy 01: PK Parameter: AUC of Bavtavirine
timeFrame: Day 1 up to Day 11
measure: Substudy 01: PK Parameter: Plasma Concentration of Bavtavirine
timeFrame: Days 8 and 11
measure: Substudy 02: PK Parameter: Cmax of GS-1720
timeFrame: Days 1 and 2: Predose, 0.5, 1, 2, 3, 4, 5, 6, 8 and (optional) 12 hours postdose
measure: Substudy 02: PK Parameter: AUC of GS-1720
timeFrame: Day 1 up to Day 11
measure: Substudy 02: PK Parameter: Plasma Concentration of GS-1720
timeFrame: Days 8 and 11
measure: Substudy 03: PK Parameter: Cmax of GS-6212
timeFrame: Days 1 and 10 (Predose, 0.25, 0.5, 1, 2, 3, 4, 6, 8 and (optional) 12 hours postdose)
measure: Substudy 03: PK Parameter: AUC0-8h of GS-6212
timeFrame: Days 1 and 10 (Predose, 0.25, 0.5, 1, 2, 3, 4, 6, 8 and (optional) 12 hours postdose)
measure: Substudy 03: PK Parameter: AUCtau of GS-6212
timeFrame: Day 10 (Parameter estimated based on observed data from 0 to 8 hours postdose)
measure: Substudy 03: PK Parameter: Plasma Concentration of GS-6212
timeFrame: Days 1 and 10: 8 hours postdose
measure: Substudy 03: PK Parameter: Ctrough of GS-6212 (Day 10)
timeFrame: Day 10 (Parameter estimated based on observed data from 0 to 8 hours postdose)
measure: Substudy 03: PK Parameter: Cavg of GS-6212 (Day 10)
timeFrame: Day 10 (predose to 8 hours postdose)
measure: Substudies 01, 02 and 03: Percentage of Participants at Any Measurement Achieving HIV-1 RNA < 50 Copies/mL by Day 11 at Each Dose Level
timeFrame: Up to Day 11
measure: Substudies 01, 02 and 03: Percentage of Participants With Emergence of Viral Resistance to the ARV Class of the Given Drug
timeFrame: Up to Day 11
measure: Substudy 01: Maximum Inhibitory Quotient (IQ) of Bavtavirine by Mean Plasma Concentration (Ct) up to Day 11
timeFrame: Up to Day 11
measure: Substudy 02: Inhibitory Quotient (IQ) of GS-1720 by Mean Plasma Concentration (Ct) at Day 11
timeFrame: Day 11
measure: Substudy 03: Inhibitory Quotient (IQ) of GS-6212 by Ctrough at Day 11
timeFrame: Day 11
Other outcomes:
Locations:
city: Long Beach
country: United States
facility: Long Beach Education and Research Consultants,Substudy-03
state: California
city: Los Angeles
country: United States
facility: Mills Clinical Research,Substudy-02
state: California
city: Los Angeles
country: United States
facility: Mills Clinical Research,Substudy-03
state: California
city: San Francisco
country: United States
facility: Quest Clinical Research,Substudy-01
state: California
city: San Francisco
country: United States
facility: Quest Clinical Research,Substudy-02
state: California
city: San Francisco
country: United States
facility: Quest Clinical Research,Substudy-03
state: California
city: New Haven
country: United States
facility: Yale University; School of Medicine; AIDS Program (Administrative & Study Supplies),Substudy-03
state: Connecticut
city: New Haven
country: United States
facility: Yale University,Substudy-02
state: Connecticut
city: Washington
country: United States
facility: Washington Health Institute,Substudy-01
state: District of Columbia
city: Washington
country: United States
facility: Washington Health Institute,Substudy-02
state: District of Columbia
city: Washington
country: United States
facility: Washington Health Institute,Substudy-03
state: District of Columbia
city: DeLand
country: United States
facility: Midland Florida Clinical Research Center, LLC,Substudy-02
state: Florida
city: DeLand
country: United States
facility: Midland Florida Clinical Research, LLC,Substudy-03
state: Florida
city: Fort Pierce
country: United States
facility: Midway Immunology and Research Center,Substudy-01
state: Florida
city: Fort Pierce
country: United States
facility: Midway Immunology and Research Center,Substudy-02
state: Florida
city: Fort Pierce
country: United States
facility: Midway Immunology and Research Center,Substudy-03
state: Florida
city: Orlando
country: United States
facility: Bliss Health,Substudy-02
state: Florida
city: Orlando
country: United States
facility: Bliss Health,Substudy-03
state: Florida
city: Orlando
country: United States
facility: Orlando Immunology Center,Substudy-01
state: Florida
city: Orlando
country: United States
facility: Orlando Immunology Center,Substudy-03
state: Florida
city: West Palm Beach
country: United States
facility: Triple O Research Institute, P.A.,Substudy-01
state: Florida
city: West Palm Beach
country: United States
facility: Triple O Research Institute, P.A.,Substudy-03
state: Florida
city: Decatur
country: United States
facility: Infectious Disease Specialists of Atlanta,Substudy-01
state: Georgia
city: Indianapolis
country: United States
facility: Indiana CTSI Clinical Research Center,Substudy-01
state: Indiana
city: Cincinnati
country: United States
facility: University of Cincinnati College of Medicine,Substudy-02
state: Ohio
city: Cincinnati
country: United States
facility: University of Cincinnati College of Medicine,Substudy-03
state: Ohio
city: Austin
country: United States
facility: Central Texas Clinical Research,Substudy-01
state: Texas
city: Austin
country: United States
facility: Central Texas Clinical Research,Substudy-03
state: Texas
city: Dallas
country: United States
facility: Prism Health North Texas,Substudy-02
state: Texas
city: Dallas
country: United States
facility: Prism Health North Texas,Substudy-03
state: Texas
city: Dallas
country: United States
facility: North Texas Infectious Diseases Consultant, P.A.,Substudy-02
state: Texas
city: Dallas
country: United States
facility: North Texas Infectious Diseases Consultants, P.A.,Substudy-03
state: Texas
city: El Paso
country: United States
facility: AXCES Research,Substudy-02
state: Texas
city: El Paso
country: United States
facility: AXES Research Group LLC,Substudy-03
state: Texas
city: Houston
country: United States
facility: Therapeutic Concepts, PA,Substudy-02
state: Texas
city: Houston
country: United States
facility: Therapeutic Concepts, PA,Substudy-03
state: Texas
city: Houston
country: United States
facility: The Crofoot Research Center, Inc.,Substudy-01
state: Texas
city: Spokane
country: United States
facility: MultiCare Rockwood Main Clinic- Research,Substudy-03
state: Washington
city: Santo Domingo
country: Dominican Republic
facility: Instituto Dominicano de Estudio Virologicos - IDEV,Substudy-02
city: Bangkok
country: Thailand
facility: The HIV Netherlands Australia Thailand Research Collaboration (HIV-NAT),Substudy-02
city: Bangkok
country: Thailand
facility: The HIV Netherlands Australia Thailand Research Collaboration (HIV-NAT),Substudy-03
city: Khon Kaen
country: Thailand
facility: Faculty of Medicine, Srinagarind Hospital, Khon Kaen University,Substudy-03
Study officials:
affiliation: Gilead Sciences
name: Gilead Study Director
role: STUDY_DIRECTOR
References:
citation: Carl J. Fichtenbaum, Mezgebe Berhe, Jose Bordon, et al, Antiviral Activity, Safety, and Pharmacokinetics of GS-1720: A Novel Weekly Oral INSTI. Conference on Retroviruses and Opportunistic Infections, 2024, 3-6 March.