Study to Evaluate the Safety and Efficacy of Vesatolimod in Antiretroviral Treated Human Immunodeficiency Virus (HIV-1) Infected Controllers

A Phase 1b, Randomized, Double-Blind, Placebo-controlled Study to Evaluate the Safety and Efficacy of GS-9620 in Antiretroviral Treated HIV-1 Infected Controllers

The primary objective of this study is to evaluate the safety and tolerability of a 10-dose regimen of vesatolimod in HIV-1 infected controllers on antiretroviral treatment (ART) and during analytical treatment interruption (ATI) following vesatolimod dosing.

Study Overview

• Status: Completed
• Conditions: HIV-1 Infection
• Intervention / Treatment: Drug: Vesatolimod; Drug: ART; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 25
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Los Angeles, California, United States, 90069
      • Mills Clinical Research
    • San Francisco, California, United States, 94110
      • Zuckerberg San Francisco General
  • Florida
    • Fort Pierce, Florida, United States, 34982
      • Midway Immunology & Research Center
    • Orlando, Florida, United States, 32803
      • Orlando Immunology Center
  • Texas
    • Austin, Texas, United States, 78705
      • Central Texas Clinical Research
  • Washington
    • Seattle, Washington, United States, 98104
      • Peter Shalit, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Key Inclusion Criteria:

• Plasma HIV-1 ribonucleic acid (RNA) levels < 50 copies/mL at screening
• Chronic HIV-1 infection (for ≥ 6 months) prior to ART initiation
• Pre-ART Plasma HIV-1 RNA set point between 50 and ≤ 5,000 copies/mL measured within two years prior to ART initiation
• On ART for ≥ 6 consecutive months prior to screening
• Documented plasma HIV-1 RNA < 50 copies/mL for ≥ 6 months preceding the screening visit (or undetectable HIV-1 RNA level according to the local assay being used if the limit of detection is ≥ 50 copies/mL). Unconfirmed virologic elevations of ≥ 50 copies/mL (transient detectable viremia, or "blip") prior to screening are acceptable.
• No documented history of resistance to any components of the current ART regimen
• Availability of a fully active alternative ART regimen, in the opinion of the Investigator, in the event of discontinuation of the current ART regimen with development of resistance.
• Hemoglobin ≥ 11.5 g/dL (males) or ≥ 11 g/dL (females)
• White Blood Cells ≥ 2,500 cells/μL
• Platelets ≥ 125,000/mL
• Absolute Neutrophil Counts ≥ 1000 cells/μL
• Cluster of Differentiation 4 (CD4)+ count ≥ 500 cells/μL
• Alanine aminotransferase (ALT), aspartate aminotransferase (AST) or bilirubin ≤ 2 × upper limit of normal (ULN)
• Estimated glomerular filtration rate ≥ 60 mL/min
• No autoimmune disease requiring on-going immunosuppression
• No evidence of current hepatitis B virus (HBV) infection
• No evidence of current hepatitis C virus (HCV) infection (positive anti-HCV antibody and negative HCV polymerase chain reaction (PCR) results are acceptable)
• No documented history of pre-ART CD4 nadir < 200 cells/μL (unknown pre-ART CD4 nadir is acceptable)
• No history of opportunistic illness indicative of stage 3 HIV
• No acute febrile illness within 35 days prior to Pre-Baseline/ Day -13

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: DOUBLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Vesatolimod; Participants in Period 1 will receive 10 doses of vesatolimod (4 mg to 8 mg) once every 14 days over a 20-week period along with their prescribed ART. Participants in Period 2 (ATI) will discontinue ART and vesatolimod and will be monitored for rebound in HIV-1 plasma viremia for 24 weeks. Participants who restart ART during Period 2 due to virologic rebound will complete the ART Re-Initiation Visits, and then Post-ART Re-suppression Visits monthly for 6 additional months. Participants who complete 24 Weeks of ATI without restarting ART will move onto Period 3 and have 2 options. They can remain off ART for up to an additional 24 weeks. Those who restart ART at the start of Period 3 will complete ART Re-initiation Visits and then Post-ART Re-suppression Visits monthly for 6 additional months.	Drug: Vesatolimod; Tablets Administered orally; Other Names: GS-9620; Drug: ART; ART regimens administered in accordance with their prescribing information. The following agents are allowed as part of the ART regimen: nucleoside reverse transcriptase inhibitors, raltegravir, dolutegravir (DTG), rilpivirine, and maraviroc.
EXPERIMENTAL: Placebo; Participants in Period 1 will receive 10 doses of placebo matched to vesatolimod once every 14 days over a 20-week period along with their prescribed ART. Participants in Period 2 (ATI) will discontinue ART and placebo and will be monitored for rebound in HIV-1 plasma viremia for 24 weeks. Participants who restart ART during Period 2 due to virologic rebound will complete the ART Re-Initiation Visits, and then Post-ART Re-suppression Visits monthly for 6 additional months. Participants who complete 24 Weeks of ATI without restarting ART will move onto Period 3 and have 2 options. They can remain off ART for up to an additional 24 weeks. Those who restart ART at the start of Period 3 will complete ART Re-initiation Visits and then Post-ART Re-suppression Visits monthly for 6 additional months.	Drug: ART; ART regimens administered in accordance with their prescribing information. The following agents are allowed as part of the ART regimen: nucleoside reverse transcriptase inhibitors, raltegravir, dolutegravir (DTG), rilpivirine, and maraviroc.; Drug: Placebo; Tablets Administered orally

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants Experiencing Treatment Emergent Serious Adverse Events (TESAEs) and Treatment Emergent Adverse Events (TEAEs)	AE was any untoward medical occurrence in a clinical study participant administered a medicinal product (MP), which did not necessarily had a causal relationship with treatment. AE was therefore any unfavorable and/or unintended sign, symptom, or disease temporally associated with use of MP, whether or not considered related to MP. TEAEs: AE with an onset date on or after the study drug start date and no later than 30 days after study drug stop date; or any AE leading to study drug discontinuation. TESAEs: event that resulted in following: death; life-threatening situation; in-patient hospitalization or prolongation of existing hospitalization; persistent or significant disability or incapacity; congenital anomaly or birth defect; medically important event or reaction: such events might not have been immediately life-threatening or resulted in death or hospitalization but may jeopardize participant or may require intervention to prevent one of the other outcomes constituting SAEs.	From first dose up to 30 days after permanent discontinuation of study drug (assessed maximum up to 33 months and 5 days)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Plasma Log 10 HIV-1 RNA by Taqman 2.0	Plasma log 10 HIV-1 RNA was measured using Taqman version 2.0 assay with limit of quantification of 20 copies/mL.	Baseline and Dose 1: Days 2,8; Dose 2: Days 1,8; Dose 3: Days 1,8; Dose 4: Days 1,2,4,8; Dose 5: Day 1,8; Dose 6: Days 1,4,8; Dose 7: Days 1,8; Dose 8: Days 1,8; Dose 9: Days 1,8; Dose 10: Days 1,2,4,8,14
Time to Virologic Rebound	Time to virologic rebound was analyzed using the Kaplan-Meier method at two cut-off values; ≥ 50 copies/mL and ≥ 200 copies/mL. Virologic rebound at ≥ 50 copies/mL was defined as 2 consecutive HIV-1 RNA measurements ≥ 50 copies/mL. Virologic rebound at ≥ 200 copies/mL was defined as 2 consecutive HIV-1 RNA measurements ≥ 200 copies/mL. The date of rebound was the first time HIV-1 RNA measurement ≥ 50 copies/mL or ≥ 200 respectively.	From Day 1 (Period 1) up to 24 weeks of Period 2 plus 6 months following virologic re-suppression on ART, an average of 17 months
Peak HIV-1 Viral Load During Period 2	For participants who did not restart ART, the maximum value of HIV-1 RNA measurements during ATI was used as the peak value and for participants who restarted ART, the maximum value of HIV-1 RNA measurements during ATI before the restart of ART was used as the peak value.	From Week 1 up to Week 24
Change in Plasma Viral Load Set-Point Following ATI	Plasma viral load set-point values were calculated at pre-ART stage and following ATI. Change in plasma viral load set-point following ATI = viral set-point following ATI minus pre-ART set point. The plasma viral set-point following ATI was calculated as the geometric mean of all the HIV-1 RNA measurements between a start date and an end date. The start date and end date was provided by clinical based on blinded individual participant's data review.	Pre-ART (Initial Screening Visit) and 24 weeks plus 6 months following virologic re-suppression on ART (maximum 33 months and 5 days)
Change From Baseline in Levels of Serum Cytokines	Following Serum Cytokines Levels were evaluated: interferon-a (IFN-a), interleukin-1 receptor antagonist (IL-1RA), inducible protein-10 (IP-10) and inducible T cell alpha chemoattractant (ITAC).	Baseline and Dose 1: Day 2,8; Dose 4: Days 1,2,8; Dose 10: Days 1,2,8; ATI Remission Visit (12 weeks post ATI Visit: evaluated at maximum of 24 weeks); Early study drug discontinuation (7 days post- last ATI visit at Week 24)
Fold Change in Messenger Ribonucleic Acid (mRNA) of Interferon-Stimulated Genes (ISGs) in Whole Blood	Following ISGs Levels were evaluated: Interferon-stimulated Gene 15 (ISG15), Oligoadenylate synthase-1 (OAS-1), and interferon-induced guanosine triphosphate-binding protein MX1. Fold change was calculated as postbaseline value divided by baseline value.	Baseline and Dose 1: Day 2; Dose 4: Days 1,2; Dose 10: Day 1,2; Early Study Drug Discontinuation (7 days post- last ATI visit at Week 24)
Change From Baseline in Immune Cell Activation	Activation of Immune cells (T cells: CD4/CD38/HLADR, CD8/CD38/HLADR and NK cells: CD69+CD56+CD16+, CD69+CD56dimCD16neg, CD69+CD56brCD16dim) was measured by cytometry.	Baseline and Dose 4: Days 1,2,4; Dose 6: Days 1,4; Dose 10: Days 1,2,4,14; ATI Remission Visit (12 weeks post ATI Visit: evaluated at maximum of 24 weeks)
Pharmacokinetic (PK) Parameter: Cmax of Vesatolimod	Cmax is defined as the maximum concentration of drug.	Pre-dose (≤ 5 minutes prior to dosing), 0.5, 1, 2, 4, 6, 8, 10, and 24 hours post dose at Dose 1-Day 1 visit.
PK Parameter: AUClast of Vesatolimod	AUClast is defined as the concentration of drug from time zero to the last observable concentration.	Pre-dose (≤ 5 minutes prior to dosing), 0.5, 1, 2, 4, 6, 8, 10, and 24 hours post dose at Dose 1-Day 1 visit.
PK Parameter: AUCinf of Vesatolimod	AUCinf was defined as the concentration of drug extrapolated to infinite time.	Pre-dose (≤ 5 minutes prior to dosing), 0.5, 1, 2, 4, 6, 8, 10, and 24 hours post dose at Dose 1-Day 1 visit.
PK Parameter: %AUCexp of Vesatolimod	%AUCexp is defined as the percentage of AUC extrapolated between AUClast and AUCinf.	Pre-dose (≤ 5 minutes prior to dosing), 0.5, 1, 2, 4, 6, 8, 10, and 24 hours post dose at Dose 1-Day 1 visit.
PK Parameter: Tmax of Vesatolimod	Tmax is defined as the time (observed time point) of Cmax.	Pre-dose (≤ 5 minutes prior to dosing), 0.5, 1, 2, 4, 6, 8, 10, and 24 hours post dose at Dose 1-Day 1 visit.

Collaborators and Investigators

• Sponsor: Gilead Sciences

Publications and helpful links

General Publications

• SenGupta D, Ramgopal M, Brinson C, DeJesus E, Mills A, Shalit P, et al. Safety and Analytic Treatment Interruption Outcomes of Vesatolimod in HIV Controllers. Oral Presentation at CROI 2020, Boston, USA. Abstract 3982.

Study record dates

Study Major Dates

• Study Start (ACTUAL): May 9, 2017
• Primary Completion (ACTUAL): February 13, 2020
• Study Completion (ACTUAL): February 13, 2020

Study Registration Dates

• First Submitted: February 17, 2017
• First Submitted That Met QC Criteria: February 17, 2017
• First Posted (ACTUAL): February 23, 2017

Study Record Updates

• Last Update Posted (ACTUAL): April 21, 2021
• Last Update Submitted That Met QC Criteria: March 29, 2021
• Last Verified: March 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Anti-Infective Agents; Antiviral Agents; Vesatolimod
• Other Study ID Numbers: GS-US-382-3961

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No