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

• ClinicalTrials.gov Identifier: NCT03060447
• Recruitment Status: Completed
• First Posted: February 23, 2017
• Results First Posted: April 21, 2021
• Last Update Posted: April 21, 2021
• Sponsor: Gilead Sciences
• Information provided by (Responsible Party): Gilead Sciences

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
HIV-1 Infection	Drug: Vesatolimod; Drug: Placebo; Drug: ART	Phase 1

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 25 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: May 9, 2017
• Actual Primary Completion Date: February 13, 2020
• Actual Study Completion Date: February 13, 2020

Arms and Interventions

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 Name: 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: Placebo; Tablets Administered orally; 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.

Outcome Measures

Primary Outcome Measures :

1. Percentage of Participants Experiencing Treatment Emergent Serious Adverse Events (TESAEs) and Treatment Emergent Adverse Events (TEAEs) [ Time Frame: From first dose up to 30 days after permanent discontinuation of study drug (assessed maximum up to 33 months and 5 days) ]
   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.

Secondary Outcome Measures :

1. Change From Baseline in Plasma Log 10 HIV-1 RNA by Taqman 2.0 [ Time Frame: 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 ]
   Plasma log 10 HIV-1 RNA was measured using Taqman version 2.0 assay with limit of quantification of 20 copies/mL.
2. Time to Virologic Rebound [ Time Frame: 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 ]
   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.
3. Peak HIV-1 Viral Load During Period 2 [ Time Frame: From Week 1 up to Week 24 ]
   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.
4. Change in Plasma Viral Load Set-Point Following ATI [ Time Frame: Pre-ART (Initial Screening Visit) and 24 weeks plus 6 months following virologic re-suppression on ART (maximum 33 months and 5 days) ]
   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.
5. Change From Baseline in Levels of Serum Cytokines [ Time Frame: 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) ]
   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).
6. Fold Change in Messenger Ribonucleic Acid (mRNA) of Interferon-Stimulated Genes (ISGs) in Whole Blood [ Time Frame: 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) ]
   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.
7. Change From Baseline in Immune Cell Activation [ Time Frame: 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) ]
   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.
8. Pharmacokinetic (PK) Parameter: Cmax of Vesatolimod [ Time Frame: 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. ]
   Cmax is defined as the maximum concentration of drug.
9. PK Parameter: AUClast of Vesatolimod [ Time Frame: 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. ]
   AUClast is defined as the concentration of drug from time zero to the last observable concentration.
10. PK Parameter: AUCinf of Vesatolimod [ Time Frame: 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. ]
    AUCinf was defined as the concentration of drug extrapolated to infinite time.
11. PK Parameter: %AUCexp of Vesatolimod [ Time Frame: 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. ]
    %AUCexp is defined as the percentage of AUC extrapolated between AUClast and AUCinf.
12. PK Parameter: Tmax of Vesatolimod [ Time Frame: 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. ]
    Tmax is defined as the time (observed time point) of Cmax.

Eligibility Criteria

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

Criteria

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.

Contacts and Locations

Locations

United States, California

Mills Clinical Research

Los Angeles, California, United States, 90069

Zuckerberg San Francisco General

San Francisco, California, United States, 94110

United States, Florida

Midway Immunology & Research Center

Fort Pierce, Florida, United States, 34982

Orlando Immunology Center

Orlando, Florida, United States, 32803

United States, Texas

Central Texas Clinical Research

Austin, Texas, United States, 78705

United States, Washington

Peter Shalit, MD

Seattle, Washington, United States, 98104

Sponsors and Collaborators

Gilead Sciences

Investigators

• Study Director: Gilead Study Director; Gilead Sciences

  Study Documents (Full-Text)

Documents provided by Gilead Sciences:

Statistical Analysis Plan  [PDF] March 17, 2020

Study Protocol  [PDF] February 5, 2019

More Information

Publications of Results:

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.

• Responsible Party: Gilead Sciences
• ClinicalTrials.gov Identifier: NCT03060447
• Other Study ID Numbers: GS-US-382-3961
• First Posted: February 23, 2017
• Results First Posted: April 21, 2021
• Last Update Posted: April 21, 2021
• Last Verified: March 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

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

Additional relevant MeSH terms:

Vesatolimod; Antiviral Agents; Anti-Infective Agents