A Study to Evaluate the Effects of Cenicriviroc Mesylate on Arterial Inflammation in People Living With HIV

Phase 2

Completed

Conditions: HIV-1-infection
Elevated Cardiovascular Risk

Interventions: Drug: CVC 150 mg
Other: Placebo for CVC 150 mg
Drug: CVC 300 mg
Other: Placebo for CVC 300 mg

Registration Number: NCT05630885

Lead Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

Brief Summary: The study was conducted to determine if cenicriviroc mesylate (CVC) would decrease vascular inflammation as measured by 18F-fluorodeoxyglucose (FDG)-positron emission tomography (PET)/computed tomography (CT) imaging of the aorta and carotid arteries.

Detailed Description: This was a double-blind, placebo-controlled phase II clinical trial comparing the intervention of CVC versus placebo for a duration of 24 weeks on arterial inflammation evaluated by FDG-PET/CT imaging.

A total of 110 participants were randomized 2:1 to the CVC arm (Arm A) or placebo for CVC arm (Arm B). Stratification by statin use at randomization ensured even distribution of statin use between the treatment groups.

Analyses were based on the efficacy population: all enrolled participants who completed at least 22 weeks of study treatment and remained on the same ART drug class throughout the study without use of prohibited medications.

Analysis of the primary outcome utilized multiple imputation by regression to impute missing data.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 110

Inclusion Criteria

Documented to be living with HIV-1 infection.
Currently on a stable, continuous NNRTI-based or unboosted INSTI-based ART regimen for ≥48 weeks prior to study entry with no plans to change ART during the course of the study.
At least a year of controlled HIV-1 RNA levels.
Current CD4+ cell count >200 cells/mm^3.
Elevated cardiovascular risk defined as at least one of the following:
- Clinical atherosclerotic disease (symptomatic atherosclerotic lesions in any vessel)
- Subclinical atherosclerotic disease (coronary artery calcification [CAC] >10 or presence of non-obstructive plaques)
- Diabetes mellitus (DM) or prediabetes
- Obesity
- Hypertension or blood pressure ≥130/80 mmHg
- Elevated LDL cholesterol (fasting LDL of >160 mg/dL)
- Low HDL cholesterol (<40 mg/dL)
- Current tobacco smoking
- Family history of premature coronary artery disease (CAD)
- hsCRP >2.0 mg/L

Key

Exclusion Criteria

Acute coronary syndrome
A current diagnosis of latent or active tuberculosis (TB) infection
Current diagnosis with other intracellular pathogens (Mycobacterium avium complex, Listeria monocytogenes, Toxoplasma gondii, and Cryptococcus neoformans).
Untreated hepatitis B virus (HBV) infection
Current hepatitis C virus (HCV) infection
Current, acute or clinically significant infection or illness requiring IV antibiotics or hospitalization
History of cirrhosis with severe hepatic impairment and/or hepatic decompensation
Active malignancy, except squamous cell skin cancer.
Hemoglobin A1c >8% within 90 days prior to study entry.
Initiation of statin therapy or change in statin dose within 90 days prior to study entry.
Current use of any of the statins at the doses indicated:
- Atorvastatin, >40 mg/day dose
- Rosuvastatin, ≥20 mg/day dose
Concurrent use of drugs with potential drug-drug interactions with CVC within 90 days prior to study entry.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
CVC arm (Arm A)	CVC 150 mg	Participants with pre-existing ART regimen of efavirenz (EFV) took CVC 300 mg. Participants with all other pre-existing ART regimens took CVC 150 mg.
CVC arm (Arm A)	CVC 300 mg	Participants with pre-existing ART regimen of efavirenz (EFV) took CVC 300 mg. Participants with all other pre-existing ART regimens took CVC 150 mg.
Placebo for CVC arm (Arm B)	Placebo for CVC 150 mg	Participants with pre-existing ART regimen of efavirenz (EFV) took placebo for CVC 300 mg. Participants with all other pre-existing ART regimens took placebo for CVC 150 mg.
Placebo for CVC arm (Arm B)	Placebo for CVC 300 mg	Participants with pre-existing ART regimen of efavirenz (EFV) took placebo for CVC 300 mg. Participants with all other pre-existing ART regimens took placebo for CVC 150 mg.

Primary Outcome Measures

Name	Time	Method
Change (Expressed as Ratio to Baseline) in 18-FDG-PET Target-to-background Ratio (TBR) of the Most Diseased Segment (MDS) of the Index (Most-inflamed) Vessel.	Measured at baseline and week 24	Target-to-Background Ratio (TBR) measures the intensity of inflammation of a target arterial wall (aorta, left carotid, right carotid), relative to its respective blood background. Specifically, it is the ratio of the Standardized Uptake Value (SUV) of 18-FDG-PET in the target vessel to SUV in the blood background. A negative number for the change in TBR means a reduction in the target arterial wall inflammation over time. Index vessel is the vessel with the highest vessel TBR at baseline. The most diseased segment is the approximately 1-cm section of the vessel with the highest activity at baseline. The results are expressed as the ratio of TBR at week 24 to baseline. For the statistical analyses, results for the 6 and 9 missing values in Arm A and Arm B, respectively, were imputed using multiple imputation by regression.

Secondary Outcome Measures

Name	Time	Method
Change (Expressed as Ratio to Baseline) in Aortic TBR (and Other TBRs)	Measured at baseline and week 24	Target-to-Background Ratio (TBR) measures the intensity of inflammation of a target arterial wall (aorta, left carotid, right carotid), relative to its respective blood background. Specifically, it is the ratio of the Standard Uptake Value (SUV) of 18-FDG-PET in the target vessel to SUV in the blood background. A negative number for the change in TBR implies a reduction in the target arterial wall inflammation over time. The results are expressed as the ratio of TBR at week 24 to baseline.
Change (Expressed as Ratio to Baseline) in Standardized Uptake Value (SUV) Measured in the Carotid Arteries and Aorta	Measured at baseline and week 24	Standard Uptake Value (SUV) measures the intensity of inflammation of a target arterial wall (aorta, left carotid, right carotid). Specifically, it is the average of all evaluable SUV for a given arterial vessel. A negative number for the change in SUV implies a reduction in the target arterial wall inflammation over time. The results are expressed as the ratio of SUV at week 24 to baseline.
Change in Fasting Glucose	Measured at baseline and week 24	Fasting glucose (mg/dL) measures the level of sugar (glucose) in the blood after fasting (no eating or drinking except water) for at least 8 hours. Higher value of change means an increase in glucose levels over time. The results are expressed as the change in fasting glucose from baseline to week 24.
Change (Expressed as Ratio to Baseline) in Fasting Insulin and Homeostasis Model Assessment-estimated Insulin Resistance (HOMA-IR)	Measured at baseline and week 24	Insulin is a hormone crucial in regulating blood sugar levels. HOMA-IR is a calculation used to assess insulin resistance and is calculated with the formula: insulin (uIU/mL) \* glucose (mg/dL) / 405. Higher value of change in insulin and HOMA-IR means an increase in insulin resistance over time. The results are expressed as the ratio of fasting insulin or HOMA-IR at week 24 to baseline.
Change (Expressed as Ratio to Baseline) in Biomarkers of Inflammation (IL-6, hsCRP, and MCP-1)	Measured at baseline and week 24	The cytokine, Interleukin-6 (IL-6, pg/mL); protein, high-sensitivity C Reactive Protein (hsCRP, mg/L); and chemokine, monocyte chemoattractant protein-1 (MCP-1, pg/mL) are all markers of inflammation. Higher value of change means an increase in the biomarker levels over time. Higher levels of these biomarkers indicates inflammation. MCP-1 is a ligand of CCR2 that was expected to increase with CVC. The results are expressed as the ratio of hsCRP, IL-6, or MCP-1 at week 24 to baseline.
Change in Biomarkers of Immune Activation (sCD14 and sCD163)	Measured at baseline and week 24	The soluble proteins soluble-CD14 (sCD14, ng/mL) and soluble-CD163 (sCD163, ng/mL) are all markers of monocyte/macrophage activation. Higher value of change means an increase in the biomarker levels over time. Higher levels of sCD14 and sCD163 occur in response to inflammation and infection. The results are expressed as the difference between sCD14 or sCD163 from baseline to week 24.
Change (Expressed as Ratio to Baseline) in Plasma Levels of Chemokine Receptor 5 (CCR5) Ligands (RANTES and MIP-1 Beta)	Measured at baseline and week 24	The chemokines macrophage inflammatory protein-1 alpha and beta (MIP-1 alpha and beta, pg/mL) as well as the chemokine, RANTES (ng/mL), are markers of inflammation. Higher value of change means an increase in the biomarker levels over time. Higher levels of these biomarkers indicates inflammation. RANTES and MIP-1 beta are ligands of CCR5 that were expected to increase with CVC. The results are expressed as the ratio of RANTES or MIP-1 beta at week 24 to baseline.

Trial Locations

Locations (19): University of California, Los Angeles CARE Center CRS (Site # 601)
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Los Angeles, California, United States
UCSD Antiviral Research Center CRS (Site # 701)
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San Diego, California, United States
UCSF HIV/AIDS CRS (Site # 801)
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San Francisco, California, United States
Harbor University of California Los Angeles Center CRS (Site # 603)
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Torrance, California, United States
Northwestern University CRS (Site # 2701)
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Chicago, Illinois, United States
Massachusetts General Hospital CRS (MGH CRS) (Site # 101)
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Boston, Massachusetts, United States
Brigham and Women's Hospital Therapeutics (BWH TCRS) CRS (Site # 107)
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Boston, Massachusetts, United States
Washington University Therapeutics (WT) CRS (Site # 2101)
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Saint Louis, Missouri, United States
Weill Cornell Chelsea CRS (Site # 7804)
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New York, New York, United States
Weill Cornell Uptown CRS (Site # 7803)
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New York, New York, United States
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University of California, Los Angeles CARE Center CRS (Site # 601)
🇺🇸Los Angeles, California, United States