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

Study Overview
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Brief Summary
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The study is being conducted to determine if cenicriviroc mesylate (CVC) will decrease vascular inflammation as measured by 18F-fluorodeoxyglucose (FDG)-positron emission tomography (PET)/computed tomography (CT) imaging of the aorta.

Detailed Description
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This is 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 93 participants will be randomized 2:1 to the CVC arm (Arm A) or placebo for CVC arm (Arm B). Stratification by statin use at randomization will ensure even distribution of statin use between the treatment groups.

Official Title
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A Limited-Center, Prospective, Double-Blind, Placebo-Controlled Study to Evaluate the Effects of Cenicriviroc Mesylate on Arterial Inflammation in People Living With HIV

Conditions
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HIV-1-infection

Intervention / Treatment
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* Drug: CVC 150 mg
* Drug: CVC 300 mg
* Other: Placebo for CVC 150 mg
* Other: Placebo for CVC 300 mg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Documented 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 ART interruption longer than 7 consecutive days and with no plans to change ART during the course of the study. Screening HIV-1 RNA level below the limit of quantification. All HIV-1 RNA levels within 48 weeks prior to study entry below the limit of quantification. CD4+ cell count >200 cells/mm^3 obtained within 90 days prior to study entry. At least one of the following cardiovascular risk factors (current diagnosis or receiving treatment, except where a time period is specified): Clinical atherosclerotic disease (symptomatic atherosclerotic lesions in any vessel) Subclinical atherosclerotic disease (coronary artery calcification [CAC] >10 or presence of non-obstructive plaques) DM or prediabetes (hemoglobin A1c [HbA1c] ≥5.7%) or impaired fasting glucose (documented fasting glucose of >100 mg/dL within 6 months prior to study entry) or insulin resistance (HOMA-IR ≥2.6) or any one of these laboratory values within 6 months prior to study entry Obesity (body mass index [BMI] ≥30 kg/m^2) or enlarged iliac waist circumference (>40 inches in males, >35 inches in females) History of hypertension or blood pressure ≥130/80 mmHg measured during screening Elevated LDL cholesterol (fasting LDL of >160 mg/dL; result from sample taken within 90 days prior to study entry can be used) Low HDL cholesterol (<40 mg/dL; result from sample taken within 90 days prior to study entry can be used) Smoking (any current tobacco smoking) Family history of premature CAD (first degree relative with CAD prior to age 55 for male relative and 65 for female relative; participant report is acceptable) hsCRP >2.0 mg/L within 90 days prior to study entry without an active infection or acute illness at the time the sample was obtained The following laboratory values obtained within 90 days prior to study entry: Absolute neutrophil count (ANC) >750/mm^3 Platelet count >100,000/mm^3 Aspartate aminotransferase (AST) (SGOT) ≤5x upper limit of normal (ULN) Alanine aminotransferase (ALT) (SGPT) ≤5x ULN Alkaline phosphatase ≤5x ULN Estimated glomerular filtration rate (GFR) ≥60 mL/min/1.73 m^2 as calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-Epi) equation Pre-entry FDG-PET/CT imaging (within 60 days prior to study entry) that has been deemed: Interpretable as assessed by the central imaging core laboratory AND Without incidental findings that will preclude participation in the study at the discretion of the site investigator No plans to receive immunizations 7 days prior to the week 24 study visit. For study candidates of child-bearing potential, negative serum or urine pregnancy test within 90 days prior to study entry and prior to starting study treatment at study entry. Reproductive potential is defined as individuals who have reached menarche and individuals who have not been post-menopausal for at least 12 consecutive months with follicle-stimulating hormone (FSH) ≥40 IU/mL or 24 consecutive months if an FSH is not available, or have not undergone surgical sterilization (e.g., hysterectomy, bilateral oophorectomy, tubal ligation or salpingectomy). If participating in sexual activity that could lead to pregnancy, willingness of person of childbearing potential to use two forms of contraception while receiving study medication and for 3 months after stopping study medication as required. Individuals ≥45 years of age. Ability and willingness of participant or legal guardian/representative to provide informed consent. Exclusion Criteria: Acute coronary syndrome, defined as myocardial infarction (MI) or unstable angina, within 90 days prior to study entry. A current diagnosis of latent or active tuberculosis (TB) infection, any prior untreated TB infection, inadequate treatment of active TB, or inadequate treatment of latent TB. Current diagnosis with other intracellular pathogens (Mycobacterium avium complex, Listeria monocytogenes, Toxoplasma gondii, and Cryptococcus neoformans) within 90 days prior to study entry. Untreated hepatitis B virus (HBV) infection with detectable HBV DNA within 6 months prior to study entry. Current hepatitis C virus (HCV) infection (i.e., detectable HCV RNA within 6 months prior to study entry). Acute or clinically significant infection or illness requiring IV antibiotics or hospitalization within 90 days prior to study entry. History of cirrhosis with severe hepatic impairment and/or hepatic decompensation including ascites, hepatic encephalopathy, or variceal bleeding. Active malignancy, except squamous cell skin cancer. Hemoglobin A1c >8% within 90 days prior to study entry by any laboratory that has a CLIA certification or its equivalent, or at any network-approved non-US laboratory or clinic that operates in accordance with Good Clinical Laboratory Practices (GCLP) and participates in appropriate external quality assurance programs. 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 Anticipated addition of any lipid lowering medication during the course of the study. Concurrent use of drugs with potential drug-drug interactions with CVC within 90 days prior to study entry. Known allergy/sensitivity or any hypersensitivity to components of study drug(s) or their formulation. Treatment within 30 days prior to study entry or anticipated treatment with immunomodulating agents (such as systemic corticosteroids, interleukins, interferons, cyclosporine, and tacrolimus). Immunization within 7 days prior to the pre-entry FDG-PET/CT imaging. History of radiation therapy. High radiation exposure within one year prior to entry, defined as having undergone more than two of any of the procedures below (includes having undergone the same procedure twice within one year prior to study entry): Coronary artery catheterization with or without percutaneous coronary intervention (PCI) Myocardial perfusion stress test Coronary CT angiography CT of the chest and abdomen Barium enema Currently pregnant, breastfeeding, or planning to become pregnant during the length of the study and three months after completing the study. Body weight >300 pounds or >136 kilograms. Active drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements.

Ages Eligible for Study
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Minimum Age: 45 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: At study entry, participants will be randomized 2:1 to oral CVC (Arm A) or oral placebo for CVC (Arm B) once a day. The study treatment will be added to the participants' pre-existing ARV regimens.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CVC arm (Arm A)<br>Participants with pre-existing ART regimen of EFV will take CVC 300 mg. Participants with all other pre-existing ARTs will take CVC 150 mg. | Drug: CVC 150 mg<br>* Administered as one 150-mg tablet by mouth once a day with food.<br>Drug: CVC 300 mg<br>* Administered as two 150-mg tablets by mouth once a day with food.<br>|
| Placebo Comparator: Placebo for CVC arm (Arm B)<br>Participants with pre-existing ART regimen of EFV will take placebo for CVC 300 mg. Participants with all other pre-existing ARTs will take placebo for CVC 150 mg. | Other: Placebo for CVC 150 mg<br>* Administered as one 150-mg matching placebo tablets by mouth once a day with food.<br>Other: Placebo for CVC 300 mg<br>* Administered as two 150-mg matching placebo tablets by mouth once a day with food.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in arterial most diseased segment (MDS) 18-FDG-PET target-to-background ratio (TBR) measured in the carotid arteries and aorta | To assess whether CVC treatment results in reduced arterial inflammation by comparing the changes in arterial target-to-background ratio (TBR) in the carotid arteries and aorta after treatment with CVC versus placebo. | Baseline, Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in aortic TBR (and other TBRs) |  | Baseline, Week 24 | 
| Change in standardized uptake value (SUV) measured in the carotid arteries and aorta |  | Baseline, Week 24 | 
| Change in fasting glucose |  | Baseline, Week 24 | 
| Change in homeostasis model assessment-estimated insulin resistance (HOMA-IR) |  | Baseline, Week 24 | 
| Change in biomarker of inflammation | Biomarker: IL-6 (Interleukin-6) | Baseline, Week 24 | 
| Change in biomarker of immune activation | Biomarker: sCD14 (soluble CD14) | Baseline, Week 24 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HIV