Clinical trial NCT05630885: A Study to Evaluate the Effects of Cenicriviroc Mesylate on Arterial Inflammation in People Living With HIV
Official title: A Limited-Center, Prospective, Double-Blind, Placebo-Controlled Study to Evaluate the Effects of Cenicriviroc Mesylate on Arterial Inflammation in People Living With HIV
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: HIV-1-infection
Keywords: HIV
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
Collaborators: name: AbbVie
First posted: 2022-11-30
Enrollment: 110
Sex: ALL
Minimum age (years): 45
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: At study entry, participants were randomized 2:1 to oral CVC (Arm A) or oral placebo for CVC (Arm B) once a day. The study treatment was added to the participants' pre-existing ARV regimens.
Primary purpose: TREATMENT

Brief summary: 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: 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 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.

Eligibility criteria: Inclusion Criteria:

1. Documented HIV-1 infection.
2. 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.
3. Screening HIV-1 RNA level below the limit of quantification.
4. All HIV-1 RNA levels within 48 weeks prior to study entry below the limit of quantification.
5. CD4+ cell count \>200 cells/mm\^3 obtained within 90 days prior to study entry.
6. 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
7. 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
8. 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
9. No plans to receive immunizations 7 days prior to the week 24 study visit.
10. 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).
11. 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.
12. Individuals ≥45 years of age.
13. Ability and willingness of participant or legal guardian/representative to provide informed consent.

Exclusion Criteria:

1. Acute coronary syndrome, defined as myocardial infarction (MI) or unstable angina, within 90 days prior to study entry.
2. 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.
3. Current diagnosis with other intracellular pathogens (Mycobacterium avium complex, Listeria monocytogenes, Toxoplasma gondii, and Cryptococcus neoformans) within 90 days prior to study entry.
4. Untreated hepatitis B virus (HBV) infection with detectable HBV DNA within 6 months prior to study entry.
5. Current hepatitis C virus (HCV) infection (i.e., detectable HCV RNA within 6 months prior to study entry).
6. Acute or clinically significant infection or illness requiring IV antibiotics or hospitalization within 90 days prior to study entry.
7. History of cirrhosis with severe hepatic impairment and/or hepatic decompensation including ascites, hepatic encephalopathy, or variceal bleeding.
8. Active malignancy, except squamous cell skin cancer.
9. 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.
10. Initiation of statin therapy or change in statin dose within 90 days prior to study entry.
11. Current use of any of the statins at the doses indicated:

    * Atorvastatin, \>40 mg/day dose
    * Rosuvastatin, ≥20 mg/day dose
12. Anticipated addition of any lipid lowering medication during the course of the study.
13. Concurrent use of drugs with potential drug-drug interactions with CVC within 90 days prior to study entry.
14. Known allergy/sensitivity or any hypersensitivity to components of study drug(s) or their formulation.
15. Treatment within 30 days prior to study entry or anticipated treatment with immunomodulating agents (such as systemic corticosteroids, interleukins, interferons, cyclosporine, and tacrolimus).
16. Immunization within 7 days prior to the pre-entry FDG-PET/CT imaging.
17. History of radiation therapy.
18. 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
19. Currently pregnant, breastfeeding, or planning to become pregnant during the length of the study and three months after completing the study.
20. Body weight \>300 pounds or \>136 kilograms.
21. Active drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements.

Primary outcomes:
measure: Change in arterial most diseased segment (MDS) 18-FDG-PET target-to-background ratio (TBR) measured in the carotid arteries and aorta
timeFrame: Baseline, Week 24
Secondary outcomes:
measure: Change in aortic TBR (and other TBRs)
timeFrame: Baseline, Week 24
measure: Change in standardized uptake value (SUV) measured in the carotid arteries and aorta
timeFrame: Baseline, Week 24
measure: Change in fasting glucose
timeFrame: Baseline, Week 24
measure: Change in homeostasis model assessment-estimated insulin resistance (HOMA-IR)
timeFrame: Baseline, Week 24
measure: Change in biomarker of inflammation
timeFrame: Baseline, Week 24
measure: Change in biomarker of immune activation
timeFrame: Baseline, Week 24
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: University of California, Los Angeles CARE Center CRS (Site # 601)
state: California
city: San Diego
country: United States
facility: UCSD Antiviral Research Center CRS (Site # 701)
state: California
city: San Francisco
country: United States
facility: UCSF HIV/AIDS CRS (Site # 801)
state: California
city: Torrance
country: United States
facility: Harbor University of California Los Angeles Center CRS (Site # 603)
state: California
city: Chicago
country: United States
facility: Northwestern University CRS (Site # 2701)
state: Illinois
city: Boston
country: United States
facility: Massachusetts General Hospital CRS (MGH CRS) (Site # 101)
state: Massachusetts
city: Boston
country: United States
facility: Brigham and Women's Hospital Therapeutics (BWH TCRS) CRS (Site # 107)
state: Massachusetts
city: Saint Louis
country: United States
facility: Washington University Therapeutics (WT) CRS (Site # 2101)
state: Missouri
city: New York
country: United States
facility: Weill Cornell Chelsea CRS (Site # 7804)
state: New York
city: New York
country: United States
facility: Weill Cornell Uptown CRS (Site # 7803)
state: New York
city: Rochester
country: United States
facility: University of Rochester Adult HIV Therapeutic Strategies Network CRS (Site # 31787)
state: New York
city: Chapel Hill
country: United States
facility: Chapel Hill CRS (Site # 3201)
state: North Carolina
city: Cincinnati
country: United States
facility: Cincinnati CRS (Site # 2401)
state: Ohio
city: Cleveland
country: United States
facility: Case CRS (Site # 2501)
state: Ohio
city: Columbus
country: United States
facility: Ohio State University CRS (Site # 2301)
state: Ohio
city: Pittsburgh
country: United States
facility: University of Pittsburgh CRS (Site # 1001)
state: Pennsylvania
city: Nashville
country: United States
facility: Vanderbilt Therapeutics (VT) CRS (Site # 3652)
state: Tennessee
city: Houston
country: United States
facility: Houston AIDS Research Team CRS (Site # 31473)
state: Texas
city: Seattle
country: United States
facility: University of Washington Positive Research CRS (Site # 1401)
state: Washington
Study officials:
affiliation: Massachusetts General Hospital
name: Janet Lo, MD, MMSc
role: STUDY_CHAIR
References: