PET/CT Imaging Companion Study To ACTG A5314

NCT02312219 | Completed Results DMC

• 1 other identifier: 2014P000145
• Study Type: observational
• Target: 35
• Locations: 1 country
• Sites: 1

Brief Summary

HIV-infected individuals on antiretroviral therapy (ART) are at increased risk for cardiovascular disease (CVD), likely due to chronically increased inflammation. Low-dose methotrexate (LDMTX) may reduce CVD risk in people with rheumatoid arthritis, who like those with HIV, have increased levels of inflammation. The NHLBI is funding a clinical trial targeting the excess inflammation in HIV. That "Parent Study" is a randomized, double-blind, placebo-controlled trial (NCT01949116) that will assess whether 24-week treatment with LDMTX: i) is safe, ii) reduces circulating inflammatory biomarkers and levels of immune cell activation and iii) improves brachial artery reactivity. However, neither the biomarkers nor endothelial function tests measured as part of the parent study will report on atherosclerotic inflammation, (the desired pathobiological target of LDMTX therapy in HIV). As such, the direct evaluation of arterial inflammation would substantially enhance the scientific value of the trial. In this imaging sub-study, the overall goal is to determine if treating virologically suppressed, HIV-infected individuals with LDMTX will reduce inflammation within the arterial wall. This fully integrated ancillary study would, in a subset of patients enrolled in the parent trial: (i) assess the impact of LDMTX on arterial inflammation, (ii) evaluate mechanisms responsible for arterial inflammation in HIV and iii) explore mechanisms responsible for actions of LDMTX on the artery wall. Accordingly, the proposed study would provide unique and highly complementary information that would greatly increase the knowledge and mechanistic insights gained from Parent Study. The ancillary study has two specific aims1) To determine the impact of anti-inflammatory treatment with LDMTX on arterial inflammation, as assessed by FDG-PET/CT imaging, in virally suppressed HIV-infected individuals., and 2) To evaluate the cellular and biochemical basis of the effect of LDMTX therapy on arterial inflammation in HIV.

Conditions

HIV; Inflammation; Atherosclerosis

Keywords

HIV; Inflammation; Atherosclerosis; Positron-Emission Tomography; Imaging; fluorodeoxyglucose

Outcome Measures

Primary Outcomes (1)

• Change in Arterial FDG Uptake (From Baseline) in the Most Diseased Segment

  Arterial FDG Uptake provides a measure of inflammation in the artery wall. TBR is target-to-background ratio (a measure of the ratio of the activity in the vessel wall divided by the blood background). A negative number for the change in TBR implies a reduction in activity over time. The most diseased segment is the approx 1-cm section of the vessel with the highest activity at baseline. The results are expressed as the change in the median value, of the TBR, from baseline to week 24

  baseline and 24 weeks

Secondary Outcomes (1)

• Change in Arterial FDG Uptake (From Baseline) in the Aorta

  baseline and 24 weeks

Study Arms (2)

Low Dose Methotrexate

Subjects will take 1 mg folic acid once daily plus 5 mg methotrexate (MTX) . If clinically stable at the week 1 visit, the dose of MTX will be increased to 10 mg once weekly through week 12. For subjects who remain clinically stable on 10 mg MTX or placebo through the week 12 visit, the dose of MTX will be increased to 15 mg once weekly through week 24. If the subject does not meet the criteria for dose escalation at the week 1 or 12 study visit, then the subject will remain on his/her current dose until the next study visit at which time he/she will be re-evaluated for dose escalation.

Drug: Folic Acid; Drug: Low Dose Methotrexate

Placebo

Subjects will take 1 mg folic acid once daily plus placebo once weekly. If clinically stable at weeks 1 and 12, the number of placebo tablets will be increased in a manner matching those on the MTX.

Drug: Folic Acid; Drug: Placebo

Interventions

Folic Acid DRUG

1 mg folic acid once daily

Also known as: Folate

Low Dose Methotrexate; Placebo

Placebo DRUG

placebo once weekly

Also known as: (Placebo for MTX)

Placebo

Low Dose Methotrexate DRUG

An anti-inflammatory drug

Also known as: Methotrexate

Low Dose Methotrexate

Eligibility Criteria

• Age: 40 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Probability Sample

Study Population

Subset of individuals enrolled in A5314 who undergo PET/CT imaging.

You may qualify if:

• HIV-1 infection, documented by any licensed rapid HIV test or HIV enzyme or chemiluminescence immunoassay (E/CIA) test kit at any time prior to study entry and confirmed by a licensed Western blot or a second antibody test by a method other than the initial rapid HIV and/or E/CIA, or by HIV-1 antigen, plasma HIV-1 RNA viral load.
• NOTE: The term "licensed" refers to a US FDA-approved kit, which is required for all IND studies.
• WHO (World Health Organization) and CDC (Centers for Disease Control and Prevention) guidelines mandate that confirmation of the initial test result must use a test that is different from the one used for the initial assessment. A reactive initial rapid test should be confirmed by either another type of rapid assay or an E/CIA that is based on a different antigen preparation and/or different test principle (e.g., indirect versus competitive), or a Western blot or a plasma HIV-1 RNA viral load.
• Currently on continuous ART for ≥24 weeks prior to study entry. This is defined as continuous active therapy for the 24-week period prior to study entry with no treatment interruption longer than 7 consecutive days and a total duration off treatment of no more than 14 days in the 90 days prior to study entry.
• CD4+ T-cell count ≥400 cells/mm3 obtained within 60 days prior to study entry by any US laboratory that has a Clinical Laboratory Improvement Amendments (CLIA) certification or its equivalent.
• HIV-1 RNA level below the limit of quantification using a FDA-approved assay for at least 24 weeks prior to study entry and confirmed within 60 days prior to study entry. The assay used for eligibility can be performed by any US laboratory that has a CLIA certification or its equivalent.
• NOTE: Single determinations that are between the assay quantification limit and 200 copies/mL are allowed as long as the preceding and subsequent determinations are below the level of quantification.
• The following laboratory values obtained within 60 days prior to study entry by any US laboratory that has a CLIA certification or its equivalent;
• Fasting glucose \<180 mg/dL
• ALT \[serum glutamic pyruvic transaminase (SGPT)\] \<2 times upper limit of normal (ULN)
• AST \[serum glutamic oxaloacetic transaminase (SGOT)\] \<2 x ULN
• Estimated creatinine clearance (CrCl) ≥50 mL/min by Cockcroft-Gault (see section 6.3.5 for CrCl instructions) NOTE: Candidates who are taking TDF as part of their ART regimen must have an estimated CrCl ≥60 mL/min.
• White blood cell (WBC) \>3000/mm3
• Hemoglobin \>12.0 g/dL
• Platelets \>150,000/mm3

You may not qualify if:

• Acute or serious illness requiring systemic treatment and/or hospitalization within 60 days prior to study entry.
• NOTE: Treatment must have ended at least 60 days prior to study entry for eligibility.
• Documentation of any CDC category C AIDS-indicator condition \[78\] or oropharyngeal candidiasis (thrush) within 90 days prior to study entry.
• Receipt of antibiotic therapy within 30 days prior to study entry.
• Latent TB infection (defined as a positive PPD ≥5 mm, positive interferon-gamma release assay, or positive T-spot test at any time in the past) or evidence of latent TB on the screening chest x-ray that has not been completely treated or was treated within the past 6 months prior to study entry .
• TB disease requiring treatment within 48 weeks prior to study entry.
• Life-threatening fungal infection requiring treatment, in the opinion of the site investigator, within 48 weeks prior to study entry.
• Herpes-zoster viral infection requiring treatment within 90 days prior to study entry.
• A history of or current, active hepatitis B infection defined as positive hepatitis B surface antigen test or positive HBV DNA in subjects with isolated HBcAb positivity, defined as negative HBsAg, negative HBsAb, and positive HBcAb within 24 weeks prior to study entry.
• NOTE: Subjects who are positive for hepatitis B surface antigen but who are HBV DNA negative are permitted in the study.
• Chronic hepatitis C infection defined as a positive hepatitis C antibody and positive hepatitis C RNA at any time prior to study entry.
• NOTE: Subjects who are positive for hepatitis C antibody but who are HCV RNA negative are permitted in the study.
• Previously diagnosed myelodysplasia syndrome.
• Treated lymphoproliferative disease ≤5 years prior to study entry.
• Clinically significant lung disease on the screening chest x-ray that, in the opinion of the site investigator, places the subject at increased risk of lung toxicity (e.g., history of pulmonary fibrosis, interstitial lung disease, or pulmonary lymphoproliferative disease).

Sponsors & Collaborators

• Massachusetts General Hospital: lead
• Brigham and Women's Hospital: collaborator
• Harvard School of Public Health (HSPH): collaborator
• University of California, San Francisco: collaborator

Study Sites (1)

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

Location

MeSH Terms

Conditions

Inflammation; Atherosclerosis

Interventions

Folic Acid; Methotrexate

Condition Hierarchy (Ancestors)

Pathologic Processes; Pathological Conditions, Signs and Symptoms; Arteriosclerosis; Arterial Occlusive Diseases; Vascular Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Aminopterin

Results Point of Contact

• Title: Ahmed Tawakol, MD
• Organization: Mass General Hospital

atawakol@mgh.harvard.edu

617-726-0791

Study Officials

• Ahmed Tawakol, MD

  Massachusetts General Hospital and Harvard Medical School

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Director: Integrative BioImaging Trials

Study Record Dates

• First Submitted: December 4, 2014
• First Posted: December 9, 2014
• Study Start: November 1, 2014
• Primary Completion: December 8, 2016
• Study Completion: December 8, 2016
• Last Updated: February 6, 2019
• Results First Posted: February 6, 2019

Record last verified: 2018-09

Locations

US (1)