Clinical Trials

MainTitle

Safety and Effectiveness of Low-Dose Methotrexate for Reducing Inflammation in HIV-Infected Adults on ARV Medications

This study has been completed
Sponsor
National Institute of Allergy and Infectious Diseases (NIAID)


Information provided by (Responsible Party)
National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier
NCT01949116

First received: September 19, 2013
Last updated: January 9, 2018
Last Verified: January 2018
History of Changes
Purpose

Purpose

People with HIV infection who are taking antiretroviral therapy (ART) could be at risk for cardiovascular disease (CVD), which can be caused by inflammation. Methotrexate (MTX) is a medication used to treat inflammation in people with rheumatoid arthritis. This study evaluated the safety and effectiveness of low-dose methotrexate (LDMTX) at reducing inflammation in HIV-infected adults.

Condition Intervention Phase
HIV Infections

Drug : LDMTX
Drug : Placebo
Dietary Supplement : Folic acid
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Effect of Reducing Inflammation With Low Dose Methotrexate on Inflammatory Markers and Endothelial Function in Treated and Suppressed HIV Infection

Further study details as provided by National Institute of Allergy and Infectious Diseases (NIAID):

Primary Outcome Measures

  • Number of Participants Who Reached at Least One Safety Milestone Over the Duration of Study Follow-up (36 Weeks) [ Time Frame: From study entry to week 36 ]
    Number of participants who experienced any one of the following safety milestones: Entry CD4+ T-cell count less than 700 cells/mm^3, confirmed CD4+ decline greater than 33% of baseline AND to less than 350 cells/mm^3 Entry CD4+ T-cell count greater than or equal to 700 cells/mm^3, a confirmed CD4+ decline greater than 50% of baseline Confirmed HIV-1 RNA Level Greater Than 200 Copies/mL in the Absence of an Interruption in ART New or recurrent CDC category C AIDS-indicator condition Evidence of HIV-associated infection including CMV end-organ disease, varicella zoster, EBV related clinical disease Requirement for LDMTX discontinuation for confirmed Grade 3 or higher toxicity Lymphoproliferative malignancies Pulmonary toxicity which is defined as Grade 3 or 4 dyspnea, cough, shortness of breath which in the opinion of the local investigator is related to the study drug but not related to other clinical causes such as asthma, influenza, etc.
  • Primary Efficacy Endpoint of Change From Baseline to Week 24 in Brachial Artery Flow-mediated Vasodilation (FMD) [ Time Frame: From Baseline to Week 24 ]
    Flow-mediated vasodilation is defined as the maximum FMD (%) calculated from reactive hyperemia (RH) 60 and RH 90 relative to resting artery diameter. Absolute change of FMD at week 24 is calculated from baseline FMD.
Secondary Outcome Measures:
  • Change From Baseline to Week 12 in Brachial Artery FMD [ Time Frame: From Baseline to Week 12 ]
    The absolute change from baseline to week 24 FMD (%), defined as the maximum FMD calculated from reactive hyperemia (RH) 60 and RH 90 relative to resting artery diameter.
  • Change From Baseline to Week 12 in Brachial Artery Resting Average Diameter [ Time Frame: From Baseline to Week 12 ]
    The change in resting average diameter in millimeters of the brachial artery at week 12 from baseline.
  • Change From Baseline to Week 24 in Brachial Artery Resting Average Diameter [ Time Frame: From Baseline to Week 24 ]
    The absolute change in resting average diameter in millimeters of the brachial artery at week 24 from baseline.
  • Change From Baseline to Week 24 in Reactive Hyperemic (RH) Flow Rate [ Time Frame: From Baseline to Week 24 ]
    The absolute change in RH flow rate in cc/min of the brachial artery at week 24 from baseline.
  • Change From Baseline to Week 24 in Peak Reactive Hyperemic (RH) Flow Velocity [ Time Frame: From Baseline to Week 24 ]
    The absolute change in peak RH flow velocity in cm/s of the brachial artery at week 24 from baseline.
  • Percentage Change From Baseline to Week 24 in High-sensitivity C-reactive Protein (hsCRP) [ Time Frame: From Baseline to week 24 ]
    hsCRP is a marker of inflammation. Change from baseline (Week 24 - baseline) was performed on the log10 scale and is thus presented as percentage change, i.e. (10^[fold-change] - 1) x 100%. One single hsCRP result at week 24 was above the limit of quantification, therefore excluded from analysis.
  • Percentage Change From Baseline to Week 24 in Interleukin-6 (IL-6) [ Time Frame: From Baseline to Week 24 ]
    IL-6 is a marker of systemic inflammation. Change from baseline (Week 24 - baseline) was performed on the log10 scale and is thus presented as percentage change, i.e. (10^[fold-change] - 1) x 100%.
  • Percentage Change From Baseline to Week 24 in Soluble CD 163 (sCD163) [ Time Frame: From Baseline to Week 24 ]
    sCD163 is a marker of Macrophage activation. Change from baseline (Week 24 - baseline) was performed on the log10 scale and is thus presented as percentage change, i.e. (10^[fold-change] - 1) x 100%.
  • Percentage Change From Baseline to Week 24 in D-Dimer [ Time Frame: From Baseline to Week 24 ]
    D-dimer (or D dimer) is a marker of coagulation activation. Change from baseline (Week 24 - baseline) was performed on the log10 scale and is thus presented as percentage change, i.e. (10^[fold-change] - 1) x 100%.
  • Absolute Change From Baseline to Week 24 in Monocyte Levels [ Time Frame: From Baseline to Week 24 ]
    Three categories of monocyte levels are presented: classical (CD14+CD16-), intermediate (CD14+CD16+), and non-classical (CD14dimCD16+). Absolute change from baseline (Week 24 - baseline) was analyzed on the measured scale, which is the percent of parent cells that express the subset of interest.
  • Absolute Change From Baseline to Week 24 in Adhesion and Activation Indices [ Time Frame: From Baseline to Week 24 ]
    The adhesion and activation indices of interest are the percentages of CD38+HLADR+ expressions in both parent CD4+ and CD8+ T cells. Absolute change from baseline (Week 24 - baseline) was analyzed on the measured scale, which is the percent of parent cells (either CD4+ or CD8+) that express CD38+HLADR+ cells.
  • Absolute Change From Baseline to Week 24 in Homing Molecule (CX3CR1+) Expression [ Time Frame: From Baseline to Week 24 ]
    CX3CR1+ is a cellular marker of immune activation. The outcome measured is the percentages of CX3CR1+ expressions in both parent CD4+ and CD8+ T cells. Absolute change from baseline (Week 24 - baseline) was analyzed on the measured scale, which is the percent of parent cells (either CD4+ or CD8+) that express CX3CR1+ cells.

Enrollment: 176
Study Start Date: January 31, 2014
Study Completion Date: December 8, 2016
Primary Completion Date: December 8, 2016 (Final data collection date for primary outcome measure)

Arms Assigned Interventions
Experimental: Low-dose methotrexate (LDMTX)
From study entry through Week 1, participants received 5 mg of LDMTX once a week. For participants who were clinically stable at the Week 1 study visit, the dose of LDMTX was increased to 10 mg once a week through Week 12. For participants who were clinically stable at the Week 12 study visit, the dose of LDMTX was increased to 15 mg once a week through Week 24. Participants who did not meet the criteria for dose escalation were re-evaluated at the following study visit. In addition to LDMTX, all participants also received 1 mg of folic acid once a day from study entry throughout Week 24. After taking the final dose of LDMTX, all participants continued taking folic acid for an additional 4 weeks.
Drug: LDMTX
  • LDMTX 5 mg: one 5-mg capsule by mouth once weekly
  • LDMTX 10 mg: two 5-mg capsules by mouth once weekly
  • LDMTX 15 mg: three 5-mg capsules by mouth once weekly

Other Name: Low-Dose Methotrexate
Dietary Supplement: Folic acid

1-mg tablet of folic acid by mouth once a day

Placebo Comparator: Placebo
From study entry through Week 1, participants received 5 mg of placebo once a week. For participants who were clinically stable at the Week 1 study visit, the dose of placebo was increased to 10 mg once a week through Week 12. For participants who were clinically stable at the Week 12 study visit, the dose of placebo was increased to 15 mg once a week through Week 24. Participants who did not meet the criteria for dose escalation were re-evaluated at the following study visit. In addition to placebo, all participants also received 1 mg of folic acid once a day from study entry throughout Week 24. After taking the final dose of placebo, all participants continued taking folic acid for an additional 4 weeks.
Drug: Placebo
  • Placebo 5 mg: one 5-mg capsule by mouth once weekly
  • Placebo 10 mg: two 5-mg capsules by mouth once weekly
  • Placebo 15 mg: three 5-mg capsules by mouth once weekly

Other Name: Placebo for Low-Dose Methotrexate
Dietary Supplement: Folic acid

1-mg tablet of folic acid by mouth once a day

Detailed Description:

HIV-infected people taking ART have a higher than expected risk of premature CVD. Many factors likely contribute to this risk, including chronic inflammation. Strategies to reduce inflammation in HIV-infected people may be beneficial in reducing CVD risk, as well as other conditions, including kidney disease, bone disease, and neurologic complications. MTX is an anti-inflammatory medication used to treat people with rheumatoid arthritis. This study evaluated the safety and effectiveness of LDMTX at treating inflammation and on endothelial function in virologically suppressed HIV-infected adults who had CVD or were at increased risk of CVD.
The total study duration was 36 weeks. Prior to enrolling in the study, participants had a chest X-ray. Participants were randomly assigned to receive LDMTX or placebo for 24 weeks. Participants continued taking their antiretroviral (ARV) medications as usual; ARVs were not provided by the study. At study entry, participants underwent a medical and medication history, physical examination, blood collection, and adherence assessments. From study entry through Week 1, participants received either 5 mg of LDMTX or placebo once a week. For participants who were clinically stable at the Week 1 study visit, the dose of LDMTX or placebo was increased to 10 mg once a week through Week 12. For participants who were clinically stable at the Week 12 study visit, the dose of LDMTX or placebo was increased to 15 mg once a week through Week 24. Participants who did not meet the criteria for dose escalation were re-evaluated at the following study visit. In addition to LDMTX or placebo, all participants also received 1 mg of folic acid once a day from study entry throughout Week

  1. After taking the final dose of LDMTX or placebo, all participants continued taking folic
acid for an additional 4 weeks.
Post-entry visits occurred at Weeks 1, 2, 4, 8, 12, 18, 24, and 36. These included a physical examination, blood collection, and adherence assessments; an arm ultrasound test was performed at Weeks 12 and 24. At Week 2, some participants took part in a pharmacokinetic (PK) assessment, which involved undergoing a blood collection several times over a 6-hour period.

Eligibility

Eligibility

Ages Eligible for Study: 40 Years and older  
Sexes Eligible for Study: All  
Accepts Healthy Volunteers: No  

Criteria

Inclusion Criteria:

  • 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.
  • Had to be on continuous ART for greater than or equal to 24 weeks prior to study entry. This was 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 greater than or equal to 400 cells/mm^3 obtained within 60 days prior to study entry by any U.S. 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 could be performed by any U.S. laboratory that had a CLIA certification or its equivalent. NOTE: Single determinations that are between the assay quantification limit and 200 copies/mL were 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 U.S. laboratory that has a CLIA certification or its equivalent:
    1. Fasting glucose less than 180 mg/dL
    2. Alanine aminotransferase (ALT) [serum glutamic pyruvic transaminase (SGPT)] less than 2 times the upper limit of normal (ULN)
    3. Aspartate aminotransferase (AST) [serum glutamic oxaloacetic transaminase (SGOT)] less than 2 times the ULN
    4. Estimated creatinine clearance (CrCl) greater than or equal to 50 mL/min by Cockcroft-Gault. NOTE: Candidates who were taking tenofovir disoproxil fumarate (TDF) as part of their ART regimen should have an estimated CrCl greater than or equal to 60 mL/min.
    5. White blood cell (WBC) greater than 3,000/mm^3
    6. Hemoglobin greater than 12.0 g/dL
    7. Platelets greater than 150,000/mm^3
  • Female candidates who were postmenopausal (i.e., of non-childbearing potential) were defined as having either:
    1. Appropriate medical documentation of prior hysterectomy and/or complete bilateral oophorectomy (i.e., surgical removal of the ovaries, resulting in "surgical menopause" and occurring at the age at which the procedure was performed), OR
    2. Permanent cessation of previously occurring menses as a result of ovarian failure with documentation of hormonal deficiency by a certified healthcare provider (i.e., "spontaneous menopause").
  • Male candidates must agree not to participate in a conception process (i.e., active attempt to impregnate, sperm donation). If participating in sexual activity that could lead to pregnancy, the male participant must agree to the use of TWO reliable forms of contraceptives simultaneously while on study and for a minimum of 3 months after therapy.
  • Candidates who were not of reproductive potential (defined as women who have been postmenopausal for at least 24 consecutive months or men who have documented vasectomy) were eligible for the study without requiring the use of contraceptives.
  • Moderate or high CVD risk defined as:

  • A) Documented CVD as assessed by meeting at least 1 of 3 criteria below:
    1. Coronary artery disease (CAD): prior myocardial infarction (MI) due to atherosclerosis, coronary artery bypass graft surgery, percutaneous coronary intervention, or angiographic CAD with luminal diameter stenosis of at least one coronary artery at least 50%.
    2. Cerebrovascular disease: prior ischemic stroke of carotid origin, carotid endarterectomy or stenting, or angiographic carotid stenosis of at least 50%.
    3. Peripheral arterial disease: prior lower extremity arterial surgical or percutaneous revascularization procedure, or angiographic lower extremity arterial stenosis of at least 50%.

    OR
    B) Controlled type II diabetes mellitus (HbA1C less than or equal to 8.0% within the past 90 days prior to study entry, regardless of use of medications)
    OR
    C) Any one of the following CVD risk factors below:
  • Current smoking: self-report of smoking at least a half a pack of cigarettes a day, on average, in the past month.
  • Hypertension (HTN): two consecutive blood pressure (BP) readings with either systolic greater than 140 mm Hg or diastolic greater than 90 mm Hg; or on antihypertensive medications.
  • Dyslipidemia: defined as non-high-density lipoprotein (HDL)-C greater than 160 mg/dL or HDL-C less than or equal to 40 mg/dL, regardless of medication use.
  • High-sensitivity C-reactive protein (hsCRP) greater than or equal to 2 mg/L at screening

  • Ability and willingness of candidate to provide informed consent
    • Completion of the Flow-mediated Vasodilation (FMD) assessments. NOTE: The FMD must be performed at the site and confirmed as acceptable by the University of Wisconsin Atherosclerosis Imaging Research Program (UW AIRP) core lab prior to study entry. If the FMD is deemed unacceptable, a repeat scan must be performed prior to enrollment.
    • Appropriate documentation from medical records of prior receipt of pneumococcal vaccination (with both the 13-valent conjugant vaccine [PCV13] and 23-valent pneumococcal polysaccharide vaccine [PPV23]) within the last 5 years. If no documentation is available, then the PCV13 and PPV23 series (PCV13 vaccine followed by PPV23 vaccine at least 8 weeks later) should be completed more than 14 days prior to study entry.

    • Exclusion Criteria:
    • Acute or serious illness requiring systemic treatment and/or hospitalization within 60 days prior to study entry. NOTE: Treatment should have ended at least 60 days prior to study entry for eligibility.
    • Documentation of any CDC category C AIDS-indicator condition or oropharyngeal candidiasis (thrush) within 90 days prior to study entry
    • Receipt of antibiotic therapy within 30 days prior to study entry
    • Latent tuberculosis (TB) infection (defined as a positive purified protein derivative [PPD] greater than or equal to 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 had not been completely treated or was treated within the past 6 months prior to study entry
    • TB disease that required 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 that required treatment within 90 days prior to study entry
    • A history of or current, active hepatitis B infection defined as positive hepatitis B surface antigen (HBsAg) test or positive hepatitis B virus (HBV) DNA in candidates with isolated hepatitis B core antibody (HBcAb) positivity, defined as negative HBsAg, negative hepatitis B surface antibody (HBsAb), and positive HBcAb within 24 weeks prior to study entry. NOTE: Candidates who were positive for hepatitis B surface antigen but who were HBV DNA negative were 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: Candidates who were positive for hepatitis C antibody but whowerehepatitis C virus (HCV) RNA negative are permitted in the study. Candidates who had been treated for hepatitis C should be HCV RNA negative for at least 24 weeks after completion of therapy to be eligible for the study.
    • Previously diagnosed myelodysplasia syndrome
    • Treated lymphoproliferative disease less than or equal to 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 candidate at increased risk of lung toxicity (e.g., history of pulmonary fibrosis, interstitial lung disease, or pulmonary lymphoproliferative disease)
    • Use of immunomodulators (e.g., interleukins, interferons, cyclosporine), HIV vaccine, systemic cytotoxic chemotherapy, or investigational therapy within 30 days prior to study entry
    • Change in the ART regimen in the 12 weeks prior to study entry or intended modification of ART during the study. NOTE: Modifications of ART doses during the 12 weeks prior to study entry were permitted. In addition, the change in formulation (e.g., from standard formulation to fixed-dose combination) was allowed within 12 weeks prior to study entry. A within class single drug substitution (e.g., switch from nevirapine to efavirenz or from atazanavir to darunavir) is allowed within 12 weeks prior to study entry, with the exception of a switch from any other nucleoside reverse transcriptase inhibitor (NRTI) to abacavir. No other changes in ART in the 12 weeks prior to study entry were permitted.
    • Known allergy/sensitivity or any hypersensitivity to components of study drug(s) or their formulation
    • Average daily consumption of three or more alcoholic beverages for 4 weeks prior to study entry or intention to consume an average of two or more alcoholic beverages a day during the study. NOTE: An alcohol-containing beverage is defined as 12 ounces of beer, 4 ounces of wine, or 1 ounce of spirits.
    • Active drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements
    • Changes in lipid-lowering or antihypertensive medication within 90 days prior to study entry or expected need to modify these medications during the study. NOTE: Lipid-lowering medication includes: statins, fibrates, niacin (dose greater than or equal to 250 mg daily), and fish-oil/omega 3 fatty acids (dose greater than 1000 mg of marine oils daily).
    • Vaccination (e.g., influenza, pneumococcal polysaccharide) within 14 days prior to study entry
    • Anticipated need to receive vaccination (e.g., influenza, pneumococcal polysaccharide) within 1 week prior to Week 4, 12, 24, or 36 study visits
    • Excess extracompartmental fluids including ascites, pericardial fluid, and pleural effusions which, in the opinion of the study investigators, would result in difficulty in monitoring the dose of MTX
    • Use of drugs that alter folic acid metabolism such as trimethoprim/sulfamethoxazole or reduce tubular excretion such as probenecid within 14 days prior to study entry
    • New York Heart Association Class IV congestive heart failure
    • Diabetes mellitus with HbA1C greater than 8.0% within the past 90 days prior to study
    entry

    contacts and locations

    Contacts and Locations

    Choosing to participate in a study is an important personal decision.Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below.For general information, see Learn About Clinical Studies.

    Please refer to this study by its ClinicalTrials.gov identifier: NCT01949116

    Locations

    United States, Alabama
    Alabama CRS
    Birmingham, Alabama, United States, 35294
    United States, California
    University of Southern California CRS
    Los Angeles, California, United States, 90033-1079
    UCLA CARE Center CRS
    Los Angeles, California, United States, 90035
    UCSD Antiviral Research Center CRS
    San Diego, California, United States, 92103
    Ucsf Hiv/Aids Crs
    San Francisco, California, United States, 94110
    Harbor-UCLA CRS
    Torrance, California, United States, 90502
    United States, Colorado
    University of Colorado Hospital CRS
    Aurora, Colorado, United States, 80045
    United States, Illinois
    Northwestern University CRS
    Chicago, Illinois, United States, 60611
    United States, Maryland
    Johns Hopkins University CRS
    Baltimore, Maryland, United States, 21205
    United States, Massachusetts
    Brigham and Women's Hospital Therapeutics Clinical Research Site (BWH TCRS) CRS
    Boston, Massachusetts, United States, 02115
    United States, Missouri
    Washington University Therapeutics (WT) CRS
    Saint Louis, Missouri, United States, 63110-1010
    United States, New Jersey
    New Jersey Medical School Clinical Research Center CRS
    Newark, New Jersey, United States, 07103
    United States, North Carolina
    Chapel Hill CRS
    Chapel Hill, North Carolina, United States, 27599
    Greensboro CRS
    Greensboro, North Carolina, United States, 27401
    United States, Ohio
    Cincinnati Clinical Research Site
    Cincinnati, Ohio, United States, 45219
    Case Clinical Research Site
    Cleveland, Ohio, United States, 44106
    Ohio State University CRS
    Columbus, Ohio, United States, 43210
    United States, Pennsylvania
    Penn Therapeutics, CRS
    Philadelphia, Pennsylvania, United States, 19104
    University of Pittsburgh CRS
    Pittsburgh, Pennsylvania, United States, 15213
    United States, Rhode Island
    The Miriam Hospital Clinical Research Site (TMH CRS) CRS
    Providence, Rhode Island, United States, 02906
    United States, Tennessee
    Vanderbilt Therapeutics (VT) CRS
    Nashville, Tennessee, United States, 37204
    United States, Texas
    Houston AIDS Research Team CRS
    Houston, Texas, United States, 77030

    Sponsors and Collaborators

    National Institute of Allergy and Infectious Diseases (NIAID)

    Investigators

    Study Chair: Priscilla Hsue, MD San Francisco General Hospital
    Study Chair: Judith Currier, MD, MSc University of California, Los Angeles
    More Information

    More Information

    Additional Information:

    DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, Version 1.0, December 2004 (Clarification, August 2009)

    Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)  
    ClinicalTrials.gov Identifier: NCT01949116   History of Changes  
    Other Study ID Numbers: A5314  
      11875  
    Study First Received: September 19, 2013  
    Last Updated: January 9, 2018  

    Additional relevant MeSH terms:
    Infection
    HIV Infections
    Acquired Immunodeficiency Syndrome
    Inflammation
    Folic Acid
    Methotrexate

    ClinicalTrials.gov processed this data on July 08, 2020
    This information is provided by ClinicalTrials.gov.