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

NCT01949116 | Completed Phase 2 Results DMC

• 2 other identifiers: A531411875
• Study Type: interventional
• Target: 176
• Locations: 1 country
• Sites: 22

Brief Summary

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.

Conditions

HIV Infections

Outcome Measures

Primary Outcomes (2)

• Number of Participants Who Reached at Least One Safety Milestone Over the Duration of Study Follow-up (36 Weeks)

  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.

  From study entry to week 36

• Primary Efficacy Endpoint of Change From Baseline to Week 24 in Brachial Artery Flow-mediated Vasodilation (FMD)

  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.

  From Baseline to Week 24

Secondary Outcomes (12)

• Change From Baseline to Week 12 in Brachial Artery FMD

  From Baseline to Week 12

• Change From Baseline to Week 12 in Brachial Artery Resting Average Diameter

  From Baseline to Week 12

• Change From Baseline to Week 24 in Brachial Artery Resting Average Diameter

  From Baseline to Week 24

• Change From Baseline to Week 24 in Reactive Hyperemic (RH) Flow Rate

  From Baseline to Week 24

• Change From Baseline to Week 24 in Peak Reactive Hyperemic (RH) Flow Velocity

  From Baseline to Week 24

Study Arms (2)

Low-dose methotrexate (LDMTX)

EXPERIMENTAL

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; Dietary Supplement: Folic acid

Placebo

PLACEBO COMPARATOR

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; Dietary Supplement: Folic acid

Interventions

LDMTX DRUG

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

Also known as: Low-Dose Methotrexate

Low-dose methotrexate (LDMTX)

Placebo DRUG

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

Also known as: Placebo for Low-Dose Methotrexate

Placebo

Folic acid DIETARY_SUPPLEMENT

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

Low-dose methotrexate (LDMTX); Placebo

Eligibility Criteria

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

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.
• 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:
• Fasting glucose less than 180 mg/dL
• Alanine aminotransferase (ALT) \[serum glutamic pyruvic transaminase (SGPT)\] less than 2 times the upper limit of normal (ULN)
• Aspartate aminotransferase (AST) \[serum glutamic oxaloacetic transaminase (SGOT)\] less than 2 times the ULN
• 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.
• White blood cell (WBC) greater than 3,000/mm\^3
• Hemoglobin greater than 12.0 g/dL
• Platelets greater than 150,000/mm\^3
• Female candidates who were postmenopausal (i.e., of non-childbearing potential) were defined as having either:
• 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
• 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").

You may not qualify if:

• 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

Sponsors & Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID): lead

Study Sites (22)

Alabama CRS

Birmingham, Alabama, 35294, United States

Location

University of Southern California CRS

Los Angeles, California, 90033-1079, United States

Location

UCLA CARE Center CRS

Los Angeles, California, 90035, United States

Location

UCSD Antiviral Research Center CRS

San Diego, California, 92103, United States

Location

Ucsf Hiv/Aids Crs

San Francisco, California, 94110, United States

Location

Harbor-UCLA CRS

Torrance, California, 90502, United States

Location

University of Colorado Hospital CRS

Aurora, Colorado, 80045, United States

Location

Northwestern University CRS

Chicago, Illinois, 60611, United States

Location

Johns Hopkins University CRS

Baltimore, Maryland, 21205, United States

Location

Brigham and Women's Hospital Therapeutics Clinical Research Site (BWH TCRS) CRS

Boston, Massachusetts, 02115, United States

Location

Washington University Therapeutics (WT) CRS

St Louis, Missouri, 63110-1010, United States

Location

New Jersey Medical School Clinical Research Center CRS

Newark, New Jersey, 07103, United States

Location

Chapel Hill CRS

Chapel Hill, North Carolina, 27599, United States

Location

Greensboro CRS

Greensboro, North Carolina, 27401, United States

Location

Cincinnati Clinical Research Site

Cincinnati, Ohio, 45219, United States

Location

Case Clinical Research Site

Cleveland, Ohio, 44106, United States

Location

Ohio State University CRS

Columbus, Ohio, 43210, United States

Location

Penn Therapeutics, CRS

Philadelphia, Pennsylvania, 19104, United States

Location

University of Pittsburgh CRS

Pittsburgh, Pennsylvania, 15213, United States

Location

The Miriam Hospital Clinical Research Site (TMH CRS) CRS

Providence, Rhode Island, 02906, United States

Location

Vanderbilt Therapeutics (VT) CRS

Nashville, Tennessee, 37204, United States

Location

Houston AIDS Research Team CRS

Houston, Texas, 77030, United States

Location

Related Publications (2)

• Cyktor JC, Yeh E, Ribaudo H, Hoeth D, Naqvi A, Bell T, Ridker PM, Fichtenbaum C, Daar ES, Havlir D, Tawakol A, Lederman MM, Stein JH, Deeks SG, Currier JS, Hsue PY, Mellors JW; A5314 Team. Brief Report: Low-Dose Methotrexate Does Not Affect Measures of HIV-1 Persistence in Individuals With Chronically Treated HIV-1 Infection. J Acquir Immune Defic Syndr. 2024 Aug 15;96(5):481-485. doi: 10.1097/QAI.0000000000003453.

  PMID: 39287554 DERIVED

• Hsue PY, Ribaudo HJ, Deeks SG, Bell T, Ridker PM, Fichtenbaum C, Daar ES, Havlir D, Yeh E, Tawakol A, Lederman M, Currier JS, Stein JH. Safety and Impact of Low-dose Methotrexate on Endothelial Function and Inflammation in Individuals With Treated Human Immunodeficiency Virus: AIDS Clinical Trials Group Study A5314. Clin Infect Dis. 2019 May 17;68(11):1877-1886. doi: 10.1093/cid/ciy781.

  PMID: 30219823 DERIVED

Related Links

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

MeSH Terms

Conditions

HIV Infections

Interventions

Methotrexate; Folic Acid

Condition Hierarchy (Ancestors)

Blood-Borne Infections; Communicable Diseases; Infections; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Genital Diseases; Urogenital Diseases; Immunologic Deficiency Syndromes; Immune System Diseases

Intervention Hierarchy (Ancestors)

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

Results Point of Contact

• Title: ACTG Clinicaltrials.gov Coordinator
• Organization: ACTG Network Coordinating Center, Social and Scientific Systems, Inc.

ACTGCT.Gov@s-3.com

(301) 628-3313

Study Officials

• Priscilla Hsue, MD

  San Francisco General Hospital

  STUDY CHAIR

• Judith Currier, MD, MSc

  University of California, Los Angeles

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 19, 2013
• First Posted: September 24, 2013
• Study Start: January 31, 2014
• Primary Completion: December 8, 2016
• Study Completion: December 8, 2016
• Last Updated: November 1, 2021
• Results First Posted: January 10, 2018

Record last verified: 2021-10

Locations

US (22)