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Evaluating Safety and Effectiveness of Low-Dose Methotrexate at Reducing Inflammation in HIV-Infected Adults Taking Antiretroviral Medications

This study is currently recruiting participants. (see Contacts and Locations)
Verified November 2014 by National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor:
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID) ( National Institute of Allergy and Infectious Disease (NIAID), National Heart, Lung, and Blood Institute (NHLBI) )
ClinicalTrials.gov Identifier:
NCT01949116
First received: September 19, 2013
Last updated: November 24, 2014
Last verified: November 2014
  Purpose

People with HIV infection who are taking antiretroviral therapy (ART) may 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 will evaluate the safety and effectiveness of low-dose methotrexate (LDMTX) at reducing inflammation in HIV-infected adults.


Condition Intervention Phase
HIV Infections
Drug: Methotrexate (MTX)
Drug: Placebo
Dietary Supplement: Folic acid
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, 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

Resource links provided by NLM:


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

Primary Outcome Measures:
  • For participants with 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 [ Time Frame: Measured through Week 36 ] [ Designated as safety issue: Yes ]
  • For participants with entry CD4 T-cell count greater than or equal to 700 cells/mm^3: confirmed CD4 decline greater than 50% of baseline [ Time Frame: Measured through Week 36 ] [ Designated as safety issue: Yes ]
  • Confirmed HIV-1 RNA level greater than 200 copies/mL in the absence of an interruption in ART [ Time Frame: Measured through Week 36 ] [ Designated as safety issue: Yes ]
  • New or recurrent Centers for Disease Control and Prevention (CDC) category C AIDS-indicator condition [ Time Frame: Measured through Week 36 ] [ Designated as safety issue: Yes ]
  • Evidence of HIV-associated infection, including cytomegalovirus (CMV) end-organ disease, varicella zoster, or Epstein-Barr virus (EBV)-related clinical disease [ Time Frame: Measured through Week 36 ] [ Designated as safety issue: Yes ]
  • Requirement for LDMTX discontinuation for confirmed Grade 3 or higher toxicity [ Time Frame: Measured through Week 36 ] [ Designated as safety issue: Yes ]
  • Lymphoproliferative malignancies [ Time Frame: Measured through Week 36 ] [ Designated as safety issue: Yes ]
  • Pulmonary toxicity [ Time Frame: Measured through Week 36 ] [ Designated as safety issue: Yes ]
    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.

  • Change from baseline to Week 24 in brachial artery flow-mediated vasodilation (FMD) (%) [ Time Frame: Measured through Week 24 ] [ Designated as safety issue: No ]
    Defined as the maximum FMD (%) calculated from reactive hyperemia (RH) 60 and RH 90 relative to resting artery diameter (baseline).


Secondary Outcome Measures:
  • Change from baseline to Week 12 in brachial artery FMD (%) [ Time Frame: Measured through Week 12 ] [ Designated as safety issue: No ]
  • Change from baseline to Week 12 in brachial artery diameter (mm) [ Time Frame: Measured through Week 12 ] [ Designated as safety issue: No ]
  • Change from baseline to Week 24 in brachial artery diameter (mm) [ Time Frame: Measured through Week 24 ] [ Designated as safety issue: No ]
  • Change from baseline to Week 24 in brachial artery hyperemic flow velocity (time-integrated, cm) [ Time Frame: Measured through Week 24 ] [ Designated as safety issue: No ]
  • Changes from baseline to Week 24 in levels of high-sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6), sCD163, and D-dimer [ Time Frame: Measured through Week 24 ] [ Designated as safety issue: No ]
  • Change from baseline to Week 24 in monocyte levels, adhesion and activation indices, and CX3CR1 expression [ Time Frame: Measured through Week 24 ] [ Designated as safety issue: No ]

Estimated Enrollment: 200
Study Start Date: December 2013
Estimated Primary Completion Date: August 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Low-dose methotrexate (LDMTX)
From study entry through Week 1, participants will receive 5 mg of LDMTX once a week. For participants who are clinically stable at the Week 1 study visit, the dose will be increased to 10 mg once a week through Week 12. For participants who are clinically stable at the Week 12 study visit, the dose will be increased to 15 mg once a week through Week 24. In addition to LDMTX, all participants will also receive 1 mg of folic acid once a day from study entry throughout Week 24.
Drug: Methotrexate (MTX)

MTX 5 mg: one 5-mg capsule by mouth once weekly

MTX 10 mg: two 5-mg capsules by mouth once weekly

MTX 15 mg: three 5-mg capsules by mouth once weekly

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 will receive 5 mg of placebo once a week. For participants who are clinically stable at the Week 1 study visit, the dose will be increased to 10 mg once a week through Week 12. For participants who are clinically stable at the Week 12 study visit, the dose will be increased to 15 mg once a week through Week 24. In addition to placebo, all participants will also receive 1 mg of folic acid once a day from study entry throughout Week 24.
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

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 will evaluate the safety and effectiveness of LDMTX at treating inflammation and on endothelial function in virologically suppressed HIV-infected adults who have CVD or are at increased risk of CVD.

The total study duration will be 36 weeks. Prior to enrolling in the study, participants will have a chest X-ray. Participants will be randomly assigned to receive LDMTX or placebo for 24 weeks. Participants will continue taking their antiretroviral (ARV) medications as usual; ARVs will not be provided by the study. At study entry, participants will undergo a medical and medication history, physical examination, blood collection, and adherence assessments. From study entry through Week 1, participants will receive either 5 mg of MTX or placebo once a week. For participants who are clinically stable at the Week 1 study visit, the dose of MTX or placebo will be increased to 10 mg once a week through Week 12. For participants who are clinically stable at the Week 12 study visit, the dose of MTX or placebo will be increased to 15 mg once a week through Week 24. Participants who do not meet the criteria for dose escalation will be re-evaluated at the following study visit. In addition to LDMTX or placebo, all participants will also receive 1 mg of folic acid once a day from study entry throughout Week 24.

Additional study visits will occur at Weeks 1, 2, 4, 8, 12, 18, 24, and 36. They will include a physical examination, blood collection, and adherence assessments; an arm ultrasound test will also be performed at Weeks 12 and 24. At Week 2, some participants will also take part in a pharmacokinetic (PK) assessment, which will involve undergoing a blood collection several times over a 6-hour period.

  Eligibility

Ages Eligible for Study:   40 Years and older
Genders Eligible for Study:   Both
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. More information on this criterion can be found in the protocol.
  • Currently on continuous ART for greater than or equal to 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 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 Food and Drug Administration (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 U.S. 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 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: Participants who are taking tenofovir disoproxil fumarate (TDF) as part of their ART regimen must 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 participants who are postmenopausal (i.e., of non-childbearing potential), 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"). More information on this criterion can be found in the protocol.
  • Male participants 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. More information on this criterion can be found in the protocol.
  • Participants who are not of reproductive potential (defined as women who have been postmenopausal for at least 24 consecutive months or men who have documented vasectomy) are eligible for the study without requiring the use of contraceptives. More information on this criterion can be found in the protocol.
  • 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:

  1. Current smoking: participant report of smoking at least a half a pack of cigarettes a day, on average, in the past month.
  2. 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.
  3. 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.
  4. High-sensitivity C-reactive protein (hsCRP) greater than or equal to 2 mg/L at screening

Ability and willingness of participant to provide informed consent

  • For participants taking tenofovir (TFV) as part of their ART regimen, willingness to consider participation in the PK component of the study. NOTE: Participation in the PK component of the study is optional but strongly encouraged.
  • Completion of the pre-entry FMD assessment. NOTE: At least one 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.

Exclusion Criteria:

  • 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 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 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 (HBsAg) test or positive hepatitis B virus (HBV) DNA in participants 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: Participants 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: Participants who are positive for hepatitis C antibody but who are hepatitis C virus (HCV) RNA negative are permitted in 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 participant 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 are permitted. In addition, the change in formulation (e.g., from standard formulation to fixed-dose combination) is 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 are 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
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

  Show 26 Study Locations
Sponsors and Collaborators
National Institute of Allergy and Infectious Disease (NIAID), National Heart, Lung, and Blood Institute (NHLBI)
Investigators
Study Chair: Priscilla Hsue, MD San Francisco General Hospital
Study Chair: Judith Currier, MD, MSc UCLA CARE Center
  More Information

No publications provided

Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID) ( National Institute of Allergy and Infectious Disease (NIAID), National Heart, Lung, and Blood Institute (NHLBI) )
ClinicalTrials.gov Identifier: NCT01949116     History of Changes
Other Study ID Numbers: A5314, 11875
Study First Received: September 19, 2013
Last Updated: November 24, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Acquired Immunodeficiency Syndrome
Communicable Diseases
HIV Infections
Infection
Inflammation
Immune System Diseases
Immunologic Deficiency Syndromes
Lentivirus Infections
Pathologic Processes
RNA Virus Infections
Retroviridae Infections
Sexually Transmitted Diseases
Sexually Transmitted Diseases, Viral
Slow Virus Diseases
Virus Diseases
Folic Acid
Methotrexate
Vitamin B Complex
Abortifacient Agents
Abortifacient Agents, Nonsteroidal
Antimetabolites
Antimetabolites, Antineoplastic
Antineoplastic Agents
Antirheumatic Agents
Dermatologic Agents
Enzyme Inhibitors
Folic Acid Antagonists
Growth Substances
Hematinics
Hematologic Agents

ClinicalTrials.gov processed this record on November 25, 2014