NCT01949116

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

Completed Phase 2 Results posted Last updated 1 November 2021

What this trial tests

Phase 2 trial testing LDMTX in HIV Infections in 176 participants. Completed in 8 December 2016.

Timeline

31 January 2014

Primary endpoint
8 December 2016

8 December 2016

Quick facts

Lead sponsor	National Institute of Allergy and Infectious Diseases (NIAID)
Phase	Phase 2
Status	Completed
Study type	INTERVENTIONAL
Allocation	randomized
Design	parallel
Masking	quadruple
Primary purpose	treatment
Enrollment	176
Start date	31 January 2014
Primary completion	8 December 2016
Estimated completion	8 December 2016
Sites	22 locations across United States

Drugs / interventions tested

• LDMTX — full drug profile →
• Placebo
• Folic acid (FOLIC ACID) — full drug profile →

Conditions studied

• HIV Infections — all drugs for HIV Infections →

Sponsor

National Institute of Allergy and Infectious Diseases (NIAID)

Who can join

40 and older, any sex, with HIV Infections. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

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

Group	Value	95% CI
Low-dose Methotrexate (LDMTX)	11
Placebo	5

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

Group	Value	95% CI
Low-dose Methotrexate (LDMTX)	0.24	-0.40 – 0.88
Placebo	0.15	-0.47 – 0.77

Change From Baseline to Week 12 in Brachial Artery FMD Secondary · 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.

Group	Value	95% CI
Low-dose Methotrexate (LDMTX)	0.32	-1.55 – 1.54
Placebo	-0.06	-1.3 – 1.66

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

The change in resting average diameter in millimeters of the brachial artery at week 12 from baseline.

Group	Value	95% CI
Low-dose Methotrexate (LDMTX)	0.04	-0.09 – 0.13
Placebo	0.03	-0.09 – 0.15

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

The absolute change in resting average diameter in millimeters of the brachial artery at week 24 from baseline.

Group	Value	95% CI
Low-dose Methotrexate (LDMTX)	0	-0.11 – 0.13
Placebo	0.01	-0.1 – 0.12

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

The absolute change in RH flow rate in cc/min of the brachial artery at week 24 from baseline.

Group	Value	95% CI
Low-dose Methotrexate (LDMTX)	-11.40	-97.46 – 161.64
Placebo	13.76	-135.11 – 107.73

Change From Baseline to Week 24 in Peak Reactive Hyperemic (RH) Flow Velocity Secondary · 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.

Group	Value	95% CI
Low-dose Methotrexate (LDMTX)	-0.20	-11.30 – 14.40
Placebo	-0.83	-16.80 – 16.88

Percentage Change From Baseline to Week 24 in High-sensitivity C-reactive Protein (hsCRP) Secondary · 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.

Group	Value	95% CI
Low-dose Methotrexate (LDMTX)	-3.5	-26.7 – 27.1
Placebo	5.4	-16.8 – 33.5

Percentage Change From Baseline to Week 24 in Interleukin-6 (IL-6) Secondary · 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%.

Group	Value	95% CI
Low-dose Methotrexate (LDMTX)	13.4	-1.3 – 30.3
Placebo	21.3	-0.2 – 47.4

Percentage Change From Baseline to Week 24 in Soluble CD 163 (sCD163) Secondary · 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%.

Group	Value	95% CI
Low-dose Methotrexate (LDMTX)	2.7	-4.2 – 10.1
Placebo	7.5	0.6 – 15.0

Percentage Change From Baseline to Week 24 in D-Dimer Secondary · 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%.

Group	Value	95% CI
Low-dose Methotrexate (LDMTX)	-1.5	-10.6 – 8.5
Placebo	9.9	-3.3 – 24.9

Absolute Change From Baseline to Week 24 in Monocyte Levels Secondary · 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.

Classical (CD14+CD16-)

Group	Value	95% CI
Low-dose Methotrexate (LDMTX)	-0.15	-1.39 – 1.10
Placebo	0.82	-0.42 – 2.06

Intermediate (CD14+CD16+)

Group	Value	95% CI
Low-dose Methotrexate (LDMTX)	-0.07	-0.77 – 0.62
Placebo	-0.51	-1.32 – 0.29

Non-classical (CD14dimCD16+)

Group	Value	95% CI
Low-dose Methotrexate (LDMTX)	0.21	-0.66 – 1.08
Placebo	-0.29	-0.89 – 0.31

Adverse events — posted to ClinicalTrials.gov

Time frame: Adverse Events (AEs) reported from study enrollment until study completion at 36 weeks.. Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

LDMTX

Serious: 9/86 (10%)

Deaths: 2/86

Placebo

Serious: 8/90 (9%)

Deaths: 0/90

Serious adverse events (21 terms)

Reaction	System	LDMTX	Placebo
Pneumonia	Infections and infestations	—	—
Neutropenia	Blood and lymphatic system disorders	—	—
Acute myocardial infarction	Cardiac disorders	—	—
Coronary artery stenosis	Cardiac disorders	—	—
Food poisoning	Gastrointestinal disorders	—	—
Chest pain	General disorders	—	—
Pyrexia	General disorders	—	—
Bronchitis	Infections and infestations	—	—
Gastroenteritis shigella	Infections and infestations	—	—
Pneumonia bacterial	Infections and infestations	—	—
Pneumonia pneumococcal	Infections and infestations	—	—
Subdural haemorrhage	Injury, poisoning and procedural complications	—	—
Hypophosphataemia	Metabolism and nutrition disorders	—	—
Intervertebral disc degeneration	Musculoskeletal and connective tissue disorders	—	—
Tenosynovitis	Musculoskeletal and connective tissue disorders	—	—
Carcinoma in situ	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—	—
Prostate cancer	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—	—
Syncope	Nervous system disorders	—	—
Scrotal pain	Reproductive system and breast disorders	—	—
Asthma	Respiratory, thoracic and mediastinal disorders	—	—
Chronic obstructive pulmonary disease	Respiratory, thoracic and mediastinal disorders	—	—

Other adverse events (20 terms — click to expand)

Reaction	System	LDMTX	Placebo
Blood glucose increased	Investigations	—	—
Blood cholesterol increased	Investigations	—	—
Low density lipoprotein increased	Investigations	—	—
Blood creatinine increased	Investigations	—	—
Blood sodium decreased	Investigations	—	—
Aspartate aminotransferase increased	Investigations	—	—
Blood bicarbonate decreased	Investigations	—	—
Blood bilirubin increased	Investigations	—	—
Blood glucose decreased	Investigations	—	—
Alanine aminotransferase increased	Investigations	—	—
Cough	Respiratory, thoracic and mediastinal disorders	—	—
Fatigue	General disorders	—	—
Neutrophil count decreased	Investigations	—	—
Malaise	General disorders	—	—
Pyrexia	General disorders	—	—
Blood alkaline phosphatase increased	Investigations	—	—
Blood potassium decreased	Investigations	—	—
Dyspnoea	Respiratory, thoracic and mediastinal disorders	—	—
Nausea	Gastrointestinal disorders	—	—
Pain in extremity	Musculoskeletal and connective tissue disorders	—	—

Most-reported serious reactions: Pneumonia, Neutropenia, Acute myocardial infarction, Coronary artery stenosis, Food poisoning, Chest pain, Pyrexia, Bronchitis.

Data from ClinicalTrials.gov NCT01949116 adverse events section.

Sponsor's own description

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.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

1. HIV-Related Immune Activation and Inflammation: Current Understanding and Strategies.
   Lv T, Cao W, Li T. · · 2021 · cited 145× · PMID 34631899 · DOI 10.1155/2021/7316456
2. Interleukin 6 Is a Stronger Predictor of Clinical Events Than High-Sensitivity C-Reactive Protein or D-Dimer During HIV Infection.
   Borges ÁH, O'Connor JL, Phillips AN, Neaton JD, et al · · 2016 · cited 108× · PMID 27132283 · DOI 10.1093/infdis/jiw173
3. Modulation of Macrophage Immunometabolism: A New Approach to Fight Infections.
   Gauthier T, Chen W. · · 2022 · cited 99× · PMID 35154105 · DOI 10.3389/fimmu.2022.780839
4. Immune activation and cardiovascular disease in chronic HIV infection.
   Longenecker CT, Sullivan C, Baker JV. · · 2016 · cited 85× · PMID 26599166 · DOI 10.1097/coh.0000000000000227
5. Inflammation in HIV and Its Impact on Atherosclerotic Cardiovascular Disease.
   Obare LM, Temu T, Mallal SA, Wanjalla CN. · · 2024 · cited 58× · PMID 38781301 · DOI 10.1161/circresaha.124.323891
6. Association of Arterial and Lymph Node Inflammation With Distinct Inflammatory Pathways in Human Immunodeficiency Virus Infection.
   Tawakol A, Ishai A, Li D, Takx RA, et al · · 2017 · cited 49× · PMID 27926762 · DOI 10.1001/jamacardio.2016.4728
7. 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.
   Hsue PY, Ribaudo HJ, Deeks SG, Bell T, et al · · 2019 · cited 45× · PMID 30219823 · DOI 10.1093/cid/ciy781
8. Association of Biomarker Clusters With Cardiac Phenotypes and Mortality in Patients With HIV Infection.
   Scherzer R, Shah SJ, Secemsky E, Butler J, et al · · 2018 · cited 41× · PMID 29615435 · DOI 10.1161/circheartfailure.117.004312