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

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ClinicalTrials.gov Identifier: NCT01949116

Recruitment Status : Completed

First Posted : September 24, 2013

Results First Posted : January 10, 2018

Last Update Posted : November 1, 2021

View this study on Beta.ClinicalTrials.gov

Sponsor:

Information provided by (Responsible Party):

National Institute of Allergy and Infectious Diseases (NIAID)

Study Type	Interventional
Study Design	Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
Condition	HIV Infections
Interventions	Drug: LDMTX Drug: Placebo Dietary Supplement: Folic acid
Enrollment	176

Participant Flow

Recruitment Details	Total of 176 participants randomized to A5314 - 86 in LDMTX, 90 in Placebo. The first participant enrolled on January 31, 2014; the last participant enrolled on March 31, 2016. A range of 2 to 25 participants per site enrolled across 22 clinical research sites during study accrual.
Pre-assignment Details


Arm/Group Title	Low-dose Methotrexate (LDMTX)	Placebo
Arm/Group Description	From study entry through Week 1, pa...	From study entry through Week 1, pa...
Arm/Group Description	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. 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 Folic acid: 1-mg tablet of folic acid by mouth once a day	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. 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 Folic acid: 1-mg tablet of folic acid by mouth once a day
Period Title: Overall Study
Started	86	90
Completed	78	84
Not Completed	8	6
Reason Not Completed
Death	2	0
Lost to Follow-up	1	3
Withdrawal by Subject	5	3

Baseline Characteristics

Arm/Group Title		Low-dose Methotrexate (LDMTX)	Placebo	Total
Arm/Group Description		From study entry through Week 1, pa...	From study entry through Week 1, pa...	Total of all reporting groups
Arm/Group Description		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 were 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 through 4 weeks after LDMTX is discontinued, either at Week 24 or earlier, for any reason. 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 Folic acid: 1-mg tablet of folic acid by mouth once a day	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 were 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 through 4 weeks after placebo is discontinued, either at Week 24 or earlier, for any reason. 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 Folic acid: 1-mg tablet of folic acid by mouth once a day	Total of all reporting groups
Overall Number of Baseline Participants		86	90	176
Baseline Analysis Population Description		...
Baseline Analysis Population Description		Intent-to-treat (ITT) population consists of all eligible participants who were randomized for the study.
Age, Continuous Median (Inter-Quartile Range) Unit of measure: Years
	Number Analyzed	86 participants	90 participants	176 participants
		55 (51 to 60)	53 (49 to 56)	54 (49 to 59)
Sex: Female, Male Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	86 participants	90 participants	176 participants
	Female	8 9.3%	9 10.0%	17 9.7%
	Male	78 90.7%	81 90.0%	159 90.3%
Region of Enrollment Measure Type: Count of Participants Unit of measure: Participants
United States	Number Analyzed	86 participants	90 participants	176 participants
United States		86 100.0%	90 100.0%	176 100.0%
Current Statin Use ^[1] Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	86 participants	90 participants	176 participants
	Current Statin Use	51 59.3%	52 57.8%	103 58.5%
	No Current Statin Use	35 40.7%	38 42.2%	73 41.5%
		[1] Measure Description: Current Statin Use at Study Entry - this is a stratification factor for the study.
Smoking Status Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	86 participants	90 participants	176 participants
	Current Smoker	28 32.6%	40 44.4%	68 38.6%
	Current non-smoker	58 67.4%	50 55.6%	108 61.4%
Type of CVD Risk ^[1] Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	86 participants	90 participants	176 participants
	CAD, CVD, or PAD	20 23.3%	12 13.3%	32 18.2%
	Controlled type 2 diabetes mellitus	19 22.1%	20 22.2%	39 22.2%
	Smoking/hypertension/dyslipidemia/hsCRP >= 2mg/L	47 54.7%	58 64.4%	105 59.7%
		[1] Measure Description: CVD = cardiovascular disease; CAD = coronary artery disease; PAD = peripheral artery disease; hsCRP = high-sensitivity C-reactive protein.
10 year ASCVD risk ^[1] [2] Median (Inter-Quartile Range) Unit of measure: Percent risk of ASCVD
	Number Analyzed	47 participants	58 participants	105 participants
		10.1 (5.4 to 14.3)	7.9 (5.0 to 12.4)	8.7 (5.1 to 13.0)
		[1] Measure Description: Atherosclerotic cardiovascular disease (ASCVD) is defined as coronary death or nonfatal myocardial infarction, or fatal or nonfatal stroke, based on the Pooled Cohort Equations. The 10-year risk was calculated for only those participants who fell in the CVD Risk category, "Smoking, hypertension, dyslipidemia, or hsCRP >= 2 mg/L." [2] Measure Analysis Population Description: Participants with any risk of CAD, CVD, PAD, or controlled type 2 diabetes mellitus are excluded from the ASCVD risk calculation.
CD4+ cell count Median (Inter-Quartile Range) Unit of measure: Cells/mm^3
	Number Analyzed	86 participants	90 participants	176 participants
		689 (551 to 910)	729 (569 to 947)	726 (552 to 940)
HIV-1 RNA Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	86 participants	90 participants	176 participants
	Detectable	2	4	6
	Below Assay Limit of Detection	84	84	168
	Missing	0	2	2
Brachial Artery FMD ^[1] [2] Median (Inter-Quartile Range) Unit of measure: Percent Dilation
	Number Analyzed	86 participants	87 participants	173 participants
		3.54 (2.19 to 4.91)	3.41 (1.98 to 5.03)	3.45 (2.10 to 4.91)
		[1] Measure Description: Flow-mediated vasodilation is defined as the maximum FMD (%) calculated from reactive hyperemia (RH) 60 and RH 90 relative to resting artery diameter. [2] Measure Analysis Population Description: 3 participants in the placebo group have either unsatisfactory scans or did not meet protocol requirements at the time of the FMD assessment.

Outcome Measures

1.Primary Outcome


Title	Number of Participants Who Reached at Least One Safety Milestone Over the Duration of Study Follow-up (36 Weeks)
Description	Number of participants who experienced any one of the following safety...
Description	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.
Time Frame	From study entry to week 36

Outcome Measure Data

Analysis Population Description

Intent-to-treat (ITT) population consists of all eligible participants who were randomized for the study.


Arm/Group Title	Low-dose Methotrexate (LDMTX)	Placebo
Arm/Group Description:	From study entry through Week 1, pa...	From study entry through Week 1, pa...
Arm/Group Description:	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 through 4 weeks after LDMTX is discontinued, either at Week 24 or earlier, for any reason. 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 Folic acid: 1-mg tablet of folic acid by mouth once a day	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 through 4 weeks after placebo is discontinued, either at Week 24 or earlier, for any reason. 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 Folic acid: 1-mg tablet of folic acid by mouth once a day
Overall Number of Participants Analyzed	86	90
Measure Type: Count of Participants Unit of Measure: Participants
	11 12.8%	5 5.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Low-dose Methotrexate (LDMTX), Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Non-Inferiority
	Comments	The P-value for the risk difference is from an asymptotic non-inferiority analysis for the proportion (risk) difference with a 15% non-inferiority margin.

Statistical Test of Hypothesis	P-Value	0.0367
	Comments	[Not Specified]
	Method	Farrington-Manning score (exact)
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	0.072
	Confidence Interval	(1-Sided) 90% 0.134
	Estimation Comments	LDMTX - Placebo

2.Primary Outcome


Title	Primary Efficacy Endpoint of Change From Baseline to Week 24 in Brachial Artery Flow-mediated Vasodilation (FMD)
Description	Flow-mediated vasodilation is defined as the maximum FMD (%) calculate...
Description	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.
Time Frame	From Baseline to Week 24

Outcome Measure Data

Analysis Population Description

Intent-to-treat (ITT) population consists of all eligible participants who were randomized for the study.


Arm/Group Title	Low-dose Methotrexate (LDMTX)	Placebo
Arm/Group Description:	From study entry through Week 1, pa...	From study entry through Week 1, pa...
Arm/Group Description:	From study entry through Week 1, participants received either 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 was 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. 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 Folic acid: 1-mg tablet of folic acid by mouth once a day	From study entry through Week 1, participants received either 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 was 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. 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 Folic acid: 1-mg tablet of folic acid by mouth once a day
Overall Number of Participants Analyzed	74	80
Mean (95% Confidence Interval) Unit of Measure: Percent Dilation
	0.24 (-0.40 to 0.88)	0.15 (-0.47 to 0.77)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Low-dose Methotrexate (LDMTX), Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.55
	Comments	[Not Specified]
	Method	Wilcoxon (Mann-Whitney)
	Comments	Stratified by Statin Use (study stratification factor)

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.09
	Confidence Interval	(2-Sided) 95% -0.67 to 0.85
	Estimation Comments	[Not Specified]

3.Secondary Outcome


Title	Change From Baseline to Week 12 in Brachial Artery FMD
Description	The absolute change from baseline to week 24 FMD (%), defined as the m...
Description	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.
Time Frame	From Baseline to Week 12

Outcome Measure Data

Analysis Population Description

Intent-to-treat (ITT) population consists of all eligible participants who were randomized for the study.


Arm/Group Title	Low-dose Methotrexate (LDMTX)	Placebo
Arm/Group Description:	From study entry through Week 1, pa...	From study entry through Week 1, pa...
Arm/Group Description:	From study entry through Week 1, participants received either 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 was 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. 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 Folic acid: 1-mg tablet of folic acid by mouth once a day	From study entry through Week 1, participants received either 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 was 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. 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 Folic acid: 1-mg tablet of folic acid by mouth once a day
Overall Number of Participants Analyzed	74	75
Median (Inter-Quartile Range) Unit of Measure: Percent Dilation
	0.32 (-1.55 to 1.54)	-0.06 (-1.3 to 1.66)

4.Secondary Outcome


Title	Change From Baseline to Week 12 in Brachial Artery Resting Average Diameter
Description	The change in resting average diameter in millimeters of the brachial ...
Description	The change in resting average diameter in millimeters of the brachial artery at week 12 from baseline.
Time Frame	From Baseline to Week 12

Outcome Measure Data

Analysis Population Description

Intent-to-treat (ITT) population consists of all eligible participants who were randomized for the study.


Arm/Group Title	Low-dose Methotrexate (LDMTX)	Placebo
Arm/Group Description:	From study entry through Week 1, pa...	From study entry through Week 1, pa...
Arm/Group Description:	From study entry through Week 1, participants received either 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 was 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. 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 Folic acid: 1-mg tablet of folic acid by mouth once a day	From study entry through Week 1, participants received either 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 was 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. 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 Folic acid: 1-mg tablet of folic acid by mouth once a day
Overall Number of Participants Analyzed	74	75
Median (Inter-Quartile Range) Unit of Measure: mm
	0.04 (-0.09 to 0.13)	0.03 (-0.09 to 0.15)

5.Secondary Outcome


Title	Change From Baseline to Week 24 in Brachial Artery Resting Average Diameter
Description	The absolute change in resting average diameter in millimeters of the ...
Description	The absolute change in resting average diameter in millimeters of the brachial artery at week 24 from baseline.
Time Frame	From Baseline to Week 24

Outcome Measure Data

Analysis Population Description

Intent-to-treat (ITT) population consists of all eligible participants who were randomized for the study.


Arm/Group Title	Low-dose Methotrexate (LDMTX)	Placebo
Arm/Group Description:	From study entry through Week 1, pa...	From study entry through Week 1, pa...
Arm/Group Description:	From study entry through Week 1, participants received either 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 was 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. 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 Folic acid: 1-mg tablet of folic acid by mouth once a day	From study entry through Week 1, participants received either 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 was 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. 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 Folic acid: 1-mg tablet of folic acid by mouth once a day
Overall Number of Participants Analyzed	74	80
Median (Inter-Quartile Range) Unit of Measure: mm
	0 (-0.11 to 0.13)	0.01 (-0.1 to 0.12)

6.Secondary Outcome


Title	Change From Baseline to Week 24 in Reactive Hyperemic (RH) Flow Rate
Description	The absolute change in RH flow rate in cc/min of the brachial artery a...
Description	The absolute change in RH flow rate in cc/min of the brachial artery at week 24 from baseline.
Time Frame	From Baseline to Week 24

Outcome Measure Data

Analysis Population Description

Intent-to-treat (ITT) population consists of all eligible participants who were randomized for the study.


Arm/Group Title	Low-dose Methotrexate (LDMTX)	Placebo
Arm/Group Description:	From study entry through Week 1, pa...	From study entry through Week 1, pa...
Arm/Group Description:	From study entry through Week 1, participants received either 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 was 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. 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 Folic acid: 1-mg tablet of folic acid by mouth once a day	From study entry through Week 1, participants received either 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 was 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. 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 Folic acid: 1-mg tablet of folic acid by mouth once a day
Overall Number of Participants Analyzed	74	76
Median (Inter-Quartile Range) Unit of Measure: cc/min
	-11.40 (-97.46 to 161.64)	13.76 (-135.11 to 107.73)

7.Secondary Outcome


Title	Change From Baseline to Week 24 in Peak Reactive Hyperemic (RH) Flow Velocity
Description	The absolute change in peak RH flow velocity in cm/s of the brachial a...
Description	The absolute change in peak RH flow velocity in cm/s of the brachial artery at week 24 from baseline.
Time Frame	From Baseline to Week 24

Outcome Measure Data

Analysis Population Description

Intent-to-treat (ITT) population consists of all eligible participants who were randomized for the study.


Arm/Group Title	Low-dose Methotrexate (LDMTX)	Placebo
Arm/Group Description:	From study entry through Week 1, pa...	From study entry through Week 1, pa...
Arm/Group Description:	From study entry through Week 1, participants received either 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 was 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. 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 Folic acid: 1-mg tablet of folic acid by mouth once a day	From study entry through Week 1, participants received either 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 was 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. 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 Folic acid: 1-mg tablet of folic acid by mouth once a day
Overall Number of Participants Analyzed	74	76
Median (Inter-Quartile Range) Unit of Measure: cm/s
	-0.20 (-11.30 to 14.40)	-0.83 (-16.80 to 16.88)

8.Secondary Outcome


Title	Percentage Change From Baseline to Week 24 in High-sensitivity C-reactive Protein (hsCRP)
Description	hsCRP is a marker of inflammation. Change from baseline (Week 24 - bas...
Description	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.
Time Frame	From Baseline to week 24

Outcome Measure Data

Analysis Population Description

Adequately-dosed (AD) population included 129 participants who initiated study treatment with 24-week continuous dosing to at least 8 or more 15 mg doses of LDMTX/Placebo (59 in LDMTX, 70 in Placebo). 3 of these participants were not identified at the time of the specimen request for biomarker testing, other missing data are due to missed visits.


Arm/Group Title	Low-dose Methotrexate (LDMTX)	Placebo
Arm/Group Description:	From study entry through Week 1, pa...	From study entry through Week 1, pa...
Arm/Group Description:	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 was 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. 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 Folic acid: 1-mg tablet of folic acid by mouth once a day	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 was 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. 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 Folic acid: 1-mg tablet of folic acid by mouth once a day
Overall Number of Participants Analyzed	55	69
Mean (95% Confidence Interval) Unit of Measure: Percentage Change
	-3.5 (-26.7 to 27.1)	5.4 (-16.8 to 33.5)

9.Secondary Outcome


Title	Percentage Change From Baseline to Week 24 in Interleukin-6 (IL-6)
Description	IL-6 is a marker of systemic inflammation. Change from baseline (Week ...
Description	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%.
Time Frame	From Baseline to Week 24

Outcome Measure Data

Analysis Population Description


Arm/Group Title	Low-dose Methotrexate (LDMTX)	Placebo
Arm/Group Description:	From study entry through Week 1, pa...	From study entry through Week 1, pa...
Arm/Group Description:	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 was 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. 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 Folic acid: 1-mg tablet of folic acid by mouth once a day	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 was 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. 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 Folic acid: 1-mg tablet of folic acid by mouth once a day
Overall Number of Participants Analyzed	59	70
Mean (95% Confidence Interval) Unit of Measure: Percentage Change
	13.4 (-1.3 to 30.3)	21.3 (-0.2 to 47.4)

10.Secondary Outcome


Title	Percentage Change From Baseline to Week 24 in Soluble CD 163 (sCD163)
Description	sCD163 is a marker of Macrophage activation. Change from baseline (Wee...
Description	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%.
Time Frame	From Baseline to Week 24

Outcome Measure Data

Analysis Population Description


Arm/Group Title	Low-dose Methotrexate (LDMTX)	Placebo
Arm/Group Description:	From study entry through Week 1, pa...	From study entry through Week 1, pa...
Arm/Group Description:	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 was 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. 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 Folic acid: 1-mg tablet of folic acid by mouth once a day	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 was 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. 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 Folic acid: 1-mg tablet of folic acid by mouth once a day
Overall Number of Participants Analyzed	56	69
Mean (95% Confidence Interval) Unit of Measure: Percentage Change
	2.7 (-4.2 to 10.1)	7.5 (0.6 to 15.0)

11.Secondary Outcome


Title	Percentage Change From Baseline to Week 24 in D-Dimer
Description	D-dimer (or D dimer) is a marker of coagulation activation. Change fro...
Description	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%.
Time Frame	From Baseline to Week 24

Outcome Measure Data

Analysis Population Description


Arm/Group Title	Low-dose Methotrexate (LDMTX)	Placebo
Arm/Group Description:	From study entry through Week 1, pa...	From study entry through Week 1, pa...
Arm/Group Description:	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 was 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. 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 Folic acid: 1-mg tablet of folic acid by mouth once a day	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 was 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. 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 Folic acid: 1-mg tablet of folic acid by mouth once a day
Overall Number of Participants Analyzed	56	69
Mean (95% Confidence Interval) Unit of Measure: Percentage Change
	-1.5 (-10.6 to 8.5)	9.9 (-3.3 to 24.9)

12.Secondary Outcome


Title	Absolute Change From Baseline to Week 24 in Monocyte Levels
Description	Three categories of monocyte levels are presented: classical (CD14+CD1...
Description	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.
Time Frame	From Baseline to Week 24

Outcome Measure Data

Analysis Population Description


Arm/Group Title	Low-dose Methotrexate (LDMTX)	Placebo
Arm/Group Description:	From study entry through Week 1, pa...	From study entry through Week 1, pa...
Arm/Group Description:	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 was 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. 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 Folic acid: 1-mg tablet of folic acid by mouth once a day	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 was 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. 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 Folic acid: 1-mg tablet of folic acid by mouth once a day
Overall Number of Participants Analyzed	56	68
Mean (95% Confidence Interval) Unit of Measure: Percent of Expression in Parent Cell
Classical (CD14+CD16-)	-0.15 (-1.39 to 1.10)	0.82 (-0.42 to 2.06)
Intermediate (CD14+CD16+)	-0.07 (-0.77 to 0.62)	-0.51 (-1.32 to 0.29)
Non-classical (CD14dimCD16+)	0.21 (-0.66 to 1.08)	-0.29 (-0.89 to 0.31)

13.Secondary Outcome


Title	Absolute Change From Baseline to Week 24 in Adhesion and Activation Indices
Description	The adhesion and activation indices of interest are the percentages of...
Description	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.
Time Frame	From Baseline to Week 24

Outcome Measure Data

Analysis Population Description


Arm/Group Title	Low-dose Methotrexate (LDMTX)	Placebo
Arm/Group Description:	From study entry through Week 1, pa...	From study entry through Week 1, pa...
Arm/Group Description:	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 was 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. 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 Folic acid: 1-mg tablet of folic acid by mouth once a day	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 was 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. 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 Folic acid: 1-mg tablet of folic acid by mouth once a day
Overall Number of Participants Analyzed	56	68
Mean (95% Confidence Interval) Unit of Measure: Percent of Expression in Parent Cell
(CD3+CD4+) CD38+HLADR+	-0.27 (-0.58 to 0.04)	0.22 (-0.06 to 0.50)
(CD3+CD8+) CD38+HLADR+	-1.50 (-2.06 to -0.95)	0.90 (-0.35 to 2.15)

14.Secondary Outcome


Title	Absolute Change From Baseline to Week 24 in Homing Molecule (CX3CR1+) Expression
Description	CX3CR1+ is a cellular marker of immune activation. The outcome measure...
Description	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.
Time Frame	From Baseline to Week 24

Outcome Measure Data

Analysis Population Description


Arm/Group Title	Low-dose Methotrexate (LDMTX)	Placebo
Arm/Group Description:	From study entry through Week 1, pa...	From study entry through Week 1, pa...
Arm/Group Description:	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 was 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. 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 Folic acid: 1-mg tablet of folic acid by mouth once a day	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 was 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. 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 Folic acid: 1-mg tablet of folic acid by mouth once a day
Overall Number of Participants Analyzed	56	68
Mean (95% Confidence Interval) Unit of Measure: Percent of Expression in Parent Cell
(CD3+CD4+) CX3CR1+	-0.30 (-0.80 to 0.20)	0.03 (-0.55 to 0.60)
(CD3+CD8+) CX3CR1+	-0.83 (-2.76 to 1.11)	0.39 (-1.13 to 1.92)

Adverse Events

Time Frame	Adverse Events (AEs) reported from study enrollment until study completion at 36 weeks.
Adverse Event Reporting Description	All serious adverse events, all AEs that led to a change in treatment, all signs and symptoms grade 2 or higher, all laboratory abnormalities grade 3 or higher and any of following targeted medical conditions: cardiovascular, hematologic, infectious, and neoplastic diseases (including mycobacterial infections, thrush, oral ulcers); hepatobilary, lymphoproliferative, renal, and pulmonary disorders; CDC category C AIDS conditions, regardless of grade.

Arm/Group Title	LDMTX	Placebo
Arm/Group Description	From study entry through Week 1, pa...	From study entry through Week 1, pa...
Arm/Group Description	From study entry through Week 1, participants received either 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 was 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.	From study entry through Week 1, participants received either 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 was 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.
All-Cause Mortality
	LDMTX	Placebo
	Affected / at Risk (%)	Affected / at Risk (%)
Total	2/86 (2.33%)	0/90 (0.00%)
Serious Adverse Events Serious Adverse Events
	LDMTX	Placebo
	Affected / at Risk (%)	Affected / at Risk (%)
Total	9/86 (10.47%)	8/90 (8.89%)
Blood and lymphatic system disorders
Neutropenia ^† 1	1/86 (1.16%)	0/90 (0.00%)
Cardiac disorders
Acute myocardial infarction ^† 1	1/86 (1.16%)	1/90 (1.11%)
Coronary artery stenosis ^† 1	0/86 (0.00%)	1/90 (1.11%)
Gastrointestinal disorders
Food poisoning ^† 1	1/86 (1.16%)	0/90 (0.00%)
General disorders
Chest pain ^† 1	0/86 (0.00%)	1/90 (1.11%)
Pyrexia ^† 1	0/86 (0.00%)	1/90 (1.11%)
Infections and infestations
Bronchitis ^† 1	1/86 (1.16%)	0/90 (0.00%)
Gastroenteritis shigella ^† 1	1/86 (1.16%)	0/90 (0.00%)
Pneumonia ^† 1	2/86 (2.33%)	1/90 (1.11%)
Pneumonia bacterial ^† 1	0/86 (0.00%)	1/90 (1.11%)
Pneumonia pneumococcal ^† 1	1/86 (1.16%)	0/90 (0.00%)
Injury, poisoning and procedural complications
Subdural haemorrhage ^† 1	1/86 (1.16%)	0/90 (0.00%)
Metabolism and nutrition disorders
Hypophosphataemia ^† 1	0/86 (0.00%)	1/90 (1.11%)
Musculoskeletal and connective tissue disorders
Intervertebral disc degeneration ^† 1	0/86 (0.00%)	1/90 (1.11%)
Tenosynovitis ^† 1	1/86 (1.16%)	0/90 (0.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Carcinoma in situ ^† 1	0/86 (0.00%)	1/90 (1.11%)
Prostate cancer ^† 1	1/86 (1.16%)	0/90 (0.00%)
Nervous system disorders
Syncope ^† 1	1/86 (1.16%)	0/90 (0.00%)
Reproductive system and breast disorders
Scrotal pain ^† 1	1/86 (1.16%)	0/90 (0.00%)
Respiratory, thoracic and mediastinal disorders
Asthma ^† 1	0/86 (0.00%)	1/90 (1.11%)
Chronic obstructive pulmonary disease ^† 1	1/86 (1.16%)	0/90 (0.00%)
1 Term from vocabulary, MedDRA 20.0 † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	LDMTX	Placebo
	Affected / at Risk (%)	Affected / at Risk (%)
Total	81/86 (94.19%)	76/90 (84.44%)
Gastrointestinal disorders
Nausea ^† 1	5/86 (5.81%)	2/90 (2.22%)
General disorders
Fatigue ^† 1	8/86 (9.30%)	6/90 (6.67%)
Malaise ^† 1	2/86 (2.33%)	6/90 (6.67%)
Pyrexia ^† 1	5/86 (5.81%)	6/90 (6.67%)
Investigations
Alanine aminotransferase increased ^† 1	10/86 (11.63%)	11/90 (12.22%)
Aspartate aminotransferase increased ^† 1	11/86 (12.79%)	15/90 (16.67%)
Blood alkaline phosphatase increased ^† 1	3/86 (3.49%)	6/90 (6.67%)
Blood bicarbonate decreased ^† 1	12/86 (13.95%)	9/90 (10.00%)
Blood bilirubin increased ^† 1	12/86 (13.95%)	11/90 (12.22%)
Blood cholesterol increased ^† 1	37/86 (43.02%)	27/90 (30.00%)
Blood creatinine increased ^† 1	19/86 (22.09%)	12/90 (13.33%)
Blood glucose decreased ^† 1	12/86 (13.95%)	3/90 (3.33%)
Blood glucose increased ^† 1	38/86 (44.19%)	39/90 (43.33%)
Blood potassium decreased ^† 1	5/86 (5.81%)	6/90 (6.67%)
Blood sodium decreased ^† 1	19/86 (22.09%)	14/90 (15.56%)
Low density lipoprotein increased ^† 1	21/86 (24.42%)	14/90 (15.56%)
Neutrophil count decreased ^† 1	7/86 (8.14%)	6/90 (6.67%)
Musculoskeletal and connective tissue disorders
Pain in extremity ^† 1	5/86 (5.81%)	2/90 (2.22%)
Respiratory, thoracic and mediastinal disorders
Cough ^† 1	10/86 (11.63%)	8/90 (8.89%)
Dyspnoea ^† 1	6/86 (6.98%)	5/90 (5.56%)
1 Term from vocabulary, MedDRA 20.0 † Indicates events were collected by systematic assessment

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Results Point of Contact

Layout table for Results Point of Contact information

Name/Title:	ACTG Clinicaltrials.gov Coordinator
Organization:	ACTG Network Coordinating Center, Social and Scientific Systems, Inc.
Phone:	(301) 628-3313
EMail:	ACTGCT.Gov@s-3.com

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

Layout table for additonal information

Responsible Party:	National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier:	NCT01949116
Other Study ID Numbers:	A5314 11875 ( Registry Identifier: DAIDS-ES )
First Submitted:	September 19, 2013
First Posted:	September 24, 2013
Results First Submitted:	December 4, 2017
Results First Posted:	January 10, 2018
Last Update Posted:	November 1, 2021

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