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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 : January 10, 2018
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

  Participant Flow

Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
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
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
No text entered.

Reporting Groups
  Description
Low-dose Methotrexate (LDMTX)

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

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

Placebo

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

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


Participant Flow:   Overall Study
    Low-dose Methotrexate (LDMTX)   Placebo
STARTED   86   90 
COMPLETED   78   84 
NOT COMPLETED   8   6 
Death                2                0 
Lost to Follow-up                1                3 
Withdrawal by Subject                5                3 



  Baseline Characteristics

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Intent-to-treat (ITT) population consists of all eligible participants who were randomized for the study.

Reporting Groups
  Description
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 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

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 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 Total of all reporting groups

Baseline Measures
   Low-dose Methotrexate (LDMTX)   Placebo   Total 
Overall Participants Analyzed 
[Units: Participants]
 86   90   176 
Age 
[Units: Years]
Median (Inter-Quartile Range)
     
Participants Analyzed 
[Units: Participants]
 86   90   176 
   55 
 (51 to 60) 
 53 
 (49 to 56) 
 54 
 (49 to 59) 
Sex: Female, Male 
[Units: Participants]
Count of Participants
     
Participants Analyzed 
[Units: Participants]
 86   90   176 
Female      8   9.3%      9  10.0%      17   9.7% 
Male      78  90.7%      81  90.0%      159  90.3% 
Region of Enrollment 
[Units: Participants]
Count of Participants
     
United States       
Participants Analyzed 
[Units: Participants]
 86   90   176 
United States   86   90   176 
Current Statin Use [1] 
[Units: Participants]
Count of Participants
     
Participants Analyzed 
[Units: Participants]
 86   90   176 
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] Current Statin Use at Study Entry - this is a stratification factor for the study.
Smoking Status 
[Units: Participants]
Count of Participants
     
Participants Analyzed 
[Units: Participants]
 86   90   176 
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] 
[Units: Participants]
Count of Participants
     
Participants Analyzed 
[Units: Participants]
 86   90   176 
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] CVD = cardiovascular disease; CAD = coronary artery disease; PAD = peripheral artery disease; hsCRP = high-sensitivity C-reactive protein.
10 year ASCVD risk [1] [2] 
[Units: Percent risk of ASCVD]
Median (Inter-Quartile Range)
     
Participants Analyzed 
[Units: Participants]
 47   58   105 
   10.1 
 (5.4 to 14.3) 
 7.9 
 (5.0 to 12.4) 
 8.7 
 (5.1 to 13.0) 
[1] 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] Participants with any risk of CAD, CVD, PAD, or controlled type 2 diabetes mellitus are excluded from the ASCVD risk calculation.
CD4+ cell count 
[Units: Cells/mm^3]
Median (Inter-Quartile Range)
     
Participants Analyzed 
[Units: Participants]
 86   90   176 
   689 
 (551 to 910) 
 729 
 (569 to 947) 
 726 
 (552 to 940) 
HIV-1 RNA 
[Units: Participants]
Count of Participants
     
Participants Analyzed 
[Units: Participants]
 86   90   176 
Detectable   2   4   6 
Below Assay Limit of Detection   84   84   168 
Missing   0   2   2 
Brachial Artery FMD [1] [2] 
[Units: Percent Dilation]
Median (Inter-Quartile Range)
     
Participants Analyzed 
[Units: Participants]
 86   87   173 
   3.54 
 (2.19 to 4.91) 
 3.41 
 (1.98 to 5.03) 
 3.45 
 (2.10 to 4.91) 
[1] Flow-mediated vasodilation is defined as the maximum FMD (%) calculated from reactive hyperemia (RH) 60 and RH 90 relative to resting artery diameter.
[2] 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:   Number of Participants Who Reached at Least One Safety Milestone Over the Duration of Study Follow-up (36 Weeks)   [ Time Frame: From study entry to week 36 ]

2.  Primary:   Primary Efficacy Endpoint of Change From Baseline to Week 24 in Brachial Artery Flow-mediated Vasodilation (FMD)   [ Time Frame: From Baseline to Week 24 ]

3.  Secondary:   Change From Baseline to Week 12 in Brachial Artery FMD   [ Time Frame: From Baseline to Week 12 ]

4.  Secondary:   Change From Baseline to Week 12 in Brachial Artery Resting Average Diameter   [ Time Frame: From Baseline to Week 12 ]

5.  Secondary:   Change From Baseline to Week 24 in Brachial Artery Resting Average Diameter   [ Time Frame: From Baseline to Week 24 ]

6.  Secondary:   Change From Baseline to Week 24 in Reactive Hyperemic (RH) Flow Rate   [ Time Frame: From Baseline to Week 24 ]

7.  Secondary:   Change From Baseline to Week 24 in Peak Reactive Hyperemic (RH) Flow Velocity   [ Time Frame: From Baseline to Week 24 ]

8.  Secondary:   Percentage Change From Baseline to Week 24 in High-sensitivity C-reactive Protein (hsCRP)   [ Time Frame: From Baseline to week 24 ]

9.  Secondary:   Percentage Change From Baseline to Week 24 in Interleukin-6 (IL-6)   [ Time Frame: From Baseline to Week 24 ]

10.  Secondary:   Percentage Change From Baseline to Week 24 in Soluble CD 163 (sCD163)   [ Time Frame: From Baseline to Week 24 ]

11.  Secondary:   Percentage Change From Baseline to Week 24 in D-Dimer   [ Time Frame: From Baseline to Week 24 ]

12.  Secondary:   Absolute Change From Baseline to Week 24 in Monocyte Levels   [ Time Frame: From Baseline to Week 24 ]

13.  Secondary:   Absolute Change From Baseline to Week 24 in Adhesion and Activation Indices   [ Time Frame: From Baseline to Week 24 ]

14.  Secondary:   Absolute Change From Baseline to Week 24 in Homing Molecule (CX3CR1+) Expression   [ Time Frame: From Baseline to Week 24 ]


  Serious Adverse Events


  Other Adverse Events


  Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
No text entered.


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



Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier: NCT01949116     History of Changes
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: January 10, 2018